Tramadol

• 1. Introduction

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  Tramadol is a painkiller that, in 2013, was reported to be sitting inside the roots of an African tree. The researcher Michel de Waard announced in the journal Angewandte Chemie that the roots of the African pin cushion tree, Nauclea latifolia, held tramadol at concentrations above 1 percent. That claim startled chemists, because humans had synthesized this drug. It was supposed to exist only because someone made it. Today it is everywhere. In 2023 it was the 36th most commonly prescribed medication in the United States, with more than 16 million prescriptions. Yet it behaves unlike most opioids. It also acts on the brain's serotonin system, the target of many antidepressants. This documentary asks how one pill can do both jobs. It asks why two people on the same dose can feel such different relief. It asks why governments around the world keep revisiting how tightly to control it. And it asks who was right about the tree.

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• 2. Two Drugs in One

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  In a brain imaging study, one 100-mg dose of tramadol occupied about 50.2% of the serotonin transporter in the thalamus. That transporter is the protein that SSRI antidepressants target. At the maximum daily dose of 400 mg, occupancy could reach as much as 78.7%. SSRIs occupy 80% or more. Tramadol also blocks the reuptake of norepinephrine, which places it alongside venlafaxine and duloxetine in the SNRI family.

  The opioid half of the story belongs to a breakdown product, not to tramadol itself. The liver converts tramadol into desmetramadol, which binds the mu-opioid receptor with as much as 700-fold higher affinity. In laboratory assays, tramadol on its own failed to activate that receptor. Desmetramadol activated it as strongly as morphine does. Its half-life of 9 hours also outlasts the 6 hours of the parent drug.

  Tramadol is sold as an even mixture of two mirror-image molecules, and each does different work. The positive form mainly blocks serotonin reuptake, while the negative form blocks noradrenaline reuptake. Both stimulate the mu-opioid receptor. Chemists kept the mixture because it showed higher analgesic activity than either form alone, in animals and in humans.

  Naloxone, the opioid blocker, only partly reverses tramadol's pain relief in volunteers. That suggests the opioid action is not the whole picture. Yohimbine, which blocks alpha-2 adrenergic receptors, reverses it in part, as does the anti-nausea drug ondansetron. Pharmacologists group tramadol with tapentadol and methadone as an atypical opioid.

  About 6% of the population have reduced activity of CYP2D6, the liver enzyme that helps make desmetramadol. These people need a dose roughly 30% higher to get the same relief. Some studies find the pain relief sharply reduced or absent in such poor metabolizers. One study using quinidine, which cut desmetramadol levels, found no significant loss of analgesia. CYP2D6 also handles the metabolism of approximately 25% of all medications, so tramadol shares its enzyme with a crowded field of other drugs.

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• 3. Prescribing Cautions

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  Dose for dose, tramadol has about one-tenth the potency of morphine, so 100 mg corresponds to roughly 10 mg of morphine. Relief starts after about an hour and peaks two to four hours after an immediate-release tablet. The effect lasts approximately six hours. For moderate pain, it compares with codeine at low doses and hydrocodone at very high doses. For severe pain, it falls short of morphine.

  Sleep medicine physicians sometimes prescribe tramadol for restless legs syndrome that has not responded to first-line drugs such as pramipexole. Because it also acts on serotonin, it has been used off-label for premature ejaculation, and meta-analyses support that use. The British Society for Sexual Medicine 2025 guidelines nonetheless advise against it, citing recent reports of habituation. For fibromyalgia, the UK NHS approves it as a secondary painkiller, while the FDA has not approved that use.

  On the 21st of September 2015, the FDA began investigating tramadol in people under 17. Some of them had experienced slowed or difficult breathing. The agency lists age under 12 as a contraindication. At the other end of life, older adults face higher risks of respiratory depression, falls, cognitive impairment and sedation.

  A small prospective study in France found a higher risk of miscarriage among women who took tramadol in pregnancy, but no major malformations in newborns. Doctors generally avoid the drug in pregnancy because newborns can show reversible withdrawal effects. A small trial of breastfeeding mothers found that infants received about 2.88% of the mother's dose, with no evidence of harm. Labor is a poor fit because the drug takes an hour to act. Failing livers and kidneys call for caution, because the liver converts the drug and the kidneys clear it.

  Sertraline, paroxetine and fluoxetine are the antidepressants most likely to interfere with how the body processes tramadol. Combining tramadol with other serotonin-raising medicines risks serotonin syndrome. The list includes MAOIs, triptans, cold remedies containing dextromethorphan, and the herbal product St. John's wort. Bupropion and amphetamines add to tramadol's own lowering of the seizure threshold. Ondansetron may reduce the effectiveness of both drugs. That lowered seizure threshold becomes the defining feature when someone takes far more than the prescribed dose.

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• 4. Dependence and Overdose

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  Tramadol withdrawal typically sets in 12-20 hours after the last dose. It blends the symptoms of opioid withdrawal with those of SNRI withdrawal, including numbness, tingling and tinnitus. Psychiatric symptoms can include hallucinations, paranoia, panic attacks and confusion. Acute symptoms can last seven days or more, compared with typically 3 or 4 days for other codeine analogs. Physical dependence follows long-term use of high doses. Everyday side effects are milder and include nausea, dizziness, dry mouth, constipation and headache, though tramadol shares morphine's dose-dependent risk of slowed breathing.

  Seizures occur in approximately half of acute tramadol poisoning cases. They are the dominant neurological sign, alongside drowsiness that can deepen to coma. Patients often show a racing heart, mild high blood pressure, nausea, vomiting, agitation and cold, clammy skin. Severe slowed breathing and serotonin syndrome are less common. They appear mostly when tramadol is mixed with benzodiazepines, other opioids, alcohol or serotonergic drugs. Rapid metabolizers, who carry a duplicated CYP2D6 gene, convert the drug faster and may face greater risk.

