anon schreef:
> This is not a scientific study of a controlled population sample--it is
more
> anecdotal evidence from one physician who overprescribes benzos--
Gotcha! You only read the first text which is an interview (I *knew*
this was going to happen, it's not the first time). You effectively fell
into your own trap.
of which
> there are, alas, far too many. In fact, Big Pharma has so corrupted the
> psychiatric profession in this country that SSRIs get handed out like
candy
> even though carefully vetted studies show that that most of them are no
more
> effective than--or only marginally more effective than--placebos.
The jury is still out on this, there are conflicting studies out there.
I totally agree that SRRI's are vastly overprescribed, as I said
earlier, and often at the expense of those lovely benzo's (which
actually were overprescribed in the seventies as well which gave them
their bad reputation instead of the doctors who prescribed them at
random without even a proper dagnosis). Nowadays Big Pharma has been
hyping up SSRI's just like benzos were hyped up thirty years ago so what
else is new? When properly prescribed after a serious diagnosis has been
established there is a place for both benzos and SSRI's etc. in the
treatment of Panic Disorder. As im****tant, if not more, is to find a
good CBT or REBT-therapist; the results of CBT etc. are at least as good
if not better than those of medication and often it makes sense to
combine them, at least for a period of time.
>
> The do***entation of the powerfully addictive properties of benzos is
vast,
> along with an equally vast literature demonstrating the potentially
> life-damaging side effects that can come with long-term use, including
> short-term memory loss, cognitive deficits, depression, and horrific
rebound
> anxiety and rebound insomnia during attempted withdrawal.
See the literature I posted and you refused to read.
>
> For a survey of the vast scientific literature on the horrors of benzo
> addiction withdrawal, see the references at the end of the following:
>
> http://en.wikipedia.org/wiki/Benzodiazepine_withdrawal
> All of those listings constitute SCIENTIFIC LITERATURE, not the
comforting
> anecdotal bedtime stories proferred by this self-serving, ethically
> irresponsible megalomaniac, who universalizes from his microscopic
corner of
> the universe.
Do you really think Wikipedia is *scientific*? It's totally unreliable
information brought together by whoever feels like it. In this case
Wikipedia's stance on benzos reflects the UK *Anti Benzo Squad*'s. It's
worth less than nothing.
I universalized nothing from my own personal experience, on the contrary
I presented a lot of *scientific* literature and opinions by leading
psychiatrists which you decided not to read. Maybe you could try again.
Oh, I was out of this thread.
Had to come back one more time to make it clear that I sent dozens of
peer reviewed studies accompaniet by a lot of anecdotal information and
the only thing you did is read the first entry.
Or you chose to ignore the rest because it doesn't help your agenda.
Philip (don't know why I joined this thread after years of bickering
with the anti benzo boys, but hey, I'm out of it -again ;-)
>
> "Philip Peters" <philip@[EMAIL PROTECTED]
> wrote in message
> news:4852fcbe$0$14344$e4fe514c@[EMAIL PROTECTED]
>> anon schreef:
>>> "Some" this, "some" that--all without any do***entation
>>> but with a lot of
>>> ad hominem sneering and name calling (the Anti-Benzo Squad), as though
>>> that compensates for do***entation and rational argument. This
poster's
>>> message consists entirely of personal testimony and anecdotal
>>> evidence--it's pure garbage. I've already posted the relevant
scientific
>>> do***entation from a variety of sources, none of which this snide
smear
>>> artist has bothered to try to refute.
>>
>> See below.
>>
>>
>> The point is--proceed
>>> with caution, and try to use them only on a spot or short-term basis
>>> unless a trusted doctor absolutely feels you must rely on them for a
>>> longer period.
>>
>> Now here we agree. Never self-medicate, always have meds prescribed by
a
>> trusted doctor.
>> And with this little bouquet of quotations below I gracefully bow out
of
>> this thread on to greener pastures and let everyone judge the matter
for
>> themselves. Enjoy!
>>
>> Philip
>>
>> ---------------------------------------------------------
>>
>>
>> A Conversation With a Colleague
>>
>> from Medscape General Medicine
>> http://www.medscape.com/viewarticle/457797?src=search
>>
>> Thomas A. M. Kramer, MD
>>
>>
>> The following is dialogue with a colleague who is a child psychiatrist
>> and who has recently expanded her practice to treat more adults.
