Continuing Education Activity

Responsible prescribing of controlled substances and opioids is essential for the safe and ethical use of these medications. Responsible prescribing involves a thorough evaluation of the patient's medical conditions and pain management needs, with the consideration of nonopioid alternatives before prescribing opioids. Healthcare providers must adhere to strict guidelines and regulations to mitigate the risk of their misuse. Understanding federal regulations regarding these substances, changes outlined by the Mainstreaming Addiction Treatment Act, and the recommended standards of practice when prescribing controlled substances can deter prescription drug misuse.

This activity bridges the potential practice gap by educating patients on the risks and benefits of opioid therapy, monitoring for signs of misuse or addiction, and implementing strategies to prevent overdose and diversion. This activity presents best practices for prescribing controlled substances for legitimate medical use. In addition, this activity helps interprofessional healthcare team members understand their roles in safe prescribing and preventing medication misuse.

Objectives:

• Differentiate Schedule I, II, III, IV, and V substances based on their potential for abuse, accepted medical use, and regulatory controls as defined by the Controlled Substances Act.
• Implement evidence-based strategies to minimize the risk of opioid misuse, including the use of prescription drug monitoring programs, informed consent, and treatment agreements.
• Apply appropriate dosage adjustments, alternative nonopioid therapies, or tapering plans when necessary to optimize pain management and minimize long-term opioid use.
• Collaborate with the interprofessional team, including pain specialists, addiction medicine specialists, mental health professionals, and pharmacists, to optimize patient care and coordinate comprehensive treatment approaches.

Introduction

According to the United States Drug Enforcement Administration (DEA), drugs, substances, and certain chemicals used in drug manufacturing are classified into 5 categories or schedules depending on the drug’s acceptable medical use and potential for addiction or dependency. The Controlled Substances Act (CSA) outlines criteria for scheduling a substance, including potential for misuse, scientific evidence of pharmacologic effects, current scientific knowledge, history and patterns of addiction, scope and significance of harm, risks to public health, liability for psychic or physiologic dependence, and whether the substance is an immediate precursor to a controlled substance. Controlled substances include opioids, sedatives, hypnotics, and stimulants. In the United States, federal and state regulations restrict when and how these substances may be prescribed to reduce misuse, diversion, addiction, and overdose. 

Opioids remain a central driver of overdose mortality and preventable harm, though national trends have recently improved. CDC provisional and press release reporting indicate a significant decline in overdose deaths in 2024 compared with 2023, including substantial reductions in opioid-involved deaths.[CDC. U.S. Overdose Deaths Decrease Almost 27% in 2024. May 14, 2025] In parallel, synthetic opioids (primarily illicit fentanyl) remain the dominant driver of opioid mortality and complicate clinical risk mitigation.[CDC. About Overdose Prevention. Jan 16, 2026] The epidemiology continues to vary by region and population, and clinical prescribers remain a key point of contact for prevention, safer treatment, and early identification of substance use disorders.

Clinical prescribers, dispensers, and health systems have a critical role in reducing unnecessary opioid exposure while preserving access to pain treatment. Best practice involves maximizing nonopioid and nonpharmacologic therapies, using opioids only when benefits are expected to outweigh risks, and applying structured monitoring and risk mitigation. When opioids are used, clinicians are encouraged to prescribe emergency opioid antagonists (eg, naloxone) for patients at elevated overdose risk and to educate patients and families about overdose recognition and response. These elements align with Florida’s statutory controlled-substance CE expectations, which explicitly require instruction in: current standards for prescribing controlled substances (particularly opioids), alternatives to those standards, nonpharmacological therapies, prescribing emergency opioid antagonists, and risks of opioid addiction across all stages of acute pain treatment.[Florida Senate. 2025 Florida Statutes]

Prescription opioids serve as one path into opioid misuse, especially when leftover medications are stored insecurely or shared. Leftover opioids prescribed initially for legitimate medical use are often misused, including among adolescents and other vulnerable groups.[1] 

Chronic pain is common and costly. More than one-fourth of the United States population experiences chronic pain, with annual healthcare costs exceeding 100 billion dollars due to pain management and opioid dependence.[2][3] 

Given this complexity, prescribing is not simply “opioids versus no opioids.” It is a comprehensive approach that prioritizes safer alternatives, sets measurable goals, utilizes time-limited opioid trials when indicated, and continuously reassesses the benefits, harms, and functional outcomes.

