I was taught never to prescribe tramadol. Everyone in Canada seemed to agree it's an awful drug, but then I moved to New Zealand.
Few patients are on opioids in New Zealand, unlike North America, but tramadol kept popping up on medication lists during my first few shifts. It was being used for chronic pain, osteoarthritis, headaches, and sprained ankles, even daily by multiple patients with epilepsy. I don't think I am seeing any overall difference in opioid use compared with Canada, just different opioids being used, with tramadol leading the way.
I decided a literature review about tramadol was in order, and it confirmed my initial teaching—tramadol is a horrible drug.
Tramadol is an opioid, but it does not bind directly to opioid receptors (or it binds so weakly that it might as well not bind at all). Its opioid action is the result of the metabolite O-desmethyltramadol, which means it requires metabolism through the P450 enzymes to work, much like codeine. That is a problem. A significant portion of the population has no activity at the necessary enzyme (CYP2D6), so it provides no pain relief for some patients.
On the other hand, ultra-metabolizers get much higher concentrations and larger doses of the active opioid. (Clin Pharmacol Ther. 2007;82:41; http://bit.ly/31vNZH7; Pharmacogenet Genomics. 2014;24:374; http://bit.ly/31uabkN; J Pediatr Health Care. 2019;33:117; http://bit.ly/31vyKOu.) Instead of prescribing a known dose of an opioid, you are gambling with tramadol, and your patient is the one who could lose. This is the same reason codeine is such a horrible drug. (First10EM. May 20, 2019; http://bit.ly/31uXPcn.)
Complicating matters, tramadol also acts as a serotonin and norepinephrine reuptake inhibitor (SNRI), although none of its breakdown products do. What you get with tramadol is an unpredictable mix of opioid and SNRI pharmacology. 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.
A ‘Weak’ Opioid
A fundamental misunderstanding underlies a lot of tramadol prescribing. People 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 same way. 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 opioid dose, just give a lower dose of morphine rather than changing to tramadol.
Ultimately, when tested clinically, tramadol is not an effective analgesic. It has been found to be equally effective to acetaminophen for abdominal pain but worse than NSAIDs for biliary colic. (Eur Rev Med Pharmacol Sci. 2012;16:1983; http://bit.ly/307BJiA; Arzneimittelforschung. 1993;43:1216.) Giving 100 mg of tramadol is inferior to giving a combination of 5 mg of hydrocodone and 500 mg of acetaminophen for relieving acute musculoskeletal pain. (Ann Emerg Med. 1998;32:139.)
A meta-analysis demonstrated that a combination of tramadol and acetaminophen was as effective as 400 mg of ibuprofen for postoperative pain. (J Pain Symptom Manage. 2002;23:121; http://bit.ly/305j9rf.) A review looking at five randomized, controlled trials found that 75 mg of tramadol plus 650 mg of paracetamol was no more effective than 400 mg of ibuprofen. (Prescrire Int. 2003;12:211.)
Multiple other studies have found equivalence with ibuprofen. (Contraception. 2008;77:56; J Indian MedAssoc. 2011;109:619; J Minim Invasive Gynecol. 2012;19:581.) Overall, tramadol has limited analgesic effect at the doses normally prescribed (and zero analgesic effect for part of the population because of genetic polymorphisms).
More Harm than Good
Tramadol is an opioid agonist, and will therefore have the same dose-dependent opioid-related respiratory depression. (Prescrire Int. 2016;25:45.) There is, however, an added risk because of the CYP polymorphisms. Some individuals are ultra-metabolizers, resulting in higher than expected doses and respiratory depression even at usual doses. (Pediatrics. 2015;135:e753; http://bit.ly/31FnLSR; J Pediatr Health Care. 2019;33:117; http://bit.ly/31vyKOu.)
Tramadol is associated with seizures in overdose and when taken at usual doses. (Med J Aust. 2005;182:42; Pharmacotherapy. 2000;20:1423; http://bit.ly/31sgjdC; Clin Toxicol [Phila]. 2015;53:545.) This link seems pretty certain in overdoses, 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?
Multiple case reports have shown 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 can provoke unintended opioid withdrawal while also unintentionally increasing SNRI activity.
