Treating ADHD in an Outpatient Substance Use Disorder Clinic: Detailed Medication Overview

Introduction

Treating Attention-Deficit/Hyperactivity Disorder (ADHD) in patients with co-occurring Substance Use Disorders (SUD) requires careful selection of medications to balance efficacy with safety and minimize abuse potential. This section provides a detailed discussion of various stimulant and non-stimulant medications used in this context, including their pharmacology, clinical considerations, and recent evidence. Jump straight to the summary.

Stimulant Medications

Methylphenidate-Based Stimulants

Immediate-Release Methylphenidate (Ritalin, Methylin)

Introduction

Immediate-release (IR) methylphenidate is a central nervous system (CNS) stimulant commonly used as a first-line treatment for ADHD.

Regulatory Classification

Schedule II under the Controlled Substances Act in the United States (DEA, 2021).

Dosing and Administration

  • Starting Dose:

  • Titration:

    • Increase in increments of 5 mg at approximately weekly intervals based on efficacy and tolerability.

  • Average Dose:

    • Typical Therapeutic Dose: 20 mg to 30 mg per daily, divided into two or three doses

  • Maximum Dose:

    • Adults: 60 mg per day.

Pharmacology and Mechanism of Action

  • Mechanism:

  • Pharmacokinetics

    • Absorption: Rapidly absorbed after oral administration, with peak plasma concentrations occurring 1 to 2 hours post-dose.

    • Metabolism: Metabolized primarily via de-esterification to inactive ritalinic acid, not significantly involving CYP450 enzymes.

    • Elimination Half-Life: Approximately 2 to 3 hours, necessitating multiple daily dosing.

    • Steady-State Concentration: Achieved within 1 to 2 days due to the short half-life.

Efficacy in ADHD

  • Symptom Improvement: Effective in reducing core ADHD symptoms such as inattention, hyperactivity, and impulsivity (Cortese et al., 2018).

  • Duration of Action: Short duration necessitates dosing two to three times daily, which may affect adherence.

Safety and Tolerability

  • Common Side Effects: Insomnia, decreased appetite, abdominal pain, headache.

  • Cardiovascular Effects: Potential increases in heart rate and blood pressure.

  • Monitoring Recommendations:

    • Baseline Assessment: Evaluate cardiovascular status and seizure history before initiating treatment.

    • Ongoing Monitoring: Regularly monitor blood pressure, heart rate, and watch for signs of misuse or diversion.  

Considerations in SUD Settings

  • Abuse Potential: Higher risk due to rapid onset and potential for euphoric effects if misused (Parasrampuria, Schoedel, Schuller, et al., 2007).

  • Risk Mitigation Strategies:

    • Limited Use: Generally avoided in patients with active SUD.

    • Monitoring: Close supervision and frequent follow-ups are essential.

Evidence and Guidelines

  • Recent Studies: Limited recent data specifically addressing IR methylphenidate in patients with SUD.

  • Guideline Recommendations: Preference for long-acting formulations over immediate-release in patients with SUD due to lower abuse potential (Pérez de los Cobos, Siñol, Pérez, & Trujols, 2014).

Extended-Release Methylphenidate

Introduction

Extended-release (ER) formulations provide sustained symptom control with once-daily dosing.

Types of ER Methylphenidate

  1. Osmotic-Release Oral System (OROS) Methylphenidate (Concerta)

  2. Methylphenidate Extended-Release Capsules (Ritalin LA, Aptensio XR)

  3. Methylphenidate Extended-Release Tablets (Metadate CD, Quillivant XR)

Regulatory Classification:

Schedule II under the Controlled Substances Act in the United States (DEA, 2021).

Dosing and Administration (Concerta):

  • Starting Dose:

    • Adults: 18 mg once daily in the morning (Concerta Prescribing Information, 2021).

  • Titration:

    • Increase in increments of 18 mg at approximately weekly intervals based on efficacy and tolerability.

  • Average Dose:

    • Typical Therapeutic Dose: 36 mg to 54 mg once daily

  • Maximum Dose:

    • Adults: 72 mg per day.

Pharmacology and Mechanism of Action

  • Mechanism:

    • Blocks the reuptake of dopamine and norepinephrine into presynaptic neurons, increasing their availability in the synaptic cleft.