>>
>> Dr K: When do you actually use benzodiazepines to treat anxiety? I
>> mean, how many other drugs will the patient actually have to fail
>> before you would prescribe them?
>>
>> Dr. F: Well, sometimes none. A lot of the time, I would use them right
>> away. First-line.
>>
>> Dr K: Really?
>>
>> Dr. F: Sure. It wasn't that long ago that benzos were used routinely
>> as first-line treatment for generalized anxiety. It's only fairly
>> recently that they've been supplanted by SSRIs and SNRIs.
>>
>> Dr K: And aren't those drugs better? Don't benzos tend to make
>> patients sleepy, stupid, and addicted? I mean, not using benzos as
>> first-line treatment is a step forward, right?
>>
>> Dr F: Certainly, SSRIs and SNRIs are im****tant treatment options. But
>> benzos have their virtues, too. They work right away; antidepressants
>> in general take a few weeks to work. When dosed appropriately, they
>> don't make people sleepy or stupid. As far as addiction goes, that's
>> pretty controversial, but my feeling is that the risk of addiction for
>> benzos is grossly overstated. Certainly, in a vulnerable population,
>> like people with substance abuse history or strong family histories of
>> substance abuse, tolerance and dependence can be a problem. But that
>> is a very small percentage of patients who present for treatment for
>> anxiety. I've seen a lot of patients who have taken 10 mg a day of
>> Valium for years with good result. They don't escalate the dose, and
>> if they try to come off it or miss a few doses, all that happens is
>> that they get anxious again. Benzos don't really have very many side
>> effects besides the ones you mentioned, and since antidepressants have
>> side effects of their own, there are some patients who can tolerate
>> benzos who cannot tolerate antidepressants.
>>
>> Dr K: So why don't we use them any more?
>>
>> Dr F: I do. But the sense I get, in what little adult work I do, is
>> that they have really fallen out of favor.
>>
>> Dr K: You're right, but I don't think that's for good reason. I think
>> that's basically a function of marketing.
>>
>> Dr F: You mean, drug companies are trying to get us to write for their
>> SSRIs and SNRIs for anxiety as opposed to benzos?
>>
>> Dr K: Exactly. The other side of that coin is that nobody is marketing
>> benzos at the moment. That may change soon with the launch and
>> subsequent marketing of rapidly dissolving Klonopin and Xanax XR, but
>> for the time being, all of the marketing efforts of the pharmas for
>> anxiety treatments are focused on antidepressants.
>>
>> Dr F: So you are saying that we all are really controlled by the
>> pharmaceutical industry? That their marketing efforts really do
>> control our behavior?
>>
>> Dr K: Well, no. I do think that at least some of us are capable of
>> independent thought. The problem, I think, has more to do with sources
>> of information. So much research and educational programming is funded
>> by pharmas that they have an enormous amount of influence over what is
>> defined as the state of the art. While they may not have direct
>> control over the results of published research, or the content of
>> educational programs at meetings, or the information that is sent to
>> us in the mail, they have enough influence to determine a lot of what
>> it is you are going to see when you go to "read the literature." You
>> end up thinking that the treatments for which they choose to fund
>> research and programs are indeed the state of the art. After all, you
>> read all of these advantages of these new treatments. No one's putting
>> material in front of you telling you about the advantages of the older
>> treatments.
>>
>> Dr F: And no one is funding head-to-head studies between the new and
>> the old treatments, either.
>>
>> Dr K: Exactly. Why should they? The only people who fund clinical
>> trials these days are pharmas -- although that has changed a little
>> bit with some new NIMH studies that are actually comparing different
>> treatments without any pharma funding -- and pharmas are certainly not
>> going to fund such a study because it may not look so good for them.
>> Look, I have nothing against marketing. I think that the pharma
>> industry, like any other industry, is entitled to promote its
>> products. I am also sympathetic to the fact that is not easy for them
>> to do this. It is hard to get the attention of busy physicians. My
>> concern is that some things are marketing that aren't labeled as such.
>> I am tired of hearing the words "unrestricted educational grant."
>> There ain't no such animal. Simply deciding what it is you're going to
>> fund with such an unrestricted educational grant gives you a fair
>> amount of discretion as to what clinicians will hear about and know.
