What is the interaction between Duloxetine (Cymbalta) and Codeine?

From the Guidelines

Duloxetine and codeine can be used together with caution, but patients should be aware of potential interactions, particularly the increased risk of serotonin syndrome and respiratory depression, as noted in the SPAQI consensus statement 1. When combining these medications, it is essential to start with lower doses of codeine and monitor for increased side effects such as drowsiness, dizziness, confusion, and respiratory depression.

Key Considerations

• Duloxetine (brand name Cymbalta) is an antidepressant that also treats pain conditions, while codeine is an opioid pain reliever.
• The interaction occurs because duloxetine may inhibit enzymes that metabolize codeine, potentially increasing codeine's effects and side effects, although this specific interaction is not explicitly mentioned in the provided study 1.
• Patients with liver or kidney disease, the elderly, and those taking other central nervous system depressants should be particularly careful.
• Signs of serotonin syndrome (agitation, hallucinations, rapid heart rate, fever, muscle stiffness, coordination problems) should prompt immediate medical attention.

Monitoring and Precautions

• Always inform your healthcare provider about all medications you're taking, and never adjust dosages without medical supervision.
• This combination may be necessary for some patients, but alternatives should be considered when possible, especially in patients with renal insufficiency or those taking other medications that increase serotonergic and/or noradrenergic activity 1.
• The study highlights the importance of careful medication management in the perioperative period, particularly for patients receiving long-term opioid therapy, who may require higher than usual opioid dosing or adjunctive nonopioid analgesia 1.

From the Research

Interaction between Duloxetine and Codeine

• There is limited direct evidence on the interaction between Duloxetine (Cymbalta) and Codeine.
• However, studies have investigated the interaction between opioids and serotonergic medications, including duloxetine 2.
• One study found that the combination of subeffective doses of codeine with selective serotonin reuptake inhibitors (SSRIs) led to an accentuated reduction in immobility time in a mice model of depression, but the combination of codeine with duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), did not produce a significant effect 3.
• Another study found that opioids, including codeine, can increase intrasynaptic levels of serotonin, which can lead to serotonin toxicity, especially when administered with other serotonergic medications, including SSRIs and SNRIs like duloxetine 2.
• The interaction between duloxetine and codeine may be related to their effects on the serotonin system, but more research is needed to fully understand their interaction.

Clinical Implications

• Clinicians should be aware of the potential risks of serotonin toxicity when prescribing duloxetine with opioids, including codeine 2.
• The combination of duloxetine and codeine may not produce a significant antidepressant-like effect, according to one study in a mice model of depression 3.
• More research is needed to fully understand the interaction between duloxetine and codeine and to determine their safety and efficacy in clinical practice.

Related Studies

• Studies have investigated the interaction between gabapentin and opioids, which may be relevant to the interaction between duloxetine and codeine, as both gabapentin and duloxetine are used to treat pain and depression 4, 5, 6.
• These studies found that the combination of gabapentin and opioids may increase the risk of respiratory events and major medical complications, but did not increase mortality risk 4, 5, 6.