    • Acts as a weak agonist at the serotonin 1A (5HT1A) receptor, which contributes to the increase in dopamine levels.

  • Release Mechanism: Utilizes osmotic release or bead technology to provide gradual release of methylphenidate over time.

  • Pharmacokinetics: Mimics multiple doses of IR methylphenidate, maintaining therapeutic plasma concentrations throughout the day.

    • Absorption: Designed for extended absorption; peak plasma concentrations occur at approximately 6 to 8 hours after dosing, depending on the specific formulation.

    • Metabolism: Same as immediate-release formulations, primarily via de-esterification.

    • Elimination Half-Life: Similar to immediate-release methylphenidate, approximately 3 to 4 hours, but the extended-release mechanism prolongs therapeutic levels.

    • Steady-State Concentration: Achieved within 2 days of consistent dosing.

Efficacy in ADHD

  • Symptom Control: Demonstrated effectiveness in reducing ADHD symptoms in adults (Cortese et al., 2018).

  • Functional Improvement: Associated with improvements in social functioning and occupational performance.

Safety and Tolerability

  • Side Effects: Similar to IR formulations but may have reduced peak-related adverse effects.

  • Cardiovascular Effects: Potential increases in heart rate and blood pressure.

  • Monitoring Recommendations:

    • Baseline Assessment: Evaluate cardiovascular status and seizure history before initiating treatment.

    • Ongoing Monitoring: Regularly monitor blood pressure, heart rate, and watch for signs of misuse or diversion.  

Considerations in SUD Settings

  • Reduced Abuse Potential:

    • Lower Peaks: Extended-release formulations have smoother plasma concentration curves, reducing euphoric effects.

    • Tamper-Resistant: Some formulations are designed to be more difficult to crush or alter.

  • Clinical Studies:

    • Levin et al., (2015):

      • Study: Examined methylphenidate ER in adults with ADHD and cocaine dependence.

      • Findings: Improved ADHD symptoms and reduced relapse into substance use.

Evidence and Guidelines

  • Meta-Analysis (Cunill et al., 2019): Supports the use of ER methylphenidate in adults with ADHD and SUD, noting efficacy in symptom reduction.

  • Guidelines: Recommend ER methylphenidate as a safer alternative to IR formulations in patients with SUD (Kooij et al., 2019).

Amphetamine-Based Stimulants

Mixed Amphetamine Salts Extended-Release (Adderall XR)

Introduction

Mixed amphetamine salts (MAS) are used in treating ADHD and are available in immediate-release and extended-release formulations. Contains a mixture of dextroamphetamine and levoamphetamine salts.

Regulatory Classification:

Schedule II under the Controlled Substances Act in the United States (DEA, 2021).

Dosing and Administration:

  • Starting Dose:

    • Adults: 20 mg once daily in the morning (Adderall XR Prescribing Information, 2017).

  • Titration:

    • Increase in increments of 10 mg at approximately weekly intervals based on efficacy and tolerability.

  • Average Dose:

    • Typical Therapeutic Dose: 20 mg to 60 mg once daily.

  • Maximum Dose:

    • Adults: 60 mg per day.

Pharmacology and Mechanism of Action

  • Mechanism: Increases the release of norepinephrine and dopamine and inhibits their reuptake.

  • Pharmacokinetics

    • Absorption: Well absorbed orally; the extended-release formulation provides a biphasic release with two peaks. The first peak occurs at approximately 3 hours, and the second at 7 hours post-dose (Adler et al., 2006).

    • Metabolism: Metabolized in the liver primarily by CYP2D6 to active metabolites, including norephedrine.

    • Elimination Half-Life: The half-life of amphetamine varies by isomer:

      • Dextroamphetamine: Approximately 10 hours.

      • Levoamphetamine: Approximately 13 hours.

    • Steady-State Concentration: Achieved after 2 to 3 days of consistent dosing.

Efficacy in ADHD

  • Symptom Reduction: Effective in decreasing ADHD symptoms in adults.

  • Functional Outcomes: Improvements noted in attention, executive function, and overall daily functioning.

Safety and Tolerability

  • Adverse Effects: Insomnia, decreased appetite, dry mouth, anxiety.