Healthcare Provider Knowledge Deficit

Evidence shows knowledge gaps regarding the appropriate prescribing of controlled substances. Deficiencies include understanding research, legislation, and best prescribing practices, and a practice gap persists between recommended best practices for preventing prescription drug misuse and current clinical practice.[4] 

A common misconception equates addiction with dependence. Dependence is an expected physiologic adaptation that can occur with ongoing exposure to opioids, benzodiazepines, and other medications. Addiction (or substance use disorder) involves compulsive use despite harm and impaired control, and it is not synonymous with withdrawal or tolerance alone.

Bridging the knowledge-to-practice gap requires standard workflows: diagnosis and function-based pain assessments, documenting alternatives tried and planned, informed consent, duration, careful titration, PDMP review, overdose risk mitigation, including naloxone, and treatment of addiction. 

Definitions

Clinicians should be familiar with key terms associated with addiction and substance use disorders, as they are frequently used in medical literature. Clear definitions help establish diagnostic criteria, enabling providers to identify individuals needing treatment. 

• Addiction: According to the American Society of Addiction Medicine (ASAM), addiction is a treatable, chronic medical disease involving complex interactions among brain circuits, genetics, the environment, and an individual's life experiences.[ASAM. Glossary of Addiction] Individuals with addiction engage in behaviors that become compulsive despite adverse consequences. ASAM identifies 5 characteristics: craving; dysfunctional emotional response; failure to recognize significant problems; inability to abstain consistently; and impaired control of behavior.

• Substance use disorder: The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) combines previously used terms “abuse” and “dependence” into substance use disorders categorized as mild, moderate, or severe based on the number of criteria met within 12 months.[5]

• Abuse: Older term for use of an illegal substance or a maladaptive pattern of substance use for a nonmedical purpose other than pain relief.[8] The term should be avoided as it can carry unneeded additional blame for already stigmatized patients who have often been the victims of abuse themselves.

• Dependence: Physiological reliance on a drug resulting in a withdrawal syndrome with cessation or reduction in the amount of drug administered.[6]

• Diversion: Transferring a controlled substance from an authorized person's use to an unauthorized person's use for distribution or possession.

• Misuse: Use of a medication in a manner different than how it was prescribed.

• Pseudoaddiction: Pursuit of additional medication due to poor pain control, with the cessation of drug-seeking behavior upon achievement of appropriate pain control.

• Tolerance: The lessened effect of a substance after being exposed to that substance or the need to escalate doses to achieve the same result.[7]

Etiology

Risk factors for substance use disorders vary by medication class, patient, and treatment context. An understanding of the DEA schedules under the CSA is essential when prescribing controlled substances.

Schedule I: High misuse potential, no accepted medical use. Examples include heroin, lysergic acid diethylamide, cannabis, 3,4-methylenedioxymethamphetamine (ecstasy), methaqualone, and peyote.

Schedule II: High potential for misuse, with accepted medical use. Examples include morphine, amphetamines, methadone, hydromorphone, meperidine, oxycodone, fentanyl, phencyclidine, and methylphenidate.

Schedule III: Lower misuse potential than Schedules I and II, with accepted medical use. Examples include codeine, ketamine, anabolic steroids, and testosterone.

Schedule IV: Lower misuse potential than Schedule III, and accepted for medical use. Examples include benzodiazepines, carisoprodol, zolpidem, and tramadol. 

Schedule V: Lower misuse potential compared to Schedule IV, and accepted for medical use. Examples include codeine cough preparations, diphenoxylate/atropine, and pregabalin. 

