Question

Topic: Nurs 6630

Reports continue to appear describing serotonin syndrome following combined use of tramadol (Ultram) with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephrine reuptake inhibitors (SNRIs). Because serotonin syndrome can be serious and is often difficult to detect, it is important for health professionals to be alert for this reaction. A recent study from Australia found that many patients are exposed to drug interactions that can result in serotonin syndrome.

What Is Serotonin Syndrome?

Serotonin syndrome is due to excessive serotonin effects in the central nervous system and usually results from concurrent administration of 2 or more serotonergic drugs. Serotonin syndrome also can occur with excessive doses of a single serotonergic drug.

What Are the Symptoms of Serotonin Syndrome?

Some of the symptoms, such as confusion, agitation, and fever, are relatively nonspecific and can be caused by many disorders other than serotonin syndrome. Other symptoms are more specific, however, and thus are more useful in the early detection of serotonin syndrome. These include myoclonus (muscle jerking), muscle rigidity, and tremor. Serotonin syndrome also can cause sweating, incoordination, seizures, and coma. Severe cases of serotonin syndrome can be fatal.

What About Tramadol?

Many case reports exist of patients taking SSRIs or SNRIs who developed serotonin syndrome while taking concurrent tramadol. Reported cases involved combining tramadol with citalopram, fluoxetine, paroxetine, nefazodone, sertraline, and venlafaxine. Some evidence suggests that mirtazapine also may interact with tramadol, but confirmation is needed.

Are There Risk Factors for This Interaction?

Available evidence suggests that higher plasma concentrations of tramadol and/or SSRIs increase the risk of serotonin syndrome. Some patients have tolerated the combinations, only to develop serotonin syndrome when the dose of one or both drugs is increased. Also, tramadol is metabolized by CYP2D6, and some SSRIs are moderate- to-potent inhibitors of CYP2D6 (eg, fluoxetine, paroxetine, duloxetine). Finally, genetic deficiencies in the CYP450 isozymes that metabolize tramadol or SSRIs may increase the risk of serotonin syndrome by increasing plasma concentrations. One patient who developed serotonin syndrome following tramadol and citalopram had decreased activity of the isozymes involved in the metabolism of both tramadol (CYP2D6) and citalopram (CYP2C19).

Is Tramadol the Only Opioid Analgesic That Interacts?

Meperidine has long been known to have serotonergic effects and has produced severe serotonin syndrome when combined with drugs such as nonselective monoamine oxidase inhibitors (eg, tranylcypromine). Cases of serotonin syndrome have been reported when meperidine was combined with SSRIs. Fentanyl also has serotonergic effects and, like meperidine, has been associated with serotonin syndrome when combined with SSRIs. Morphine does not appear to have serotonergic effects and may be safer when combined with serotonergic drugs.

Conclusion

Concurrent administration of tramadol (and probably meperidine or fentanyl) with SSRIs or SNRIs appears to increase the risk of serotonin syndrome. In people who may require larger doses of tramadol, it would be prudent to avoid the combinations. If the combination is used, patients should be advised to watch for the telltale signs of serotonin syndrome, such as muscle jerking, muscle rigidity, and tremors, especially if accompanied by other symptoms, such as sweating, fever, and agitation. They should be advised to contact their prescriber should evidence of serotonin syndrome appear.

Welcome and Stay safe!

Horn. J Hansten, P., (2009). Tramadol and Seratonin  New York, NY pharmacy Times.

Answer

Nurs 6630

What Is Serotonin Syndrome?

Serotonin syndrome occurs due to excessive accumulation of high levels of the chemical serotonin in an individual’s body as a result of medications (Kim, 2016). Naturally, the human body produces serotonin that is needed for the brain and nerve cells to function. However, too much serotonin causes symptoms and signs that can be mild such as diarrhea and shivering to severe such as fever, muscle rigidity, and seizures. Severe serotonin syndrome can also result in death if not treated. In most cases, serotonin syndrome occurs when a patient increases the dosage of a certain medication or receives an additional drug to their regimen. Some dietary supplements and illegal drugs also cause serotonin syndrome (Kim, 2016).

