Prescription of Controlled Substances: Benefits and Risks

In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan.


One of the most difficult challenges for any prescriber is distinguishing between the legitimate prescription of controlled substances versus the prescription potentially used for illegitimate purposes. To discern the difference, prescribers need to understand the signs, symptoms, and treatment of acute and chronic pain and the signs and symptoms of patients misusing controlled substances.

A common reason people seek the care of medical professionals is pain relief. While many categories of pain medications are available, opioid analgesics are FDA-approved for moderate to severe pain. As such, they are a common choice for patients with acute, cancer-related, neurologic, and end-of-life pain. Prescribing opioid analgesics for chronic pain is controversial and fraught with inconclusive standards.

In the 1990s, due to the chronic failure of health professionals to undertreat severe pain, opioid analgesic prescribing was expanded. Unfortunately, this led to increased overuse, diversion of drugs, opioid use disorder, and overdose. The "Catch-22" seems to be either health professionals undertreat, and there is needless suffering, or they overtreat, with a potential to cause adverse effects like increased opioid analgesic use disorder and potential overdose.

The prescribing of opioid analgesics peaked in 2011. Since then, both prescribing and overdose have been declining, yet as a society, in both the lay and scientific literature, there are grave concerns that we are still in the middle of an opioid crisis.

Perhaps the biggest challenge of caring for patients with pain is that individuals have different tolerance levels and require variable opioid doses to obtain adequate pain relief. Patients may have a range of behavioral, cultural, emotional, and psychologic responses to pain versus a substance use disorder; often, it is challenging to tell the difference. All health professionals engaged in pain management need an understanding of the treatment recommendations and safety concerns in prescribing opioid analgesics. Appropriate opioid prescribing requires a thorough patient assessment, short and long-term treatment planning, close follow-up, and continued monitoring. All providers need to be aware of appropriate patient assessment and treatment planning, and the possibility of use disorder, diversion, and potentially dangerous behavioral responses to controlled substances, e.g., opioid analgesics differ from pseudoaddiction and physical dependence.

It is unfortunately clear that many clinicians know little about opioid use disorder. They do not understand it is a disease, and many believe opioid dependence is the same as opioid use disorder. Lack of a clear understanding results in clinicians confusing a patient with chronic non-use disorder with the one misusing their prescribed opioid. Lack of training and educational deficits often interfere with the appropriate prescription of opioid analgesic agents. To prevent the misuse of controlled substances, providers that prescribe controlled substances should learn prescribing practices that minimize or prevent adverse consequences.


  1. Addiction - according to the American Society of Addiction Medicine (ASAM): "Addiction is a primary, chronic disease of brain reward, motivation, memory, and related circuitry. Dysfunction in these circuits leads to characteristic biological, psychological, social, and spiritual manifestations. This is reflected in an individual pathologically pursuing reward or relief by substance use and other behaviors." Addiction is now termed "use disorder," and is characterized by an inability to consistently abstain, craving the drug, impairment in behavioral control, diminished ability to recognize significant problems with one's behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, use disorder often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, use disorder is progressive and can result in disability or premature death."

  1. Appropriate opioid analgesic prescribing: This involves providing pain control while minimizing toxicity, use disorder, or the risk of use disorder and implementing safeguards to reduce drug diversion.

  1. Inappropriate opioid analgesic prescribing: non-prescribing, inadequate prescribing, excessive prescribing, or continued prescribing despite evidence of the lack of effective opioid analgesic treatment.

  1. Controlled substances: These are drugs or medications that possess the potential for being misused and are considered to be substances that have a substantially high risk of resulting in substance use disorder.

  1. Opioid analgesics: these are drugs that dull the senses and relieve pain, e.g., morphine. Also, these medications may induce sleep. Please note that the Drug Enforcement Administration (DEA, USA) uses the term "narcotic" to refer to drugs that are opioid analgesics.