The drivers of opioid-related harm include (1) exposure (dose, duration, formulation), (2) patient vulnerability (substance use and trauma history, psychiatric illness, medical comorbidity), (3) environment (social instability, household exposure, access to illicit opioids), and (4) system factors (fragmented care, limited access to nonopioid therapies, inconsistent monitoring). Many patients begin opioids in legitimate medical settings; for some, exposure evolves into long-term therapy, misuse, or OUD—particularly with longer duration, higher doses, or limited use of alternatives and functional goal setting. Harm also occurs in patients without OUD, especially with overdose risk factors such as concomitant benzodiazepines, sleep-disordered breathing, hepatic/renal impairment, and frailty.

Risk Factors for Prescription Drug Use Disorder

A key population-level predictor of prescription drug misuse is the quantity of controlled substances prescribed for legitimate medical reasons. Rising stimulant prescribing for ADHD, opioid prescribing, and increasing benzodiazepine prescribing have each been associated with increased misuse and/or overdose mortality.[8][9][10][11] Individual risk increases with prior substance use disorders, including nicotine, psychiatric disorders, including PTSD and pain-related anxiety, and family history of substance use disorders.[12][13][14][15]

Chronic pain is strongly associated with prescription opioid misuse; risk rises further with co-occurring chronic pain, substance use disorders, and psychiatric illness.[16][17] Adult attention-deficit hyperactivity disorder often coexists with substance use disorders and correlates with greater severity.[18] Additional risk factors for opioid-related harm include high dose, long duration, concurrent benzodiazepines or other sedatives, sleep apnea, chronic lung disease, older age, hepatic/renal impairment, and prior overdose.

Risk stratification should guide monitoring and harm-reduction measures (such as naloxone, avoiding sedative co-prescribing, and closer follow-up), rather than serving as a rationale to deny pain care.

Epidemiology

Among patients treated for chronic pain, opioid prescription misuse occurs in an estimated 21% to 29%, while addiction rates are estimated 8% and 12%.[19] SAMHSA survey reporting shows substantial prevalence of substance use disorders and prescription misuse.[SAMHSA. Highlights for the 2021 National Survey on Drug Use and Health] The US overdose crisis has shifted over time; earlier phases involved prescription opioids and heroin, while recent mortality data are dominated by illicit synthetic opioids, primarily fentanyl.[CDC. About Overdose Prevention. Jan 16, 2026]

Historical practice patterns changed in the 1990s amid "pain as the fifth vital sign," with aggressive pharmaceutical marketing downplaying risks of addiction.[20][21]

By 2004, the extended-release form of oxycodone became the most commonly abused drug in the United States.[22] The United States now consumes over 80% of all opioids produced worldwide.[23][24] Increased opioid exposure was associated with a dramatic rise in morbidity and mortality.[25][26] 

According to SAMHSA, in 2020, approximately 2.7 million individuals aged 12 or older had opioid use disorder in the United States, including 2.3 million individuals with a prescription opioid use disorder.[SAMHSA. The National Survey on Drug Use and Health: 2020] In 2022, out of the 107,081 reported drug overdose deaths in the United States, 68% of these deaths were caused by synthetic opioids, particularly illegally manufactured fentanyl.[CDC. Illicitly Manufactured Fentanyl–Involved Overdose Deaths with Detected Xylazine — United States, January 2019–June 2022] 

Pathophysiology

Dopamine is central to drug seeking and craving, and many substances increase dopamine signaling in reward circuits.[27] Addiction physiology is not limited to dopamine; other neurotransmitters contribute to reinforcement and conditioning.[27] Many addictive substances target the μ-opioid receptor.[27] Full μ-opioid agonists produce stronger rewarding effects than partial agonists such as buprenorphine.[28]

Repeated exposure produces conditioned learning and neuroadaptation, including decreased baseline dopamine release and increased craving and seeking, contributing to tolerance and compulsive use.[28] Genetics contributes to vulnerability; polygenic risk is likely, with associations with the OPRM1and stress/reward circuitry genes.[28] Environmental factors, such as peer/family exposures, early access, and adverse childhood events, also increase risk.[29][30] Epigenetic changes may contribute to long-term neuroadaptations.[31]

Clinically, risk arises from repeated exposure interacting with vulnerability and the environment; therefore, limiting dose escalation, shortening acute pain duration, avoiding high-risk combinations, and intervening early in cases of misuse are meaningful prevention strategies. 

