The Corpus Callosum

FDA Approves Tapentadol


is a drug for pain.  It was approved by the US FDA for the
treatment of moderate to severe pain.  The FDA
news release
was dated 24 November 2008, although the actual
approval was a few days earlier.

Tapentadol acts on μ-opioid receptors, making it similar to
and its ilk.  Do we need another opioid agonist?  And
if so,
why?  Suspicions deepen because it was produced by the same
company that makes tramadol.  Indeed, it is similar to
tramadol in
many ways.  Tramadol is the active ingredient in
Ultram®, now
available as a generic.  This is sounding like a familiar
drug story.  

On the other hand, chronic pain is a common

pain prevalence estimates were
10.1% for back pain, 7.1% for pain in the legs/feet, 4.1% for pain in
the arms/hands, and 3.5% for headache. Chronic regional and widespread
pain were reported by 11.0% and 3.6% of respondents, respectively.

Existing treatments often are not satisfactory.  With opioid
medications, there is risk of psychological dependence and various
kinds of diversion and misuse.  People put it in their noses
veins and things like that.  Perhaps more importantly, though,
the fact that some people develop adverse effects at the doses required
to achieve adequate pain control.  

So what makes tapentadol different?  

Much of the information presented here comes from this article:

Hydrochloride (Tapentadol HCl): a Novel µ-Opioid Receptor
Agonist/Norepinephrine Reuptake Inhibitor with Broad-Spectrum Analgesic

First, let’s look at tramadol.  Tramadol is an agonist for
μ-opioid receptors, but it also inhibits reuptake of serotonin
norepinephrine (monoamines).  It appears that the effect on
monoamines is something that is important for the analgesic effect of
tramadol.  After all, tramadol is a rather weak agonist of
opioid receptors.  

Tramadol, however, has several problems.  The weakness of its
effect on opioid receptors means that it would not be expected to have
a robust effect on acute pain.  The fact that tramadol depends
upon the monoamine effect for its action, means that it often works
better for chronic pain.  (Note that the use of weasel words,
e.g. “expected,” “often” is intentional; it reflects the fact that
different people respond differently.)

Furthermore, tramadol by itself is not very effective unless some of it
is metabolized to O-desmethyl-tramadol.
 This requires an enzyme, cytochrome P450 2D6 (CYP2D6).
 Persons who are relatively deficient in CYP2D6 activity, or
who are also taking a drug that blocks CYP2D6, may not get the full

Lastly, tramadol is a racemic mixture; that is, it comes in left- and
right-handed versions.  The actions of the two versions are
different, and the actions of the two versions of the metabolite are
different.  This is not necessarily a problem, but it is a
complicating factor.

With the understand on tramadol, we now can take a look at tapentadol
to see if it offers any meaningful advantage.

The key differences are: tapentadol has a stronger effect on the
reuptake of norepinephrine than serotonin, it does not depend on CYP2D6
activity, and it is not a racemic mixture.  All of these
factors are advantageous, at least theoretically.  Based upon
these findings, one would expect that tapentadol would be less prone to
cause adverse effects, and that it would be much less likely to be
involved in drug interactions.  Premarketing
are encouraging, though.

Additionally, tapentadol is more
than tramadol at the μ-opioid
receptor, but less potent than morphine.  Note, however, that
higher potency does not necessarily translate into higher clinical

I tend to think that the advantages are great enough to justify the
development of tapentadol for the market.  There are so
caveats, however.  It is not possible to make any firm
assessment of a risks of a drug, prior to its release into the wider
market.  That is, the basic pharmacology suggests that most
patients will be less likely to have adverse effects, but this remains
to be seen.  

Also, as is the case with any opioid agonist, the potential for
diversion and abuse cannot be assessed fully.  There are
examples of drugs that were thought to present a minimal risk of abuse,
prior to being released into the wild, but for which that turned out
not to be the case.  Talwin, Stadol, and of course Oxycontin,
come to mind in this respect.  Iwould be very cautious about
making any assumptions about the potential for diversion and abuse with
tapentadol.  In fact, the DEA has yet to assign the drug into
one of its schedules.

As for what I think of tapentadol, I suspect that it will turn out to
be useful, but not a blockbuster.  If the safety profile is
significantly better than that for tramadol, it may be possible to use
it at higher doses, which might translate into greater clinical

I do have two big questions, though.  One: is this drug really
any better than a combination of a medium-strength opioid, say
hydrocodone, along with a norepinephrine reuptake inhibitor, say
nortriptyline?  Both are pretty inexpensive, so for the
tapentadol to have a rational place in our pharmacopoeia, it would have
to have some benefit that cannot be gotten for less money.
 (Not that markets are always rational, but still…)

Two: what it is potential for lowering the seizure threshold?
 Tramadol does this.  It usually is not an issue
unless a person takes a great deal more than what was prescribed, or it
there is a drug interaction.  The drug interaction should not
be a problem with tapentadol, but we can assume that many persons will
take doses that are larger than prescribed.  Tapentadol
presumably will come with a warning about that, but that won’t stop
many people.  Note that I do not consider this a reason to
keep the drug off the market, but I do think that clinicians should
keep the possibility in mind.
Disclosure: I don’t own any pharmaceutical stocks (not directly,
anyway; I probably have some small bit in a mutual fund somewhere), nor
do I work for any company that has anything to do with any of the
products mentioned.  


