Tramadol

Other opioids

ATC code: N02AX02 (Tramadol)

Brand names

Ultram, Tramal

Mechanism of action

Atypical opioid with dual action. Weak μ-opioid agonist and simultaneous serotonin and norepinephrine reuptake inhibitor (SNRI component). The active metabolite O-desmethyltramadol (M1) has substantially greater opioid potency than the parent drug. Metabolism via CYP2D6 — ultra-rapid metabolizers (about 7 % of Europeans) face increased opioid toxicity risk; poor metabolizers experience reduced effect. The serotonergic component creates serotonin syndrome risk when combined with antidepressants, triptans, or MAOIs.

Indications

Acute moderate-to-severe pain

Second line

Per the CDC 2022 Opioid Prescribing Guideline, tramadol is not first-line for acute pain — recommended as second-line after acetaminophen and NSAIDs fail. Modern meta-analyses (BMJ 2022, Wertli et al.) show tramadol effects in acute and chronic musculoskeletal pain are modest and comparable to NSAIDs, with worse safety due to dependence, sedation, and serotonin syndrome risk. Dose: 50–100 mg four times daily, max 400 mg/day. In patients over 75: max 300 mg/day.

Drug–drug interactions

25 pairs found. Sorted from critical to minor.

Critical

Diazepam

Anxiolytics. Benzodiazepine derivatives

Mechanism

Tramadol is a weak opioid with additional serotonin–norepinephrine reuptake inhibition. With diazepam, the risk is doubled: additive CNS and respiratory depression plus a lowered seizure threshold (tramadol provokes seizures on its own).

Symptoms

Drowsiness, slowed breathing. Seizures may occur, especially in patients with prior epilepsy or with dose excess. Serotonin syndrome is less common unless other serotonergics are added.

Management

Avoid where possible. If unavoidable, minimal doses of both and a short course. Alternative analgesia: paracetamol with an NSAID; alternative anxiolytics: gabapentinoids or hydroxyzine.

Sources

Pair details →

Critical

Linezolid

Oxazolidinone antibiotic

Mechanism

Tramadol is an opioid with serotonin–norepinephrine reuptake inhibition. Linezolid reversibly inhibits MAO. Co-administration causes a sharp rise in synaptic serotonin and risk of serotonin syndrome.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.

Management

The combination is not prescribed. Stop tramadol 24–72 hours before starting linezolid. For analgesia, use paracetamol, NSAIDs (if not contraindicated), or pure opioid agonists such as morphine or oxycodone with no serotonergic activity.

Sources

FDA: Zyvox (linezolid) prescribing information (2020)

Critical

Methylthioninium chloride (methylene blue)

Antidotes (V03AB17). The drug has one FDA-approved indication – methaemoglobinaemia. Biohacker use is off-label.

Mechanism

IV methylene blue reversibly inhibits MAO-A. Tramadol inhibits serotonin and norepinephrine reuptake (plus weak opioid activity). Co-administration sharply raises monoamine levels.

Symptoms

Management

Avoid the combination. Methylene blue is reserved for emergencies with tramadol withdrawn 24–72 hours in advance. For analgesia in patients who may require methylene blue, use paracetamol, NSAIDs, or a pure opioid (morphine, oxycodone).

Sources

FDA: FDA Drug Safety Communication: Updated information about the drug interaction between methylene blue and serotonergic psychiatric medications (2011)

Major

Alprazolam

Benzodiazepines. Short-to-medium-acting anxiolytics

Mechanism

Alprazolam and tramadol depress the central nervous system and respiratory centre. Tramadol additionally lowers the seizure threshold and raises serotonergic activity. Fatal overdoses have been reported.

Symptoms

Drowsiness, sedation, slowed breathing. Seizures may occur (tramadol) and syncope from orthostatic hypotension. Older patients: fall risk.

Management

Avoid the combination. For analgesia on alprazolam, use paracetamol, an NSAID, or morphine/oxycodone (with respiratory depression warning). Alternative anxiolytics: hydroxyzine or gabapentinoids.

Sources

FDA: Ultram (tramadol HCl) prescribing information (2017)

Pair details →

Major

Amiodarone

Class III antiarrhythmics (Vaughan Williams)

Mechanism

Dual mechanism: tramadol weakly prolongs QT (additive with amiodarone) and lowers the seizure threshold. Amiodarone also blocks CYP2D6 – the main tramadol activation route – so analgesia weakens while serotonergic activity persists.

Symptoms

QT prolongation on ECG, palpitations, syncope. Seizures may occur, especially in patients with prior epilepsy. Weakened tramadol analgesic effect.

Management

Avoid the combination. For analgesia in patients on amiodarone, use paracetamol, NSAIDs (with caution in heart failure), or morphine/oxycodone (pure opioids without QT effect).

