Newsgroups: sci.med.pharmacy
Subject: Re: Talwin/NX
From: dyer@spdcc.com (Steve Dyer)
Date: Mon, 16 Apr 2001 05:37:46 GMT

In article <3iEB6.2090$Fh.56041@nnrp1.ptd.net>,
Aimee G <pharmacist@iwon.com> wrote:
>Addictive enough that they have to formulate it as Talwin + NX...
>"Saturn123ABC" <saturn123abc@aol.com> wrote in message
>news:20010412212551.09766.00001672@ng-cc1.aol.com...
>> How effective is this med for pain? How addictive is it?

That was probably too short an answer by Aimee, who would otherwise
have to bill your insurance company for "value-added cognitive services". :-)

Pentazocine (Talwin) itself is an interesting drug.  It was synthesized in the
early 1960's by the late medicinal chemist Sydney Archer of Winthrop Labs
(now Sanofi) and a professsor of medicinal chemistry at RPI, in a somewhat
quixotic attempt to develop morphine-like pain relievers that lacked addiction
and abuse liability.  It tooks them about a decade to realize that that wasn't
quite what they'd created.

This was based on the early observations of the pharmacological effects of a
slight molecular modification of morphine (N-allyl-normorphine, or nalorphine).
Nalorphine was the first "narcotic antagonist":  if a laboratory rat or a
patient were given too high a dose of morphine and stopped breathing, an
injection of nalorphine would completely reverse the effects of the morphine:
respiration rate went back to normal, their activity/alertness returned to
normal, and the pain relief went away as well.  Also, if the animal or
person had already become physically dependent on morphine or another related
opiate, an injection of nalorphine would immediately precipitate an unusually
intense opiate withdrawal syndrome.

Did nalorphine relieve pain when given alone?  Sure enough, it did, and
just about as well as morphine.  But people who were given it really
didn't like they way it made them feel: especially as the dose was
increased, they became more and more nervous, and "felt creepy". If you
gave people the drug long enough at high enough doses, they could become
physically dependent on it, but no one ever liked the drug enough to keep
taking it, even if it meant going through a withdrawal syndrome after
stopping it.

The nature and degree of the withdrawal syndrome was also somewhat
different and milder than what you'd see with morphine, and the affected
individuals rarely asked for more nalorphine to make them feel better.
To drug researchers, these qualities seemed to move them  closer to a
"better" morphine: one that could stop pain, but that people wouldn't
want to take if they weren't in pain.  However, nalorphine itself, when
it was given alone as a pain killer, seemed to cause too many unpleasant
reactions in the people given it.

No one really understood very much about why morphine and nalorphine behaved
this way; that would have to wait until the mid 1970's with the discovery of
opiate receptors, and well past that into the 1980's thru today.

However, Archer was experimenting with variants of the basic morphine skeleton
known as benzomorphans, and had in fact, developed several useful synthetic
morphine-like drugs.  He developed one drug, cyclazocine, which was the
N-cyclopropyl-methyl benzomorphan analog of morphine.  Cyclazocine was also an
opiate antagonist, had the advantage of being orally active, also had analgesic
properties, and blocked the effects of other opiates administered at the same
time.  (Which might have suggested its regular administration to post-addicts
to prevent the effects of opiates having any effect.)  Unfortunately, like
nalorphine, cyclazocine also proved to cause too many unpleasant psychological
effects in people--people simply would not take it voluntarily.

The N-(2,2-dimethyl-allyl) congener of cyclazocine, pentazocine,
was the first really useful example of an opioid drug then called an
"agonist/antagonist".  Pentazocine appeared to act as an opiate
antagonist, though it wasn't as potent as nalorphine in this regard;
in fact, it would precipitate a withdrawal syndrome in people already
physically dependent on morphine.  It had decent analgesic actions,
and didn't quite seem to cause the same degree of euphoria that the
existing opiates did.  At very high doses, it sometimes caused the
same feelings of "craziness" and "nervousness" reported with nalorphine
and cyclazocine, but not usually at more typical doses.  Furthermore,
it was reported that people really didn't like the drug all that much
to become addicted, and that withdrawal, on those rare times someone
became physically dependent on the drug, was rather mild.