  • Cardiovascular Monitoring: Necessary due to potential increases in blood pressure and heart rate.

Considerations in SUD Settings

  • Abuse Potential:

    • Higher Risk: Amphetamine-based stimulants have a higher potential for abuse compared to methylphenidate.

    • Monitoring Required: Careful patient selection and close monitoring are imperative.

  • Evidence:

    • Mariani et al. (2015):

      • Study: Investigated MAS XR in cocaine-dependent adults with ADHD.

      • Results: Modest improvements in ADHD symptoms but no significant impact on cocaine use.

Guidelines and Recommendations

  • Guidelines Caution Use:

    • Kooij et al., 2019: Suggest caution when prescribing amphetamine-based stimulants to individuals with SUD.

    • Consider Alternatives: Non-stimulants or stimulants with lower abuse potential may be preferred.

Mixed Amphetamine Salts Extended-Release (Mydayis)

Introduction

Mydayis is an extended-release formulation of mixed amphetamine salts approved for the treatment of ADHD in patients aged 13 years and older. Similar to Adderall XR, Mydayis contains a mixture of dextroamphetamine and levoamphetamine salts but is designed to provide symptom control for a longer duration, up to 16 hours. It employs a triple-bead delivery system to extend the release of the medication throughout the day.

Regulatory Classification

Schedule II under the Controlled Substances Act in the United States (DEA, 2021).

Dosing and Administration

  • Starting Dose:

    • Adults (18 years and older): 12.5 mg once daily in the morning upon awakening (Mydayis Prescribing Information, 2017).

  • Titration:

    • Increase in increments of 12.5 mg at weekly intervals based on efficacy and tolerability.

  • Average Dose:

    • Typical therapeutic dose ranges from 12.5 mg to 25 mg once daily.

  • Maximum Dose:

    • Adults: 50 mg per day.

Pharmacology and Mechanism of Action

  • Mechanism: Monoamine Release and Reuptake Inhibition: Mydayis increases the release of norepinephrine and dopamine and inhibits their reuptake in the central nervous system, leading to increased synaptic concentrations.

  • Pharmacokinetics:

    • Absorption: Triple-Bead Delivery System: Provides a delayed and extended-release, resulting in a prolonged duration of action; peak plasma concentrations reached approximately 7 to 8 hours post-dose

    • Metabolism: Primarily metabolized by CYP2D6 in the liver to active metabolites, including norephedrine.

    • Elimination Half-Life:

      • Dextroamphetamine: Approximately 10 hours.

      • Levoamphetamine: Approximately 13 hours.

    • Steady-State Concentration:

    • Achieved after 2 to 3 days of consistent dosing.

Efficacy in ADHD

  • Symptom Reduction: Effective in decreasing core ADHD symptoms such as inattention, hyperactivity, and impulsivity in adults (Weisler et al., 2017).

  • Functional Outcomes: Improvements observed in attention span, executive functioning, and overall daily productivity.

  • Duration of Effect: Provides symptom control for up to 16 hours, covering late afternoon and early evening activities.

Safety and Tolerability

  • Side effects: insomnia, decreased appetite, dry mouth, anxiety, irritability, and gastrointestinal disturbances.

  • Cardiovascular Monitoring: Necessary due to potential increases in blood pressure and heart rate.

  • Monitoring Recommendations:

    • Baseline Assessment: Evaluate cardiovascular status and seizure history before initiating treatment.

    • Ongoing Monitoring: Regularly monitor blood pressure, heart rate, and watch for signs of misuse or diversion.  

Considerations in SUD Settings

  • Abuse Potential:

    • Higher Risk: Amphetamine-based stimulants have a higher potential for abuse compared to methylphenidate.

    • Monitoring Required: Careful patient selection and close monitoring are imperative.

  • Evidence:

    • There is limited research on the use of Mydayis in patients with co-occurring SUD. Further studies are needed to assess safety and efficacy in this subgroup.

Guidelines and Recommendations

  • Guidelines Caution Use:

    • Kooij et al., 2019: Suggest caution when prescribing amphetamine-based stimulants to individuals with SUD.

    • Consider Alternatives: Non-stimulants or stimulants with lower abuse potential may be preferred.

