Responsible Controlled Substance and Opioid Prescribing

Etiology

Risk factors for substance use disorders, particularly prescription use disorder, vary depending on the type of drug prescribed. An understanding of the DEA schedules under the CSA is mandatory for healthcare providers, particularly when prescribing or dispensing these agents to individuals with known risk factors for addiction. The DEA classifies controlled substances into 5 schedules, outlined as follows:

Schedule I: Drugs or substances with high potential for abuse and no currently accepted medical use in the United States. Examples include heroin, lysergic acid diethylamide, marijuana (cannabis), 3,4-methylenedioxymethamphetamine (ecstasy), methaqualone, and peyote.

Schedule II: Drugs or substances with high potential for abuse; however, they also have a currently accepted medical use in the United States. Examples include cocaine, morphine, methamphetamine, methadone, hydromorphone, meperidine, oxycodone, fentanyl, amphetamine, dextroamphetamine, phencyclidine, and methylphenidate.

Schedule III: Drugs or substances with less potential for abuse compared to those in Schedules I and II, and they are currently accepted for medical use in the United States. Examples include codeine products combined with acetaminophen or aspirin, ketamine, anabolic corticosteroids, and testosterone.

Schedule IV: Drugs or substances with low potential for abuse relative to those in Schedule III, and they are currently accepted for medical use in the United States. Examples include benzodiazepines, such as alprazolam, clonazepam, lorazepam, and diazepam; carisoprodol; pentazocine; zolpidem; tramadol; and dextropropoxyphene. Flunitrazepam, a benzodiazepine, is classified as Schedule IV but carries Schedule I trafficking penalties due to its association with drug-facilitated sexual assault.

Schedule V: Drugs or substances with lower potential for abuse compared to those in Schedule IV, and they are currently accepted for medical use in the United States. Examples include cough preparations containing codeine, diphenoxylate/atropine, difenoxin hydrochloride/atropine, pregabalin, and attapulgite. 

Risk Factors for Prescription Drug Use Disorder

The greatest risk factor for prescription drug misuse is the quantity of controlled substances prescribed for legitimate medical reasons. Prescription drug use is directly associated with the increased prescribing of controlled substances for accepted medical reasons. Research has shown that the growing identification and treatment of attention-deficit hyperactivity disorder has contributed to a rise in the misuse of medications used to treat the condition.[11] Similarly, the increased use of opioids for various medical conditions has been linked to a surge in opioid abuse, and a higher number of benzodiazepine prescriptions has been associated with a greater risk of overdose-related deaths from these drugs.[12][13]

A prior history of substance use disorders, including nicotine use disorder, is associated with an increased risk of prescription misuse when controlled substances are prescribed for appropriate reasons.[14][15] Mental health disorders, particularly pain-related anxiety and post-traumatic stress disorder, increase the risk of prescription opioid use and sedative and hypnotic use disorders.[16][15][17] Similarly, a family history of substance use disorders further increases the risk of prescription misuse in patients.[15]

Chronic pain is strongly associated with prescription opiate misuse. The combination of chronic pain and coexisting substance use disorders or mental health conditions significantly increases the risk of prescription medication use disorder.[18][19] Attention-deficit hyperactivity disorder in adults often coexists with substance use disorders and has been linked to higher severity of substance use disorders.[20]

Epidemiology

The rate of opioid prescription misuse among patients treated for chronic pain ranges from 21% to 29%, whereas the rate of addiction is between 8% and 12%.[21] The SAMHSA, a branch of the United States Department of Health and Human Services, published a report summarizing findings from the 2021 National Survey on Drug Use and Health. This report illustrates the prevalence of substance use disorders and the frequency of prescription misuse and abuse in the United States population.[SAMHSA. Highlights for the 2021 National Survey on Drug Use and Health] The survey findings for individuals aged 12 and older who are noninstitutionalized include:

• Approximately 40.0 million individuals reported using illicit drugs, equating to more than 1 in 10 Americans (14.3%).
• Prescription pain medication misuse was second only to marijuana for illicit drug use.
• In the preceding year, 9.2 million individuals misused opioids, including 8.7 million who used prescription pain medications and 1.1 million who used heroin. Among them, 547,000 individuals used both prescription pain relievers and heroin.

