What are the risks and alternatives when using linezolid and tramadol (nonsteroidal anti-inflammatory drugs) concurrently?

From the Guidelines

Concurrent use of linezolid and tramadol should be avoided due to the serious risk of serotonin syndrome, which can be life-threatening. Linezolid is an antibiotic that also functions as a monoamine oxidase inhibitor (MAOI), while tramadol is an opioid pain medication with serotonergic properties, as noted in a study published in the Journal of the National Comprehensive Cancer Network 1. When used together, they can cause excessive serotonin accumulation in the brain, leading to symptoms such as agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, and in severe cases, seizures or coma.

The risks associated with this combination are further highlighted by a consensus statement from the Society for Perioperative Assessment and Quality Improvement (SPAQI) published in Mayo Clinic Proceedings 1, which emphasizes the importance of avoiding coadministration of serotonergic opioids like tramadol with medications that increase serotonin levels, such as linezolid.

If pain management is necessary while a patient is on linezolid, safer alternatives include:

• Acetaminophen (Tylenol)
• Non-serotonergic opioids like morphine, hydromorphone, or oxycodone at appropriate doses, as suggested by guidelines for adult cancer pain management 1 It's also important to note that tramadol is not a nonsteroidal anti-inflammatory drug (NSAID) but an opioid analgesic. If anti-inflammatory effects are specifically needed and there are no contraindications, true NSAIDs like ibuprofen or naproxen could be considered as alternatives, though they carry their own risks including gastrointestinal bleeding and kidney injury, as discussed in the context of perioperative management of opioid and nonopioid analgesics 1. Any patient who develops symptoms of serotonin syndrome while taking these medications should seek immediate medical attention.

From the FDA Drug Label

Caution is advised when tramadol hydrochloride is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John’s Wort If concomitant treatment of tramadol hydrochloride with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases

The use of linezolid and tramadol concurrently may increase the risk of serotonin syndrome, a potentially life-threatening condition.

• Key risks associated with this combination include:
  • Mental-status changes (e.g., agitation, hallucinations, coma)
  • Autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia)
  • Neuromuscular aberrations (e.g., hyperreflexia, incoordination)
  • Gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea)
• Alternatives to consider:
  • Non-serotonergic antibiotics instead of linezolid
  • Non-opioid analgesics instead of tramadol
• Precautions to take when using this combination:
  • Careful observation of the patient, particularly during treatment initiation and dose increases
  • Monitoring for signs and symptoms of serotonin syndrome 2

From the Research

Risks of Using Linezolid and Tramadol Concurrently

• The use of linezolid, a reversible, nonselective monoamine oxidase inhibitor, with serotonergic drugs like tramadol, a nonsteroidal anti-inflammatory drug, may increase the risk of serotonin syndrome 3, 4, 5.
• Serotonin syndrome is a potentially life-threatening condition caused by an excess of serotonin in the central nervous system, and its symptoms include cognitive and behavioral changes, autonomic instability, and neuromuscular abnormalities 4.
• Studies have reported cases of serotonin syndrome associated with the concomitant use of linezolid and serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) 3, 4, 6, 5.

Alternatives to Using Linezolid and Tramadol Concurrently

• If the clinical situation warrants the use of linezolid in a patient receiving tramadol, linezolid may be used concomitantly with careful monitoring for signs and symptoms of serotonin syndrome 3.
• Alternative antibiotics or pain management strategies may be considered to avoid the potential risk of serotonin syndrome associated with the concomitant use of linezolid and tramadol.
• Clinicians should obtain complete drug histories to identify patients at risk, strictly monitor drug therapy, including concomitant drugs, and receive education about this potential drug interaction and the symptoms of serotonin syndrome 5.

Incidence of Serotonin Syndrome

• The incidence of serotonin syndrome with the concomitant use of linezolid and serotonergic drugs is relatively low, ranging from 0.4% to 3% in different studies 3, 7, 6.
• The risk of serotonin syndrome may be higher with the concomitant use of linezolid and certain serotonergic drugs, such as SSRIs and SNRIs, compared to the use of linezolid alone 6.
• Further study is needed to evaluate the short-term risk of serotonin syndrome associated with the concomitant use of linezolid and tramadol 7.