Five Characteristics of Addiction/Use Disorder (ASAM)

  1. Craving for drug or reward

  2. Diminished recognition of significant problems in one's behavior

  3. Dysfunctional emotional response

  4. Impairment in behavioral control

  5. Inability to consistently abstain

Drug Schedules of Controlled Substances

All providers should be familiar with the guidelines and laws for each schedule, which have, as their basis, the purpose of the drug and the risk of use disorder. In the United States, controlled substances are under strict regulation by both federal and state laws that guide their manufacture and distribution. Controlled substances have a high risk of resulting in addiction and substance use disorder. As the schedules decrease, I-V, the drugs listed within each category have a lower potential to cause a substance use or addiction disorder.

Controlled Substance Act

In the United States, the Comprehensive Drug Abuse Prevention and Control Act was passed in 1970, and it included the Controlled Substance Act. The Controlled Substance Act covers drug:

  1. Classification and regulation, according to their content and purpose.

  2. Manufacturing

  3. Distribution

  4. Exportation and sale

The Controlled Substance Act established five drug schedules and classified them to control their manufacture and distribution. Part of the regulation requires providers prescribing scheduled drugs and pharmacists filling them to obtain a license from the Drug Enforcement Administration. Health professionals' licenses include specific license numbers allowing controlled substance prescriptions to be tracked and linked to a particular provider or distributor.

Each of the five schedules has parameters based on their medical value, the risk of addiction, and the ability to cause harm. The schedules range from Schedule I (most potential for addiction/use disorder) to Schedule V (least potential for addiction/use disorder).

Schedule I

  1. Schedule I drugs possess the highest potential for use disorder and misuse. They have no medical use and are illicit or "street" drugs.

  2. Examples of Schedule I drugs include heroin, lysergic acid diethylamide, mescaline, methylenedioxymethamphetamine (MDMA), and methaqualone.

  3. Marijuana, which is legal in some states, is still classified as a Schedule I drug at the federal level as of this writing.

Schedule II

  1. Schedule II drugs have a reduced potential for use disorders than Schedule I. They are at high risk for both physical and psychological dependence. They have a high capacity for both use disorder and misuse. They are typically prescribed to treat severe pain, anxiety, insomnia, and ADHD.

  2. Examples of Schedule II substances include fentanyl, hydromorphone, meperidine, methadone, morphine, oxycodone, fentanyl, dextroamphetamine, methylphenidate, methamphetamine, pentobarbital, and secobarbital.

  3. They previously had to be prescribed only via paper prescription but now are permitted to be electronically transmitted. (Electronic Prescribing of Controlled Substances or EPCS).

  4. No refills are allowed.

  5. Schedule II drugs have the tightest regulations when compared to other prescription drugs.

Schedule III

  1. Schedule III drugs have a lower misuse potential than I and II. Drugs in this category may cause physical dependence but more commonly lead to psychological dependence. Medications in this category are often used for pain control, or anesthesia, or appetite suppression.

  2. Examples of Schedule III substances include benzphetamine, ketamine, phendimetrazine, and anabolic steroids.

  3. Opioid analgesics in this schedule include products containing not more than 90 milligrams of codeine per dosage unit and buprenorphine.

  4. Schedule III drugs are prescribable verbally over the phone, with a paper prescription, or via EPCS.

  5. Within a six-month time frame, refill requirements are such that the drug can only have five refills.

Schedule IV

  1. Schedule IV drugs have an even lower misuse potential than I, II, or III. They have a limited risk of physical or psychological dependence.

  2. Examples of Schedule IV substances include: alprazolam, carisoprodol, clonazepam, clorazepate, diazepam, lorazepam, midazolam, temazepam, tramadol, and triazolam.

  3. Drugs in this class may be utilized for pain control as long as the provider deems the drug medically necessary and the patient would benefit.