• Approximately 46.3 million individuals aged 12 and older reported a current substance use disorder diagnosis, categorized as follows:
  • Adults aged 18 to 25: 8.6 million (25.6%)
  • Adults aged 26 and older: 35.5 million (16.1%)
  • Adolescents aged 12 to 17: 2.2 million (8.5%)

Historically, healthcare providers in the United States reserved opioid prescriptions primarily for chronic cancer pain. This approach shifted in the 1990s when Dr James Campbell addressed the American Pain Society in 1995, urging healthcare providers to treat pain as the fifth vital sign.[22] Simultaneously, pharmaceutical companies aggressively marketed these medications while downplaying the risks, particularly addiction.[23]

By 2004, the extended-release form of oxycodone became the most commonly abused drug in the United States.[24] The United States now consumes over 80% of all opioids produced worldwide.[25][26] With the increased use of opioids, the associated problems have also grown, leading to a dramatic rise in the number of individuals abusing opioid analgesics.[27][28]

Pathophysiology

Dopamine plays a central role in the physiology of drug reward. Substances with addictive potential work by increasing dopamine levels in the brain.[29] However, studies on mice have demonstrated that dopamine-deficient mice can still develop an addiction, suggesting the involvement of other neurotransmitters, such as serotonin. Similarly, animal studies have revealed that multiple agents, including heroin, other opioid drugs, alcohol, cocaine, and nicotine, target the μ-opioid receptor.[29]

The agonistic efficacy of substances, particularly different opioid formulations, influences their rewarding effects at the μ-opioid receptor. Opioid drugs with full agonist effects at these receptors produce stronger rewarding effects compared to partial agonists such as buprenorphine.[30]

Drugs of addiction trigger dopamine release in the nucleus accumbens (NAc) and may increase levels of endogenous opioids and cannabinoids. This rapid release of dopamine and its binding to D1 receptors (D1R) in the NAc and dorsal striatum stimulate cyclic AMP (cAMP) signaling, which is associated with euphoria and pleasure. Repeated exposures to these substances trigger conditioning of this response. Once a substance use disorder develops, a decrease in baseline dopamine release in the NAc is observed, resulting in a diminished increase in dopamine levels and reducing the drug's rewarding effects, such as tolerance.[30] 

Genetics plays a vital role in addiction and the development of substance use disorders. Studies have shown a strong heritable component to addiction vulnerability. However, identifying specific genetic foci for substance use disorders remains challenging, suggesting that, like other psychiatric disorders, these conditions are likely polygenic.[30] Several genes have been identified as increasing vulnerability to substance use disorders, particularly opioid use disorder, including the following:

• Opioid receptor μ-1 (OPRM1) mutations result in altered μ-opioid receptor expression.
• Cornichon family AMPA receptor auxiliary protein 3 (CNIH3) appears to alter or influence control over opioid use.
• Brain-derived neurotrophic factor (BDNF) is believed to moderate the propensity to drug-seeking behavior.
• Monoamine oxidase A (MAOA) alters the tendency for externalizing behaviors.
• Catechol-O-methyltransferase (COMT) modulates activity in the prefrontal cortex, amygdala activity, and reward circuitry.
• FK506-binding protein 5 (FKBP5) moderates responses to stress.
• Homer1, Homer 2, and Homer3 influence responses to rewards.
• Matrix metalloproteinase (MMP9) moderates the propensity for drug-seeking behavior.

Environmental factors play a significant role in adolescents and during the earlier stages of substance use.[31] These environmental factors include early drug exposure through peers and family and a history of adverse childhood events. According to a study, adolescents who experienced adverse childhood events had a higher odds ratio of opioid misuse, with the population-attributable percentage of opioid misuse related to events estimated at 71.6%.[32]

Moreover, research shows that the transition from drug experimentation to addiction, following repeated exposures, is associated with disruptions in several brain circuits. These circuits encompass those involved in conditioning, reward sensitivity, self-regulation, and mood.[29] 

Genetic and environmental factors influence the neuroadaptations resulting from repeated drug exposure. Animal studies have shown that these substances affect epigenetic markers, causing posttranslational histone modifications, DNA methylation, and hydroxymethylation.[33] These alterations are associated with long-term neuroadaptations and lasting behavioral effects of drug abuse in animal models.[33]

The interplay between positive reinforcement, characterized by increased reward, and negative reinforcement, aimed at avoiding pain and withdrawal, leads to learned associations or conditioning. Neuroadaptation resulting from repeated drug use involves the desensitization and internalization of receptors and impaired signaling with modulation of intracellular effectors.[30]

History and Physical

The US Preventive Services Task Force (USPSTF) recommends screening all adults for unhealthy alcohol use.[34] In addition, the USPSTF advises screening for unhealthy use of other substances.[35] Although screening and brief interventions have not been shown to reduce drug use, they are critical for promoting responsible prescribing practices for controlled substances. 