>> And as far as research is concerned, it seems to me that the results
>> of studies sponsored by pharmas seem to almost always be good news for
>> the company actually doing the sponsoring. I'm not saying that they
>> manipulate the data, but I am saying that they have a fair amount of
>> control over what data you see and what data never sees the light of
>> day.
>>
>> Dr F: I can see a little bit of this happening now with ADHD
>> treatments. While stimulants can have bad side effects, particularly
>> weight loss and insomnia, they do work for most kids, and as we start
>> to get alternatives to stimulant medications for ADHD, some materials
>> and programs I've seen are starting to imply that stimulants may
>> become obsolete. Immediate-release stimulants are a very good example
>> of what you're talking about. They're treated in current discussion as
>> if they're obsolete, but they can have a great deal of clinical
>> utility, particularly as augmenting medications.
>>
>> Dr K: I think the best example of this phenomenon is lithium. Lithium
>> is a fabulous drug. Unfortunately, nobody is marketing it presently,
>> and there's a lot of aggressive marketing of other medications for
>> bipolar disorder. As a result, I think a lot of clinicians are
>> becoming convinced that lithium is an inferior drug. There have even
>> been a few papers written by old-timer psychopharmacologists defending
>> lithium as a treatment of choice, particularly for classic, nonrapid
>> cycling bipolar I disorder. I have even seen things written saying
>> that lithium has become less effective over time. That's crazy.
>> Lithium may have been used less than successfully for bipolar subtypes
>> for which it is less effective, such as rapid cycling or mixed
>> dysphoric states, but for classic mania it really works, and these
>> days clinicians really need to be reminded of that fact. This kind of
>> marketing has almost relegated a useful medication to the status of
>> historical artifact.
>>
>> Dr F: Interesting.
>>
>> Dr K: Yeah, and you know what else? I think we just wrote my next
>> column.
>>
>>
>>
>> Thomas A. M. Kramer, MD, Associate Professor of Psychiatry, University
>> of Chicago, Chicago, Illinois
>>
>>
>>
>> Medscape General Medicine 5(3), 2003. © 2003 Medscape
>>
>>
>>
>> A study by Charles Medwar a member of the WHO's Advisory Panel on Drug
>> Policies and management suggests that benzodiazepine withdrawal is less
>> severe than that from some SSRIs.
>>
>> In particular Dr Medwar review of UK safety data shows that from 1963
>> to 1997, just over 230 million prescription for temazepam and diazepam
>> generated only 25 notifications of withdrawal reactions. In the 10
>> years to 1997, 5 million paroxetine (Paxil) prescription resulted in
>> 802 notifications. In the 10 years that SSRIs have been available in
>> Britain, 17,845 there have been official notifications of adverse
>> effects from GPs.
>>
>> (Source: The International Journal of Risk and Safety in Medicine, vol
>> 10, pge75.)
>>
>>
>>
>> >From Psychiatric Annals 25:3.March 1995 RE: Benzodiazepine Use:
>> David G.Benzer, DO; David E. Smith, MD; Norman S. Miller, MD
>>
>> Pharmacological dependence is not the same as addiction and is not a
>> reason for discontinuing therapy; it is an adaptation of the central
>> nervous system to the persistent presence of the sedative drug. It is
>> critical to slowly taper benzodiazepines in patients who are
dependent;...
>>
>> Addiction refers to a preoccupation with acquiring a drug and the
>> compulsive use of that drug despite the recurrence of adverse
>> consequences. The loss of control over the use of the drug is the
hallmark
>> of addiction, an illness to which there seems to be a biologic
>> predisposition. There is evidence that addiction-prone individuals
>> subjectively perceive the effects of benzodiazepines differently. A
study
>> of alprazolam (1 mg "Xanax") in alcoholic and nonalcoholic men produced
>> positive mood changes in alcoholics *not* re****ted by the
nonalcoholics.
>>
>> Patients who are dependent on benzodiazepines merely need to be safely
>> tapered off the drug when the course of therapy has ended. Addicts
require
>> the same careful discontinuation as well as treatment addressing their
>> underlying addiction.
