What is the best initial medication for an adult patient with a history of opioid use disorder, no prior psychiatric history, and medically cleared status, who presents with psychosis and delusions 2 weeks after weaning off Suboxone (buprenorphine/naloxone)?

Acute Psychosis Following Suboxone Discontinuation: First-Line Treatment

Start haloperidol, olanzapine, or risperidone immediately for this patient's acute psychotic symptoms with delusions. 1

Primary Recommendation

Initiate an antipsychotic medication as first-line treatment for this acute psychotic episode. The NCCN guidelines specifically recommend neuroleptic drugs such as haloperidol, olanzapine, or risperidone for managing severe hyperactive delirium and psychotic symptoms in patients with opioid-related complications. 1 While these guidelines address cancer pain populations, they represent the highest-quality evidence available for opioid-related neuropsychiatric complications and are directly applicable to this clinical scenario.

Specific Medication Options:

• Haloperidol: Traditional first-line agent for acute psychosis, particularly effective for delusions and agitation 1
• Olanzapine: FDA-approved for schizophrenia and acute psychosis, may be especially helpful in this context 1, 2
• Risperidone: Alternative atypical antipsychotic with strong evidence for acute psychotic symptoms 1

Clinical Context and Mechanism

This presentation represents opioid withdrawal-induced psychosis, a rare but documented phenomenon. 3, 4, 5 The temporal relationship is critical: psychotic symptoms appearing 2 weeks after Suboxone discontinuation strongly suggests a causal association. 3, 5 Case reports and systematic reviews demonstrate that psychotic symptoms typically emerge days to weeks after opioid cessation in patients without prior psychiatric history. 3, 4, 5, 6

Key Distinguishing Features:

• Rule out delirium first: The ACR guidelines emphasize that secondary psychosis must not be better explained by delirium, which involves altered consciousness and inattention. 1 Since this patient is medically cleared with intact awareness, this favors primary psychosis over delirium.
• No prior psychiatric history: This makes primary psychiatric illness (schizophrenia, bipolar disorder) less likely and strengthens the case for substance-related psychosis. 1, 3
• Temporal association: The 2-week timeframe post-discontinuation is consistent with reported cases of opioid withdrawal-induced psychosis. 3, 5

Treatment Algorithm

Immediate Management (First 24-48 Hours):

1. Start antipsychotic medication immediately - Choose haloperidol, olanzapine, or risperidone based on side effect profile and patient factors 1
2. Monitor for response - Psychotic symptoms should begin improving within days of antipsychotic initiation 4, 6
3. Assess for concurrent withdrawal symptoms - Look for autonomic hyperactivity, anxiety, insomnia, or gastrointestinal symptoms that may require additional symptomatic management 1

Consider Opioid Reintroduction:

If psychotic symptoms do not respond adequately to antipsychotics within 3-5 days, consider reintroducing buprenorphine. 5 A systematic review found that most cases of opioid withdrawal-induced psychosis improved with reintroduction of the opioid, suggesting opioids may have antipsychotic properties in certain contexts. 5 This is a critical clinical decision point that prioritizes patient safety and symptom resolution over complete abstinence.

Specific approach if antipsychotics fail:

• Restart buprenorphine/naloxone at low dose (4-8 mg daily) and titrate based on symptom response 7, 8
• Continue antipsychotic medication while reintroducing opioid 4
• Transition to medication-assisted treatment (MAT) with appropriate counseling and behavioral therapy 7, 9

Critical Clinical Pitfalls to Avoid

Do not assume this is primary schizophrenia or bipolar disorder without considering the temporal relationship to opioid discontinuation. 3, 5 The absence of psychiatric history and the clear temporal association with Suboxone weaning make substance-induced psychosis the most likely diagnosis.

Do not delay antipsychotic treatment while waiting for further workup. 1 Acute psychosis with delusions requires immediate pharmacologic intervention to prevent harm and reduce suffering.

Do not rule out the possibility of persistent psychosis. 4 One case report documented de novo persistent psychotic disorder after opioid withdrawal that required ongoing antipsychotic treatment, even after the acute withdrawal period resolved. 4

If the patient was tapering too rapidly, this may have precipitated the psychosis. 1 The consensus panel on opioid tapering recommends slow tapers (10% per month or slower) for patients on long-term opioid therapy to minimize withdrawal complications. 1

Monitoring and Follow-Up

• Reassess within 24-72 hours to evaluate antipsychotic response and adjust dosing 1
• Screen for substance use including return to illicit opioid use, which increases overdose risk 7, 9
• Provide naloxone kit for overdose prevention if there is any risk of return to opioid use 7
• Arrange psychiatric follow-up to determine duration of antipsychotic treatment and assess for underlying psychiatric illness 1, 4

Duration of Treatment

Plan for short-term antipsychotic treatment initially (weeks to months), with reassessment for need for longer-term therapy. 4, 6 Most cases of opioid withdrawal-induced psychosis resolve with antipsychotic treatment, though some may require prolonged therapy. 4 The case report of persistent psychosis after opioid withdrawal required ongoing olanzapine treatment, demonstrating that some patients may develop lasting neuropsychiatric effects. 4