Screening with any validated screening tool is considered acceptable. According to the USPSTF report, the structured diagnostic interview is widely regarded as the reference standard for assessment.[35] The Structured Clinical Interview for DSM-5 (SCID-5) is a semistructured interview guide provided by the American Psychiatric Association (APA) that aids in identifying DSM-5 diagnoses.

Addiction Risk Assessment and Recommended Screening Tools

Clinicians should consider information from patient history, physical examination, family members, prescription monitoring programs, and screening tools to assess the risk of developing an adverse behavioral response to prescription opioids and other controlled substances. Patients can be stratified into 3 risk levels based on responses to screening tools:

• Low risk: Standard monitoring, vigilance, and care are required.[27]
• Moderate risk: Additional monitoring and more frequent provider contact are necessary.[36]
• High risk: Intensive and structured monitoring, frequent follow-up contact, consultation with an addiction psychiatrist, and limited monthly prescriptions of short-acting opioids are recommended.[37]

A single-item screening method is reasonable because it is less time-consuming and easy to administer. Patients are asked: How many times in the past year have you used an illegal drug or a prescription medication for nonmedical reasons? A validating study reported that this tool was 100% sensitive and 73.5% specific for detecting a drug use disorder.[38] This tool showed similar sensitivity and specificity for drug use compared to the 10-item Drug Abuse Screening Test (DAST).[38]

The 10-item DAST screening tool consists of 10 yes-or-no questions evaluating the consequences and severity of drug use over the past 12 months.[39] This tool has been validated in multiple studies and translated into many languages, with most studies reporting excellent validity and reliability. Worldwide application of this screening tool has shown high internal consistency, with reported values between 0.86 and 0.94.[39]

The Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) is another validated screening tool frequently used in clinical studies. This tool has the advantage of identifying individuals who use multiple psychoactive substances and providing insights into the severity of their substance involvement.[40] However, a potential disadvantage in the clinical setting is that the ASSIST may involve over 80 items when assessing individuals who use multiple substances, making it potentially too time-consuming to administer.

In addition to using screening tools and assessing personal substance use history, clinicians should obtain information regarding the patient's family history of substance use, current social support system, family or social environments that may contribute to misuse, and any comorbid untreated psychiatric conditions before prescribing controlled substances. This comprehensive approach helps minimize the risk of prescription drug misuse.[41]

Identifying individuals who meet the criteria for an substance use disorder is paramount for ensuring they receive appropriate treatment. According to the DSM-5-TR, a problematic pattern of use with clinically significant impairment is diagnostic of a substance use disorder if 2 or more of the following criteria are demonstrated 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, with unsuccessful efforts.
• Much time is spent obtaining, using, or recovering from the subsubstance'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.

The DSM-5-TR classifies substance use disorder severity based on the number of criteria met—mild if 2 to 3 criteria are met, moderate if 4 to 5 criteria are met, and severe if 6 or more criteria are met.

Evaluation

Drug testing is essential before prescribing controlled substances. In addition to obtaining a thorough history and performing a comprehensive physical examination to detect underlying uncontrolled psychiatric illnesses and substance use, drug testing also provides objective data to confirm adherence to prescribed medications. Random drug testing is preferred over scheduled testing as it is more likely to detect undisclosed substance use.[42] Patient consent should be obtained before testing, which is generally included in the treatment contract for prescribing controlled substances.