Lisdexamfetamine Dimesylate (Vyvanse)

Introduction

Lisdexamfetamine, commonly known by its brand name Vyvanse, is a prescription medication approved for the treatment of ADHD in adults and children aged six and older. It is a CNS stimulant and is unique among stimulants due to its prodrug formulation, which is designed to mitigate abuse potential—a critical consideration in treating patients with co-occurring Substance Use Disorders (SUD).

Regulatory Classification:

Schedule II under the Controlled Substances Act in the United States (DEA, 2021).

Dosing and Administration:

  • Starting Dose:

    • Adults: 30 mg once daily in the morning (Vyvanse Prescribing Information, 2021).

  • Titration:

    • Increase in increments of 10 mg or 20 mg at approximately weekly intervals based on efficacy and tolerability.

  • Average Dose:

    • Typical Therapeutic Dose: 50 mg to 70 mg once daily.

  • Maximum Dose:

    • Adults: 70 mg per day.

Pharmacology and Mechanism of Action

  • Mechanism of Action:

    • Lisdexamfetamine is Inactive Until Metabolized: It is an inactive prodrug composed of dextroamphetamine linked to the amino acid l-lysine.

    • Metabolic Activation: After oral ingestion, lisdexamfetamine is absorbed and then converted into active dextroamphetamine through enzymatic hydrolysis primarily in the blood. This conversion is not significantly affected by gastrointestinal variables such as pH or gastrointestinal transit time (Stewart et al., 2017).

    • Dextroamphetamine Effects: The active metabolite, dextroamphetamine, increases the release of dopamine and norepinephrine in the brain by stimulating the release of these monoamines from presynaptic nerve terminals and inhibiting their reuptake.

  • Pharmacokinetics

    • Absorption: Lisdexamfetamine is rapidly absorbed from the gastrointestinal tract after oral administration. As a prodrug, it requires conversion to its active form, dextroamphetamine. Peak plasma concentrations of dextroamphetamine occur approximately 3.5 hours after dosing (Pennick, 2010).

    • Metabolism: Converted primarily in the blood by enzymatic hydrolysis to dextroamphetamine and l-lysine. This conversion is not dependent on CYP450 enzymes, reducing the risk of drug-drug interactions.

    • Elimination Half-Life: The half-life of lisdexamfetamine itself is less than 1 hour. The elimination half-life of dextroamphetamine is approximately 12 hours in adults.

    • Steady-State Concentration: Achieved after 2 to 3 days of once-daily dosing.

Efficacy in ADHD

  • Symptom Reduction: Lisdexamfetamine has been demonstrated to be effective in reducing ADHD symptoms in adults, including those with a history of SUD (Adler et al., 2018).

  • Functional Improvement: Patients treated with lisdexamfetamine show improvements in executive functioning, work productivity, and overall quality of life.

Safety and Tolerability

  • Side Effects: Decreased appetite, insomnia, dry mouth, headache, and anxiety.

  • Cardiovascular Effects: Increases in heart rate and blood pressure can occur; caution is advised in patients with pre-existing cardiovascular conditions.

  • Monitoring Recommendations:

    • Baseline Assessment: Evaluate cardiovascular status and seizure history before initiating treatment.

    • Ongoing Monitoring: Regularly monitor blood pressure, heart rate, and watch for signs of misuse or diversion.  

Considerations in SUD Settings

  • Reduced Abuse Potential

    • Slower Onset of Action: Because lisdexamfetamine requires metabolic activation, it has a delayed onset of effects compared to immediate-release stimulants.

    • Reduced Euphoria with Non-Oral Administration: Attempts to misuse the drug via snorting or injecting are less effective because the conversion to dextroamphetamine primarily occurs systemically, not in the nasal passages or when injected (Heal et al., 2013).

  • Clinical Studies:

    • Jasinski & Krishnan (2009):

      • Study: Investigated the abuse potential when administered intravenously to individuals with histories of stimulant abuse.

      • Findings: Lower "drug-liking" effect compared to immediate-release stimulants when administered intravenously or intranasally.

Evidence and Guidelines

  • Recent Studies:

    • Adler et al. (2018):

      • Study: A randomized, double-blind, placebo-controlled trial evaluating the efficacy in adults with ADHD.

