Tramadol provides suboptimal pain relief, is a high risk for abuse and addiction, has multiple drug-drug interactions and bad side effects. So why in the world is it surging in popularity?
A conversation between Drs. Sergey Motov and Nicholas Genes.
Nicholas Genes: Is it just my imagination, or am I seeing a rise in tramadol prescriptions? It’s not just patients coming into the ED with the prescriptions from other providers – I think I’m seeing my own PAs and residents ordering it in the ED, and prescribing it. Am I imagining this?
Sergey Motov: You are not imagining it. You are witnessing an uncontrolled surge in tramadol prescribing across multiple medical specialties including EDs across the US. For example, between 2008 and 2014, rates of annual tramadol prescribing doubled from 22 million to 44 million . Data from IMS Health’s National Prescription Audit Plus Report demonstrated that between 2009 and 2011 significantly more prescriptions were written for tramadol than for any other opioid other than hydrocodone and oxycodone. In 2012, tramadol outranked oxycodone and became the second most commonly prescribed opioid in the United States after hydrocodone . Similarly, due to laxity of international opioid regulations, tramadol global consumption has increased by 186% from 2000 to 2012 . So, as you can see, tramadol is becoming an increasingly popular opioid analgesic.
Genes: Why should this be? Do they all think it’s a less addictive (or less euphoric) opioid? Or it’s a better pain medication?
Motov: The painful reality is that a misleading marketing campaign in 1995 proclaimed tramadol to be as effective as other opioids but with the lack of risk for abuse and dependency. This was largely overlooked by the FDA, which failed to acknowledge research demonstrating that the oral form of tramadol had similar abuse liability as oxycodone (OxyContin). Because of this misinformation, tramadol was not restricted under the Controlled Substance Act . In the end, this marketing campaign led to virtually uncontrolled prescribing of tramadol. But the truth, based on the post-marketing research, is that tramadol provides suboptimal analgesia, possesses high abuse and addiction risk, has multiple drug-drug interactions, and has an unfavorable (unique) side effect profile [5,6]. As a result of “perceived” safety, the number of tramadol-related ED visits involving misuse or abuse increased about 250 percent from 6,255 visits in 2005 to 21,649 in 2011. The number of tramadol-related ED visits due to adverse effects increased by 300% from 6,207 in 2004 to 25,558 in 2011, and ED visits due to tramadol-related suicide attempts increased by nearly 400% from 1,742 in 2004 and 5,692 in 2011 .
Genes: Well then. What is tramadol’s mechanism of action? And how does it compare to other commonly prescribed opioids?
Motov: Tramadol is a central acting synthetic opioid analgesic that is frequently prescribed in the United States to treat a variety of acute and chronic painful conditions. As a racemic mixture, tramadol has dual mechanisms of action: It binds to mu opioid receptors and, simultaneously, blocks the re-uptake of serotonin and norepinephrine. Tramadol’s active metabolite, M1 (O-desmethyltramadol) has higher affinity to mu receptors than the parent drug, but this affinity is approximately 100 times less than that of morphine . This weak opioid agonism results in tramadol having modest-at-most analgesic efficacy. In fact, tramadol administration to patients with acute traumatic musculoskeletal pain resulted in lesser degree of pain relief than acetaminophen/hydrocodone combination . Similarly, a combination of APAP/hydrocodone was found to have greater analgesic efficacy and longer time to re-medication in patients after oral surgery in comparison to APAP/tramadol combination .
Furthermore, tramadol was found to result in similar change in pain score as acetaminophen in patients with non-traumatic acute abdominal pain, and lesser degree of pain relief in comparison to NSAID (metamizole) in patients with biliary colic [10,11].
Lastly, a Cochrane review that compared analgesic efficacy of acetaminophen/tramadol combination to either acetaminophen or ibuprofen alone demonstrated superior analgesia of this combination to acetaminophen alone, but similar and even inferior pain relief to 400 mg of ibuprofen. Of note, the acetaminophen/tramadol combination did not result in superior analgesia when it was compared to acetaminophen given at 975 mg per dose .
When it comes to euphoria, multiple surveillance reports and data from SAMHSA and DAWN clearly demonstrate a dose-dependent opioid-induced euphoric effects of tramadol that is similar to oxycodone and heroin [2,13]. As an example, Senay et al reported high rates of physical dependence to tramadol based on the surveillance data and even higher rates (about 40%) of typical (opioid-like) and 5-8% of atypical (NE/serotonin) withdrawal symptoms related to abrupt cessation of tramadol use that included hallucinations, paranoia, extreme anxiety, panic attacks, confusion and unusual sensory experiences such as numbness and tingling in one or more extremities . These reports are the reasons that tramadol was finally placed into Schedule IV of the Controlled Substance Act .
