Summary

Fluoxetine significantly reduces codeine's effectiveness by inhibiting the CYP2D6 enzyme responsible for converting codeine to its active form, morphine. This interaction can result in inadequate pain relief and may require alternative pain management strategies.

Introduction

Fluoxetine (brand name Prozac) is a selective serotonin reuptake inhibitor (SSRI) antidepressant commonly prescribed for depression, anxiety disorders, and obsessive-compulsive disorder. Codeine is an opioid analgesic used for mild to moderate pain relief and cough suppression. Both medications are frequently prescribed, making their potential interaction clinically significant for healthcare providers and patients.

Mechanism of Interaction

The interaction occurs through fluoxetine's potent inhibition of the cytochrome P450 2D6 (CYP2D6) enzyme. Codeine is a prodrug that requires conversion to morphine via CYP2D6 to produce its analgesic effects. When fluoxetine blocks this enzyme, codeine cannot be effectively metabolized to its active form, resulting in significantly reduced or absent pain relief. This pharmacokinetic interaction can render codeine therapeutically ineffective in patients taking fluoxetine.

Risks and Symptoms

The primary risk is inadequate pain management due to reduced codeine efficacy, potentially leading to breakthrough pain and patient discomfort. Patients may experience persistent pain despite taking prescribed codeine doses, which could result in dose escalation attempts or seeking additional pain medications. This interaction is particularly concerning for post-operative patients or those with chronic pain conditions who rely on effective analgesia. The interaction may also affect codeine's antitussive (cough suppressant) properties.

Management and Precautions

Healthcare providers should consider alternative analgesics when prescribing pain medication to patients taking fluoxetine. Non-opioid options like acetaminophen, NSAIDs, or opioids that don't require CYP2D6 activation (such as morphine, oxycodone, or hydromorphone) may be more appropriate. If codeine must be used, patients should be closely monitored for pain relief effectiveness. Dose adjustments of codeine are generally not recommended as they won't overcome the enzymatic inhibition. Patient education about potential reduced effectiveness is essential, and alternative pain management strategies should be discussed proactively.

Fluoxetine interactions with food and lifestyle

Alcohol: Fluoxetine may increase the sedative effects of alcohol and impair cognitive and motor performance. Patients should avoid or limit alcohol consumption while taking fluoxetine. Grapefruit juice: May increase fluoxetine blood levels, though this interaction is generally considered minor. St. John's Wort: Should be avoided as it may increase the risk of serotonin syndrome when combined with fluoxetine.

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.