I have never prescribed tramadol. I was taught that, for a variety of reasons, it’s an awful drug. In Canada, everyone seemed to agree. But then I moved to New Zealand.
During my orientation in New Zealand I was told that, unlike North America, very few patients were on opioids. However, over my first few shifts, tramadol kept popping up on medication lists. It was being used for chronic pain, osteoarthritis, headaches, and sprained ankles. It was being used daily by multiple patients with known epilepsy (who presented to the ED after a seizure). Overall, I don’t think I am seeing any difference in the rate of opioid use, at least when compared to Canada. I am just seeing different opioids being used, with tramadol leading the way.
I came to New Zealand to learn; to see how medicine was practiced in a different country. I was hoping to see different practices, which could open my eyes to dogma that may have found its way into the way that I practice medicine. These differences will probably prompt a number of blog posts over the coming year. However, after reviewing the literature around tramadol, I have to say that my initial teaching was correct. Tramadol is a horrible drug that I will probably never prescribe.
Tramadol is an opioid, but it does not bind directly to opioid receptors (or, at least, it binds so weakly that it might as well not bind at all). Its opioid action is the result of a metabolite (O-desmethyltramadol if you really wanted to know), which means, much like codeine, it requires metabolism through the P450 enzymes before it starts working. That is a problem. A significant portion of the population (approximately 3-10% in Caucasians) has no activity at the necessary enzyme (CYP2D6). Therefore, you are prescribing a pain medication that provides no pain relief for some of your patients. On the other hand, there are ultra-metabolizers that get much higher concentrations and larger doses of the active opioid. (Stamer 2007; Gong 2014; Fortenberry 2019) So instead of prescribing a known dose of an opioid, you are gambling, but your patient is the one who could lose. (This is the same reason that codeine is such a horrible drug.)
To complicate matters, tramadol acts as a serotonin and norepinephrine reuptake inhibitor (SNRI), although none of its break down products do. This becomes an issue when looking at the side effects of tramadol, which I will come back to shortly.
What you get with tramadol is an unpredictable mix of opioid and SNRI pharmacology. Why gamble? If you want opioid activity, prescribe the appropriate dose of morphine. If you think an SNRI is appropriate, prescribe one. At least prescribed separately, you will get a predictable dose of the medication you actually want to give.
There seems to be a fundamental misunderstanding that underlies a lot of tramadol prescribing. People seem to want a “weak” opioid, without really considering what that means. Morphine is “weaker” than fentanyl, but clinically they are equally effective because we give 10 mg of morphine where we might give 100 mcg of fentanyl. Tramadol is weaker in the exact same way. To get equal analgesia you need a higher dose. So we prescribe 100 mg of tramadol when we might use 10 mg of morphine, but at the end of the day, both are acting at the opioid receptors. Both are opioids. Period. If you really want to give a lower dose of morphine, rather than changing to tramadol, you can just give a lower dose of morphine.
Ultimately, when tested clinically, tramadol is not a very effective analgesic. It has been found to be equally effective to acetaminophen for abdominal pain, and worse than NSAIDs for biliary colic. (Oguzturk 2012; Schmieder 1993) 100 mg of tramadol is inferior to a combination of 5 mg of hydrocodone and 500 mg of acetaminophen for relieving acute MSK pain. (Tuturro 1998) For postoperative pain, a meta-analysis demonstrated that a combination of tramadol and acetaminophen was similarly effective to 400 mg of ibuprofen. (Edwards 2002) A review looking at 5 RCTs found that 75 mg of tramadol plus 650 mg of paracetamol was no more effective than 400 mg of ibuprofen. (Prescrire 2003) Multiple other studies have found equivalence with ibuprofen. (Romero 2008; Banerjee 2011; Karabayirli 2012)
Overall, tramadol has limited analgesic effect at the doses normally prescribed (and zero analgesic effect for a reasonable percentage of the population because of genetic polymorphisms).