  4. Schedule IV drugs are prescribable verbally over the phone, with a paper prescription, or via EPCS.

  5. Refills are permitted up to five times in a six-month timeframe from the issuance date.

Schedule V

  1. Schedule V drugs are the least likely of the controlled substances to be misused. They result in very limited physical or psychological dependence.

  2. Examples include cough medicines with codeine, antidiarrheal medications that contain atropine/diphenoxylate, pregabalin, and ezogabine.

  3. Despite their low abuse potential, they still need to be managed appropriately and administered with care.

  4. When they contain codeine, it must have less than 200 mg of codeine per 100 mL.

  5. Partial prescription fills cannot occur more than six months after the issue date. When a partial fill occurs, it is treated in the same manner and with the same rules as a refill of the drug.

Drug Use Disorder, Abuse, and Misuse

The use disorder of a drug differs from abuse and misuse of a drug.

The drugs taken may be illicit street or stolen drugs or obtained via a legal prescription. Misusing a drug usually involves taking the drug in a harmful or detrimental way, resulting in personal, professional, or social problems. A patient abusing an opioid analgesic may no longer be appropriately interacting with their family or friends or be able to perform their duties at work.

Misuse of a controlled substance refers to using a prescribed drug in a way that was not intended. It may be deliberate or accidental. A negative result may or may not occur. Examples of misuse include taking too much of a drug, using an incorrect dose, an incorrect route, or using prescription drugs written for another person.

Controlled substances include both prescription drugs and illicit drugs with no recognized medical value. Both have the potential to be abused or misused. While Schedule I drug use is illegal, prescription drugs found in Schedules II-V are also commonly abused and misused, and their misuse is a challenging problem that has increased over the last several years.

The Centers for Disease Control and Prevention has declared prescription drug abuse a problem of epidemic proportions. The CDC believes that absent checks and balances on the prescription and distribution of controlled substances, including those prescribed for medical use, have the potential for abuse and that misuse will continue to increase.

Prescriber Shopping

Unfortunately, a common practice among those that deliberately misuse controlled substances is to seek out multiple sources of drugs. They do this by seeing different health care providers and presenting with a list of complaints that are often fictitious and different for each provider. The patient may be able to obtain multiple prescriptions and then fill them at different pharmacies. Many states have enacted systems that allow providers to see all of the prescriptions written for each patient. The use of these systems is gradually curbing "prescriber shopping."


Some prescription drugs will sell on the street for as much as $50 a tablet. Diversion is when a patient sells their drugs as a method of earning money. Drugs may also be sold to buy food, pay expenses, or purchase more potent street drugs. Worse, in some cases, healthcare providers may divert drugs from patients for the providers' personal use or sell them to someone else.

Some individuals use controlled substances in ways for which they were not originally intended. Rather than pain control, they may be used to stay awake, induce sleep, or get "high." Before the popularity of prescription drug diversion, the only method to obtain illicit drugs was to import from other countries or manufacture them in private labs. Today, law enforcement agencies have the tremendous challenge of dealing with prescription drugs sold by diversion and illicit drugs imported or manufactured. In both instances, these drug sales and usage result in increased criminal activity, dangerous overdoses, and death.

Methods of Obtaining Prescription Drugs

A review of multiple studies demonstrates a variety of ways individuals obtain prescription drugs. The following summarizes the studies' findings.

  1. 55% free from a friend or relative

  2. 20% from a prescriber

  3. 10% purchased from a friend or relative

  4. 5% stolen from a friend or relative

  5. 5% purchased from a drug dealer

  6. 2% from multiple doctors

  7. 1% from theft from medical practice or pharmacy

  8. Less than 1% obtain them from the internet

Studies also reveal the source of the majority of these drugs was a single legal prescriber.