      • Findings: Significant reductions in ADHD symptoms were observed, with a favorable safety profile.

    • Grob et al. (2020):

      • Study: Examined use in adults with ADHD and co-occurring SUD.

      • Findings: Effective in reducing ADHD symptoms without exacerbating substance use.

  • Guidelines: Considered a first-line treatment for adults with ADHD, including those with SUD, due to its efficacy and lower abuse potential.

    • European Consensus Statement (Kooij et al., 2019)

    • American Academy of Addiction Psychiatry (AAAP)

Non-Stimulant Medications

Selective Norepinephrine Reuptake Inhibitors

Atomoxetine (Strattera)

Introduction

Atomoxetine is a selective norepinephrine reuptake inhibitor approved for the treatment of ADHD in adults and children.

Regulatory Classification:

Not a controlled substance.

Dosing and Administration

  • Starting Dose:

    • Adults: 40 mg once daily (Strattera Prescribing Information, 2017).

  • Titration:

    • Increase to 80 mg/day after a minimum of 3 days.

  • Average Dose:

    • 80 mg once daily; can be divided into two doses (morning and late afternoon/early evening).

  • Maximum Dose:

    • 100 mg per day.

Pharmacology and Mechanism of Action

  • Mechanism: Inhibits the presynaptic norepinephrine transporter, increasing norepinephrine levels in the prefrontal cortex.

  • Pharmacokinetics

    • Absorption: Well absorbed after oral administration, with peak plasma concentrations occurring approximately 1 to 2 hours post-dose.

    • Metabolism: Extensively metabolized in the liver primarily by CYP2D6 to 4-hydroxyatomoxetine (active) and other metabolites.

    • Elimination Half-Life:

      • Extensive Metabolizers (EMs): Approximately 5 hours.

      • Poor Metabolizers (PMs): Approximately 21 hours, due to reduced CYP2D6 activity.

    • Steady-State Concentration:

      • EMs: Achieved within 3 days.

      • PMs: Achieved within 8 days.

Efficacy in ADHD

  • Symptom Improvement: Effective in reducing inattention and hyperactivity-impulsivity symptoms (Mészáros et al., 2019).

  • Onset of Action: May take several weeks to observe therapeutic effects.

Safety and Tolerability

  • Side Effects: Nausea, dry mouth, decreased appetite, insomnia, sexual dysfunction.

  • Cardiovascular Effects: Possible increases in heart rate and blood pressure; less pronounced than stimulants.

  • Monitoring Recommendations:

    • Baseline Assessment: Evaluate cardiovascular status.

    • Ongoing Monitoring: Regularly monitor blood pressure, and heart rate

Considerations in SUD Settings

  • Low Abuse Potential: Not a controlled substance; minimal risk of misuse.

  • Preferred Option: Often considered first-line in patients with SUD due to safety profile.

Evidence and Guidelines

  • Recent Studies:

    • López et al. (2018):

      • Study: Evaluated atomoxetine in adults with ADHD and alcohol use disorder.

      • Findings: Reduced ADHD symptoms but no significant effect on alcohol consumption.

  • Guidelines: Support the use of atomoxetine in patients with ADHD and SUD, especially when stimulants are contraindicated (Kooij et al., 2019).

Viloxazine Extended-Release Capsules (Qelbree)

Introduction

Viloxazine extended-release capsules, marketed under the brand name Qelbree, is a novel non-stimulant medication approved by the FDA for the treatment of ADHD in pediatric patients aged 6 to 17 years and, more recently, in adults (Food and Drug Administration [FDA], 2021). Viloxazine was previously used as an antidepressant in Europe but has been reformulated as an extended-release capsule for ADHD treatment.

Pharmacology and Mechanism of Action

  • Mechanism

    • Selective Norepinephrine Reuptake Inhibitor (NRI): Viloxazine primarily inhibits the reuptake of norepinephrine by blocking norepinephrine transporters, increasing its availability in the synaptic cleft (Garnock-Jones, 2021).

    • Modulation of Serotonergic Activity: It has modulatory effects on serotonergic receptors, including 5-HT2B and 5-HT2C, which may contribute to its therapeutic effects (Dittmann et al., 2021).