>>
>> ~~~~~~~~~~~~~~~~~
>>
>> >From Psychiatric Annals 25:3.March 1995 RE: Benzodiazepine Use:
>> David G.Benzer, DO; David E. Smith, MD; Norman S. Miller, MD
>>
>> Dependence often accompanies the use of benzodiazepines for panic
>> disorder. For example, alprazolam used at doses of 2mg or greater for
more
>> than 6 weeks must be assumed to create dependence. This is not
necessarily
>> a problem; it is neither a reason to not use benzodiazepines in these
>> conditions nor is it a justification for discontinuing the medication
>> prematurely. The patient and physician must mutually be aware to never
>> abruptly discontinue the benzodiazepines. Gradual tapering is the
method
>> that will safely and efficaciously allow the patient to discontinue
>> benzodiazepine therapy when appropriate.
>>
>> ~~~~~~~~~~~~~~~~~
>>
>> Title: Addiction to benzodiazepines--how common?
>> Title Abreviation: Arch Fam Med Date of Pub: 1995 Nov
>> Author: Piper A Jr; Issue/Part/Supplement: 11 Volume Issue: 4
>> Pagination: 964-70 Journal Title Code: BX6 Publication Type: JOURNAL
>> ARTICLE
>> Date of Entry: 951228N Entry Month: 9602 Country: UNITED STATES
>> Index Priority: 1 Language: Eng Unique Identifier:96074207
ISSN:1063-3987
>>
>> Abstract: Benzodiazepines have compiled an impressive record of safety
and
>> efficacy. Despite this record, however, physicians and laypersons
>> frequently worry about the drugs' addictive potential. Overemphasizing
>> these concerns may discourage prescription of benzodiazepines, thereby
>> impeding treatment of anxiety disorders. This review first defines the
>> term addiction. It then examines how frequently conditions meeting that
>> definition occur in patients without histories of substance abuse, who
are
>> prescribed benzodiazepines under medical supervision. In such patients,
>> benzodiazepines almost never induce
>> behavior that satisfies any reasonable definition of addiction.
>> Abstract By: Author
>> Number of References: 111
>>
>>
>>
>> >From the APP Textbook of Psychopharmacology (Schatzberg & Nemeroff,
>> eds.), p.
>> 224 (chapter on benzodiazepines):
>>
>> "The controversy surrounding BZ administration and potential abuse or
>> addiction
>> in routine patient use is generally not sup****ted by the available
>> scientific
>> evidence. (See Shader and Greenblatt 1993 for an excellent review of
this
>> complex area.) In a large community study of long-term alprazolam
users,
>> Romach and colleagues (1992) found that dosage did not escalate over
>> prolonged
>> use and that most patients used the BZs as prescribed. In fact, if
>> deviations
>> occurred, it was generally that a patient took less than the prescribed
>> dosage."
>>
>> and p. 710 (in the chapter on substance abuse):
>>
>> "Most patients who are in fact physiologically dependent on
>> benzodiazepines do
>> not increase the dose of medication above the physician's prescription
or
>> in
>> any other way abuse the prescribed medication. However, if the
>> benzodiazepine
>> were to be abruptly discontinued, the patient would, in all
probability,
>> go
>> through a withdrawal abstinence syndrome that could be extremely
severe.
>> ...
>> The fact that patients become physiologically dependent on therapeutic
>> doses of
>> benzodiazepines has led some in the field to equate any use of
>> benzodiazepines,
>> in any patient for long-term treatment, with abuse of the drug. This
is
>> undoubtedly an overstatement of the abuse of these agents. Significant
>> abuse
>> of benzodiazepines does in fact occur, but it is usually seen in
patients
>> also
>> abusing other drugs, _not_ in the patient kept carefully monitored and
>> kept
>> stable on therapeutically indicated benzodiazepines."
>>
>>
>> Written by a psychiatris who is also an associate Professor at
University
>> of Ky. The article was written on how to DC the Benzo Xanax, but in the
>> text of this paper it explains how this drug works and why it is often
the
>> first choice for pure panic anxiety. Hope it helps you start to
understand
>> what is happening and how to deal with your problems of this disorder.
I
>> have lived with all the symptoms of PNE without medication for years.
Thus
>> I have been through both methods of dealing with this problem. What I
have
>> learned in all the years of PNE is stopping the symptoms will start you
>> into recovery sooner.
>> lori
>> For the layperson ---
>> Dr. Steve's Guidelines for Discontinuing Xanax (alprazolam)
>> Stephen Cox MD, Asst Clinical Professor of Psychiatry, UKMC
>> This article is written in lay terminology and with analogies to make
>> complicated medical science
>> understandable.