Tramadol is an opioid agonist and therefore will have the same dose dependant opioid related respiratory depression as all opioids. (Prescrire 2016) However, there is an added risk because of the CYP polymorphisms. Much like codeine, some individuals are ultra-metabolizers, resulting in higher than expected doses, and respiratory depression even at usual doses. (Orliaguet 2015; Fortenberry 2019)
Seizures and other neurologic disorders
Tramadol is associated with seizures, both in overdose, and when taken in at usual doses. (Labate 2005; Gardner 2012; Ryan 2015) This link seems pretty certain in overdoses (although these are always complicated by potential polypharmacy), but is not yet definitive in standard doses. The absolute risk does not seem high, but it is an extra risk not seen with morphine, so why take it?
There is also an association between long term use of tramadol and neurologic disorders such as Alzheimer’s disease and Parkinson’s disease. (Raj 2019)
There are multiple case reports of tramadol being involved with serotonin syndrome, when combined with other medications. The absolute risk seems very low.
Because tramadol requires the CYP2D6 pathway to become an opioid, inhibitors of CYP2D6 (of which there are many) can provoke unintended opioid withdrawal, while also unintentionally increased SNRI activity.
Hypoglycemia and hyponatremia
Tramadol is associated with hypoglycemia, which makes sense considering its pharmacologic similarities to SNRIs (a class of drugs known to cause hypoglycemia). (Fournier 2015) In the subgroup of patients with type 1 diabetes, the rate of hypoglycemia is almost 50%. (Golightly 2017) Tramadol has also been associated with an increased chance of admission to hospital for hyponatremia. (Fournier 2015)
Association with increased mortality
Despite providing no more pain relief that simple NSAIDs in multiple studies, a recent very large propensity matched observational cohort in patients being treated for osteoarthritis demonstrated an association between tramadol use and increased mortality when compared to naproxen, diclofenac, celecoxib, and etoricoxib. (Zeng 2019)
Warnings in pediatrics
For the reasons outlined above, the US FDA states that tramadol is contraindicated in patients younger than 12 years of age, as well as in patients between 12 and 18 years of age after tonsillectomy. In addition to these strong warnings, the FDA also cautions against using tramadol in all pediatric aged patients with obesity or any breathing problems. (Food and Drug Administration 2018)
Although tramadol is often marketed as a non-addictive opioid alternative, that is simply untrue. It acts at the opioid receptor the same way all other opioids do and therefore has the same risk of dependence and addiction. (Unless you are one of the patients who lacks the appropriate CYP2D6, in which case you never actually received any opiate.)
There is a massive amount of tramadol abuse around the world. In one addiction center in Sweden 95% of patients who tested positive for opioids tested positive for tramadol. (Olsson 2017) The rate of tramadol use and tramadol related death was steadily increasing in the UK until the drug was reclassified as a controlled substance. (Chen 2018) Among abusers of tramadol, there are clear physical signs of dependance, and euphoria is rated the same as heroin use. (Zhang 2013) There is fMRI evidence that taking tramadol activates the areas of the brain known to be related to addiction. (Asari 2018) Patients that abruptly stop tramadol also get classic opioid withdrawal symptoms. (Senay 2013) Additionally, about 1 in 8 patients get worse, atypical withdrawal symptoms, such as anxiety, panic attacks, insomnia, hallucinations, confusion, paranoia, and unusual sensory changes, probably related the the SNRI effects of the drug. (Senay 2013).
The recreational use of tramadol may be better documented in the lay media than the medical literature. You can read about its massive abusive in Egypt in this Economist article. This article in the Wall Street Journal discusses the abuse of tramadol throughout Africa and the Middle East.
There is no existing evidence that tramadol is any less risky than morphine. (Prescrire 2016)
Overall, the abuse and dependency issues with tramadol are probably somewhat lower than other opioids. This is likely a combination of the fact that tramadol has no opioid (or analgesic) effect in a significant percentage of the population, and the fact that other opioids are so easy to obtain. However, tramadol clearly results in both dependency and addiction. This is not a reason to choose it over a relatively non-euphoric opioid like morphine.
EDIT: On the day after I published this post, a new paper was published in the BMJ that demonstrated an association between short term tramadol use after surgery and persistent opioid use. Persistent opioid use was higher among patients prescribed tramadol than among patients prescribed other short acting opioids. (Thiels 2019) I will cover this paper in more detail in the next “Research Roundup” publication. A similar association was seen in another database study, in which tramadol was the highest risk short acting opioid, with increased persistent opioid use at both 1 and 3 years. At 1 year, 14% of the patients prescribed tramadol were still taking an opioid, as compared to 5-9% if the initial prescription was for another short acting opioid. (Shah 2017)
There is really no logical reason to prescribe tramadol. It is an unpredictable medication. Some patients will get no pain relief at all. Others will get much higher opioid concentrations than you expect. It results in dependence, addiction, and abuse like all opioids, but seems to cause more adverse events that other opioids because of its SNRI actions.