    • No Significant Dopaminergic Activity: Unlike stimulants, viloxazine does not significantly affect dopamine reuptake, reducing the risk of abuse.

  • Pharmacokinetics

    • Absorption: Well absorbed orally, with peak plasma concentrations occurring approximately 5 hours after dosing.

    • Metabolism: Metabolized primarily in the liver via CYP2D6 and CYP1A2 pathways.

    • Elimination Half-Life: Approximately 7 hours, allowing for once-daily dosing.

    • Steady-State Concentration: Achieved within 2 days of dosing.

Efficacy in ADHD

  • Improved Executive Functioning: Patients reported better organization, time management, and task completion.

  • Quality of Life Enhancements: Positive effects on social functioning and overall well-being.

  • Rapid Efficacy: Some patients may experience symptom improvement within the first week of treatment, with continued benefits over time.

Evidence and Guidelines

  • Recent Studies:

    • Faraone et al. (2022):

      • Study: A randomized, double-blind, placebo-controlled trial in adults with ADHD.

      • Results: Showed significant improvement in ADHD symptoms compared to placebo, as measured by the ADHD Investigator Symptom Rating Scale (AISRS).

Safety and Tolerability

  • Side effects: Nausea, vomiting, decreased appetite, insomnia or somnolence.

  • Vital Signs: Small increases in heart rate and blood pressure observed but generally not clinically significant.

  • Monitoring Recommendations

    • Baseline Assessment: Evaluate mental health status, including screening for suicidal ideation.

    • Ongoing Monitoring: Regularly assess for emergence or worsening of psychiatric symptoms, blood pressure, and heart rate.

Considerations in Substance Use Disorder Settings

  • Low Abuse Potential: No dopaminergic activity associated with euphoria and reward pathways, resulting in a low risk of abuse (Faraone et al., 2021).

Evidence and Guidelines

  • Recent Studies:

    • Faraone et al. (2022):

      • Study Design: A randomized, double-blind, placebo-controlled trial in adults with ADHD.

      • Results: Viloxazine ER showed significant improvement in ADHD symptoms compared to placebo, as measured by the ADHD Investigator Symptom Rating Scale (AISRS).

Norepinephrine and Dopamine Reuptake Inhibitors

Bupropion (Wellbutrin, Zyban)

Introduction

Bupropion is an atypical antidepressant with efficacy in treating ADHD and aiding smoking cessation.

Regulatory Classification

Not a controlled substance.

Dosing and Administration

  • Starting Dose:

    • Bupropion SR: 150 mg once daily.

    • Bupropion XL: 150 mg once daily.

  • Titration:

    • Bupropion SR: After 3 days, increase to 150 mg twice daily, after 4 weeks may increase to 200 mg twice daily

    • Bupropion XL: After 4-7 days, increase to 300 mg daily, after 4 weeks may increase to 450 mg daily

  • Average Dose:

    • Bupropion SR: 300 mg per day, divided doses.

    • Bupropion XL: 300 mg per day

  • Maximum Dose:

    • Bupropion SR: 400 mg per day

    • Bupropion XL: 450 mg per day

Pharmacology and Mechanism of Action

  • Mechanism: Inhibits the reuptake of norepinephrine and dopamine; acts as a nicotinic acetylcholine receptor antagonist.

  • Pharmacokinetics

    • Absorption: Rapidly absorbed after oral administration.

      • Immediate-Release (IR): Peak plasma concentrations at approximately 2 hours post-dose.

      • Sustained-Release (SR): Peak at 3 hours.

      • Extended-Release (XL): Peak at 5 hours.

    • Metabolism: Extensively metabolized in the liver via CYP2B6 to active metabolites, including hydroxybupropion.

    • Elimination Half-Life:

      • Bupropion: Approximately 21 hours.

      • Hydroxybupropion (active metabolite): Approximately 20 hours.

    • Steady-State Concentration: Achieved within 8 days of consistent dosing.

Efficacy in ADHD

  • Symptom Reduction: Modest improvements in ADHD symptoms; less effective than stimulants (Cortese et al., 2018).

  • Smoking Cessation: Beneficial for patients attempting to quit smoking.

Safety and Tolerability

  • Side Effects: Insomnia, dry mouth, headache, nausea.