Sources

FDA: Cordarone (amiodarone HCl) prescribing information (2018)

Pair details →

Major

Amitriptyline

Tricyclic antidepressants (TCA)

Mechanism

Dual risk. Tramadol blocks serotonin and norepinephrine reuptake and lowers seizure threshold. Amitriptyline (TCA) also blocks both reuptakes and itself provokes seizures in overdose. Combined action – serotonin syndrome and seizure risk.

Symptoms

Serotonin syndrome (agitation, tremor, tachycardia, hyperthermia) plus seizure risk. QT prolongation – both drugs contribute. Older patients: ataxia and fall risk.

Management

Avoid the combination. For neuropathic pain on a TCA, choose gabapentin or pregabalin. For analgesia on amitriptyline, use paracetamol, an NSAID, or morphine/oxycodone.

Sources

FDA: Ultram (tramadol HCl) prescribing information (2017)

Major

Bupropion

Other antidepressants (NDRI)

Mechanism

Bupropion blocks CYP2D6 – the route converting tramadol to its active M1 metabolite. Analgesia falls but parent tramadol accumulates, raising seizure risk. Both drugs also lower the seizure threshold.

Symptoms

Seizures (generalised tonic-clonic or focal), agitation, tremor, insomnia. Patients with prior epilepsy or eating disorders are at particular risk.

Management

Avoid the combination. For analgesia on bupropion, use paracetamol, an NSAID, or morphine/oxycodone. For neuropathic pain, gabapentin or pregabalin.

Sources

FDA: Wellbutrin (bupropion hydrochloride) prescribing information (2017)

Major

Ciprofloxacin

Fluoroquinolone antibacterials

Mechanism

Dual risk: both drugs lower the seizure threshold. Ciprofloxacin also blocks CYP1A2 (a minor tramadol activation route) and weakly affects serotonergic activity.

Symptoms

Seizures, especially in patients with prior epilepsy or head injury. Serotonin syndrome may occur with other serotonergics on board (agitation, tremor, hyperthermia).

Management

Avoid the combination in patients with prior epilepsy. Alternative antibiotics: a cephalosporin or nitrofurantoin (no seizure threshold effect). Alternative analgesics: paracetamol, an NSAID, or morphine.

Sources

FDA: Ultram (tramadol HCl) prescribing information (2017)

Pair details →

Major

citalopram

SSRI (selective serotonin reuptake inhibitor)

Mechanism

Dual risk. Citalopram (SSRI) raises synaptic serotonin and prolongs QT. Tramadol blocks serotonin and norepinephrine reuptake and lowers seizure threshold. Effects add up.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.

Management

Avoid the combination. For analgesia on citalopram, use paracetamol, an NSAID, or morphine/oxycodone. For neuropathic pain, gabapentin or pregabalin.

Sources

FDA: Ultram (tramadol) prescribing information (2017)

Major

Dronedarone

Class III antiarrhythmic

Mechanism

Additive QT risk. Tramadol weakly prolongs QT and blocks serotonin/norepinephrine reuptake. Dronedarone is a potent QT prolonger. Tramadol also lowers seizure threshold.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination. For analgesia on dronedarone, use paracetamol, an NSAID, or morphine/oxycodone (no QT effect).

Sources

FDA: Multaq (dronedarone) prescribing information (2020)

Pair details →

Major

duloxetine

SNRI

Mechanism

Dual risk. Duloxetine (SNRI) raises synaptic serotonin and norepinephrine. Tramadol blocks serotonin and norepinephrine reuptake and lowers seizure threshold. Combined action amplifies serotonergic activity.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.

Management

Avoid the combination. For analgesia on duloxetine, use paracetamol, an NSAID, or morphine/oxycodone. For neuropathic pain, gabapentin or pregabalin.

Sources

FDA: Cymbalta section 7 (2017)

Major

Escitalopram

Selective serotonin reuptake inhibitors (SSRIs)

Mechanism

Escitalopram (SSRI) raises synaptic serotonin; tramadol blocks serotonin and norepinephrine reuptake. Combined action sharply amplifies serotonergic transmission – serotonin syndrome risk.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.

Management

Avoid the combination. For analgesia on escitalopram, use paracetamol, an NSAID, or morphine/oxycodone. For neuropathic pain, gabapentin or pregabalin.

Sources

FDA: Lexapro (escitalopram) prescribing information (2017)

Major

Fluoxetine

Selective serotonin reuptake inhibitors

Mechanism

Dual mechanism. Fluoxetine (SSRI) raises synaptic serotonin; tramadol weakly inhibits serotonin reuptake – combined serotonergic activity adds up. Fluoxetine also blocks CYP2D6 – the route activating tramadol to O-desmethyltramadol – so analgesia weakens.

Symptoms

Management

Avoid the combination. For analgesia on fluoxetine, use paracetamol, an NSAID, or pure opioid agonists such as morphine/oxycodone. Alternative antidepressant: mirtazapine or agomelatine.

