Let’s get this out of the way, shall we?
Not a word, you say? Look it up.
The exhortation to avoid tramadol is met either with a sage nodding of the head, or with one of two other responses, occasionally draped in hostility:
“But I’ve (taken it/prescribed it) and seen it work. Tylenol, ice packs and a dose of SuckItUp™ for everyone? Is that your plan, you anti-opioid zealot?”
“Why not? We need analgesic options. And besides, tramadol has two —TWO!— mechanisms of action. I learned that at a CME event last month (where the strip loin and Bordeaux were fantastic, btw …)
Let’s also get this out of the way: Tramadol can help some people (although “work” is the wrong construct, as we’ll discuss later). And yes, it does have two mechanisms of analgesic action.
So, why not use it? Read on.
Background and Pharmacology
Tramadol was developed in 1962 by the German pharmaceutical company Grünenthal, the same good people who graced humanity with thalidomide. For some reason it wasn’t licensed in Germany until 1977, and in the U.S. until 1995. But over the past decade or so, it has garnered its share of medical devotees. More than 40 million tramadol prescriptions are now issued each year in the United States alone.
Tramadol is generally viewed as a weak opioid, more or less on par with codeine. It’s therefore often perceived to be a more appropriate initial opioid than, say, morphine or oxycodone. But I like to think of tramadol as what would happen if codeine and Prozac had a baby, and that baby grew into a sullen, unpredictable teenager who wore only black and sometimes kicked puppies and set fires.
In fact, tramadol itself is hardly even an opioid. It binds to mu opioid receptors so weakly (with an affinity about 1/6000th that of morphine) that this doesn’t realistically contribute to its analgesic effect. What it does do, however, is inhibit the reuptake of serotonin and norepinephrine, more or less like venlafaxine. In fact, look at the structures, squint hard, rub your eyes, and you can start to see the resemblance:
And because tinkering with monoamines in the dorsal horn of the spinal cord modulates pain transmission, that is tramadol’s analgesic mechanism of action #1.
So why is tramadol lumped in with opioids? Because one of its metabolites (O-desmethyltramadol; ODT) is a genuine agonist at mu opioid receptors, binding with an affinity 300 times that of tramadol itself. (Note: ODT should not be confused with founding member of the Wu-Tang Clan, ODB (Ol’ Dirty Bastard), who collapsed and died in 2004 with cocaine and — I kid you not — tramadol in his system.)
What does all this mean?
What it means is that while tramadol is an SNRI (serotonin-norepinephrine reuptake inhibitor), its metabolite ODT (also sometimes referred to as “M1”) is an opioid. This, my friends, is the basis of the “dual mechanism of action” claim that has led so many clinicians to drink the tramadol Kool-Aid.
Except the story doesn’t end there. The conversion of tramadol to ODT happens in the liver – obviously. That’s where one of the cytochrome P450 enzymes (CYP2D6) removes a methyl group, magically converting an SNRI (tramadol) into an opioid (ODT).
And this is where tramadol starts falling apart.
Why? Because CYP2D6 activity varies tremendously among individuals and across ethnic groups. Somewhere between 3-10% of Caucasians are “poor metabolizers”, meaning they have no functional CYP2D6. Most exhibit an ‘intermediate” or “extensive” (that is, normal) metabolizer phenotype, while some (2-10% or more, depending on the country of origin) are “ultrarapid metabolizers”.
Check out how CYP2D6 genotype influences ODT after a fixed dose of tramadol. The poor metabolizers (“PMs” in the figure below) generate virtually none.
All this pharmaco-gobbledygook has an important clinical implication: When you give a patient tramadol, you have no idea whether you’re giving an SNRI or an SNRI-opioid combo. In other words, prescribing tramadol is like prescribing venlafaxine and morphine in an unknown ratio. And seriously, why do that?
Let’s step back for a moment and reflect on the goal of drug therapy for pain. When we prescribe an analgesic, the goal isn’t simply pain relief. The goal is to impart more benefit (including analgesia, improved function, improved quality of life) than harm. Sounds obvious, yes? Every time you start a new drug for pain, you’re conducting an experiment on an individual patient, aiming to help more than harm. Into that experiment, tramadol introduces needless pharmacologic unpredictability.