Provider Opioid Knowledge Deficit

There are substantial knowledge gaps around appropriate and inappropriate opioid analgesic prescribing, including deficits in understanding current research, legislation, and appropriate prescribing practices. Providers often have knowledge deficits that include:

  1. Understanding of addiction

  2. At-risk opioid addiction populations

  3. Prescription vs. non-prescription opioid addiction

  4. The belief that addiction and dependence on opioids are synonymous

  5. The belief that opioid addiction is a psychological problem instead related to a chronic painful disease

With a long history of misunderstanding, poor society, provider education, and inconsistent laws, prescribing opioids has resulted in significant societal challenges that will only resolve with significant education and training.

Misuse of Controlled Substances

Unfortunately, the misuse of controlled substances resulting in morbidity and mortality is rampant. According to the National Survey on Drug Use and Health, 2016, performed by the US Department of Health and Human Services, over 10 million people misuse prescription pain medications, and over 2 million misuse sedatives, stimulants, and tranquilizers each year. The same study found that the most common reason for misuse is for treating physical pain. The Center for Disease Control estimates more than 40,000 people die each year die from an opioid overdose.

Controlled Substances

Three common classes of controlled substances are commonly misused: opioids, depressants, and stimulants.


Opioids are prescribed for pain control by binding to mu-opioid receptors in the central nervous system reducing pain signals to the brain as well as receptors in the GI tract and respiratory system, and are used to treat pain, diarrhea, and cough.

Common Opioids

Codeine - One of the most commonly taken opioid medications. It is at the center of the opioid addiction problem in the United States and thus is highly regulated. Its main indications are pain and cough.

FDA-Approved Indication


Codeine plays a role in the treatment of mild to moderate pain. Its use is recognized in chronic pain due to ongoing cancer and palliative care. However, the use of codeine to treat other types of chronic pain remains controversial. Chronic pain, defined by the International Association for the Study of Pain, is pain persisting beyond the standard tissue healing time, which is three months.[1] The most prevalent causes of non-cancer chronic pain include back pain, fibromyalgia, osteoarthritis, and headache.

Non-FDA Approved Indications


Codeine is useful in the treatment of various etiologies producing chronic cough. Also, 46% of patients with chronic cough do not have a distinct etiology despite a proper diagnostic evaluation. Codeine produces a decrease in cough frequency and severity in these patients. However, there is limited literature demonstrating the efficacy of codeine in chronic cough. The dose can vary from 15 mg to 120 mg a day. It is, however, indicated in the management of prolonged cough (in specific populations like lung cancer) usually as 30 mg every 4 to 6 hours as needed.

Restless Leg Syndrome

Codeine is effective in treating restless leg syndrome when given at night time, especially for those whose symptoms are not relieved by other medications.

Persistent Diarrhea (Palliative)

Codeine and loperamide are equally effective, and the choice between them has its basis in the assessment of the physician evaluating the small but undoubted addictive potential of codeine versus the higher cost of loperamide and an individual difference in patient's vulnerability to adverse effects.

Fentanyl - Transdermal patch and IV, commonly abused and used in mixture with other drugs. Fentanyl is a synthetic opioid that is 80 to 100 times stronger than morphine and is often added to heroin to increase its potency. It can cause severe respiratory depression and death, particularly when mixed with other drugs or alcohol. It has high addiction potential.

Hydrocodone - Hydrocodone is a schedule II semi-synthetic opioid medication used to treat pain. Immediate-release (IR) hydrocodone is available as a combination product (combined with acetaminophen, ibuprofen, etc.) and is FDA approved for the management of pain severe enough to require an opioid analgesic and for which alternative (non-opioid) treatments are inadequate. Single-entity hydrocodone is only available in extended-release (ER) formulations. It is FDA approved to treat persistent pain severe enough to require 24-hour, long-term opioid treatment, for which alternative treatments are inadequate. Hydrocodone is also an antitussive and is indicated for cough in adults.