When tramadol is consumed repetitively and/or for prolonged periods, its use is associated with high risk of addiction. In fact, a report from the Wall Street Journal clearly states that tramadol is the leading cause of opioid abuse and addiction worldwide with the exception of the United States . Once again, the “perceived safety” of tramadol leads to a false belief among doctors and patients that it is less harmful and addictive than oxycodone and oxycontin. In addition, factors that contribute to addiction include ease of obtaining tramadol from hundreds of websites without prescriptions and a cost of as little as $0.12 per tablet. Not to mention, it’s easy to tamper with the extended release capsules, to get instantaneous euphoric effects similar to heroin, but longer-lasting .
Genes: So how bad is tramadol with respect to the adverse effects?
Motov: Tramadol’s simultaneous opioid agonist action and serotonin (5-HT) and norepinephrine reuptake inhibitory effects result in a unique side effect profile and important drug interactions. To start, tramadol’s opioid analgesic potency is influenced by the individual’s CYP2D6 enzyme genetic polymorphism. In other words, “ultra-rapid” metabolizers have an increased risk of overdose and even death .
Tramadol use in higher doses or abuse and overdose are associated with a high rate of neurotoxicity that includes seizures and lethargy due to the blockade of serotonin and norepinephrine re-uptake [17,18]. Of note, several case series and chart reviews pointed out that the minimal tramadol dose that might lead to seizure ranges between 200-500mg [19,20].
Tramadol consumption has a potential to cause hypoglycemia. According to Fournier and colleagues, patients taking tramadol had higher risk of hypoglycemia requiring hospitalization in comparison to patients taking codeine. Interestingly, that risk was the highest in the first 30 days of tramadol use . In addition, tramadol use for the first 30 days is associated with 2-3-fold increased risk of hospitalizations for hyponatremia in comparison to codeine .
When tramadol is used or abused in combinations with selective serotonin re-uptake inhibitors and tricyclic antidepressants, the serotonergic effects are enhanced that lead to development to serotonin syndrome with occasional lethal outcomes . Thus, it is imperative to EM clinicians to not to prescribe tramadol to patients taking agents that increase serotonin concentrations, or at least execute extreme caution .
Genes: Yeesh. Beyond the adverse effects, though, there are some patients that swear by it. I get that it’s unpredictable, but if a patient comes in on tramadol and it’s helping their pain, should I recommend a different med, or leave well enough alone? Is long-term use a risk? What drug-drug interactions should I worry about?
Motov: Patients on long-term opioid therapy that includes tramadol represents the greatest challenge to EM clinicians. We should make a real effort in discussing risks of long-term tramadol use with referrals to an addiction specialist who can assist in weaning off or replacing this opioid analgesic by enrolling into medication-assisted therapy (MAT) programs with buprenorphine as an example. You should not abruptly stop patients from taking tramadol as withdrawal is associated with severe morbidity. Long-term use of tramadol has a high risk of leading to addiction.
Genes: You’ve talked a lot about alternatives to opioids (like topical meds in our last interview, or superior NSAID prescribing earlier this year). But if we do decide to prescribe an opioid, what should it be? Percocet? Vicodin?
Motov: I am a big proponent of morphine sulfate immediate release (MSIR) tablets for acute pain in the ED and at discharge. Limited research demonstrates similar analgesic efficacy of MSIR in comparison to hydrocodone and oxycodone but significantly lower rates of likeability (euphoria) and abuse liability (recreational use) . In addition, several randomized controlled trials that included morphine failed to demonstrate statistically significant abuse potential or reinforcing effects of morphine [26-28]. When morphine was given in high doses, it was found to have predominantly dysphoric effects and increased negative side effects that included dry mouth and flushing [27,28]. Furthermore, “take again” and to be “wanted” rating for morphine were less likely than placebo . The MSIR is available in tablets and liquid form with dosing ranging from 10 to 15 mg per dose for opioid-naïve patients. The only limiting step in prescribing of MSIR is a lack of availability in many local pharmacies.
- Drug Abuse Warning Network Report May 14, 2015. Accessed on 10/13/17. https://www.samhsa.gov/data/sites/default/files/report_1966/ShortReport-1966.html
- Diversion Control Division Report. Federal Register Volume 78, Number 213 (Monday, November 4, 2013). Accessed on 10/13/17 https://www.deadiversion.usdoj.gov/fed_regs/rules/2013/fr1104.htm
- Tramadol: The Opioid Crisis for the Rest of the World. The Wall Street Journal. Accessed on 10/13/17. https://www.wsj.com/articles/tramadol-the-opioid-crisis-for-the-rest-of-the-world-1476887401
- Drug tramadol escapes stricter regulation.Watchdog report, JSOnline, 12/21/13. Accessed on 10/13/15. http://archive.jsonline.com/watchdog/watchdogreports/drug-tramadol-escapes-stricter-regulation-b99158486z1-236900801.html/
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