With those somewhat rose-colored test tubes, pentazocine was released as
an injectable liquid for IV, IM and SC administration; 30mg was roughly
the equivalent to 10mg of morphine. It was also released as an oral tablet,
which was much less potent and powerful due to first-pass metabolism in the
liver: 50mg was roughly equivalent to 60mg of codeine.  Initially, neither
was a controlled substance when it was first marketed in the US; only a
prescription drug.

Although pentazocine has pharmacological qualities that make it unlikely
to be an established opiate addict's drug of choice, there were to become
a large number of pentazocine users who were not addicted to opiates at
the time they were prescribed this drug, but who came to appreciate pent-
azocine's qualities despite its aforementioned drawbacks.  Also, unlike
in the 80's and later when injectable preparations were largely found only
in hospitals, there was quite a bit of outpatient prescribing of this
"non-addictive" analgesic for self-injection by people suffering from
chronic pain. Unfortunately for them, it turned out that pentazocine
lactate is extremely irritating, and when injected into the same general
areas chronically, can cause fibrosis and scarring of the skin and
underlying tissue.

The oral form of pentazocine wasn't all that impressive a pain reliever or a
drug of abuse.  However, it gained notoriety in Europe among street addicts by
dissolving the tablet:  talc, other excipients as well as a small amount of
drug, in water, and then injecting _THAT_ mixture IV <shudder>.  It became even
more popular as part of a combination of tablets disssolved in water and the
sludge injected called "T's and Blue's":  consisting of the Talwin tablet and a
blue tablet of the CIBA antihistamine PBZ, or tripelennamine.  This was supposed
to give the mixture much more of a "kick", although there's no reason why I
would expect this to be so, unless you like the way any antihistamine makes you
drowsy.

Eventually, both oral and injectable forms of pentazocine were classified
as C-IV controlled substanced with the DEA.  And to stem the diversion of
Talwin tablets for IV injection, a small amount of naloxone 0.4mg was added
to the tablet (hence, "Talwin Nx").  Naloxone is a newer opiate antagoonist
than nalorphine: it's considered more "pure" because it has no obvious effects
of its own except to block the effects of any opiate drugs given at the same
time or shortly before.  It can also precipitate a violent withdrawal syndrome
in anyone dependent on an opiate.  However, it's not absorbed to any appreciable
extent when taken by mouth at a dose of 0.4mg.  So, the tablets are still
somewhat useful for treating mild/moderate pain such as might be treated
with codeine or, perhaps Darvon (propoxyphene), and their abuse potential
is roughly about the same.

Nowadays, many of these "agonist/antagonist" drugs are thought to
work by acting as antagonists (or only partial agonists) at the
"mu opiate" receptor (the one most often associated with traditional
opiates' analgesic and respiratory depressant effects and the development
of tolerance to same), while acting as agonists at the "kappa opiate"
receptor, which are also involved in analgesia and respiratory depression,
but often have a "ceiling" effect beyond which they don't increase
their effects.  So, for the severest forms of pain, such as you might see
in late states of terminal cancer, they are less popular than more
traditional opiates.





--
Steve Dyer
dyer@ursa-major.spdcc.com

Newsgroups: sci.med.pharmacy
Subject: Re: Talwin/NX
From: dyer@spdcc.com (Steve Dyer)
Date: Mon, 16 Apr 2001 23:51:03 GMT

In article <KlDC6.5720$cC2.1823180@news1.elmhst1.il.home.com>,
rxempress <rxempress@home.com> wrote:
>Still waiting for ultram nx

I'd be interested in your impressions as a pharmacist as to whether
you think there's much illicit _IV_ abuse of oral tramadol (as opposed
to abuse or diversion of the prescribed drug, taken orally.)

One of the explanations for tramadol's supposed low abuse liability
is that the parent compound has virtually no affinity for mu-receptors.
Injecting it intravenously sort of misses the point of intravenous
drug abuse--high levels of active drug hitting the brain all at once.
since tramadol has to be metabolized first to a more potent opioid.

So you then have to ask what's gained by this method of administration
(other than an ever better chance of seizures.)  Tramadol does come in
parenteral dosage forms outside the USA, though that always struck me
as kind of strange.

--
Steve Dyer
dyer@ursa-major.spdcc.com