(The same is true, by the way, of codeine, which does nothing until CYP2D6 converts it to morphine. In other words, giving a known dose of codeine is the same as giving an unknown amount of morphine. It’s yet another inherently irrational opioid.)
Can tramadol “work” (meaning help more than harm)? Sometimes. But it seems to me that anyone willing to roll the tramadol dice hasn’t given the drug’s pharmacology quite enough thought.
But wait, there’s more!
As if its unpredictable kinetics weren’t enough, tramadol has plenty of other baggage worth mentioning. In no particular order:
Tramadol seems especially prone to cause seizures, presumably on account of the monoaminergic effects of the parent compound. In this series of patients presenting with a first seizure, tramadol was the leading drug-related cause, with half of patients taking 100 milligrams or less per day. And in this series of 71 tramadol overdoses (many involving coingestants), seizures occurred in 11%.
While tramadol causes seizures and an opioid toxidrome following overdose, it doesn’t seem to cause much in the way of serotonin toxicity. But combined with other serotonergic drugs, it can. The risk of this seems genuinely low, but some reports are quite compelling. To be fair, tramadol is hardly the only opioid associated with serotonin toxicity.
But it’s just one more thing to worry about, particularly given the prevalence of antidepressant use.
Other drug interactions
Imagine your patient is taking 150 milligrams of tramadol a day for chronic pain and is doing well. Then you start bupropion for smoking cessation. Or paroxetine for depression. Or terbinafine for a fungal nail infection. Or maybe celecoxib for ongoing pain. And a few days later, the patient is back in your office complaining of new-onset abdominal pain, diarrhea and insomnia. That’s because these new drugs inhibit CYP2D6 to varying degrees. In a patient on tramadol, they’ll effectively turn off ODT production and precipitate opioid withdrawal (assuming the patient has the genetic good fortune to convert tramadol to ODT in the first place). This phenomenon—turning a CYP2D6 extensive metabolizer (EM) or ultrarapid metabolizer (URM) into a poor metabolizer (PM)—is referred to as phenocopying, and it’s easy to mistake for something else.
I’m not exactly sure why tramadol causes hypoglycemia, but it does, as evidenced by at least one well-designed observational study and several well-documented case reports. Here’s the money shot from one particularly striking report:
In a series of almost 3000 patients, tramadol was associated with hypoglycemia in almost half of patients with DM1, about 17% of patients with DM2, and almost 5% of those without diabetes.
Interestingly, hypoglycemia has also been described with venlafaxine. What’s the mechanism? A quick literature review reveals a lot of hand-waving about increased peripheral glucose uptake and reduced hepatic gluconeogenesis, but honestly I have no idea. The important thing is to be aware of it, especially the next time you encounter refractory seizures in a patient on tramadol.
Dependence, addiction and death
It should come as no surprise that, as an SNRI and sometimes-opioid, tramadol can cause physical dependence. Since pain medicine is about experiments that yield anecdotes, here’s one of mine about a man who cold-called me at my office. He’d been on tramadol for more than a year, after opting for it over Percocet for a shoulder problem (he wanted to avoid opioids). Attempts to self-taper from 150 milligrams per day were met with crippling insomnia. Like countless other people on tramadol, he needed it simply because he’d been taking it. (The denouement? We worked with a compounding pharmacy, dropped his daily dose by 5 milligrams every week, and he took his last dose of tramadol about 6 months later. He tells me he’s never felt better.)
Tramadol addiction is a huge issue in many parts of the world, particularly the Middle East and Africa. If you happen to have access to the Wall Street Journal, this story tells the tale, but the upshot is that tramadol is not subject to the same international controls as, say, morphine. India and China export massive amounts of cheap, generic tramadol around the world. Here’s another story describing the growing popularity of tramadol in Egypt where, as with many other parts of Africa and the Middle East, CYP2D6 activity tends to be on the high side.
Tramadol-related deaths have been on this rise in many parts of the world, and unsurprisingly correlate with prescription volumes in developed countries. It’s worth taking a look at what happened to tramadol utilization and tramadol-related deaths in England and Wales after the government finally classified it as a scheduled drug in 2014:
What’s the Bottom Line?