If your patient needs an opioid, there is no reason to choose tramadol over morphine.
This post has been recreated as an article in EM News.
Check out the companion piece about codeine.
There is an audio version of this rant available on the Royal New Zealand College of Urgent Care podcast
Tramadol? Think of it more as ‘Tramadont’ on Canadiem
Tramadol or Tramadont on REBELEM
The Painful Reality Behind America’s Surge in Tramadol Prescriptions
The Therapeutics Letter: Tramadol: Where do we go from here?
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Asari, Y., Ikeda, Y., Tateno, A. et al. Psychopharmacology (2018) 235: 2631. https://doi.org/10.1007/s00213-018-4955-z
Banerjee M, Bhaumik DJ, Ghosh AK. A comparative study of oral tramadol and ibuprofen in postoperative pain in operations of lower abdomen. Journal of the Indian Medical Association. 2011; 109(9):619-22, 626. [pubmed]
Chen T, Chen L, Knaggs RD. A 15-year overview of increasing tramadol utilisation and associated mortality and the impact of tramadol classification in the United Kingdom Pharmacoepidemiol Drug Saf. 2018; 27(5):487-494.
Fournier JP , Azoulay L , Yin H , et al . Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med 2015;175:186–93.doi:10.1001/jamainternmed.2014.6512
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Food and Drug Administration. FDA Drug Safety Communication: FDA requires labeling changes for prescription opioid cough and cold medicines to limit their use to adults 18 years and older. 2018.
Fortenberry M, Crowder J, So TY. The Use of Codeine and Tramadol in the Pediatric Population-What is the Verdict Now? Journal of pediatric health care : official publication of National Association of Pediatric Nurse Associates & Practitioners. 2019; 33(1):117-123. [pubmed]
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Golightly LK, Simendinger BA, Barber GR, Stolpman NM, Kick SD, McDermott MT. Hypoglycemic effects of tramadol analgesia in hospitalized patients: a case-control study J Diabetes Metab Disord. 2017; 16(1).
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Labate A, Newton MR, Vernon GM, Berkovic SF. Tramadol and new-onset seizures. The Medical journal of Australia. 2005; 182(1):42-3. [pubmed]
Karabayirli S, Ayrim AA, Muslu B. Comparison of the analgesic effects of oral tramad0l and naproxen sodium on pain relief during IUD insertion. Journal of minimally invasive gynecology. ; 19(5):581-4. [pubmed]
Oguzturk H, Ozgur D, Turtay MG, Kayaalp C, et al.Tramadol or paracetamol do not effect the diagnostic accuracy of acute abdominal pain with significant pain relief – a prospective, randomized, placebo controlled double blind study. Eur Rev Med Pharmacol Sci. 2012 Dec;16(14):1983-8.
Olsson MO, Öjehagen A, Brådvik L, Kronstrand R, Håkansson A. High Rates of Tramadol Use among Treatment-Seeking Adolescents in Malmö, Sweden: A Study of Hair Analysis of Nonmedical Prescription Opioid Use. Journal of addiction. 2017; 2017:6716929. [pubmed]
Orliaguet G, Hamza J, Couloigner V, et al. A case of respiratory depression in a child with ultrarapid CYP2D6 metabolism after tramadol. Pediatrics. 2015; 135(3):e753-5. [pubmed]
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Prescrire. “Weak” opioid analgesics. Codeine, dihydrocodeine and tramadol: no less risky than morphine” Prescrire Int 2016; 25 (168): 45-51
Raj K, Chawla P, Singh S. Neurological disorders associated to long term tramadol utilization: Pathological mechanisms and future perspective CNSNDDT. 2019; 18.
