From the Guidelines
The number needed to treat (NNT) to cause serotonin syndrome with tramadol is not precisely established in medical literature, but the risk is significantly increased when combined with other serotonergic medications. Serotonin syndrome with tramadol alone is relatively rare, but the risk increases significantly when tramadol is combined with other serotonergic medications such as SSRIs, SNRIs, MAOIs, or other opioids 1. The risk of serotonin syndrome is dose-dependent and varies based on individual factors including age, renal function, hepatic function, and genetic variations in CYP2D6 metabolism. Patients taking multiple serotonergic medications simultaneously are at highest risk.
Some key points to consider when prescribing tramadol include:
- Starting at the lowest effective dose (50mg every 4-6 hours, maximum 400mg daily for immediate release)
- Avoiding combination with other serotonergic medications when possible
- Monitoring for early symptoms of serotonin syndrome including agitation, tremor, hyperreflexia, clonus, diaphoresis, and hyperthermia. The mechanism behind tramadol's serotonergic effects involves both inhibition of serotonin reuptake and increased serotonin release, which can lead to excessive serotonin activity in the central nervous system when combined with other serotonergic agents 1.
In terms of specific guidelines, the NCCN panel recommends a maximum daily dose of 400 mg for IR formulations (100 mg 4 times a day), or 300 mg/day for ER formulations, for adults with normal hepatic and renal function 1. Lower doses are recommended for older adults (75 years and older) and those with hepatic and/or renal dysfunction to reduce the risk of seizures. Clinicians should exercise caution when prescribing tramadol, especially in patients with a history of serotonin syndrome or those taking other serotonergic medications.
From the FDA Drug Label
The development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including tramadol hydrochloride, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, and triptans, with drugs which impair metabolism of serotonin (including MAOIs), and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors).
The FDA drug label does not provide a specific number needed to treat to cause serotonin syndrome with tramadol (tramadol hydrochloride) [ 2 ].
From the Research
Serotonin Syndrome and Tramadol
- The combination of tramadol and selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) can result in serotonin syndrome, characterized by neuromuscular and autonomic nervous system excitation and altered mental state 3.
- The incidence of serotonin syndrome with this combination of drugs is low, and the serotonin syndrome is generally mild or moderate in form, but can be life threatening and is more easily prevented than treated 3.
Risk Factors for Serotonin Syndrome
- Increased age, higher dosages, and use of concomitant potent cytochrome P450 2D6 inhibitors are associated with a greater risk of serotonin syndrome when tramadol is combined with antidepressants 4.
- CYP2D6 poor metabolizers are at a greater risk of serotonin syndrome and an inadequate analgesic effect when tramadol and SSRIs are coadministered 5.
Number Needed to Treat to Cause Serotonin Syndrome
- There is no specific number needed to treat (NNT) to cause serotonin syndrome with tramadol (tramadol hydrochloride) mentioned in the provided studies.
- However, it is noted that the combination of tramadol and SSRIs/SNRIs can result in serotonin syndrome, but the incidence is low 3, 6.
Prevalence of Co-Prescribing Tramadol with Serotonergic Antidepressants
- In the US, approximately 2.0% of all office-based physician visits resulted in the prescribing of ≥1 opioid medication with a triptan or an SSRI/SNRI, with tramadol being one of the most commonly co-prescribed opioids 6.
- About one-fifth of opioid co-prescribing was attributable to higher-risk opioids, predominantly tramadol 6.