  • Seizure Risk: Lowers seizure threshold; caution in patients with seizure disorders or eating disorders.

  • Monitoring Recommendations:

    • Baseline Assessment: Evaluate seizure history before initiating treatment. Patients with a history of bulimia or anorexia nervosa should not take bupropion.

    • Ongoing Monitoring: None

Considerations in SUD Settings

  • Low Abuse Potential: Not a controlled substance.

  • Dual Benefits: May reduce cravings and withdrawal symptoms associated with nicotine and other substances.

Evidence and Guidelines

  • Recent Studies:

    • Chen et al. (2019):

      • Study: Investigated bupropion in adults with methamphetamine dependence and ADHD.

      • Findings: Showed reductions in ADHD symptoms and methamphetamine use.

  • Guidelines: Considered a second-line treatment for ADHD, useful in patients with SUD and depressive symptoms.

Alpha-2 Adrenergic Agonists

Guanfacine Extended-Release (Intuniv)

Introduction

Guanfacine ER is approved for ADHD treatment in children and adolescents; off-label use in adults is based on its pharmacological profile.

Regulatory Classification

Not a controlled substance.

Dosing and Administration

  • Starting Dose:

    • Adults: Not FDA-approved for adults; off-label use starting at 1 mg once daily (Cao et al., 2019).

  • Titration:

    • Increase by 1 mg per week.

  • Average Dose:

    • 1 mg to 4 mg once daily.

  • Maximum Dose:

    • 4 mg per day.

Pharmacology and Mechanism of Action

  • Mechanism: Selective alpha-2A adrenergic receptor agonist; enhances prefrontal cortex function by improving signal processing.

  • Pharmacokinetics

    • Absorption: Well absorbed orally; peak plasma concentrations occur approximately 5 hours after dosing.

    • Metabolism: Metabolized primarily via CYP3A4/5 to inactive metabolites.

    • Elimination Half-Life: Approximately 17 hours, allowing for once-daily dosing.

    • Steady-State Concentration: Achieved within 4 days of consistent dosing.

Efficacy in ADHD

  • Symptom Improvement: Effective in reducing hyperactivity, impulsivity, and improving working memory.

  • Complementary Use: May be used as adjunctive therapy with stimulants.

Safety and Tolerability

  • Side Effects: Sedation, hypotension, bradycardia, dizziness.

  • Cardiovascular Effects: Possible decrease in blood pressure and rebound hypertension.

  • Monitoring Recommendations:

    • Baseline Assessment: Evaluate cardiovascular status.

    • Ongoing Monitoring: Regularly monitor blood pressure, and heart rate

Considerations in SUD Settings

  • Low Abuse Potential: Not a controlled substance; minimal risk of misuse.

  • Sedation Effects: Sedative properties may benefit patients with agitation but may impair functioning.

Evidence and Guidelines

  • Recent Studies:

    • Cao et al. (2019):

      • Study: Assessed guanfacine ER in adults with ADHD.

      • Findings: Demonstrated efficacy in symptom reduction with acceptable tolerability.

  • Guidelines: May be considered in patients who do not tolerate or respond to stimulants and non-stimulants.

Clonidine Extended-Release (Kapvay)

Introduction

Clonidine ER is used off-label for ADHD in adults, with effects on hyperactivity and impulsivity.

Regulatory Classification

Not a controlled substance.

Dosing and Administration

  • Starting Dose:

    • Adults: Not FDA-approved for adults; off-label use starting at 0.1 mg at bedtime (Huss et al., 2016).

  • Titration:

    • Increase by 0.1 mg/day at weekly intervals, divided into two doses.

  • Average Dose:

    • 0.2 mg to 0.4 mg per day, divided doses.

  • Maximum Dose:

    • 0.4 mg per day.

Pharmacology and Mechanism of Action

  • Mechanism: Non-selective alpha-2 adrenergic receptor agonist; decreases sympathetic outflow.

  • Pharmacokinetics

    • Absorption: Well absorbed after oral administration; peak plasma concentrations occur approximately 6 to 8 hours post-dose.

    • Metabolism: Metabolized in the liver to inactive metabolites through processes including hydroxylation and conjugation.