The bottom line is that tramadol is a weird drug with unpredictable kinetics and a litany of dangerous toxicities and drug interactions.
- Can it sometimes help people with pain? Yes.
- Is it a rational drug to initiate? No.
- Does criticizing tramadol sometimes invite hostility? Yes.
And with that . . . Release the hounds!
Thomas Albers says
Doing some data analysis on our systems opioid prescribing habits. We made some progress on Long Acting Opioids but it looked like we were a little stalled with Short Acting. I ran the overall volumes per drug and noticed a ton of Tramadol prescriptions. Filtered tramadol out of the short acting stats and viola we improve. Our providers our subbing tramadol for other short acting opioids probably because they think its safer because of its MOA and Schedule Class.
Hopefully the stats will help to promote education.
Why does it say TRUMP ? On the box? Am I missing something???
not sure but my guess……. both are described as erratic, dangerous, and generally not advisable
While Bill may not be wrong, it is actually the brand name of tramadol not marketed in the US.
Anony mouse says
Informative, practice changing and an ODB about out – what more could I possibly ask for? Will have to dive deeper into ultram as a hypoglycemic agent for my own personal edification. I got away from the drug some time ago after finding 1) anecdotally many pts don’t like it for either poor analgesia or an ADR, 2) seizure threshold and 3) many more drug drug interactions that alternatives. That being said, if there’s no risk or h/o seizure, no major drug interactions and the pt is doing well on it, I typically don’t have major qualms w continuing it. Keep up the good work.
Matt Voll says
Why the politics?? Scott, you’re better than this, absolutely beneath you. Yes, this is your forum, but what has always been impressive is that you give the data, a little personal perspective, but ultimately let the physician decide. You’ve already committed a cardinal sin in that many readers won’t even read the article and absorb the information, because you’ve tainted it. Don’t be a child. And for references for what I’m referring to read “Thinking Fast and Slow”
Especially since universal healthcare destroys healthcare and kills the poor. Capitalism has always produced the best and cheapest products and healthcare is no different.
Scott Weingart, MD FCCM says
I take no editorial control on any posts except EMCrit-RACC. We are a collection of independent blogs/podcasts each with an independent editorial leadership. That said, that is a real product shot–they didn’t photoshop. Not even a chuckle, not even a little one…
Trump (FM) (Form Not Given) Alkem, Philipp. Philippines 8403827 TRAMADOL -DRUGDEX
The symbol (FM) denotes a preparation which is discontinued or no longer actively marketed.
Hi!! I really laughed a lot with the review. I think it is a great combination of humor and medicine!!
Max Taylor says
Do you know a M. Rubin MD from University of Ottowa School of Medicine? Because when I look at his blog here https://stopioid.com/f/tramadol-or-trama-dont – it really seems like he knows you and follows your work closely. Oddly he isn’t citing your content though…
Ernesto de Bernardis says
I’m just citing this page in an article on synthetic opioids for the Italian Journal of Addictions (MDD) – thank you David!
this might be just what is needed… easy to convert from Tramadont to other pain meds.
You may have a point, but try to be less obnoxious about the way you write it…
Steven Jenkins says
This is interesting. When my late wife was undergoing chemo for uterine papillary serous carcinoma, she was prescribed Tramadol for neuropathic pain in her legs and feet. She took it only PRN and usually only for a day or so at a time. It generally gave immediate relief accompanied by drowsiness. We were grateful for it. Maybe not skeptical enough.
Not trying to play doctor here; maybe the fact that her 5-year survival probability was 10% entered into the decision to prescribe. (She survived 31 months after diagnosis.)
Great article! If someone is intolerant of codeine (i.e. I assume they are an ultrametabolizer), is it more likely that they will also be a tramadol ultrametabolizer?
JIm Farrell says
Intolerant in what fashion… no pain relief because they are a poor metabolizer (no copies of cyp2D6)?
Intolerant because they’re also on paroxetine,or bupropion ( causing a ‘pheno-copying’ response. A responce like that of a poor metabolizer, even though their genotype is normal metabolizer. )
Intolerant because they’re an ultra-rapid or a rapid metabolizer, and they had too much conversion too quickly.
