Can Codeine Cause Hallucinations?
Yes, codeine can cause hallucinations, though this is a recognized but uncommon adverse effect of opioid therapy that occurs as part of opioid-induced neurotoxicity.
Mechanism and Evidence
Opioids as a class, including codeine, are recognized causes of central nervous system (CNS) toxicity that manifests as hallucinations, confusion, delirium, cognitive impairment, and myoclonic jerks 1. The 2022 World Journal of Emergency Surgery guidelines specifically identify opioids among drugs potentially responsible for delirium and hallucinations 1.
Direct Evidence for Codeine
- A case report documented acute psychosis with hallucinations and paranoid symptoms in a patient following ingestion of 540 mg codeine over 36 hours, requiring hospitalization but resolving completely within 72 hours 2
- Research comparing opioids found that oxycodone causes "somewhat less nausea, hallucinations and pruritus than morphine," indicating that hallucinations occur with codeine-related opioids but at varying rates 3
- A systematic review of cancer pain studies found hallucinations occurred at incidence rates of 5% or below across opioid medications including codeine 4
Risk Factors for Opioid-Induced Hallucinations
Higher risk occurs with:
- Rapid dose escalation or high doses - Neuropsychiatric effects are more likely during treatment initiation, dose titration, or with high-dose therapy 5
- Metabolite accumulation - Codeine is metabolized via the P450 pathway, and accumulation of metabolites in patients with liver or renal dysfunction increases neurotoxicity risk 1, 5
- Ultrarapid metabolizers - Patients with CYP2D6 gene duplication convert codeine to morphine approximately 50% more efficiently, resulting in higher morphine plasma concentrations and increased risk of exaggerated opioidergic effects including sedation 6
- Liver cirrhosis - The 2022 Korean guidelines specifically warn that codeine metabolites may accumulate in patients with liver cirrhosis, causing side effects including respiratory depression, and recommend avoiding codeine in this population 1
Clinical Implications and Management
If hallucinations occur with codeine:
- Discontinue codeine immediately - The case report demonstrated complete resolution of hallucinations within 72 hours of stopping the medication 2
- Consider opioid rotation - Switch to an alternative opioid with different metabolic properties, such as fentanyl, which lacks active metabolites and may be safer in patients with renal or hepatic impairment 5, 7
- Dose reduction - If pain control allows and switching is not immediately possible, reducing the opioid dose may alleviate CNS toxicity 1, 7
Important Caveats
Codeine should be avoided entirely in breastfeeding women due to unpredictable metabolism and risk of severe neonatal depression in infants of ultrarapid metabolizers, despite regulatory variation on this issue 1. The 2020 Association of Anaesthetists guideline recommends against codeine use in breastfeeding unless regulatory advice changes, as safer alternatives exist 1.
Misdiagnosis risk: A 2024 case report highlighted that opioid-induced hallucinations can be misdiagnosed as primary psychiatric disorders like schizophrenia, emphasizing the importance of careful medication history in psychiatric assessments 8.
Monitoring Recommendations
- Patients starting codeine should be informed about the possibility of hallucinations and other neuropsychiatric effects 5
- Those with history of opioid-induced neurotoxicity require closer monitoring as they are at higher risk for recurrence 5, 7
- Patients with renal or hepatic insufficiency require special caution due to potential metabolite accumulation 5, 7