>> You've no doubt heard negative things about Xanax. We have all read
>> stories of some negative aspect of the use of Xanax. These stories are
>> surprising. I, personally, have seldom experienced difficulty in
tapering
>> Xanax in patients with panic disorder. This may be a surprise to those
who
>> are not experienced in prescribing psychoactive medicants for anxiety
>> disorders.
>> The fact is that Xanax works very well indeed in treating panic
disorder.
>> Tolerance develops to the initial dose. Dose increases are necessary in
>> the first weeks of therapy. Why the tolerance? This is a very good
>> question and should be answered before you start taking Xanax. You
can't
>> possibly know how to go off Xanax unless you understand what happens to
>> your body as you are going on it.
>> There is a neurotransmitter in your brain called GABA. It stands for
gamma
>> amino butyric acid. GABA is your natural God-given tranquilizer. It is
>> present at 80% of the nerve connections in your brain. When you are too
>> nervous your brain cells release GABA which causes negatively charged
>> chlorine atoms to stream into your nerve cells. That's good because it
>> makes it harder for other stimulating neurotransmitters to trigger the
>> firing of that nerve. If your brain were a car, anxiety might be like
the
>> car speeding down a hill toward a sharp curve. As it comes to a curve
it
>> must slow down. The car brakes are applied so that the car can
negotiate
>> the curve and not burst through the guard rail. The GABA molecules of
your
>> brain are like the brakes in your car. If you don't have enough GABA,
your
>> brain is going to be like the car speeding toward a curve with worn out
>> brakes! Xanax acts by making what little GABA you do have work more
>> strongly. This is sort of like applying stronger pressure on worn out
>> brakes so that your car will negotiate a curve safely.
>> When you take Xanax for a couple of weeks it usually works great for
panic
>> disorder but then it does not seem to work as well as time goes on.
This
>> is to be expected. Why? This could be for two reasons. One possibility
is
>> that your brain cuts back on the release of GABA. It is sort of like
your
>> brain says, "Gosh, things are a lot calmer in here. I don't think I
need
>> to make as much GABA as I used to." Well, you likely didn't have enough
>> GABA to begin with. And now your brain makes even less than it did
before
>> you started taking Xanax. Naturally, the Xanax wouldn't work as well
once
>> GABA is reduced.
>> A second reason for tolerance may be down in your liver. Your liver
gets
>> rid of Xanax ultimately by making enzymes which destroy Xanax. After
you
>> are on Xanax for awhile it is as if your liver says, "Hey we sure are
>> getting a lot of Xanax these days. Let's make more Xanax-destoying
>> enzymes." And so it does. Let's say your dose that you started out on
was
>> giving you a blood level of, say, 100 units. But after your liver makes
>> more of this destroying enzyme you have a level of, say, 55 units of
>> Xanax. No wonder you feel like the Xanax isn't working as well. It
isn't!
>> Even though you're taking the same dose, your blood level dropped.
>> Remember, it does not really make any difference how many milligrams
you
>> swallow. What really matters is how much is
>> running around in your bloodstream.
>> So, tolerance normally develops to Xanax and it may be due to either or
>> both of the above reasons. If you didn't understand those two things,
go
>> back and read it again because what follows won't make much sense
unless
>> you understand those two ideas.
>> Now, let's say we have a 26 year old woman, Monica, who has been on 6
mg
>> of Xanax for panic disorder for 3 years. She's doing great. She can
drive
>> anywhere she wants and no panic attacks have occurred for 2 years. She
>> even flew from Cincinnati to Cancun Mexico without a problem. She asked
>> her psychiatrist if it would OK if she went off the Xanax now to see if
>> she still needed it. The psychiatrist said yes, 'but you must not do it
>> faster than I order'. The patient was relieved to hear her psychiatrist
>> was urging a gradual decline. You see, the patient's roommate, Suzy,
had
>> taken herself off Xanax from 6 mg per day to 3mg a day suddenly. And
after
>> only a week she stopped it completely. She thought she would die, she
felt
>> so bad; and, she blamed it on 'the
>> addictive nature of Xanax'. Fortunately, Monica was told by her
>> psychiatrist to cut her daily dose from 6.0 mg per day to 5.75 mg per
day
>> and to stay on that dose for two weeks. Then she was told to cut to 5.5
mg
>> a day for another 2 weeks, and so on by 0.25 mg off her daily dose
every 2
>> weeks. Monica's psychaitrist explained that there was no way to tell if
>> she still had panic disorder or not and by going down that slowly, if
>> Monica should experience any anxiety symptoms, it would be due to the
>> reappearance of panic disorder symptoms that were inadequately treated
by
>> her lower dose of medicine. This would mean that Monica still was
>> afflicted with panic disorder and needed continued treatment, at least
for
>> the time being. If, on the other hand, she gradually
>> tapered the Xanax down to zero and had no panic attacks, she would
>> officially be either well or in remission.
