The Corpus Callosum

Rocket Xanax: Fail!

Sometimes  I see news about upcoming drugs, and hope that it
works out.  Sometimes, I don’t see the point.
 Rarely, I actively hope that it does not
work out.
 Staccato® alprazolam is one that I hope does not work out.

It’s a form of alprazolam
that goes in an inhaler.  It is heated by a little electrical
circuit, vaporized, then inhaled.  The idea it to give it a
faster onset of action.


First, a little background.  Alprazolam is a member of the
family.  Benzodiazepines were developed in the late 1950s,
then marketed in the 1960s, intended as safer alternatives to other
sedatives.  Compared to the barbiturates and the like, e.g.
meprobamate, they are a lot safer.  

Alprazolam was developed by Upjohn in the 1970s, finally coming to
market in 1981.  It became used widely for the treatment of
anxiety, particularly .  Upjohn later developed an
extended-release form of the drug, Xanax-XR.  For unclear
reasons, they did not market it.  Several years ago, when
Upjohn became
part of Pfizer, Pfizer went ahead and marketed it.  The patent
expired two years later, so now both alprazolam, and alprazolam-XR, are
available as generics.  

The process of modifying existing drugs and remarketing them, thus
extending the patent, can be controversial.  In the case of
Xanax-XR, though, the new product really was helpful.

Now, along comes Alexza, with yet
alprazolam product.  
Is there
any clinical  rationale for this?


The product under development is called AZ-002, or Staccato®
Alprazolam.  Staccato is the name that Alexza uses to describe
the device.  The device is described in some detail on the
company website, here.

There are four other drugs that they are testing in the device,
including fentanyl, prochlorperazine, loxapine, and zaleplon.

They have suspended their development efforts on the fentanyl product,
which had been intended to be used for pain.  Development is
ongoing for the others.

The (Duragsic®) product strikes me
as a bad idea.  Although it probably is safe for persons who
are opioid tolerant, it probably would pose a substantial risk for
anyone else.  In fact, it likely would be fatal for the
uninitiated, especially children.  The little inhalers are
cute.  Bad idea.

The (Compazine®) product is
a good idea.  We will see if it works out.  We could
use another option for persons with migraine.  Might also be
an OK option for nausea.  I could see a use for this in chemo
patients, for example, who don’t want yet another

The (Loxitane®) product is weird.
 At first glance, it seems like a fair idea.  But the
times it would really be useful, are the times when someone is
uncooperative.  If someone is uncooperative, why would they
use an inhaler?  If they are willing to cooperate, just give
them a liquid concentrate, or an orally disintegrating tablet.
 We already lots of those.  So I don’t see what the
inhaler is good for.

(Sonata®) product is intended to treat insomnia.  OK, fine,
whatever; we have lots of products for insomnia, and I am not sure we
need another one.  I guess the idea is to put someone to sleep
fast.  Perhaps a few people could benefit, but I doubt it
would make sense to do this often, or for very many people.
 Some people do have really nasty, treatment refractory,
insomnia.  But if it only happens every once in a while, it is
not a huge clinical problem.  If is is chronic, I doubt the
product would be effective for very long.  Final judgment will
have to await the results of the studies.

That brings us to Staccato® Alprazolam.  Perhaps, at
first glance, it seems reasonable.  People do have panic
attacks.  They are terrible.  They want them to go
away as fast as possible.  What Rocket Xanax is supposed to
do, it get the drug to the brain as quickly as possible, increase the
brain concentration as steeply as possible, and make the panic go away

There are only two problems.  For one, it is a bad idea.
 Two, there is no evidence that it works.

Announces Preliminary Results From its AZ-002 (Staccato(R)
Alprazolam) Phase 2a Proof-of-Concept Trial in Patients With Panic

By: iStockAnalyst  
Monday, June 09, 2008

MOUNTAIN VIEW, Calif., June 9 /PRNewswire-FirstCall/ — Alexza
Pharmaceuticals, Inc. (Nasdaq: ALXA) announced today preliminary
results from its Phase 2a proof-of-concept clinical trial with AZ-002
(Staccato(R) alprazolam) in patients with panic disorder. The study did
not meet its two primary endpoints, which were the effect of AZ-002 on
the incidence of adoxapram-induced panic attack and the effect of
AZ-002 on the duration of adoxapram-induced panic attack, both as
compared with placebo. There were no serious adverse events in the
clinical trial, and AZ-002 was safe and well tolerated in the study
patient population. AZ-002 is being developed through Symphony Allegro,
a development collaboration formed between Alexza and Symphony Capital
LLC in 2006.

Sure, that does not prove that it does not work, but it is hardly a
resounding success.  There is room for hope, as panic induced
(there is no such thing as adoxapram) are not the same as panic attacks
that occur naturally.  I suspect that Staccato Alprazolam
would work better panic attacks that occur naturally, but the results
and the early (phase 2a) study can doubt on the notion that this will
be a remarkable — or even significant — advance.

If it does turn out to work as intended, though, what would be an
appropriate use for this product?  

Usually, when people have panic disorder, the most important thing to
do, therapeutically, is to help them attain some degree of acceptance.
 That is, to get them to refocus, away from their natural
inclination to try to stop the panic as quickly as possible.
 Instead, what is most helpful is to have the people learn to
focus on minimizing the disruption to their lives.  