Tramadol is also associated with hypoglycemia, which makes sense given its pharmacologic similarities to SNRIs, which are known to cause hypoglycemia. (Am J Med. 2015;128:418.) The rate of hypoglycemia is almost 50 percent in patients with type 1 diabetes. (J Diabetes Metab Disord. 2017;16:30; http://bit.ly/31wLqEL.) Tramadol has also been associated with increased hospital admission for hyponatremia. (Am J Med. 2015;128:418.)
Despite providing no more pain relief than simple NSAIDs, a large propensity-matched observational cohort of osteoarthritis patients demonstrated an association between tramadol use and increased mortality compared with naproxen, diclofenac, celecoxib, and etoricoxib. (JAMA. 2019;321:969; http://bit.ly/31vSwt7.)
For these reasons, the U.S. Food and Drug Administration stated that tramadol is contraindicated in patients under 12 and between 12 and 18 after tonsillectomy. The FDA also cautioned against using tramadol in all pediatric patients with obesity or any breathing problems. (http://bit.ly/31vTZ2B.)
Same as Opioids
Tramadol is often marketed as a nonaddictive opioid alternative, but that is simply untrue. It acts at the opioid receptor the same way all opioids do and has the same risk of dependence and addiction as other opioids. A massive amount of tramadol abuse is seen around the world. Ninety-five percent of patients who tested positive for opioids were positive for tramadol at one addiction center in Sweden. (J Addict. 2017;2017:6716929; http://bit.ly/31vEnMC.)
The rates of tramadol use and tramadol-related death were steadily increasing in the United Kingdom until the drug was reclassified as a controlled substance. (Pharmacoepidemiol Drug Saf. 2018;27:487; http://bit.ly/30fxLEV.) Abusers of tramadol show clear physical signs of dependence, and euphoria is rated the same as that from heroin use. (Biomed Res Int. 2013;2013:283425; http://bit.ly/303butL.)
There is fMRI evidence that taking tramadol activates areas of the brain known to be related to addiction. (Psychopharmacology [Berl]. 2018;235:2631.) Patients who abruptly stop tramadol also get classic opioid withdrawal symptoms. (Drug Alcohol Depend. 2003;69:233.) About one in eight patients also gets worse atypical withdrawal symptoms, such as anxiety, panic attacks, insomnia, hallucinations, confusion, paranoia, and unusual sensory changes, probably related to the SNRI effects of the drug. (Drug Alcohol Depend. 2003;69:233.)
The recreational use of tramadol may be better documented in the lay media. The massive abuse in Egypt (The Economist. April 18, 2015; https://econ.st/31wU4TE) and the abuse of tramadol throughout Africa and the Middle East (The Wall Street Journal. Oct. 19, 2016; https://on.wsj.com/31wJU5p) have been well documented.
No evidence shows that tramadol is any less risky than morphine. (Prescrire Int. 2016;25:45.) Thiels, et al., found that persistent opioid use was higher among patients prescribed tramadol than those prescribed other short-acting opioids. (BMJ. 2019;365:l1849; http://bit.ly/31vVXjv.) Tramadol was also the highest-risk short-acting opioid with increased, persistent opioid use at one and three years in another study. Fourteen percent of patients prescribed tramadol were still taking an opioid at one year compared with five to nine percent of those prescribed a short-acting opioid. (MMWR Morb Mortal Wkly Rep. 2017;66:265; http://bit.ly/303PIWS.)
Abuse and dependency on tramadol are probably somewhat lower than other opioids, probably because tramadol has no opioid effect in a significant percentage of the population and other opioids are so easy to obtain. Tramadol clearly results in dependency and addiction, however. It also causes more adverse events than other opioids because of its SNRI actions. If your patient needs an opioid, there is no reason to choose tramadol over morphine.
Dr. Morgensternis a community emergency physician currently practicing at Taranaki Base Hospital in New Plymouth, New Zealand. His blog, https://First10EM.com, is dedicated to resuscitation and evidence-based medicine and encourages skepticism and a mindset of constant questioning, humility, and scientific reasoning in medicine. Follow him on Twitter@First10EM.