History and Physical

The US Preventive Services Task Force (USPSTF) recommends screening all adults for unhealthy alcohol and drug use.[32][33] Screening supports safer prescribing by identifying risk and guiding monitoring intensity.  

The structured diagnostic interview is widely regarded as the reference standard for assessment.[33] For opioid decisions, history and exam should define the pain diagnosis, pain type (nociceptive vs neuropathic vs mixed), severity, functional impact, prior treatments, and comorbidities. Functional assessment should address sleep, work, activity tolerance, and daily living tasks; psychiatric assessment should address depression, anxiety, trauma symptoms, and sleep disorders.

Addiction risk assessment should incorporate patient history, collateral information when available, PDMP review, and validated tools. A practical framework stratifies patients into low-, moderate-, and high-risk groups, with progressively greater monitoring intensity.[25][34][35]

A single-item screen ("How many times in the past year have you used an illegal drug or a prescription medication for nonmedical reasons?) has reported 100% sensitive and 73.5% specific for detecting a drug use disorder[36], similar to the 10-item Drug Abuse Screening Test (DAST).[36][37]

The Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) is another validated screening tool, but it is time-consuming.[38] Clinicians should also assess family history, social supports, and comorbid psychiatric and pain conditions before prescribing controlled substances.[39]

DSM-5-TR diagnostic criteria for substance use disorder require 2 or more of the following within 12 months:

• The substance is taken in more significant amounts or for a longer duration than intended. 
• There is a persistent desire to reduce use, but these efforts have been unsuccessful.
• Much time is spent obtaining, using, or recovering from the substance's effects.
• There is an intense desire or craving to use the substance.
• Persistent use leads to failure to fulfill work, school, or home obligations.
• Continued use despite recurrent social or interpersonal problems.
• Giving up important social, occupational, or recreational activities due to substance use.
• Persistent use despite physically hazardous effects.
• Continued use despite awareness of recurrent physical or psychological problems caused by use.
• Evidence of tolerance is indicated by the need for increased amounts of the substance to achieve the desired effect or a reduced effect when using the same amount.
• Evidence of withdrawal, such as physical or psychological symptoms, occurs when the substance use is reduced or stopped.

Evaluation

Drug testing can be useful before and during therapy when prescribing controlled substances. Random testing is preferred over scheduled testing as it is more likely to detect undisclosed substance use.[40] Consent should be obtained and included in treatment agreements.

Urine is the most commonly used specimen; blood, hair, sweat, and oral fluids may also be used, though with trade-offs.[41][42][43][44] Urine results reflect metabolite levels and elimination rather than serum levels [43] and can vary with hydration.[44] Water-soluble substances such as opioids, benzodiazepines, and amphetamines are typically eliminated from the urine in 1-3 days; fat-soluble substances like cannabis can remain in the body longer if used chronically. Point-of-care (POC) testing provides rapid results but is more susceptible to handling errors without adequate training.[45]

Interpretation must account for assay limitations and cross-reactivity. For example, morphine may reflect morphine, codeine, or heroin, and hydromorphone may suggest the use of hydromorphone, hydrocodone, or morphine.[43] Unexpected results should be confirmed when clinical decisions depend on accuracy; confirmatory tests, such as gas chromatography, may be limited by availability.[43] False-positive results occur when substances cross-react with the immunoassays used on a drug test, leading to an incorrect positive result.[43] Common examples include:

• Amphetamines: Amantadine, bupropion, chlorpromazine, desipramine, dextroamphetamine, labetalol, methylphenidate, pseudoephedrine, ranitidine, selegiline, thioridazine, trazodone
• Benzodiazepines: Oxaprozin, sertraline
• Cannabinoids: Dronabinol, efavirenz, proton pump inhibitors, and some nonsteroidal anti-inflammatory drugs
• Opioids: Dextromethorphan, quinine, quinolones, rifampin, verapamil, and labetalol. Dietary consumption of poppy seeds may yield cross-reactivity and false-positive test results for opioids.
• Phencyclidine: Dextromethorphan, diphenhydramine, ibuprofen, ketamine, meperidine, thioridazine, tramadol, venlafaxine[46][47]