Urine is the most commonly used biological sample for drug testing. Alternative specimens such as blood or serum, hair, sweat, and oral fluids may also be used.[43] These alternatives offer benefits such as reduced risk of adulteration and extended detection windows. However, a significant disadvantage is that these samples often contain very low drug concentrations, requiring high-sensitivity techniques for detection.[44] Therefore, urine testing remains the most commonly used and recommended method, as it allows easy collection and offers sufficient sensitivity and specificity to detect widely used drugs.[45][46]

Urine testing also allows for longer detection windows than serum testing. Clinicians should note that urine drug concentrations do not correlate directly with serum concentrations. Instead, they measure drug metabolites, reflecting how rapidly a person metabolizes and eliminates the drug (see Table. Urinary Drug Testing Detection).[45] Consequently, urine drug testing can vary drastically based on the individual's hydration status.[46]

In addition to standard laboratory testing, point-of-care (POC) testing is a viable alternative. POC testing offers advantages such as simplicity and rapid result turnaround; however, this type of testing is more susceptible to mishandling, mainly when performed by non-laboratory staff, potentially leading to inaccurate results. Proper training is crucial to ensure the correct collection, handling, and interpretation of POC test results.[47]

Table 1. Urinary Drug Testing Detection

Notably, positive test results for opioids and benzodiazepines may be due to the presence of various other drugs. For example, detecting morphine in a urine sample could indicate the ingestion of morphine, codeine, or heroin. Similarly, the presence of hydromorphone may suggest the use of hydromorphone, hydrocodone, or morphine.[45] 

A negative test result may indicate that the patient is not taking the prescribed substance or medication or that the drug is rapidly metabolized to undetectable levels. Ideally, confirmatory testing differentiates true-negative results (when the patient is not taking the substance or the prescribed medication) from false-negative results (due to rapid metabolism to undetectable levels in urinary testing).

Confirmatory tests, such as gas chromatography, high-performance liquid chromatography, and mass spectrometry, precisely identify these agents. However, these advanced testing methods are not readily available in most clinical laboratories.[45]

False-Positive Results

False-positive results occur when other medications or ingested substances cross-react with the immunoassays used to detect drugs of abuse, leading to an incorrect positive result.[45] Commonly prescribed medications that may cause false-positive results on urine drug testing 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. 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

Treatment / Management

Before prescribing controlled substances or initiating opioid therapy for chronic pain, the clinician and patient should agree on practical goals regarding pain relief, functionality with activities of daily living, and managing coexisting conditions such as anxiety and depression. The treatment plan should include therapy selection, progress measures, and involvement of other specialty providers if needed. When developing a pain management plan that involves opioids, the clinician should:

• Start at the lowest possible dose and titrate to effect.
• Begin with short-acting opioid formulations.
• Discuss the need for frequent risk and 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 opioid prescribing regulations.
• 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.

Consent and Treatment

According to the American Medical Association, a clinician can proceed with informed consent after assessing the patient's ability to understand the medical information to make an independent decision.[49] The informed consent process should include a discussion of the following:

• Patient diagnosis
• Purpose of recommended treatment
• Risks and benefits of treatment
• Alternative treatment or no treatment, including their associated risks and benefits   

Informed consent for controlled substances and opioids should include the following potential risks:

• Physical adverse effects and complications such as constipation and QT prolongation
• Addiction risk
• Physical dependence
• Cognitive effects
• Psychological dependence
• Tolerance
• Hyperalgesia
• Patient victimization [49] 

Prescribing policies should be clearly described, including guidelines regarding the number and frequency of refills and procedures for handling lost or stolen medications.

Patient and Physician Treatment Agreement

Although there is no standardized agreement or contract for controlled substance or opioid use, such agreements are essential for promoting open communication, ensuring treatment adherence, and establishing an understanding of treatment goals.[49]

Clinicians often include provisions in the agreement that outline the patient's commitment to refrain from doctor shopping and provide consent for drug testing. Clinicians also assume an active role in the agreement by addressing treatment plan concerns and scheduling follow-up visits to evaluate the effectiveness of the interventions.  