>> So, if you want to go off Xanax, ask your doctor how to do it. If there
is
>> a rush, it can be done faster than the above method. But usually there
is
>> no rush. And it is usually best to go slowly.
>> Now, let's review. Why didn't our patient Monica have any withdrawal
when
>> she tapered off Xanax, whereas her roommate, Suzy had severe
withdrawal?
>> The answer is that both women had a very, very low level of GABA
>> production and a very high level of liver Xanax-destroying enzymes.
When
>> Suzy cut herself off over a week's time, she thought she was tapering
off
>> but it was actually much too fast. It takes a long time for the brain
to
>> figure out that it needs to make more GABA and to do so. It also takes
a
>> long time for the liver to quit making so much Xanax-destroying
enzymes.
>> Monica's psychiatrist wisely told her to make these tiny cuts in the
>> Xanax dose that were barely perceptible to her as far as the way she
felt.
>> And equally wisely she had her go 2 weeks on that dose to let her brain
>> GABA increase and liver enzymes decrease before cutting the dose
further.
>> Dr. David Sheehan of the University of South Florida suggested this
method
>> to me at a meeting in Tampa years ago. I cannot recall any of my
patients
>> experiencing any bothersome withdrawal discomfort in going off Xanax by
>> the above method. Any difficulties I witnessed were relapses of a
>> clinically silent panic disorder that was previously adequately treated
by
>> the Xanax at the pre-taper dose.
>> You should never, never, never decide to go off Xanax on your own
without
>> your physician's counsel and guidance. Xanax is a remarkably safe
medicine
>> except for two things: overdosing on it can be extremely hazardous to
>> driving safety. Sudden or rapid stopping Xanax at daily doses of 4 mg
or
>> more can cause moderate to severe withdrawal and, in very rare
instances,
>> a convulsion could occur.
>> You should carefully weigh the decision to go off Xanax with medical
>> counsel. Is this a good time to go off it? Is this a stressful time? If
>> so, you should wait until a calmer time. Are you being pressured into
>> going off Xanax prematurely by well-meaning, but uninformed family or
>> friends who value more your 'being off medicine' than they do the
relief
>> of your suffering with panic attacks and avoidance behavior. Panic
>> disorder is not a trivial thing. It, untreated, is associated with the
>> highest suicide attempt rate of all medical disorders. It, untreated,
also
>> has a higher mortality risk from cardiovascular cause than non-panic
>> disorder persons. The general principles we have discussed with Xanax
also
>> holds true for other high potency benzodiazepines like
>> lorazepam (Ativanô) and clonazepam (Klonopinô). The dosages however are
>> all different and the mg reductions do not apply to these other
medicants.
>> Despite popular beleif, it is my opinion that Xanax is under-utilized
by
>> clinicians in their patients. Such medicines are remarkably safe. Panic
>> disorder patients seem rarely to abuse such medicine. Compliance
problems
>> (patients not following doctors orders) with panic disorder patients on
>> Xanax are rare; and, when seen are most often a matter of the patient
not
>> taking as much medicine as is prescribed rather than taking too much.
>> Dr. Stephen Cox
>> http://lexington-on-line.com/naf_xanax.html
>>
>>
>> To quote Dr Roy Baker, a board member of the American Society of
>> Addiction Medicine [2]:
>>
>> :: All drugs with the potential to cause addictions share certain
common
>> :: neurobiological characteristics: they activate the mesolimbic
system,
>> :: principally the nucleus ac***bens, causing increased dopaminergic
>> :: activity in that area of the brain. This results in an increase in
>> hedonic
>> :: tone.