There are three elements to panic disorder: the panic attacks
themselves, what is called anticipatory anxiety, and a set of avoidance
behaviors that develop as a result of the panic and anticipatory
anxiety.  The anticipatory anxiety and the avoidance behavior
are the elements that lead to the greatest disruption of the person’s
life, even if they are less dramatic symptoms.

When people have panic attacks, what they want is for the panic to
simply go away and never come back. Sometimes, that is possible, with
medication, psychotherapy, or both.  But often it is not.

Often, medication and/or psychotherapy will reduce the frequency and/or
intensity of the attacks.  That can be extremely helpful.
 Sometimes it is sufficient.  

But most people have panic attacks for years before they come for
treatment.  By then, most have developed anticipatory anxiety
and avoidance behaviors.  Those can be addressed in
psychotherapy, often with decent results.  However, in
psychotherapy, it generally is best to not focus on making the panic go
away.  In fact, such a focus can be countertherapeutic.
 (understanding, of course, that everyone is different; what
is countertherapeutic for one person might be helpful to another.)

So from a psychotherapeutic standpoint, what would be the effect of the
availability of a drug that it hyped as something that can zap panic
almost instantly?  First, the majority of people will want to
try it.  They will be upset if you don’t give them a chance to
try it.  It will erode the therapeutic alliance, which is the
therapist’s most important tool.  

Second, even if it does work for the panic, that will leave the
anticipatory anxiety and the avoidance behavior unaddressed.
 You could address those problems in therapy, but it will be
much harder to take the focus away from the less-productive — but
highly alluring — goal of stopping the panic instantly.  

Again, some people might find the product useful, and not find it to be
counterproductive in away way.  But others will actually have
their progress delayed by the product.  Although it is
impossible to predict what proportion would be helped vs. hurt, I would
guess that more people would be hurt than helped.

If I were on an FDA panel reviewing this product, I would insist on
seeing long-term studies that assess all three elements of the problem:
panic, anticipatory anxiety, and avoidance behavior.  I would
want to see the company enlists a study population that had problems
with all three, and I would want to see what the outcome is, in all
three areas.  

What worries me, is that the language in the company press releases is
all about the acute treatment of individual panic attacks.
 That simply fails to address the most important part of the
problem.  The whole point of treatment is to improve the
person’s life.  If you treat only one element of the problem,
you run the risk of getting something that looks good on paper, but is
useless in clinical practice.  Even more disconcerting, you
run the risk of something that looks as though it helps (in the short
term) but makes things worse in the long run.


  1. #1 TheNerd
    June 23, 2008

    I have had panic attacks, and I can understand the desire for a “fix it” pill. But after reading up about it, it is quite clear to me why that wouldn’t work. I think doctors need to be do their best to avoid offering “fix it” pills. Education is the first step to an improved condition of living.

  2. #2 marjan benedetic
    June 24, 2008


    I think that the main question here is: will it be fun?

    I know someone shouldn’t think about the recreational potential of a legal drug that is intended for sick people, but still, I can not help and wonder…

    Think oxycontin!

    love, m

  3. #3 fearfactor
    June 24, 2008

    I am sorry, CC, but I do not agree with you about the effectiveness of this drug for panic. As a current sufferer, I will tell you that all I want is a drug that can stop these horrid attacks on my nervous system dead in their tracks. I truly believe that if they were stopped, my avoidance would be nada. The fear of the dizziness, sweating, heart rate increases and other symptoms are the major contributors to the avoidance aspect of this disease. If they could be curtailed, then I would be happy to shoot myself in the lungs every so often while I go about my business. Thus far, cognitive behavioral therapy has not made a dent in my ability to withstand this autonomic unpleasantness; therapeutic alliance or no. The facts are, for me at least, that a drug like this would work wonders– provided the effects would not knock me off my feet. The major problems with the benzo group is that the sedation is too high a price to pay for relief. Relief that comes in the form of instant gratification sounds much better if it does not zonk me out for the rest of the day. Plus, the added benefit of having a method of control that actually works, unlike relaxing, fighting, accepting, or whatever CBT method you choose, is another reason that this drug would be a major improvement on my miserable life.

  4. #4 scicurious
    June 27, 2008

    I have to say that putting a benzodiazepine in an inhaler is no more of a good idea than putting an opioid in an inhaler. Benzodiazepines are addictive (thought not perhaps as bad as opioids), and route of administration can be a very big factor in how addictive a form of a drug is (as with oral vs snorted methylphenidate). Also, because benzodiazepines are physically addictive, they have withdrawal side effects, and those could be worse if you’re taking small fast shots of drug as opposed to a long acting low dose.

  5. #5 Dirk Hanson
    June 27, 2008

    With a time of onset in pill form on the average of an hour or so for Xanax, I’m also not convinced that in MOST cases a “Speedy Alka-Seltzer” version is the answer to any particular felt need. Plus, as mentioned above: Short, sharp, frequent intakes of an addictive drug can be asking for trouble–consider the machine-rolled cigarette.

  6. #6 robert burke
    February 16, 2010

    i think everyone here is missing the big idea, were not here to discuss how addictive something is, people in pain will have painkillers and people with severe anxiety will have benzos, whether there addictive or not is not the question, its how fast can the drug be administered, to effectivly treat the patient, i personally think once it is kept safe, the fentanyl inhaler idea is a master-stroke, as nearly all patients have a very uncomfortable waiting time, while they wait for there drugs to kick in through other methods. it has my full support. an excellant idea!

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