Treatment / Management

Before initiating controlled substances or opioids for chronic pain, the clinician and patient should agree on measurable goals for pain relief and function, along with management plans for comorbid conditions, such as anxiety, depression, and insomnia. A contemporary standard (especially for flagship opioid CE) requires an explicit, practical discussion of alternatives to opioid prescribing and a multimodal plan. This is not optional in Florida: the mandated controlled-substance CE must include alternatives to opioid prescribing standards, nonpharmacologic therapies, emergency opioid antagonists, and risks of opioid addiction across stages of acute pain management.[Florida Senate. 2025 Florida Statutes]

Core Opioid Prescribing Practices

• Start at the lowest possible dose and titrate to effect.
• Begin with immediate-release formulations.
• Discuss the importance of regular risk-benefit assessments.
• Educate the patient and family members on recognizing signs and symptoms of respiratory depression.
• Reassess risks and benefits with each dose increase.
• Exercise caution and justify the rationale when prescribing ≥50 morphine milligram equivalents (MME) per day.[48]
• Stay informed about federal and state regulations governing opioid prescribing.
• Be knowledgeable about patient monitoring, equianalgesic dosing, and cross-tolerance with opioid conversion.
• Augment treatment with nonopioid therapies or, if necessary, prefer immediate-release opioids over long-acting opioids.
• Taper the opioid dose whenever possible to minimize long-term dependence and reduce risk.

Alternatives to Opioid Prescribing

Nonpharmacologic alternatives should be framed as primary therapy and tailored to the diagnosis and function. Approaches include activity modification with graded return to function; physical therapy and exercise-based rehabilitation; heat/ice/compression/elevation; ergonomic interventions; sleep optimization; weight management; cognitive behavioral therapy for pain and insomnia; mindfulness/stress reduction; and treatment of comorbid mood and anxiety disorders. Selected patients may benefit from spinal manipulation, massage, acupuncture, and yoga as adjuncts.[49]

Nonopioid pharmacologic alternatives should match the pain mechanism. For nociceptive/inflammatory pain, acetaminophen and NSAIDs are typical first-line options; topical NSAIDs may help localized osteoarthritis or musculoskeletal pain when systemic risks exist. For neuropathic pain, tricyclic antidepressants, SNRIs (including duloxetine), and anticonvulsants (eg, pregabalin, gabapentin, oxcarbazepine) are commonly explored before opioids.[49] Topical lidocaine can help with localized neuropathic pain. Headache disorders require condition-specific therapy and avoidance of routine opioids to reduce medication-overuse headache and dependence. For diagnosis-driven pain, interventional approaches (eg, steroid injections, nerve blocks, radiofrequency ablation) or surgery may be appropriate and should be considered before long-term opioid escalation when feasible.[50]

Acute Pain Opioid-Sparing Strategy: For many acute pain syndromes (eg, sprains/strains, low back pain, dental pain, headache), nonopioid therapies are often as effective as opioids and carry less risk.[49] If opioids are used, limit quantity to the expected duration of severe pain, provide a discontinuation plan, and avoid inadvertent “bridge” prescribing that converts acute pain into long-term therapy.

Harm Reduction and Monitoring

Naloxone coprescribing is recommended for patients at increased overdose risk (higher doses, concurrent benzodiazepines or CNS depressants, prior overdose, substance use disorder history, sleep-disordered breathing, significant medical comorbidity).[49] PDMP review should occur before prescribing and periodically during therapy to identify high-risk combinations, multiple prescribers, and patterns suggestive of misuse or fragmented care.[49]

Consent and Treatment

Informed consent should be structured, not signature-only. It should include diagnosis, purpose, risks, and alternatives (including no opioids), plus realistic expectations emphasizing functional improvement rather than zero pain.[51] Opioid specific risks include constipation, QT prolongation, overdose, addiction, physical dependence, cognitive impairment, tolerance, hyperalgesia, and diversion/victimization risk.[51]

Prescribing policies (refills, early refills, lost/stolen medications) should be explicit.