What Are the Symptoms of Serotonin Syndrome?

The onset of serotonin syndrome is normally several hours after increasing the dosage of a drug a patient was already taking or taking a new drug. The signs and symptoms of serotonin syndrome include heavy sweating, agitation, and restlessness, dilated pupils, rapid heart rate, and muscle rigidity, high blood pressure, loss of muscle coordination, and twitching muscles, shivering, headache, diarrhea, and goosebumps (Liu et al., 2019). On the other hand, severe serotonin syndrome can result in life-threatening signs and symptoms, including unconsciousness, high fever, seizures, and irregular heartbeat (Liu et al., 2019). 

What about Tramadol?

Tramadol functions as an opioid and is normally administered to patients to control pain as it presents a lower risk for respiratory depression and addiction compared to other opioids. However, tramadol also has norepinephrine and serotonin reuptake inhibitory effects, which makes the drug have a unique adverse effect profile. One of the central adverse events that can result from the administration of tramadol is serotonin syndrome (Scotton et al., 2019). Most case reports of serotonin syndrome have therefore been reported among patients who take a combination of tramadol and SNRIs or SSRIs. Some reported cases involve combining tramadol with fluoxetine, citalopram, paroxetine, venlafaxine, sertraline. The prevalence of tramadol-induced serotonin syndrome is modest across populations but can result in high mortality and morbidity if left untreated. Early detection and management of tramadol-induced serotonin syndrome are therefore essential (Scotton et al., 2019).

Are There Risk Factors for This Interaction?

The risk factors for Tramadol induced serotonin syndrome include tramadol opioid effects, use of higher doses of tramadol and the concomitant use of medication that can increase serotonin levels in the central nervous system, and concomitant use of medication that inhibit the metabolism of tramadol in an individual’s body(Kim, 2016). Among patients with depression, they may frequently experience chronic pain. Such patients might receive tramadol for their pain and also receive SSRI for depression. The co-administration of these drugs can therefore result in the development of serotonin syndrome. The plasma concentration of tramadol can also influence the development of serotonin syndrome. High doses of tramadol compound the risk of the onset of serotonin syndrome, especially during administration with an SSRI.  Opioids can also cause disinhibition and result in an increase in serotonin release in patients, which can result in the onset of serotonin syndrome (Kim, 2016). 

Is Tramadol the Only Opioid Analgesic That Interacts?

Other analgesics that interact include meperidine and fentanyl. When fentanyl is combined with SSRIs, it can therefore result in Serotonin syndrome.  On the other hand, when meperidine is combined with SSRIs, it also results in serotonin syndrome (Scotton et al., 2019). 

Conclusion

The co-administration of tramadol and SNRIs, and SSRIs greatly increases the risk of serotonin syndrome. For patients with severe pain and alternative pain control medication should therefore be considered for low doses of tramadol. Patients taking a combination of tramadol and SNRIs and SSRIs should also be educated on the symptoms of serotonin syndrome, Such as diarrhea, shivering headache, heavy sweating, muscle rigidity, and loss of muscle coordination. Patients should therefore report the onset of symptoms to their healthcare providers.

References

Kim, A. (2016). A Complex Case of Suspected Serotonin Syndrome. American Journal of Psychiatry Residents’ Journal, 11(11), 8–10. https://doi.org/10.1176/appi.ajp-rj.2016.111104

Liu, Y., Yang, H., He, F., Xu, P., Tong, H., Liu, Y., Ni, J., Zhang, Q., & Wang, J. (2019). An atypical case of serotonin syndrome with normal dose of selective serotonin inhibitors. Medicine, 98(19), e15554. https://doi.org/10.1097/md.0000000000015554

Scotton, W. J., Hill, L. J., Williams, A. C., & Barnes, N. M. (2019). Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions. International Journal of Tryptophan Research, 12, 117864691987392. https://doi.org/10.1177/1178646919873925