Tramadol

Is tramadol safe?

Not as safe as its reputation. Tramadol is often prescribed as a milder alternative to oxycodone and other strong opioids, and it is less tightly controlled. But it is still an opioid, with a boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary on addiction, overdose and fatal breathing problems, and it has two extra risks that other opioids mostly do not: seizures and serotonin syndromeSerotonin syndromeA reaction caused by too much serotonin in the body, usually from combining medicines that raise it. Symptoms range from shivering to high fever.More in the glossary. We score it 34, above oxycodone (26) and below alprazolam (40).

The US label limits it to pain severe enough to need an opioid when other treatments have not worked or cannot be used, at no more than 400 mg a day.

Two drugs in one, and why genes matter

Tramadol works in two ways. The drug itself weakly blocks the reuptake of serotonin and noradrenaline, a little like an antidepressant, and binds weakly to opioid receptors. The liver enzyme CYP2D6CYP450 enzymesA family of liver enzymes that break down many medicines. When another drug or supplement speeds them up or slows them down, drug levels change.More in the glossary then turns it into a metabolite, M1 (O-desmethyltramadol), which binds opioid receptors about 200 times more strongly in animal studies.

How fast that happens varies by genotype. The label estimates that 1% to 10% of white people, 3% to 4% of Black people and 1% to 2% of East Asians are ultra-rapid metabolisers, and more than 10% in some groups, including people of North African, Middle Eastern and Ashkenazi Jewish origin. They make more M1 and can be overdosed on a normal dose. Children have died this way, which is why the FDA has contraindicatedContraindicationA situation in which a medicine should not be used, because the risk clearly outweighs any benefit, such as a known allergy to it.More in the glossary tramadol under 12, and under 18 after tonsil or adenoid surgery, since April 2017. The label also advises against breastfeeding.

Other medicines shift the balance too. Fluoxetine, paroxetine and other CYP2D6 inhibitors raise tramadol levels, increasing seizure and serotonin risks, while cutting M1 and pain relief. Stopping such a drug later can push M1 up and cause opioid toxicity.

Seizures and serotonin syndrome

Seizures have been reported at recommended doses, and the risk rises above them and with:

• SSRIs, tricyclic antidepressants, other opioids, MAOIs and antipsychotics
• epilepsy, head injury, or alcohol or drug withdrawal

Serotonin syndromeSerotonin syndromeA reaction caused by too much serotonin in the body, usually from combining medicines that raise it. Symptoms range from shivering to high fever.More in the glossary, which causes agitation, fever, fast heart rate, muscle stiffness and diarrhoea, can occur within hours to days of combining tramadol with SSRIs such as sertraline, SNRIs, tricyclics, triptans, mirtazapine, trazodone, some muscle relaxants, linezolid or MAOIs. MAOIs, including use in the past 14 days, are a contraindicationContraindicationA situation in which a medicine should not be used, because the risk clearly outweighs any benefit, such as a known allergy to it.More in the glossary.

Other warnings on the label

Tramadol can cause severe low sodium, most often in women over 65 within the first week, and low blood sugar, mainly in people with diabetes or kidney disease. The label says not to prescribe it to people who are suicidal or prone to addiction. Constipation (46%), nausea (40%) and dizziness (33%) were common by 90 days in long-term trials.

Controls and misuse

The DEA placed tramadol in Schedule IVControlled substanceA medicine or drug that the law restricts because it can be misused or cause dependence. Countries group them into schedules or classes.More in the glossary on 18 August 2014, and the UK made it a Class C, Schedule 3 drug on 10 June 2014. In England and Wales, tramadol was mentioned on 213 drug poisoning death certificates registered in 2024, down from a peak of 240 in 2014, and in 64 of them no other drug was involved (ONS). In August 2026 the DEA used its emergency powers to place M1 itself in Schedule I until 2028, after forensic labs found it on its own in drug seizures in 30 states; it is not an approved medicine.

Combination products

Ultracet and generic versions combine 37.5 mg of tramadol with 325 mg of acetaminophen. The label allows at most 8 tablets a day and no more than 5 days of use. Taking extra acetaminophen products on top can harm the liver.

Who should be careful

Talk to your doctor or pharmacist before taking tramadol if you take an antidepressant, triptan, benzodiazepine or other opioid, drink alcohol, have epilepsy or a head injury, have diabetes, kidney or liver disease, are over 65, have had depression or a substance use problem, or are pregnant or breastfeeding. Keep it locked away from children, ask about naloxone, and do not stop suddenly after regular use without a plan from your prescriber.

How we scored it

Track record (85) is the only strong factor. Interactions (15) and regulatory warnings (15) are in the lowest band because of the opioid boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary, the MAOI contraindicationContraindicationA situation in which a medicine should not be used, because the risk clearly outweighs any benefit, such as a known allergy to it.More in the glossary and the many serotonin and CYP2D6CYP450 enzymesA family of liver enzymes that break down many medicines. When another drug or supplement speeds them up or slows them down, drug levels change.More in the glossary interactions. Dependence (30) and overdose marginOverdose marginHow far a normal dose is from a harmful one. A wide margin means an accidental extra dose is unlikely to cause serious harm.More in the glossary (30) are slightly better than for oxycodone, reflecting its Schedule IVControlled substanceA medicine or drug that the law restricts because it can be misused or cause dependence. Countries group them into schedules or classes.More in the glossary status, while serious side effects (38) include risks oxycodone does not have.