Patient and Physician Treatment Agreement

Controlled substance treatment support shared understanding of goals and safety expectations.[51]

Common elements include a single prescriber/pharmacy when feasible, consent for drug testing when indicated, PDMP review, safe storage and disposal, and clear criteria for modifying or discontinuing opioids (eg, no functional benefit, intolerable adverse effects, aberrant use). Discontinuing should usually involve tapering; specialist involvement may be needed if tapering is difficult or if aberrant behavior emerges.[52][53] Agreements should be framed as standardized safety tools rather than punitive measures.

Recommended Guidelines for Responsible Prescribing of Opioids

CDC's 2022 guidelines emphasize maximizing nonopioid therapies as first-line and as adjuncts, preferring nonopioid therapy for subacute and chronic pain, and using immediate-release formulations when initiating opioids.[49] For opioid-naive patients, the lowest effective dose is recommended; the typical starting range is 5 to 10 MME per dose or 20 to 30 MME/day. Avoid abrupt discontinuation unless overdose is imminent; taper gradually when discontinuing, often 10% per month or slower for longer-term therapy.

For acute pain, prescribe no more than the expected duration of severe pain. For subacute and chronic pain, reassess within 1 to 4 weeks of initiation or dose escalation. Periodically discuss risk mitigation (including naloxone) and review PDMP data. Use extreme caution with concurrent benzodiazepines or other central nervous system depressants. If opioid use disorder is suspected or diagnosed, offer evidence-based treatment; detoxification without medications for opioid use disorder is not recommended.

Table

Table 2. Morphine Equivalence Conversion Factors of Commonly Prescribed Opioids.

MME is a reference for relative potency, not a sole determinant for switching therapies. Incomplete cross-tolerance and pharmacokinetics variability require a dose calculated by MME when converting.[49][54] During discontinuation or tapering, counsel that overdose risk increases if patients return to prior doses of opioids after tolerance decreases; provide naloxone when risk is elevated.[49] 

Recommended Guidelines for Responsible Prescribing of Sedatives and Benzodiazepines

No universally accepted benzodiazepine guidelines exist; practice typically follows CSA requirements and specialty guidance (eg, APA) for anxiety disorders and insomnia. Benzodiazepines are approved for generally recommended short-term (often 4 weeks or less) use due to dependence, cognitive impairment, falls, and overdose risk, particularly with opioids.[55] Nonpharmacological and non-benzodiazepine measures should be maximized; if long-term use has occurred, gradual tapering is recommended.

Prescription Requirements

Under the CSA, controlled-substance prescriptions must be for a legitimate medical purpose by a registered practitioner acting in the usual course of professional practice. Required elements include patient identifiers, date, prescription identifiers including DEA number, drug details and directions, quantity, and signature. 

Schedule II prescriptions generally cannot be refilled; sequential prescriptions may cover up to 90 days, with the earliest-fill date. Schedule III/IV may have up to 5 refills within 6 months; Schedule V as authorized. State requirements vary and change; the operational best practice is to embed state-required items (PDMP documentation, acute vs nonacute designation, exception rationale) into standardized EHR templates. Florida’s statute governing required controlled-substance CE content is explicit about alternatives, nonpharmacologic therapies, naloxone, and addiction risk across acute pain stages.[Florida Senate. 2025 Florida Statutes]

Differential Diagnosis

A differential diagnosis for pain supports mechanism-based, opioid-sparing treatment. Chronic pain may reflect osteoarthritis, radiculopathy, sacroiliac dysfunction, inflammatory disorders, neuropathy, central sensitization syndromes, autoimmune disease, or overlapping conditions. Treatment selection should match mechanism (eg, NSAIDs for inflammatory pain, neuropathic agents for nerve-related pain, physical therapy when indicated). Consider opioid-induced hyperalgesia in patients on chronic opioids.[56]

