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 the way.
I came to New Zealand to learn; to see how medicine was practiced in a different country. I was hoping 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). It’s 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, which I will explore more in the near future).
To complicate matters, tramadol acts as a serotonin and norepinephrine reuptake inhibitor (SNRI), although none of it’s 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)
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 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.
Want more high quality medical education? Make sure to subscribe to this blog:
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
Edwards JE, McQuay HJ, Moore RA. Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain. Journal of pain and symptom management. 2002; 23(2):121-30. [pubmed]
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]
Fournier J, Yin H, Nessim SJ, Montastruc J, Azoulay L. Tramadol for Noncancer Pain and the Risk of Hyponatremia The American Journal of Medicine. 2015; 128(4):418-425.e5.
Gardner JS, Blough D, Drinkard CR, et al. Tramadol and Seizures: A Surveillance Study in a Managed Care Population Pharmacotherapy. 2000; 20(12):1423-1431.
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).
Gong L, Stamer UM, Tzvetkov MV, Altman RB, Klein TE. PharmGKB summary Pharmacogenetics and Genomics. 2014; 24(7):374-380.
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]
Prescrire. Paracetamol + tramadol: new preparation. No advance. Prescrire international. 2003; 12(68):211-3. [pubmed]
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.
Shah A, Hayes CJ, Martin BC. Characteristics of Initial Prescription Episodes and Likelihood of Long-Term Opioid Use – United States, 2006-2015. MMWR. Morbidity and mortality weekly report. 2017; 66(10):265-269. [pubmed]
Senay EC, Adams EH, Geller A, et al. Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur. Drug and alcohol dependence. 2003; 69(3):233-41. [pubmed]
Stamer UM, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F. Concentrations of Tramad0l and O-desmethyltramadol Enantiomers in Different CYP2D6 Genotypes Clin Pharmacol Ther. 2007; 82(1):41-47.
Thiels CA, Habermann EB, Hooten WM, Jeffery MM. Chronic use of tramadol after acute pain episode: cohort study. BMJ (Clinical research ed.). 2019; 365:l1849. [pubmed]
Turturro MA, Paris PM, Larkin GL. Tramad0l versus hydrocodone-acetaminophen in acute musculoskeletal pain: a randomized, double-blind clinical trial. Annals of emergency medicine. 1998; 32(2):139-43. [pubmed]
Zhang H, Liu Z. The investigation of tramadol dependence with no history of substance abuse: a cross-sectional survey of spontaneously reported cases in Guangzhou City, China. BioMed research international. 2013; 2013:283425. [pubmed]
Zeng C et al. Association of Tramadol With All-Cause Mortality Among Patients with Osteoarthritis. JAMA 2019. PMID: 30860559