From the FDA Drug Label
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including sertraline, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). If concomitant use of sertraline with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases Treatment with sertraline and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated
In a situation where a chronic pain patient is taking both sertraline and tramadol and experiences serotonin syndrome, the best course of action is to:
- Discontinue both sertraline and tramadol immediately, as they are both serotonergic agents that can contribute to the development of serotonin syndrome.
- Initiate supportive symptomatic treatment to manage the symptoms of serotonin syndrome. 1
From the Research
In a case of serotonin syndrome in a patient taking both sertraline and tramadol, immediate discontinuation of both medications is recommended. Serotonin syndrome is a potentially life-threatening condition requiring prompt intervention. Both medications should be stopped completely rather than weaned, as the priority is to rapidly reduce serotonergic activity. The patient should be evaluated in an emergency setting where supportive care can be provided, including IV fluids, temperature management, and benzodiazepines for agitation or tremor. Cyproheptadine, a serotonin antagonist, may be administered at an initial dose of 12 mg orally, followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg daily, as suggested by the management of serotonin syndrome 2.
Once the patient has stabilized and symptoms have resolved (typically within 24-72 hours), a careful reassessment of pain and depression management is needed. Alternative non-serotonergic pain medications like acetaminophen, NSAIDs, or certain anticonvulsants might be considered for pain control. If antidepressant therapy remains necessary, options with lower serotonergic activity or different mechanisms may be selected after a washout period. This approach is necessary because the combination of SSRIs like sertraline with tramadol significantly increases serotonin levels by inhibiting both serotonin reuptake and, in tramadol's case, increasing serotonin release, as highlighted in the review of tramadol's pharmacology and risk factors for serotonin syndrome 3.
Key considerations in managing serotonin syndrome include:
- Prompt recognition of the condition
- Immediate discontinuation of serotonergic medications
- Supportive care in an emergency setting
- Administration of serotonin antagonists if necessary
- Reassessment of pain and depression management after resolution of symptoms
- Awareness of the potential for serotonin syndrome when prescribing medications with serotonergic activity, as emphasized in the discussion of serious interactions among frequently used drugs for chronic pain 4 and the overview of serotonin syndrome 2.
The most recent and highest quality study relevant to this scenario is from 2021, which reports a case of serotonin syndrome in a patient with chronic pain taking analgesic drugs, including tramadol and duloxetine, and highlights the importance of clinician awareness of this potential condition 5.