  1. #1 Daniel Newby
    December 8, 2008

    Interesting. This is definitely not a me too drug. It’s a modified phenethylamine, in the same family as amphetamine, methyphenidate, bupropion, and friends. It may very well have effects on dopamine release, serotonin receptors, the sigma receptor, etc. that give unique advantages w.r.t. other painkillers. I just hope they had the sense to screen it for psychedelic and fibrotic effects, or their party could be over real quick.

    “One: is this drug really any better than a combination of a medium-strength opioid, say hydrocodone, along with a norepinephrine reuptake inhibitor, say nortriptyline?”

    Nortriptyline does have significant antimuscarinic (constipation) and antihistaminic (weight gain) effects. Neither of those are likely to be welcomed by a chronic pain patient. Does anybody ever use atomoxetine or classical stimulants for pain?

  2. #2 Joseph j7uy5
    December 10, 2008

    It would make sense to try to use atomexetine or reboxetine adjuctively for pain control, but the leterature is very sparse. The rationale for adding nortriptyline is that it is reasonably well-established and it is inexpensive. Part of what makes a drug a “me too” drug is the idea that the newer drug has no advantages in terms of cost-effectivness.

    There are papers on the adjuctive use of methylphenidate for pain. People do use it from time to time. It is not an FDA approved use, and sometimes the insurance companies balk, but it is a strategy worth considering in selected situations.

    While nortriptyline does have the potential adverse effects that you mention, in practice they are not always significant. It all depends on what dose is required to achieve the desired effect of pain relief. Often that can be achieved at doses much lower than the doses used for treatment of depression.

  3. #3 Neal Cohen
    December 27, 2008

    A discussion of seizure threshold is outside my realm of knowledge. However, I want to contribute a few words to the, “…is this better…” question. In particular, I want to introduce the patient’s perspective into the dialogue. This perspective introduces some important variables such as patient literacy, expectancy and medication compliance.

    In regards to patient literacy, patients often experience increased concern/anxiety when they discover that their prescribed medication is not “indicated” for their problem. The forums on patient oriented sites routinely field questions such as, “Why is my doctor prescribing an anti-depressant? I’m not depressed. I am in pain.”

    In regards to expectancy, a patient who shows inadequate pain relief on an older medication may benefit from expectancy/hope when prescribed the “latest and greatest” medication for their problem (notable is that insurance may pay for a trial of new medication if there are failed trials of first-line medication).

    In regards to compliance, clinical experience suggests that “keeping it simple” facilitates most pharmacological interventions and reduces the chance for error.

  4. #4 Diane
    December 28, 2008

    Thanks for this article.
    Just found your blog and find it so interesting and wel researched and written.

    This article especially since I have been taking MSContin for the last 9 years. I have found it to be a lifesaver as I can get out of bed and move!!! I was only 45 when I became disabled and in chronic pain.
    It’s great to know they are working on new pain meds and taking chronic pain seriously.

  5. #5 S. Dyer
    January 1, 2009

    Perhaps tapentadol is more of a “me too” drug than you imagined.

    Its chemical structure and pharmacological activity of tapentadol is somewhat reminiscent of lefetamine, aka SPA, tradename Santenol. Lefetamine is the levo isomer of N,N-dimethyl alpha-phenyl phenethylamine; that is, an amphetamine analogue with an alpha-phenyl ring in place of the alpha-methyl group of amphetamine. It’s claimed to have central stimulant effects similar to amphetamine or methylphenidate, but with an affinity for opiate receptors as well. As far as I can tell, this drug is primarily an obscure curiosity, but has been marketed in Japan and Italy, where it has some reputation as a drug of abuse.

  6. #6 S. Bednar
    January 30, 2009

    The question of whether or not we need another opiate agonist is not really applicable to tapentadol in my opinion because tapentadol isnt just another opiate agonist. This is part of a new series of opiate agonists that has extra features: it is an opiate agonist and an antidepressant. My doctor is considering putting me on this medication once it is available not because its a painkiller but because it might be able to limit the amount of medications I, along with many other chronic pain sufferers, have to take. The function as an NRI make it theoretically possible to eliminate the antidepressant for patients who suffer from pain and depression. Plus its function as an NRI might limit its abuse potential because it is has a more complex function in the body so if, as it becomes widely used and known, this is included in its information I doubt it will become as widely abused or known by drug abusers as drugs like hydrocodone and oxycodone are now. I personally hope the DEA approves it as somewhere in schedules III-V because its medical use would be underutilized and less widespread if it ends up schedule II. And of course in schedule I it might as well not even exist because thats pretty much a death sentence for a medicine god I hate the war on drugs

  7. #7 Otto Wolke
    February 26, 2009

    Like your review and your understanding of pain treatment. If u do not mind I am going to take it to an advisory Bd which is focused on Tapentadol. Otto

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