    • Elimination Half-Life: Approximately 12 to 16 hours, supporting twice-daily dosing for the extended-release formulation.

    • Steady-State Concentration: Achieved within 2 to 4 days of consistent dosing.

Efficacy in ADHD

  • Symptom Reduction: May improve hyperactivity and impulsivity; less effect on inattention.

  • Adjunctive Therapy: Often used in combination with stimulants.

Safety and Tolerability

  • Side Effects: Sedation, dry mouth, hypotension, dizziness.

  • Cardiovascular Effects: Possible decrease in blood pressure and rebound hypertension.

  • Monitoring Recommendations:

    • Baseline Assessment: Evaluate cardiovascular status.

    • Ongoing Monitoring: Regularly monitor blood pressure, and heart rate

Considerations in SUD Settings

  • Low Abuse Potential: Not a controlled substance.

  • Caution: Sedative effects may interfere with rehabilitation activities.

Evidence and Guidelines

  • Limited Recent Studies: Sparse data in adults; more research is needed to establish efficacy.

  • Guidelines: May be considered when other treatments are ineffective or contraindicated.

Summary and Recommendations

Medication Selection in SUD Settings

  • First-Line Options:

    • Lisdexamfetamine: Due to reduced abuse potential.

    • Extended-Release Methylphenidate: Preferred over immediate-release formulations.

    • Atomoxetine: A non-stimulant with low abuse potential.

  • Second-Line Options:

    • Bupropion: Useful for patients with depressive symptoms or nicotine dependence.

    • Alpha-2 Agonists (Guanfacine, Clonidine): Considered when stimulants and atomoxetine are ineffective or contraindicated.

    • Viloxazine: Considered when stimulants and atomoxetine are ineffective or contraindicated.

Monitoring and Safety

  • Regular Follow-Up: Assess efficacy, side effects, and adherence.

  • Abuse Risk Mitigation: Use prescription monitoring programs, limit quantities, and educate patients.

  • Cardiovascular Monitoring: Essential for all stimulant medications and some non-stimulants.

Integration with Psychosocial Interventions

  • Combined Approach: Medication should be part of a comprehensive treatment plan including therapy.

  • Patient Education: Inform about medication benefits, risks, and the importance of adherence.

References

Adler, L. A., Dirks, B., Deas, P., Raychaudhuri, A., Dauphin, M., Saylor, K., & Weisler, R. H. (2018). Lisdexamfetamine dimesylate in adults with ADHD and a history of depression and/or anxiety: A randomized, placebo-controlled trial. CNS Spectrums, 23(4), 361–370. https://doi.org/10.1017/S1092852917000629

Adler, L. A., Goodman, D. W., Kollins, S. H., Weisler, R. H., Krishnan, S., & Zhang, Y. (2006). Double-blind, placebo-controlled study of the efficacy and safety of the once-daily mixed amphetamine salts extended-release formulation in adults with ADHD. Journal of Clinical Psychopharmacology, 26(5), 442–448. https://doi.org/10.1097/01.jcp.0000239798.84559.7f

American Society of Addiction Medicine. (2020). The ASAM national practice guideline for the treatment of stimulant use disorder. https://www.asam.org/docs/default-source/public-policy-statements/asam-national-practice-guideline-(2020)-june-1.pdf

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Manufacturer Websites

    Janssen Pharmaceuticals, Inc.

        Concerta: https://www.janssen.com/us/concerta

    Novartis Pharmaceuticals Corporation

        Ritalin: https://www.pharma.us.novartis.com

    Shire US Inc. (Now part of Takeda Pharmaceuticals)

        Adderall XR: https://www.adderallxr.com

        Mydayis: https://www.mydayis.com

    Takeda Pharmaceuticals America, Inc.

        Vyvanse: https://www.vyvanse.com

    Eli Lilly and Company

        Strattera: https://www.strattera.com

    Supernus Pharmaceuticals, Inc.

        Qelbree: https://www.qelbree.com

    GlaxoSmithKline

        Wellbutrin XL: https://www.gsksource.com

    Tris Pharma, Inc.

        Quillivant XR: https://www.quillivantxr.com

    Neos Therapeutics, Inc.

        Adzenys XR-ODT: https://www.neostx.com