The treatment agreement should clearly outline the potential reasons for modifying or discontinuing opioid therapy. These reasons include situations where pain is minimal or resolved, significant adverse effects develop, analgesia is inadequate, quality of life is not improved, function has deteriorated, or evidence of aberrant medication use is present. In addition, the agreement can include monitoring strategies and establish mechanisms for safely storing and disposing of unused medications. Prescribers should consider ending opioid treatment under these circumstances and should taper opioids slowly to minimize withdrawal symptoms. An addiction specialist may need to be involved in cases of aberrant behavior or when tapering is difficult to tolerate.[50][51]

Recommended Guidelines for Responsible Prescribing of Opioids

Among the controlled substances prescribed for medical use, opioids carry the highest risk for misuse and addiction, causing significant societal harm. In response to this issue, the United States Centers for Disease Control and Prevention (CDC) published the Clinical Practice Guideline for Prescribing Opioids in 2022.[52] These guidelines primarily address the use of opioids for pain management. A summary of the recommendations made in this clinical practice guideline is provided below:(A1)

• Nonopioid therapies should be maximized as first-line and adjunct therapy if no contraindications exist.
• Before prescribing opioids for acute pain, the realistic benefits of opioid therapy and the risks of opioid therapy should be thoroughly discussed with the patient.
• Nonopioid therapies are preferred for subacute and chronic pain.
• If opioid therapy is prescribed for acute, subacute, or chronic pain, immediate-release formulations are preferred over extended-release and long-acting formulations.
• In opioid-naive patients, the lowest effective dose should be prescribed. The recommended starting dose for opioid-naive patients is 5 to 10 MME per dose or a daily dosage of 20 to 30 MME/d.
• Unless there are signs of impending overdose, opioid therapy should not be discontinued abruptly.
• When opioids are discontinued, they should be gradually tapered off. For patients taking opioids for extended durations (≥1 year), the recommended taper rate is 10% per month or slower, as this rate is better tolerated than more rapid tapers.
• For acute pain, the prescribed quantity of opioid medications should not exceed the expected duration of pain.
• For subacute and chronic pain, the benefits and risks of continued opioid therapy should be discussed with patients within 1 to 4 weeks of initiation.
• The risk of opioid therapy should be discussed periodically during the treatment, with a clear discussion on ways to mitigate harm, including using naloxone.
• Before prescribing opioid therapy for acute, subacute, or chronic pain, and periodically during opioid therapy, the prescriber should review the patient's controlled substance prescription history using prescription drug monitoring program data.
• Extreme caution is advised when prescribing opioid pain medication and benzodiazepines (or other central nervous system depressants) concurrently due to the risk of respiratory compromise.
• If opioid use disorder is suspected or diagnosed, treatment should be offered. Detoxification without medications for opioid use disorder is not recommended.

According to the CDC, nonopioid therapies are at least as effective as opioids for managing acute pain.[52] Causes of acute pain for which nonopioid therapies are preferred include low back pain, neck pain, sprains, strains, tendonitis, bursitis, dental pain, kidney stone pain, and headaches.[52] Nonpharmacological options such as ice, heat, elevation, and mobility restriction or therapy should be offered and maximized.(A1)

When managing chronic pain, nonpharmacological strategies should be prioritized as the initial approach. The methods, including exercise, physical therapy, psychological and stress reduction therapy, spinal manipulation, laser therapy, massage therapy, acupuncture, and yoga, should be optimized for maximum benefit.[52] If there is an insufficient response to these therapies, nonsteroidal anti-inflammatory drugs or duloxetine should be considered as the first-line option. In cases where neuropathic pain is present, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and anticonvulsants, such as pregabalin, gabapentin, and oxcarbazepine, should be explored before opioid therapy.[52](A1)

The CDC guideline repeatedly emphasizes reevaluation of ongoing opioid therapy to determine whether the expected benefit is achieved. If opioid therapy for subacute or chronic pain has exceeded 4 weeks, a dose escalation beyond the lowest dose can be considered. This decision should follow a discussion between the clinician and the patient regarding the risks and benefits of escalating therapy. However, the CDC guideline states that in most cases, there is no further benefit (in pain relief or function) from escalating opioid therapy to ≥50 MME/d.[52] Increasing opioids beyond 50 MME/d exposes the patient to a progressively higher risk of misuse or addiction and physical complications of therapy without further clinical benefit (see Table. Morphine Equivalence Conversion Factors of Commonly Prescribed Opioids).(A1)