In any of these scenarios a patient may report their experience as intolerance.
Great blog post
Karen E says
Thank you for all of that information.
I knew some dangers of tramadol – but not to the extent that you do, and it’s been great to read.
Now I’m going to sound like a venomous snake but in my opinion this is important. You, like many who take Tramadol, KNOW the side-effects of giving up cold turkey. But there are many being forced to do so because when they swap surgeries, and there is a delay because of registration policies, (IE where I live one must visit the surgery before they can be registered, so if you’re bedbound you’ve got a huge problem which will take the clinical commission is about a month to sort out) and the general medical services refuse to give the tramadol because they cannot find medical records, this is totally wrong..
I’ve come across this quite a few times over the last five or so years, and I seriously think there should be a law to force out-of-hours doctors to write TRAMADOL prescriptions in the emergency services when this sort of situation happens, and if the out-of-hours services are unable to get rid of the patient’s medical records -because somebody somewhere else in NHS hasn’t bothered to do their job correctly – so long as there is something to prove tramadol has been taken before such as the previous months empty boxes or the green receipt that comes with the prescription.
To make it extra secure, maybe there should be a tramadol taker register per city or town, but the patient must be in control, not the doctor, not to. R down to the doctors decision to decide that he or she has the right to stop tramadol just like that so the patients don’t have to go through those horrible evil painful spasmodic side-effects.
Does anybody have any views about this? I even think it should come under human rights laws.
I’ve been on 0-400mg tramadol/day (w/ oral morphine for breakthrough pain) for years. I also take gabapentin, an SNRI and a mood stabiliser, among other things, and sometimes need benzos for spasticity. Occasional mild withdrawal (sweating, itching, slight nausea) when I’ve had to take a lot for a long time with no break, but it’s just a bit annoying for a day or two. Otherwise no probs.
Oh, I did have mild serotonin syndrome twice, but that was because I double-dosed my SNRI by mistake (massive insomnia means it’s hard to keep track of what day it is).
Harrell Guy Graham says
Wall Street Journal article you cite is readable apparently only by subscribing. Here is a link to and an excerpt from another article about Tramadol that is accessible. From the Center For Strategic & International Studies.
“In the Middle East and Africa, the less potent opioid tramadol, not fentanyl, is responsible for the opioid crisis. India is the biggest supplier.
“Tramadol is a less powerful opioid, though more potent if taken orally than injected due to its chemical makeup, and it is not regulated by international conventions nor in many countries. Tramadol is prescribed as a pain medication, but because of tramadol’s stimulant effects, it can allow people to feel high-functioning while taking dangerously high doses. This combination is dangerous: cities with high tramadol abuse have reported increasingly high rates of traffic accidents. In Garoua, Cameroon, hospitals can trace 80 percent of all traffic accidents resulting in hospital visits to tramadol,8 suggesting that at least half of adults in the city use tramadol. To make it even more apparent how dire tramadol addiction has become, hospital staff reported that people waiting for patients outside of the hospital gates would start convulsing, the sign of a tramadol overdose.9 In some countries, tramadol deaths outnumber heroin deaths.”
Tramadol: The Opioid Crisis for the Rest of the World”
The Dangerous Opioid from India | Center for Strategic and International Studies
US Tramadol 100mg says
Jerry Wilxon says
I’ll take my chances. I won’t get into my many illnesses and causes of pain, but the only three or four years of my life that were for the most part liveable and enjoyable, were when I was being prescribed Ultram
That was taken away when hydrocodone was sheduled, and I’ve been in pain and miserable ever since. I’ll find more eventually, and alleviation of suffering can continue
Alexandre Mello says
Very informative reading which will definitely make me think twice before considering prescribing tramadol. My only criticism would be the comment about thalidomide in the beginning of the text. The tragic teratogenicity of the drug should not make us look at it (or the people who have developed it) as evil. In fact, if it wasn’t for thalidomide, anti-angiogenic and immunomodulatory drugs like lenlidomide and pomalidomide would never have seen the light. These molecules have completely changed the landscape for people with multiple myeloma. Thanks to the “German bastards” who gave us thalidomide.