What are the potential risks and management strategies for an adult patient with a history of opioid use disorder and psychiatric conditions, taking brexpiprazole (Rexulti), buprenorphine/naloxone (Suboxone), doxepin, hydroxyzine, and topiramate?

Management of Complex Polypharmacy in Opioid Use Disorder with Psychiatric Comorbidities

This medication regimen requires immediate attention to critical drug-drug interactions, particularly the combination of Suboxone (buprenorphine/naloxone) with multiple CNS depressants (doxepin and hydroxyzine), which significantly increases respiratory depression and overdose risk. 1

Critical Safety Priorities

Immediate Risk Assessment

• Patients taking opioids with other CNS depressants require monitoring more frequently than every 3 months, with specific attention to sedation, slurred speech, and respiratory depression during the first weeks of treatment. 2
• The combination of buprenorphine with sedating antihistamines (hydroxyzine) and tricyclic antidepressants (doxepin) creates additive CNS depression that demands heightened vigilance. 1
• Patients with mental health conditions (which this patient clearly has given brexpiprazole use) have increased risk for opioid use disorder and drug overdose, requiring additional caution and increased monitoring. 1

Suboxone (Buprenorphine/Naloxone) Management

• Continue Suboxone as prescribed—this is the first-line, evidence-based treatment for opioid use disorder and should be maintained long-term rather than tapered, as maintenance therapy significantly reduces relapse rates and mortality. 3, 4, 5
• Buprenorphine maintenance at fixed dosages of at least 7 mg per day is effective, with 16 mg per day clearly superior to placebo for treatment retention and decreased opioid use. 5
• The buprenorphine/naloxone combination formulation is preferred over buprenorphine alone due to safety features preventing misuse by injection. 3

Medication-Specific Concerns and Modifications

Brexpiprazole (Rexulti) Considerations

• Brexpiprazole carries risks of somnolence (5% incidence), sedation (2% incidence), and dizziness (3% incidence) that compound CNS depression from other medications. 6
• The FDA label warns about potential for cognitive and motor impairment, orthostatic hypotension, and falls—all amplified when combined with other sedating agents. 6
• Continue brexpiprazole for psychiatric stabilization, but recognize it contributes to overall CNS depression burden and fall risk. 6

Doxepin (Tricyclic Antidepressant)

• Doxepin should be carefully evaluated for necessity—while tricyclic antidepressants can provide analgesic and antidepressant effects in patients with depression and chronic pain, the sedating properties create significant interaction risk with buprenorphine. 1
• If used for pruritus (itching), consider that sedating antihistamines like hydroxyzine or diphenhydramine are alternatives, though these also cause sedation. 1
• For depression management in patients with substance use disorders, consider whether alternative antidepressants (SSRIs, SNRIs) might provide similar benefit with less sedation risk. 1, 2

Hydroxyzine (Sedating Antihistamine)

• Hydroxyzine is particularly problematic in this regimen as it significantly potentiates CNS depression from buprenorphine and should be tapered to the lowest effective dose or discontinued entirely. 2
• If used for anxiety, transition to evidence-based alternatives including SSRIs (escitalopram, sertraline) or SNRIs (venlafaxine) combined with cognitive behavioral therapy. 2
• If used for pruritus related to opioid therapy, consider rotating to non-sedating antihistamines or addressing the underlying cause. 1
• The CDC guidelines specifically warn about combining opioids with other CNS depressants, and hydroxyzine falls squarely into this high-risk category. 1

Topiramate

• Topiramate has no direct pharmacodynamic interaction with buprenorphine and can be safely continued for its indicated use (likely mood stabilization, migraine prophylaxis, or adjunctive psychiatric treatment). 3
• Monitor for cognitive side effects that may compound any cognitive impairment from other medications. 6

Structured Management Algorithm

Step 1: Stabilize Opioid Use Disorder Treatment

• Maintain Suboxone at current therapeutic dose—do not taper or discontinue. 3, 4, 5
• Implement comprehensive monitoring including prescription drug monitoring program (PDMP) checks and urine drug testing at least annually. 1
• Prescribe naloxone for overdose reversal given the presence of multiple CNS depressants. 1, 3

Step 2: Address CNS Depressant Burden

• Initiate gradual taper of hydroxyzine with goal of discontinuation or lowest effective dose. 2
• Evaluate doxepin necessity—if treating depression, consider transitioning to SSRI/SNRI; if treating insomnia, consider non-pharmacologic interventions or non-sedating alternatives. 1, 2
• Never abruptly discontinue any medication—taper gradually while monitoring for symptom recurrence. 7

Step 3: Optimize Psychiatric Management

• Continue brexpiprazole for psychiatric stability while monitoring for additive sedation. 6
• Continue topiramate as prescribed. 3
• Ensure treatment for underlying psychiatric conditions is optimized through coordination with mental health specialists. 1

Step 4: Implement Intensive Monitoring Protocol

• Schedule visits more frequently than every 3 months during medication adjustments, specifically assessing for sedation, respiratory depression, cognitive impairment, and fall risk. 2
• Use validated instruments (GAD-7, PHQ-9) to monitor anxiety and depression symptoms. 1
• Conduct random urine drug testing and PDMP checks to monitor for additional substance use or medication diversion. 1, 5
• Assess functional outcomes systematically rather than relying solely on subjective reports. 7

Step 5: Coordinate Multidisciplinary Care

• Involve or consult addiction medicine specialists and psychiatry given the complexity of managing opioid use disorder with multiple psychiatric medications and CNS depressants. 2
• Coordinate with all prescribers to ensure unified treatment plan and avoid conflicting medication changes. 2

Common Pitfalls to Avoid

• Never discontinue Suboxone abruptly unless life-threatening issues arise—this dramatically increases relapse and overdose risk. 7
• Do not underestimate the cumulative CNS depression from combining buprenorphine, doxepin, hydroxyzine, and brexpiprazole—this creates substantial respiratory depression risk. 1, 2
• Avoid adding benzodiazepines to this regimen under any circumstances, as they increase overdose risk 3- to 10-fold when combined with opioids. 3, 2
• Do not rely solely on patient-reported symptoms—use objective measures including vital signs, cognitive assessments, and validated screening tools. 1, 7
• Sporadic opioid use in the first months of medication-assisted treatment is not uncommon and should be addressed with increased visit frequency and behavioral therapy engagement, not medication discontinuation. 5

Medication-Specific Adverse Effects to Monitor

• Opioid-related: Constipation (initiate prophylactic bowel regimen with senna ± docusate), nausea (typically resolves within days), endocrinopathy with long-term use. 1
• Brexpiprazole-related: Akathisia (9% incidence in depression trials), weight gain (7% incidence), metabolic changes including hyperglycemia and dyslipidemia. 6
• Combined CNS depression: Excessive sedation, cognitive impairment, orthostatic hypotension, falls, respiratory depression. 1, 6

Behavioral and Supportive Interventions

• Combine medication-assisted treatment with evidence-based behavioral therapies including motivational interviewing, cognitive behavioral therapy, and contingency management for optimal outcomes. 3
• Implement fall prevention strategies given multiple medications affecting balance and cognition. 1, 6
• Provide patient education about avoiding risky behaviors including obtaining medications from multiple prescribers and saving unused medications. 1
• Address constipation proactively with bowel regimen when initiating or maintaining opioid therapy. 1