Table 2. Morphine Equivalence Conversion Factors of Commonly Prescribed Opioids

Using the conversion factor provided, a prescription for oxycodone 10 mg taken twice daily (20 mg of oxycodone daily) is equivalent to 30 MME daily. The MME serves as a reference to indicate the potency of the prescribed opioid therapy; however, it should not be used to determine the dosage of an opioid when switching therapies. Patients typically have incomplete tolerance between opioid medications, and individual opioid pharmacokinetics vary substantially. Therefore, when converting between opioids, the new opioid medication should be dosed at a substantially lower dose than the calculated MME dose.[52][53](A1)

When opioid therapy is discontinued or tapered, clinicians must repeatedly emphasize and educate patients regarding the risk of overdose if they return to the previous dose of the medication.[52] Opioid overdose education should be provided at every visit during this process, and naloxone should be co-prescribed. During this period, clinician vigilance regarding the emergence of anxiety, depression, and opioid use disorder is essential to ensure that these conditions are identified early and treated appropriately.(A1)

Recommended Guidelines for Responsible Prescribing of Sedatives and Benzodiazepines

According to the Agency for Healthcare Research and Quality, there is no universally accepted prescription guideline for benzodiazepines and other prescription sedatives and hypnotics. The general practice in the United States follows the federal regulations outlined in the CSA.

The current standard of practice in the United States follows practice guidelines published by the APA for anxiety disorders and insomnia. Benzodiazepines are approved for treating generalized anxiety disorder, insomnia, seizures, panic disorders, social phobia, and certain other conditions. However, their use is recommended only for the short term, typically not exceeding 4 weeks.[54] The APA does not recommend benzodiazepines as a first-line treatment for any of these diagnoses, nor does it endorse their long-term use.(B3)

The National Health Service of the United Kingdom, however, has provided the following guidelines for the use of prescription benzodiazepines:

• Benzodiazepines should be used only for short-term treatment, typically 2 to 4 weeks.
• Benzodiazepines should be prescribed only for anxiety and insomnia that are severe, disabling, or causing extreme distress.
• The health record should document the discussion between the healthcare provider and the patient, outlining the risks of physical and psychological dependence, which can occur even at therapeutic doses.
• Alternative nonpharmacological and pharmacological measures should be emphasized and maximized.

For patients who have been using benzodiazepines for more than 4 weeks, especially if they are taking the medication on most days of the week, a slow taper should be implemented to mitigate the risk of withdrawal.

Prescription Requirements

Clinicians and dispensing pharmacists must ensure that controlled substance prescriptions meet the federally mandated guidelines. According to the CSA information on the DEA's website, a prescription for a controlled substance must be issued for a legitimate medical purpose by a registered practitioner acting in the usual course of sound professional practice. Pharmacists must verify that the prescription includes all of the following:

• Name and address of the patient
• Date of issue
• Name, practice address, and DEA registration number of the prescribing practitioner
• Drug name, strength, dosage form, and specific directions of use
• Quantity prescribed
• Signature of the prescriber

Notably, there are no federal time limits on when a Schedule II prescription must be filled. According to the United States Code of Federal Regulations (Title 21 Chapter II Part 1306), a Schedule II medication may only be called in during emergencies. If this occurs, the prescriber is required to provide a written and signed prescription to the pharmacy within 7 days.

The United States Code of Federal Regulations specifies that refilling a prescription for a controlled substance listed in Schedule II is prohibited. Patients receiving schedule II substances for chronic therapy may be prescribed a 90-day supply with multiple prescriptions, each with 0 refills. The prescriptions should indicate the earliest date they can be filled. Schedule III or IV substances may have up to 5 refills within 6 months, and Schedule V medications may be refilled as authorized by the prescriber.

Differential Diagnosis

Developing a differential diagnosis for chronic pain involves a thorough assessment of potential underlying causes. Identifying the disease process helps the clinician develop an appropriate treatment plan. For example, a patient's chronic hip and leg pain could be attributed to osteoarthritis of the hip, lumbar radiculopathy, or sacroiliac joint dysfunction. Each of these underlying conditions may require distinct management approaches.