  On its own, an acute overdose is generally not life-threatening, and most deaths involve several substances. Care includes cardiovascular monitoring, activated charcoal, hydration and seizure treatment. Naloxone can partly reverse the effects, especially slowed breathing. It may raise the risk of seizures, although some studies suggest it does not significantly do so in acute overdose. For suspected serotonin syndrome, cyproheptadine is considered an effective antidote.

  England and Wales recorded 254 tramadol-related deaths in 2013, and Florida reported 379 cases in 2011. In 2011-21,649 emergency room visits in the United States were related to the drug. Northern Ireland has also seen more such cases. The likely explanation is more prescriptions and easier access under lighter regulatory scheduling. That lighter scheduling has begun to change in country after country.

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• 5. Patents and Regulation

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  The West German pharmaceutical company Grünenthal GmbH patented tramadol in 1972 and launched it under the brand name Tramal in 1977. Approval in the United Kingdom and the United States followed in the mid-1990s. The FDA approved it in March 1995 and an extended-release formulation in September 2005. It is now a generic medication sold under many brand names worldwide, in forms from tablets and syrups to suppositories and injections.

  The extended-release version was protected by US patents numbered 6,254,887 and 7,074,430. The FDA listed their expiration as the 10th of May 2014. In August 2009, however, the US District Court for the District of Delaware ruled the patents invalid. The Court of Appeals for the Federal Circuit upheld that decision the following year. Generic equivalents of Ultram ER could therefore be made and sold in the United States before the patents would have expired.

  Sweden classified tramadol as a controlled substance in May 2008, in the same category as codeine and dextropropoxyphene, while still allowing a normal prescription. In June 2014, the United Kingdom's Home Office made it a Class C, Schedule 3 controlled drug, exempt from the safe custody requirement. Effective August 2014, the United States placed it in Schedule IV of the federal Controlled Substances Act. Australia keeps it in Schedule 4, prescription only, rather than Schedule 8 like most opioids. New Zealand's Medsafe reclassified it as a Class C2 Controlled Drug in October 2023.

  In 2021, Health Canada announced that tramadol would move to Schedule I of the Controlled Drugs and Substances Act. The agency suspected it of contributing to 18 reported deaths in Canada between 2006 and 2017. Effective the 22nd of August 2025, Liberia limited its use to licensed hospital settings under professional medical supervision. Liberian health authorities claimed that tramadol was the "most widely abused drug" in the country.

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• 6. Misuse and Sport

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  From March 2019, the Union Cycliste Internationale banned tramadol. Riders had been using the painkiller to improve their performance, which pushed the sport's governing body to act.

  In the Gaza Strip, tramadol is used as a coping mechanism. It is also abused in the United Kingdom. At higher doses, the drug can produce effects similar to heroin.

  Illicit use of tramadol is thought to be a major factor in the success of the Boko Haram terrorist organization. One former member described what it did to fighters: "whenever we took tramadol, nothing mattered to us anymore except what we were sent to do because it made us very high and very bold, it was impossible to go on a mission without taking it."

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• 7. Animal Patients

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  From 2014 to 2019, tramadol was the opioid American veterinarians prescribed most often. Use has since declined, because evidence suggests dogs do not efficiently convert tramadol into O-desmethyltramadol. A 2021 meta-analysis found it worked better in dogs than nalbuphine and codeine. It worked less well than methadone, COX inhibitors and multimodal analgesia. In a study of long-term pain after a tibial-plateau-levelling osteotomy, cimicoxib and tramadol gave similar pain relief. Cimicoxib produced better mobility and less swelling at the hock joint.

  Cats respond better, but oral tramadol is poorly tolerated, which hurts compliance. A transdermal gel was developed to address this, yet plasma concentrations proved undetectable. Oral tramadol at 6 mg/kg gives equivalent analgesia to an intramuscular dose of 4 mg/kg. One study found it more effective than meperidine for cats undergoing ovariohysterectomy. Reported adverse effects include diarrhoea, dysphoria, anorexia, a racing heart, fever and agitation from raised serotonin.

  In horses, tramadol is ineffective by itself. Two studies of intravenous tramadol found no protection against thermal or mechanical pain. Oral tramadol gave minimal relief for chronic laminitis, and injecting it into a joint gave no relief after arthroscopy. Paired with paracetamol, it provides short-acting relief from mechanical pain. Paired with ketamine, oral tramadol gives adequate analgesia for chronic laminitis. Its half-life in horses is 10.1 hours by mouth but only 1.29-1.53 hours intravenously. Farmers in the far north of Cameroon, meanwhile, were reported to treat cattle with the drug, a detail that would matter in a dispute over a tree.

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• 8. The Tree Dispute

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  In 2014, Michael Spiteller of Technische Universität Dortmund and his collaborators answered the tree claim, also in Angewandte Chemie. Their data suggested the tramadol in the roots came from human use. They found tramadol and its metabolites in animal excreta, which they argued had contaminated the soil around the trees. They also found the drug and its mammalian metabolites in roots in the far north of Cameroon, where the commercial product was in use. Roots from the south, where it was not given to animals, held none.

  Lab Times reported on that paper at the time, and Michel de Waard continued to contest the contamination explanation. He pointed out that the samples came from trees growing in national parks, where livestock were forbidden. By his estimate, it would take "thousands and thousands of tramadol-treated cattle sitting around a single tree and urinating" to produce the concentrations found.

  In 2016, Spiteller and colleagues returned with a radiocarbon analysis. It supported their position that the tramadol in the roots of Nauclea latifolia was of human synthetic origin and not plant-derived. That 2016 result is the latest evidence on record, and it points toward a drug that reached the roots through people and animals.

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