Summary

The combination of diphenhydramine and codeine can result in enhanced central nervous system depression, leading to increased sedation, drowsiness, and potentially dangerous respiratory depression. This interaction requires careful monitoring and may necessitate dose adjustments or alternative medications.

Introduction

Diphenhydramine is a first-generation antihistamine commonly used to treat allergic reactions, insomnia, and motion sickness. It belongs to the ethanolamine class of antihistamines and is available over-the-counter under brand names like Benadryl. Codeine is an opioid analgesic and antitussive medication used for mild to moderate pain relief and cough suppression. It is classified as a Schedule II controlled substance and is often combined with other medications like acetaminophen or promethazine in prescription formulations.

Mechanism of Interaction

The interaction between diphenhydramine and codeine occurs through additive central nervous system (CNS) depressant effects. Diphenhydramine blocks histamine H1 receptors in the brain and has significant anticholinergic properties, causing sedation and drowsiness. Codeine, after conversion to morphine by the CYP2D6 enzyme, binds to mu-opioid receptors in the CNS, producing analgesic effects and respiratory depression. When used together, these medications enhance each other's sedative effects through different but complementary mechanisms, potentially leading to excessive CNS depression.

Risks and Symptoms

The primary clinical risks of combining diphenhydramine and codeine include excessive sedation, impaired cognitive and motor function, and potentially life-threatening respiratory depression. Patients may experience profound drowsiness, confusion, difficulty concentrating, and increased fall risk. The combination can also cause hypotension, constipation, and urinary retention due to the anticholinergic effects of diphenhydramine and opioid effects of codeine. Elderly patients and those with respiratory conditions are at particularly high risk for serious complications, including respiratory failure.

Management and Precautions

When this combination cannot be avoided, start with the lowest effective doses of both medications and monitor patients closely for signs of excessive sedation or respiratory depression. Consider spacing the administration times to minimize peak concentration overlap. Educate patients about avoiding alcohol and other CNS depressants while using these medications together. Regular assessment of respiratory rate, oxygen saturation, and level of consciousness is essential. Consider alternative medications such as non-sedating antihistamines (loratadine, cetirizine) or non-opioid analgesics when appropriate. Patients should be advised not to drive or operate machinery while taking this combination.

Codeine interactions with food and lifestyle

Alcohol: Avoid alcohol while taking codeine as it can increase the risk of serious side effects including severe drowsiness, slowed or difficult breathing, and potentially life-threatening respiratory depression. The combination of codeine and alcohol can also increase the risk of liver damage and enhance sedative effects, leading to dangerous levels of central nervous system depression.