Romero I, Turok D, Gilliam M. A randomized trial of tramad0l versus ibuprofen as an adjunct to pain control during vacuum aspiration abortion. Contraception. 2008; 77(1):56-9. [pubmed]
Ryan NM, Isbister GK. Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely Clinical Toxicology. 2015; 53(6):545-550.
Schmieder G, Stankov G, Zerle G, Schinzel S, et al. Observer-blind study with metamizole versus tramad0l and butylscopolamine in acute biliary colic pain. Arzneimittelforschung. 1993 Nov;43(11):1216-21.
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Morgenstern, J. Don’t prescribe tramadol, First10EM, May 13, 2019. Available at:
24 thoughts on “Don’t prescribe tramadol”
You’re lucky to not have to deal with opioids or that pressure to give a patient tramadol. It’s overused when it shouldn’t be
This guy do not know whats he talking about AT ALL. Thats the state of the press today.
Agree. It is impossible to apply logic to how people feel. And he thinks he knows and give some references to “support” his dogma.
I tried all antidepressants out there for years, SSRI, SNRI, Anphetamines, Modafinil, Bupropion,Ketamine infusions, LSD microdosing, Yes, even that. Nothing worked.
But Tramadol 50mg twice a day work incredible well. From day one. No more negative thoughts, bottle half full attitude. Positive, optimist, calmed, receptive to myself and others, able to enjoy music, to be unbiased, to enjoy life. I can’t still believe that was possible.
The author of this article call himself “Evidence based medicine junkie”, but he doesn’t have any evidence. There can’t be any evidence for something you can’t feel. He only have false beliefs.
“This Guy” is not a member of “the press.”
Tramadol is an opiate or narcotic agony medicine accessible as broadened discharge tablets for nonstop treatment of mellow to tolerably extreme torment.
“no more pain relief than NSAIDs” “tramadol prescriptions lead to persistent opioid use” make up your mind. This article reeks of uselessness, but then again, I wouldn’t expect much more from the guy who also bought you ‘don’t prescribe codeine’
He contradicted himself multiple times in this article. Lost all validity in my opinion.
Where do you think the contradictions are?
Seems you do not understand how receptors work. What the Doc was sharing was with many humans, they get the addictive properties WITHOUT analgesia, whereas with true opioids you get both. Combined with the serotonin issues, why bother. There are better targeted, mature analgesics that do not have the genetic issues as tramodol.
Are used to go to work every day
In the UK tramadol is Class C and morphine is Class A under the misuse of drugs act 1971, it this not the reason tramadol is being prescribed and the paperwork involved with controlled drugs and the storage thereof on site? In a hospital setting morphine seems a no brainer, in the community tramadol is more acceptable than morphine in society and a doctor may think they both have same potential for diversion but diverting one is less criminal than the other, the elderly and perhaps others often share medication with family and friends, being caught with tramadol is a lot less serious than morphine, basically it’s politically motivated.
This is an interesting article and you raise many good points. However, as a long term tramadol user, due to complex chronic pain, I can say it has been a god send for me. Yes, when I take it daily for more than a week or two I have mild opoid withdrawal symptoms. I moderate my use to avoid this as much as possible but mild withdrawal symptoms occasionally is better than pain every day! Long term daily use invites a horrible withdrawal for me, but again, it has been worth it during particularly bad times for the long term pain relief. I can enjoy a normal life with my family and work that I wouldn’t have without suitable pain relief. I’ve tried many alternatives and they just don’t work as well as tramadol does for me.
I appreciate the points you raise but please don’t rule out tramadol as a highly suitable analgesic for some people.
Hi Justin. Tramdol has been ridiculously helpful for some people. All pharmas have risk of side effects and some have risk withdrawal. If you want to contact me, my email is attached to this comment at your end.
