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
why? Suspicions deepen because it was produced by the same
company that makes tramadol. Indeed, it is similar to
many ways. Tramadol is the active ingredient in
available as a generic. This is sounding like a familiar
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
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
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
data are encouraging, though.
Additionally, tapentadol is more
potent 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