What are the risks and considerations for adding lithium, mirtazapine, and olanzapine to the medication regimen of a patient with opioid use disorder on Suboxone (buprenorphine/naloxone), Abilify (aripiprazole), fluoxetine, trazodone, and omeprazole?

Managing Polypharmacy in Opioid Use Disorder: Critical Drug Interactions and Safety Considerations

Immediate Safety Assessment Required

This medication regimen presents multiple serious safety concerns that require urgent clinical review, particularly the combination of buprenorphine with CNS depressants and the potential for serotonin syndrome. 1

Critical Drug Interaction: Buprenorphine + CNS Depressants

The concurrent use of buprenorphine (Suboxone) with multiple CNS depressants creates substantial overdose risk:

• Avoid prescribing opioids and benzodiazepines concurrently whenever possible due to 3- to 10-fold increased risk of fatal overdose compared to opioids alone 2, 1
• The combination of buprenorphine with aripiprazole (Abilify), trazodone, and potentially adding olanzapine creates additive sedation and respiratory depression risk 1, 3
• Prescribe naloxone with instruction in its use for overdose reversal given this high-risk combination 1, 3

Serotonin Syndrome Risk: Fluoxetine + Mirtazapine + Trazodone

Adding mirtazapine to a regimen already containing fluoxetine and trazodone creates significant serotonin syndrome risk:

• The concomitant use of multiple serotonergic agents substantially increases risk of serotonin syndrome, a potentially life-threatening condition 4
• Serotonin syndrome symptoms include mental status changes (agitation, hallucinations, delirium, coma), autonomic instability (tachycardia, labile blood pressure, hyperthermia), neuromuscular symptoms (tremor, rigidity, myoclonus), and seizures 4
• Monitor all patients taking mirtazapine with other serotonergic drugs for emergence of serotonin syndrome 4
• Lithium further increases this risk as it impairs serotonin metabolism 4

Specific Medication Concerns

Lithium Addition

Before adding lithium, assess for QTc prolongation risk given the existing regimen:

• Mirtazapine can prolong QTc interval, and cases of Torsades de Pointes have been reported, particularly with concomitant use of other QTc-prolonging medicines 4
• Exercise caution when mirtazapine is prescribed in patients with known cardiovascular disease or family history of QT prolongation 4
• Lithium combined with multiple serotonergic agents (fluoxetine, mirtazapine, trazodone) dramatically increases serotonin syndrome risk 4

Mirtazapine Considerations

While mirtazapine shows promise for managing opioid withdrawal symptoms (nausea, insomnia, anxiety, pruritus) 5, adding it to this complex regimen requires caution:

• Mirtazapine causes prominent sedative effects that will compound with buprenorphine, aripiprazole, trazodone, and potentially olanzapine 4
• Start at lowest dose (7.5-15 mg at bedtime) if deemed necessary 2
• Advise patients that mirtazapine may impair judgment, thinking, and motor skills due to sedative effects 4

Olanzapine Addition: Critical Contraindication

Adding olanzapine to a patient on buprenorphine requires extreme caution or should be avoided:

• If olanzapine/samidorphan (Lybalvi) is being considered, do not use it - samidorphan is an opioid antagonist that will precipitate withdrawal in patients on buprenorphine and reduce opioid tolerance, creating overdose risk if discontinued 6
• Standard olanzapine combined with multiple CNS depressants increases sedation and respiratory depression risk 2, 7
• Fatalities have been reported with concurrent use of benzodiazepines with high-dose olanzapine 7
• Olanzapine should be used with caution in elderly patients due to boxed warning regarding death in patients with dementia-related psychosis 2

Recommended Clinical Approach

Priority 1: Maintain Buprenorphine Stability

Keep buprenorphine dose stable - this provides the foundation for opioid use disorder treatment and should not be adjusted for psychiatric symptoms 2, 1

• Buprenorphine is the criterion standard medication for OUD with strong evidence for effectiveness 8
• Only 27.8% of people needing OUD treatment receive medication for OUD, making continuation critical 9

Priority 2: Simplify CNS Depressant Burden

Before adding lithium, mirtazapine, or olanzapine, consider reducing existing CNS depressant load:

• Evaluate if trazodone dose can be optimized or if non-pharmacologic sleep interventions can be implemented 2, 1
• Cognitive behavioral therapy for insomnia (CBT-I) should be first-line rather than adding more sedating medications 1, 3
• Consider whether aripiprazole dose is optimized before adding another antipsychotic 7

Priority 3: Sequential Medication Addition with Close Monitoring

If psychiatric medications must be added, do so sequentially, not simultaneously:

1. Add only ONE medication at a time to assess individual tolerability and identify adverse effects 10
2. Start with lowest effective doses 1, 4
3. Monitor at least monthly, with more frequent contact during medication changes 1

Priority 4: Mandatory Safety Monitoring

Check Prescription Drug Monitoring Program (PDMP) to identify all controlled substances the patient is receiving 1, 3

Monitor for:

• Excessive sedation, dizziness, confusion, respiratory depression at every encounter 1, 3
• Serotonin syndrome symptoms (agitation, tremor, hyperthermia, myoclonus) 4
• QTc prolongation if lithium and mirtazapine are used together 4
• Suicidal thoughts and behaviors, especially during initial treatment and dose changes 4

Safer Alternative Strategies

For Mood Stabilization

• Optimize existing fluoxetine dose before adding lithium 4
• Consider valproate or lamotrigine as alternatives to lithium that don't increase serotonin syndrome risk 2

For Insomnia

• Cognitive behavioral therapy for insomnia (CBT-I) is evidence-based and should be first-line 1, 3
• Sleep hygiene education: consistent sleep schedule, avoiding caffeine/screens before bed, optimizing sleep environment 3
• Optimize trazodone dosing (25-200 mg) before adding mirtazapine 2, 1

For Anxiety

• Offer evidence-based psychological therapies (cognitive behavioral therapy) as alternatives to additional medications 1
• Hydroxyzine as non-benzodiazepine alternative if acute anxiety management needed 1

Critical Pitfalls to Avoid

• Never add multiple psychiatric medications simultaneously - this makes it impossible to identify which medication causes adverse effects 10
• Never adjust buprenorphine dose to manage psychiatric symptoms - maintain stable dosing for OUD treatment 2, 1
• Never use olanzapine/samidorphan (Lybalvi) in patients on buprenorphine - will precipitate withdrawal and reduce opioid tolerance 6
• Never assume opioid tolerance eliminates respiratory depression risk - risk persists even in opioid-tolerant patients when combined with CNS depressants 1, 3
• Do not prescribe additional CNS depressants without considering cumulative sedation burden 1, 3

When to Refer to Specialist

Immediate psychiatric consultation is warranted for:

• Patients requiring multiple antipsychotics or mood stabilizers 2
• Complex polypharmacy with multiple drug-drug interactions 1
• History of serotonin syndrome or QTc prolongation 4
• Unstable psychiatric symptoms despite current regimen 2

Involve pharmacists and pain specialists as part of the management team when multiple controlled substances are prescribed 1, 3