Certain diagnoses may respond better to specific treatments, such as using a nonsteroidal anti-inflammatory drug for musculoskeletal pain versus a neuropathic pain medication for nerve-related pain. The clinician must also consider the available interventions to address the diagnosis, including surgical interventions, intra-articular steroid injections, epidural steroid injections, nerve blocks, or radiofrequency ablation procedures.[55]

The possibility of overlapping diagnoses in patients with chronic disease should also be considered. For instance, individuals receiving opioid therapy for chronic pain may develop opioid-induced hyperalgesia alongside their original pain condition.[56]

Chronic pain is often associated with coexisting conditions, such as major depression and sleep disorders.[57] Acknowledging these coexisting conditions allows the clinician to consider appropriate pharmacological treatments, such as utilizing a serotonin-norepinephrine reuptake inhibitor or tricyclic antidepressant to address neuropathic pain and depression symptoms. Furthermore, autoimmune diseases such as systemic lupus erythematosus, psoriasis, fibromyalgia, and central pain syndromes should be considered when chronic pain affects multiple regions of the body. Thus, clinicians must recognize that chronic pain can stem from one or multiple underlying diagnoses.

Prognosis

According to the CDC Morbidity and Mortality Report from 2016, the escalated utilization of opioid analgesics for pain management has markedly increased morbidity and mortality rates in the United States. In 2016 alone, more than 63,600 deaths were due to drug overdose in the United States, with approximately 66% of these fatalities directly linked to opioids and nearly 30% related to concurrent use of benzodiazepines with opioids.[58] By 2021, data from the National Institute on Drug Abuse (NIDA) indicated that overdose-related deaths had increased to over 106,000, with synthetic opioids involved in over 70,000 of these cases. Of those, over 16,000 involved prescription opioids.[NIH. Drug Overdose Deaths: Facts and Figures] Prescription drug use and illicit oral opioid use remain significant predictors of future heroin use.[59]

In response to these alarming trends, the Food and Drug Administration (FDA) implemented a mandatory labeling change in 2016 to help inform healthcare providers and patients about the risk of misuse, addiction, and overdose with opioid medications, especially when combined with benzodiazepines. The FDA issued a public warning about the severe dangers of respiratory depression, coma, and death when these agents are used together or with alcohol.

In 2020, the FDA further addressed concerns surrounding benzodiazepines by issuing a black box warning highlighting the lack of sufficient prescribing information and guidelines for these medications. This warning outlined the serious risks of physiological dependence, especially with long-term use and higher daily doses.[54]

Complications

Misuse, addiction, and overdose are among the most serious complications associated with prescribing controlled substances. All regulatory and guiding entities emphasize the importance of identifying individuals with signs of substance use disorders to ensure early diagnosis and appropriate treatment. According to the SAMHSA, approximately 16.5% of individuals aged 12 or older have a diagnosis of substance use disorder.[SAMHSA. SAMHSA Announces National Survey on Drug Use and Health (NSDUH) Results Detailing Mental Illness and Substance Use Levels in 2021]

According to the CDC, 106,699 overdose deaths in the United States were reported in 2021.[CDC. Drug Overdose Deaths in the United States, 2001–2021] The United S government enacted the Mainstreaming Addiction Treatment (MAT) Act of 2021 to address this crisis. This legislation aims to expedite and expand treatment options for individuals with substance use disorder, promoting better access to care and reducing barriers to evidence-based therapies. 

Mainstreaming Addiction Treatment Act of 2021

The MAT Act provision updates federal guidelines to expand the availability of evidence-based treatment to address the opioid epidemic. Previously, federal regulations required healthcare practitioners to apply for a separate waiver through the DEA to dispense buprenorphine and methadone for maintenance or detoxification treatment. The MAT Act empowers all healthcare providers with a standard controlled substance license to prescribe buprenorphine for opioid use disorder, just as they prescribe other essential medications. This legislation aims to help destigmatize the standard of care for opioid use disorder and integrate substance use disorder treatment across healthcare settings.[60] 

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 opioid use disorder, provided it is permitted under applicable state law. SAMHSA encourages practitioners to incorporate this treatment into their practice. Prescribers registered as X-Waiver prescribers receive a new DEA registration certificate reflecting this change, with no action needed from registrants.

There are no longer limits on the number of patients with opioid use disorder that a practitioner may treat with buprenorphine. In addition, 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 without needing a DATA 2000 waiver from the prescriber. However, depending on the pharmacy, the dispensing software may still require the X-Waiver information. Practitioners must still comply with applicable state limits regarding treating patients with opioid use disorder. SAMHSA provides contact information for state opioid treatment authorities, which can be found here: SAMHSA. State Opioid Treatment Authorities (SOTA).