Sources

FDA: Tramadol prescribing information (2022)

Major

fluvoxamine

SSRI

Mechanism

SSRI (fluvoxamine) + tramadol – serotonin syndrome. Tramadol also lowers seizure threshold.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.

Management

Avoid the combination. For analgesia on fluvoxamine, use paracetamol, an NSAID, or morphine/oxycodone. For neuropathic pain, gabapentin or pregabalin.

Sources

FDA: Luvox section 7 (2014)

Pair details →

Major

Gabapentin

Gabapentinoids (antiepileptics)

Mechanism

Additive CNS depression. Gabapentin does not lower the seizure threshold, but opioid-gabapentinoid combinations are associated with respiratory depression risk, especially in older patients.

Symptoms

Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.

Management

The combination is possible in neuropathic pain. Keep doses minimal, start low. Warn the patient about drowsiness and ataxia. Older patients: enhanced fall monitoring.

Sources

FDA: Ultram (tramadol) prescribing information (2017)

Pair details →

Major

Haloperidol

First-generation antipsychotics. Butyrophenone derivatives

Mechanism

Tramadol lowers seizure threshold and prolongs QT. Haloperidol is a strong QT prolonger, especially parenterally. Additive seizure and torsades de pointes risk.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination. For analgesia on haloperidol, use paracetamol, an NSAID, or morphine/oxycodone. Alternative antipsychotics: olanzapine or aripiprazole.

Sources

FDA: Ultram (tramadol HCl) prescribing information (2017)

Major

Mirtazapine

Other antidepressants (NaSSA)

Mechanism

Tramadol is a serotonergic opioid; mirtazapine raises serotonergic transmission via α2-blockade. Additive serotonin syndrome risk.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.

Management

Avoid the combination. For analgesia on mirtazapine, use paracetamol, an NSAID, or morphine/oxycodone. For neuropathic pain, gabapentin or pregabalin.

Sources

FDA: Ultram (tramadol HCl) prescribing information (2017)

Pair details →

Major

Morphine

Natural opium alkaloids

Mechanism

Additive CNS and respiratory centre depression. Tramadol is also serotonergic and lowers seizure threshold.

Symptoms

Drowsiness, slowed breathing (rate below 12/min), cyanosis of lips. Severe cases include respiratory arrest. Older patients: fall risk.

Management

Avoid the combination. To strengthen opioid analgesia on tramadol, switch to a pure opioid agonist (morphine, oxycodone) and stop tramadol. Dual opioid therapy is only used in palliative care with careful respiratory monitoring.

Sources

FDA: Ultram (tramadol HCl) prescribing information (2017)

Pair details →

Major

Pregabalin

Gabapentinoids (antiepileptics)

Mechanism

Similar to tramadol + gabapentin: additive CNS depression, seizure risk (tramadol lowers threshold). issued a 2019 warning about respiratory depression with opioid-gabapentinoid combinations.

Symptoms

Drowsiness, sedation, slowed breathing. Seizures (tramadol) and syncope from orthostatic hypotension are possible. Older patients: fall risk.

Management

The combination is possible in neuropathic pain. Keep doses minimal, start low. Warn the patient about drowsiness and ataxia. Older patients: enhanced fall monitoring. Alternative opioid for neuropathic pain: pure opioid agonist (morphine, oxycodone) without serotonergic activity.

Sources

FDA: Ultram (tramadol) prescribing information (2017)

Pair details →

Major

Quetiapine

Atypical antipsychotics

Mechanism

Additive CNS depression plus seizure threshold reduction (tramadol lowers it, quetiapine at high doses).

Symptoms

Deep sedation, drowsiness, ataxia. Seizures (especially with prior epilepsy) are possible. Older patients: fall risk.

Management

Avoid the combination with quetiapine above 300 mg. For analgesia on quetiapine, use paracetamol, an NSAID, or morphine/oxycodone (without serotonergic activity).

Sources

FDA: Ultram (tramadol) prescribing information (2017)

Pair details →

Major

Sertraline

Selective serotonin reuptake inhibitors (SSRIs)

Mechanism

Sertraline (SSRI) raises synaptic serotonin; tramadol blocks serotonin and norepinephrine reuptake. Combined action amplifies serotonergic transmission. Sertraline also blocks CYP2D6 (less than fluoxetine) – the tramadol activation route.

Symptoms

Management

Avoid the combination. For analgesia on sertraline, use paracetamol, an NSAID, or morphine/oxycodone. For chronic analgesic needs, gabapentin or pregabalin for neuropathic pain.

Sources

Major

venlafaxine

SNRI (serotonin-norepinephrine reuptake inhibitor)

Mechanism

Venlafaxine (SNRI) + tramadol – serotonin syndrome plus additive seizure risk. Tramadol itself is a weak serotonin-norepinephrine reuptake inhibitor with proconvulsant effect.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.