Depression and sleep disorders commonly accompany with chronic pain and amplify functional impairment; treating these comorbidities can improve pain outcomes and reduce reliance on opioids.[57] 

Prognosis

Opioid exposure and overdose risk have been major public health issues; more recently, national data show meaningful declines in overdose deaths in 2024 compared with 2023, including opioid-involved deaths.[CDC. U.S. Overdose Deaths Decrease Almost 27% in 2024. May 14, 2025] Despite improvement, the prognosis for individual patients depends on diagnosis, access to multimodal care, psychosocial factors, medical comorbidity, and early identification and treatment of emerging misuse. Regulatory actions and labeling changes have emphasized the increased risks associated with concurrent opioid and benzodiazepine use.[55] Patients with opioid use disorder have better outcomes with medications for opioid use disorder and ongoing support compared to detoxification-only approaches.[28]

Complications

Significant complications of controlled substances prescribing include misuse, addiction, diversion, and overdose. Long-term opioid therapy complications include constipation, endocrine effects, mood changes, falls/fractures, cognitive impairment, tolerance, dependence, hyperalgesia, and overdose. Risk is magnified by concurrent benzodiazepines, alcohol use, sleep apnea, and uncontrolled psychiatric illness. Broader complications include impaired functioning, family conflict, diversion risk, and legal consequences.

The Mainstreaming Addiction Treatment (MAT) Act expanded access to evidence-based treatment options for opioid use disorder (OUD) by removing the DATA-waiver requirement for buprenorphine prescribing; clinicians must still comply with state law and clinical standards.[58] 

Mainstreaming Addiction Treatment Act of 2021

The MAT Act updated federal guidelines to expand access to OUD treatment.[58] As of December 2022, the DATA-Waiver (X-Waiver) program was eliminated; DEA-registered practitioners with Schedule III authority may prescribe buprenorphine for OUD when permitted under state law, and the federal patient caps were removed.[58] Pharmacy staff can now fill buprenorphine prescriptions using the prescribing authority's DEA number without needing a DATA 2000 waiver from the prescriber. However, depending on the pharmacy, the dispensing software may still require the X-Waiver information. Some pharmacy systems may retain legacy fields. Clinicians should build workflows for initiation, monitoring, and continuity, and maintain referral networks.

Opioid Use Disorder Treatment

OUD is typically treated with pharmacological therapy and managed as a chronic condition with medications for opioid use disorder (MOUD).[28] Detoxification alone is not recommended due to high relapse rates and increased overdose risk after loss of tolerance.[28] Approved MOUD includes methadone, buprenorphine, and naltrexone. Methadone has strong retention and reduced illicit opioid use; overdose risk increases with misuse or sedative coingestion. Buprenorphine has a lower overdose risk due to its partial agonist properties and is often combined with naloxone. Extended-release naltrexone is an option for patients who can complete withdrawal and maintain abstinence before initiation.[28]

Buprenorphine induction generally begins when mild to moderate withdrawal is present to avoid precipitated withdrawal, often assessed via Clinical Opiate Withdrawal Scale (COWS).[59] Office or home-based induction may be appropriate. Many stabilize in the 8-16 mg/day range, with individualized strategies as needed.[60] Methadone induction typically starts at 20-30 mg with careful titration; maintenance is often 60 to 80 mg/day adjusted to clinical response.[61] Psychosocial supports, comorbidity treatment, and harm-reduction education (including naloxone) should be integrated.  

Benzodiazepine Use Disorder Treatment

Benzodiazepine use disorder is treated with gradual tapering, often using a benzodiazepine, such as diazepam. Taper speed is individualized. Cognitive-behavioral therapy improves discontinuation outcomes compared to tapering alone.[62] No other pharmacological relapse-prevention therapy has strong evidence after successful taper.