The MAT Act also promotes education for healthcare practitioners on treating opioid use disorder and encourages them to incorporate substance use disorder treatment into their practices. By promoting ongoing training and awareness, the Act aims to enhance the quality of care and improve outcomes for individuals struggling with addiction.

Opiate Use Disorder Treatment

Treatment for opioid use disorder requires pharmacological therapy.[30] Opioid use disorder should be managed as a chronic condition with medication for opioid use disorder therapy. In patients experiencing acute withdrawal, additional medication may alleviate withdrawal symptoms, including α2-agonists such as lofexidine and clonidine, which can diminish withdrawal symptoms.[30] The previous practice of detoxification and medically supervised withdrawal is no longer recommended as a standalone therapy, as most patients treated in this manner relapse quickly. Moreover, they are at a significantly higher risk of overdose due to loss of tolerance.[30]

Long-term medication for opioid use disorder therapy is the standard of care for most patients with opioid use disorder.[30] Approved therapies for this treatment include methadone, buprenorphine, and naltrexone. Methadone up to 100 mg/d is associated with higher retention in treatment, reduced heroin use during treatment, and fewer withdrawal symptoms. However, evidence supporting higher doses is less convincing.[30] Unlike buprenorphine, methadone does not have a ceiling effect, allowing for flexibility in dosing. However, high doses of methadone can pose a risk of overdose if used beyond an individual's tolerance or when combined with alcohol, sedatives, or heroin. The recommended approach for methadone as medication for opioid use disorder therapy is to start at a low dose and titrate up gradually.

Buprenorphine carries a lower risk of overdose than methadone due to its partial agonist properties.[30] Buprenorphine is often combined with naloxone to reduce the potential for abuse through intravenous injection. Naltrexone, a μ-opioid receptor antagonist available in an extended-release injectable formulation, is an alternative option for patients who have completed medically supervised withdrawal therapy.[30]

Transmucosal buprenorphine formulations combined with naloxone are the most common mode of medication for opioid use disorder therapy. Before starting buprenorphine induction, the patient must be abstinent from opioid use. The timing of induction depends on the patient's symptoms, which must be equivalent to a mild withdrawal state to initiate therapy safely. The Clinical Opiate Withdrawal Scale should be used to assess these symptoms, with a score of 12 or more used as objective evidence of mild-to-moderate withdrawal. At this stage, induction can begin, which may be conducted in the office or home setting.[61]

Buprenorphine is used to treat the withdrawal, and if tolerated, the patient may receive a prescription for the agent to self-administer at home.[30][62] The recommendation is to start at the lowest dose, but a higher dose may be required if withdrawal symptoms persist. According to the SAMHSA, the maximum recommended dose for the first day is 8 mg of buprenorphine. However, exceptions may be made for patients using high-potency opioids, such as fentanyl, at high doses. On day 2 of induction, the same dose as the first day should be given initially, with additional 4 mg buprenorphine doses as needed if withdrawal symptoms are not adequately controlled. SAMHSA advises a maximum dose of 16 mg for day 2. Most patients stabilize at doses between 8 and 16 mg, which are then continued as maintenance therapy.[63] The induction dose should not be escalated further for several weeks. 

For methadone induction, the typical initial dose is 20 to 30 mg in a single administration, with the maximum initial dose recommended by regulatory guidelines set at 30 mg.[64] Methadone should be titrated slowly, typically in 5 to 10 mg increments every few days over several weeks. A typical maintenance dose is between 60 to 80 mg once daily. If dose escalation beyond 80 mg is required, it should proceed at a rate no faster than 10 mg per week. 

Benzodiazepine Use Disorder Treatment

Benzodiazepine use disorder is treated with a benzodiazepine taper, preferably using a long-acting formulation such as diazepam. The taper should be gradual and tailored to the individual's needs, considering the specific benzodiazepine used and the daily dosage.

Nonpharmacologic therapy plays a critical role in preventing relapse after completing the taper. Cognitive-behavioral therapy is particularly beneficial and should be initiated while the patient is undergoing a medically supervised taper of benzodiazepines, as it has shown higher rates of benzodiazepine discontinuation (short-term) compared to tapering alone.[65] Currently, no other effective pharmacological therapy is available to prevent relapse following successful treatment with a medically supervised benzodiazepine taper.