The Corpus Callosum

First, a little background.  Alprazolam is a member of the benzodiazepine 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 panic disorder.  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 another 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 fentanyl (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 prochlorperazine (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 injection.

The loxapine (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.

The zalepon (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 fast.

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

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