I can personally attest that Dr. Morgenstern is right on target. Yesterday, my new pain interventional pain physician, who I saw for injections to relieve pain in my left arm that I’ve endured for almost 10 weeks (to whom I was referred by a physician’s assistant for an orthopedist), prescribed tramadol and gabapentin to hold me over for an additional 5 days while I wait longer for these injections. I never liked drugs and generally try to avoid them like the plague unless absolutely necessary. I took my first & only dose of a 50 mg tramadol pill last night at about 6 PM about 2 minutes after sitting down to my computer & almost immediately experiencing a sharp, slicing pain in my left arm, the same excruciating pain I’ve had for 9.5 weeks (since the last Tuesday of June 2021), despite 2x weekly visits to my chiropractor & physical therapist, various natural anti-inflammatory supplements, various forms of CBD (tincture, soft-gels and gummies) and now traction from my chiropractor (prescribed by my orthopedic physician’s assistant). Within about 2 hours after taking this single dose, starting about 8 PM, I started feeling dizzy, sleepy, nauseous soon afterward, queasy, a sharp rise in my body temperature (since I felt like sweating), shivering at the same time as I felt my body temperature shyrocket and soon retching. I had to rush to the bathroom several times while attempting to prepare my dinner so I could sit in front of my toilet trying to vomit, though there was nothing in my stomach to vomit & I’d eaten nothing since lunch at 12:30 PM. I couldn’t finish making my dinner and I went to bed much earlier than usual. If I’d managed to finish making dinner while feeling faint, I’d surely have vomited the entire meal up soon after starting to eat. I haven’t retched or vomited in many years, at least not since January 2009 when I had a fever. I woke up this morning with a pounding headache, residual effects of the horrific problems I had with tramadol last night. Those commenters on this forum who allege Dr. Morgenstern has no idea what he’s talking about, or that he doesn’t cite sources are projecting their own ignorance and hypocrisy onto the author. He obviously cites a multitude of medical journal articles to corroborate his elaborate technical explanations, which are wholly consistent with my experiences since last night. If I’d have known about the deeper, more dangerous problems he cites when I saw my pain physician yesterday afternoon, I’d have refused to accept it and would have sought safer alternatives whose benefits would be more reliable. The side effects I suffered far outweighed any mitigation my arm may have felt last night. I took none of the gabapentin before going to bed, as prescribed, since I knew those side effects would severely exacerbate the problems I already had with tramadol. I didn’t find this website deliberately when I searched for ways to avoid the worst side effects of tramadol. I found this article by pure serendipity and the only silver lining of this catastrophe is that I had time for the first good night’s sleep (almost 8 hours) I’ve had in a long time, only because I could go to bed extra early since I felt like I was ready to drop dead. I have no vested interest in the author’s success, but his logical explanations make perfect sense to me as a layperson. It also strkes me as mildly ironic that the nastiest critics of Dr. Morgenstern, who themselves claim to know more about tramadol or medicine generally, cannot speak proper English and sound they’ve been living under a rock. Shameless ignoramuses seem to dominate controversial public discussions all too often, proudly claiming that they know more about these issues than those who work in the professional fields themselves, much like those who promote conspiracy theories against masking and vaccinations. I subscribe to science, not conspiracy theories, so we need to focus on empirical reality for public heath’s sake.
Thank you for your review. Have you submitted a version of this article for peer review?
I have researched pain medication in the past, and I know that the literature are vast and many articles self-cite or reciprocate citing. Sometimes one fact with few data points becomes inflated. It is a real challenge to know what is primary data at the end of the day.
I appreciate the effort that you put into attempting to sort this and inform others.
I wish u r my doctor. My doc can’t understand that tramadol is also an SNRI not just “analgesic”. I was shocked that i was the one who had to ” teach” him. A week later he sheepishly told me, “You r right it’s also an SNRI not just analgesic.”
When i take tramadol i have extreme anxiety from over norepinephrine in my brain. I start to have restless leg syndrome, panic attack and feverish.
In this idiot third world country they prescribe Codeine, Tramadol and Clobazam ONLY for Methadone withdrawal. Can you believe it. Might as well give me Morphine and Benzo and then taper off that. Benzo works like a charm for me.
My methadone was at 30mg and they wanted to give me 10mg Codeine + 50mg Tramadol for the withdrawal. I couldnt stop laughing.
For Methadone legal user over a decade, 10mg codeine is like for a cockroach. Even a cockroach who has taken methadone for over a decade will still have withdrawal with 10mg of codeine, fly south.l and crash. Like WTF.
I have to quit Methadone because the clinic is closing down. Next clinic is in another town 1 hour away by car. Anyways i am sick of being sackled to the clinic.
But 10mg of codeine are u kidding me.
When you’re highly allergic to morphine and you suffer from nerve damage, tramadol is a fantastic pain reliever.