Morphine Sulfate - FDA-approved usage of morphine sulfate includes moderate to severe pain that may be acute or chronic. Most commonly used in pain management, morphine provides significant relief to patients afflicted with pain. Clinical situations that significantly benefit from medicating with morphine include managing palliative/end-of-life care, active cancer treatment, and vaso-occlusive pain during sickle cell crises. Morphine is widely used off-label for almost any condition that causes pain. In the emergency department, morphine is given for musculoskeletal pain, abdominal pain, chest pain, arthritis, and even headaches when patients fail to respond to first and second-line agents. Morphine is rarely used for procedural sedation. However, clinicians will sometimes combine a low dose of morphine with a low dose of benzodiazepine-like lorazepam for minor procedures.

Oxycodone - An opioid agonist prescription medication. The oxycodone immediate-release formulation is FDA-approved for managing acute or chronic moderate to severe pain for which other treatments do not suffice, and for which opioid medication is appropriate. The extended-release formulation is FDA-approved for the management of pain severe enough to require continuous (24 hours per day), long-term opioid treatment, and for which there are no alternative options to treat the pain. The oxycodone to morphine dose equivalent ratio is approximately 1 to 1.5 for immediate-release and 1 to 2 for extended-release formulations.

Tramadol - Tramadol is an FDA-approved medication for pain relief. It has specific indications for moderate to severe pain. It is considered a class IV drug by the FDA. Due to possible abuse and addiction potential, limitations to its use should be for pain that is refractive to other pain medication, such as non-opioid pain medication. There are two forms of tramadol: extended-release and immediate release. The immediate release is not for use as an "as needed" medication; instead, it is for pain of less than a week duration. For pain lasting more than a week, extended-release is the therapeutic choice — the indication for extended-release is for pain control under 24-hour management or an extended period.

Off-label, the drug is useful for premature ejaculation and restless leg syndrome refractory to other medications. For the off-label use of tramadol for premature ejaculation, both sporadic and daily use is effective for treating the condition. Patients indicate a preference for "as needed" therapy for premature ejaculation due to the lack of side effects compared to the daily use of tramadol.

Addiction, Dependence, and Tolerance

While each of these terms is similar, providers should be aware of the differences.

  1. Addiction - the constant need for a drug despite harmful consequences.

  2. Pseudoaddiction - constant fear of being in pain, hypervigilance; usually, there is a resolution with pain resolution.

  3. Dependence - physical adaptation to a medication where it is necessary for normal function and withdrawal occurs with lack of the medication.

  4. Tolerance - lack of expected response to a medication increasing dose to achieve the same pain relief resulting from CNS adaptation to the medication over time.

Mainstreaming Addiction Treatment (MAT) Act

The Mainstreaming Addiction Treatment (MAT) Act provision updates federal guidelines to expand the availability of evidence-based treatment to address the opioid epidemic. The MAT Act empowers all health care providers with a standard controlled substance license to prescribe buprenorphine for opioid use disorder (OUD), just as they prescribe other essential medications. The MAT Act is intended to help destigmatize a standard of care for OUD and will integrate substance use disorder treatment across healthcare settings.

As of December 2022, the MAT Act has eliminated the DATA-Waiver (X-Waiver) program. All DEA-registered practitioners with Schedule III authority may now prescribe buprenorphine for OUD in their practice if permitted by applicable state law, and SAMHSA encourages them to do so. Prescribers who were registered as DATA-Waiver prescribers will receive a new DEA registration certificate reflecting this change; no action is needed on the part of registrants.

There are no longer any limits on the number of patients with OUD that a practitioner may treat with buprenorphine. Separate tracking of patients treated with buprenorphine or prescriptions written is no longer required.

Pharmacy staff can now fill buprenorphine prescriptions using the prescribing authority's DEA number and does not need a DATA 2000 waiver from the prescriber. However, depending on the pharmacy, the dispensing software may still require the X-Waiver information in order to proceed. Practitioners are still required to comply with any applicable state limits regarding the treatment of patients with OUD. Contact information for State Opioid Treatment Authorities can be found here:

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