In combination with SSRIs/SNRIs/MAOIs, which analgesics have an increased risk of serotonin syndrome?

• A. Tramadol
• B. Fentanyl
• C. Methadone
• D. All of the above

Answer: (D)

The main idea here is that combining analgesics with drugs that boost serotonin levels can push serotonergic signaling over the threshold into serotonin syndrome. Tramadol stands out because it not only acts as a weak mu-opioid agonist but also inhibits serotonin and norepinephrine reuptake, directly raising serotonin levels. Fentanyl, while primarily a potent mu-opioid agonist, has been associated with serotonin syndrome in some cases when used with SSRIs/SNRIs or MAOIs, reflecting its potential to contribute to serotonergic activity in certain contexts. Methadone also has serotonergic properties through serotonin reuptake inhibition, and there are reports of serotonin syndrome when it is used with other serotonergic drugs. Because each of these analgesics can elevate serotonin or interact with serotonergic pathways, using any of them in combination with SSRIs, SNRIs, or MAOIs increases the risk, making all of the above the best choice.