Management

Avoid the combination. For analgesia on venlafaxine, use paracetamol, an NSAID, or morphine/oxycodone (without serotonergic activity). For neuropathic pain: gabapentin or pregabalin.

Sources

FDA: Ultram (tramadol) prescribing information (2017)

Moderate

Azithromycin

Macrolides

Mechanism

Additive QT prolongation (tramadol weakly prolongs QT). Weak serotonergic risk (tramadol inhibits serotonin reuptake).

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Rarely: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.

Management

For short azithromycin courses (3–5 days) in patients without cardiovascular disease, the combination is acceptable. In epilepsy: watch tramadol-related seizure threshold reduction. Alternative analgesic: paracetamol or morphine/oxycodone (no QT effect).

Sources

FDA: Ultram (tramadol) prescribing information (2017)

Pair details →

Moderate

Theophylline

Methylxanthine

Mechanism

Both lower the seizure threshold. Additive risk, especially in theophylline overdose or in patients with epilepsy and prior head trauma.

Symptoms

Tremor, jitters, anxiety; severe cases: seizures. Symptoms appear with theophylline or tramadol dose escalation.

Management

Avoid the combination in epilepsy or prior head trauma. At usual therapeutic theophylline doses and short tramadol courses (3–5 days), the combination is acceptable in young patients. Keep theophylline levels in the lower half of normal range (10–15 mcg/mL). Analgesic alternatives: paracetamol with codeine, or gabapentin for neuropathic pain.

Sources

FDA: Ultram (tramadol HCl) prescribing information (2017)

Pair details →

Moderate

Warfarin

Vitamin K antagonist anticoagulants

Mechanism

Tramadol indirectly affects CYP2C9-mediated warfarin metabolism via CYP2D6. INR increases of 1–2 points have been reported, especially in older patients.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

On tramadol start, check INR at 5–7 days. For pronounced pain, alternatives: paracetamol up to 2 g/day or a short tramadol course at 50 mg at night. High-dose opioids and NSAIDs are less preferred.

Sources

PubMed: Pottegard 2014 - Tramadol-warfarin INR interaction (2014)

Pair details →

Frequently asked

What is Tramadol used for?

Tramadol is evaluated for the following indications with varying evidence strength: Neuropathic pain (evidence tier B), Acute moderate-to-severe pain (evidence tier B), Mild to moderate pain in adults (evidence tier F). See the full indication matrix with dosing and citations above on this page.

What are the side effects of Tramadol?

Common side effects of Tramadol (≥ 1 in 100): Nausea, vomiting, Constipation, Dizziness, sedation, Dry mouth, Sweating, Headache. See the Safety section for uncommon and serious reactions.

Is Tramadol safe during pregnancy?

FDA category C. FDA categories were retired in 2015 (historically C). Third-trimester exposure is associated with neonatal abstinence syndrome and respiratory depression. Manufacturer label states a contraindication. In pregnancy, prefer paracetamol and non-pharmacological measures.

Is Tramadol compatible with breastfeeding?

Transfers into breast milk. In women with CYP2D6 ultra-rapid metabolism, milk concentrations of the active M1 metabolite are high — neonatal respiratory depression has been reported. Manufacturer label advises against breastfeeding.

Who should not take Tramadol?

Tramadol is contraindicated in: Acute intoxication with alcohol, hypnotics, opioids, or psychotropics; Concurrent or recent (within 14 days) MAOI; Epilepsy with poor seizure control; Age under 12; Age under 18 after tonsillectomy or adenoidectomy (FDA black box). Full list in the Safety section.

Does Tramadol carry an FDA boxed warning?

FDA boxed warning: risk of addiction, abuse, life-threatening respiratory depression, and severe sedation when combined with benzodiazepines or alcohol. In children under 12, risk of severe respiratory depression in CYP2D6 ultra-rapid metabolizers. Contraindicated in children under 18 after tonsillectomy or adenoidectomy.

tramadol is a safe analgesic, not a real opioid

tramadol is an opioid with dependence risk. Schedule IV controlled substance in the US since 2014; restricted prescription in Russia since 2008.

tramadol can be combined with antidepressants

the serotonergic component combined with SSRIs, SNRIs, MAOIs, or triptans risks serotonin syndrome — a severe and potentially lethal state. Such combinations require caution and risk assessment.

tramadol does not cause respiratory depression

in CYP2D6 ultra-rapid metabolizers and when combined with alcohol or benzodiazepines, respiratory depression risk is significant.

Mechanism of action

Indications

Practical notes

Timing and administration

Common myths

Drug–drug interactions

Check interaction with another drug

Official sources

Safety

Contraindications

Serious adverse effects

Common adverse effects

PregnancyFDA C

Frequently asked