Deterrence and Patient Education

With patient consent, family input can clarify daily functioning and risk patterns (eg, day focused on dosing, avoidance of activity, depression, alcohol/drug co-use). Patient Education should include: avoid driving heavy machinery when sedated; avoid abrupt discontinuation; avoid alcohol and nonprescribed sedatives; adhere to dosing; follow up if pain control is not adequate; safe storage (locked, away from others); do not share medications; and safe disposal (take-back programs). Overdose education should include recognition (slow breathing, unresponsiveness, cyanosis) and response, including naloxone use.

Interprofessional Approach To Preventing Opioid Misuse

Clinicians, pharmacists, nurses, and allied healthcare professionals should coordinate care to reduce fragmentation and improve safety. Pharmacists can identify early refills, multiple prescribers, and high-risk combinations; nurses reinforce education and identify adherence barriers and psychosocial stressors.[63] Interprofessional coordination supports safer multimodal pain treatment and earlier identification of misuse.

Pearls and Other Issues

Opioids may be indicated for severe acute pain when alternatives are inadequate and for cancer-related or palliative pain, but they should be avoided as first-line therapy for chronic noncancer pain. Assess risk using history, validated tools as needed, and PDMP data; assess and treat depression/anxiety; focus on function and quality of life; set measurable goals; document alternatives tried or planned. 

When initiating opioids, prefer immediate-release, use the lowest effective dose, limit acute pain quantity to expected duration, and avoid escalating greater than or equal to 50 MME/day without a clear functional benefit and document rationale. Use prescription drug monitoring programs, consider urine drug testing when indicated, coprescribe naloxone for elevated risk, and avoid opioid-benzodiazepine coprescribing when possible. Taper gradually when benefits no longer outweigh risks or misuse is identified, and offer evidence-based OUD treatment when indicated. 

Enhancing Healthcare Team Outcomes

Controlled substances are regulated under the United States Controlled Substances Act and classified by the DEA into 5 schedules based on medical utility and abuse potential. These agents, including opioids, sedatives, hypnotics, and stimulants, remain essential for treating pain and other conditions but are closely linked to misuse, addiction, and overdose. The opioid crisis represents a major public health emergency, with overdose deaths driven largely by synthetic opioids and compounded by inappropriate prescribing, diversion, and leftover medications. At the same time, chronic pain affects a substantial proportion of the population and carries profound functional, psychological, and economic consequences. Responsible prescribing requires a comprehensive, evidence-based approach that balances adequate symptom control with minimizing risks of dependence, misuse, and overdose through careful assessment, monitoring, education, and adherence to evolving clinical and regulatory guidelines.

Validated screening tools and structured workflows should be incorporated into routine practice to identify patients at risk for misuse, addiction, and overdose. Responsible controlled substance prescribing does not mean "never prescribe", but it does require a consistent opioid sparing approach, clear documentation, ongoing reassessment, and overdose prevention counseling. 

Effective management of controlled substances depends on coordinated interprofessional care. Physicians, general practitioners, and advanced practitioners are responsible for accurate diagnosis, risk stratification, informed consent, and the development of individualized treatment plans that prioritize function and safety while complying with federal and state regulations. Nurses reinforce education, monitor adherence and adverse effects, identify behavioral changes suggestive of misuse, and serve as key communicators between patients and prescribers. Pharmacists play a critical role in verifying prescription legitimacy, identifying unsafe drug combinations, monitoring refill patterns, educating patients on safe use and disposal, and alerting prescribers to concerns about diversion or toxicity. Clear communication among team members, shared use of prescription drug monitoring programs, and timely referral to pain management or addiction specialists enhance patient-centered care, improve outcomes, reduce preventable harm, and strengthen overall team performance in addressing substance-related risks. Integrated teams reduce prescription drug misuse and improve outcomes by aligning diagnosis-based care, function-based goals, multimodal therapy, and timely addiction treatment.

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Disclosure: Danielle Horn declares no relevant financial relationships with ineligible companies.

Disclosure: Ly Vu declares no relevant financial relationships with ineligible companies.

Disclosure: Burdett Porter declares no relevant financial relationships with ineligible companies.

Disclosure: Sunny Aslam declares no relevant financial relationships with ineligible companies.