>> and
>> :: "It is im****tant not to confuse physical dependence as evidenced by
>> :: benzodiazepine withdrawal syndromes with addiction or drug
dependence
>> :: (DSM-IV). "
>>
>> Benzodiazepine not only don't excite the N ac***bens but have been
>> shown to inhibit cocaine's affect on dopamine receptors in the N
>> ac***bens. [3] They should have the same positive effect on other
>> recreational drugs, for the same physiological reason. Certainly,
>> there is much evidence that benzos do reduce the withdrawal effects of
>> most recreational drugs. Consequently, benzodiazepines are being
>> increasingly used to mediate drug withdrawal in detox centers. [4]
>>
>> Another common test used to determine whether a drug is addictive is
>> to apply the "3 C" test to its users. The term was coined by Dr David
>> Smith of the Haight Ashbury Free Clinic and San Francisco Medical
>> Center and is widely used by addiction specialists. To meet the
>> addiction criterion, the patient must exhibit all three of the
>> following:
>>
>> 1: Control: when the addicted person starts using their drug they
>> episodically lose control over their ingestion.
>> This is something that rarely happens to benzodiazepine users. To
>> quote Prof Heather Ashton:
>> :: "Given the number of people who are prescribed benzodiazepines,
>> :: relatively few patients increase their dosage...."
>> http://www.a1b2c3.com/drugs/benz02.htm
>>
>> The American Psychiatrists Association made the same point in their
>> "Benzodiazepine Dependence, Toxicity, and Abuse: A Task Force
>> Re****t" To quote:
>> :: "There are no data to suggest that long-term therapeutic use of
>> :: benzodiazepines by patients commonly leads to dose escalation or to
>> :: recreational abuse"
>>
>> This is re-enforced by the recommendations in their current Panic
>> Disorder III. Treatment Principles And Alternatives web page:
>> :: "However, benzodiazepines may still be underused because of an
>> :: inappropriate fear of addiction. The studies of long-term alprazolam
>> :: treatment for panic disorder show that the doses patients use at 32
>> :: weeks of treatment are similar to those used at 8 weeks, indicating
>> :: that, as a group, patients with panic disorder do not escalate
>> :: alprazolam doses or display tolerance to alprazolam's therapeutic
>> :: effects, at least in the first 8 months of treatment. However,
>> :: studies of dose escalation following longer periods of
>> :: benzodiazepine use are generally lacking."
>> http://www.psych.org/clin_res/pg_panic_3.cfm
>>
>>
>>
>> Therefore, on all the criteria used to define addiction,
>> benzodiazepines are not addictive drugs.
>> However, they can and very often do cause dependency. Dependence is
>> produced by the presence of a drug causing changes in body systems
>> that then need to time to return to their pre drug state if the drug
>> is withdrawn. A drug doesn't have to be active in the brain for
>> dependency to develop - many cannot pass the blood-brain-barrier, but
>> they must for true addiction to develop.
>>
>> Benzodiazepines do over time produce a small bio-feedback reduction in
>> both benzodiazepine receptors and possibly expression of the
>> neurotransmitter GABA.
>>
>> If the benzodiazepine is discontinued abruptly, this reduction in
>> receptors and neurotransmitter can cause a rebound reaction with
>> symptoms similar to anxiety and panic. In most cases with a slow
>> taper, withdrawal symptoms can be minimized to a comfortable level.
>>
>> Moreover, not all withdrawal symptoms may be due to these
>> physiological changes. Some, perhaps most, can be produced by
>> psychology, that is the mind. It is well known that benzo withdrawal
>> effects can often be induced simply by making patients believe their
>> benzodiazepine dose has been reduced, even though no reduction
>> actually occurs. This has been shown in a number of studies. [6]
>>
>> There is also evidence [7] that withdrawal is more intense in some
>> patient groups, notably those who have neurotic personalities,
>> females, former/current alcoholics, the less educated, and those with
>> dependant personalities. It also appears that the worse the original
>> anxiety disorder, the more severe the withdrawal.
>>
>> Probably the best indication that many of the withdrawal problems
>> experienced by those who were taking benzodiazepines for anxiety
>> disorders are mostly psychological rather than chemical is the fact
>> that the other main benzo using patient cohort, epileptics, seem to
>> have much fewer problems. Indeed, there are very few re****ts in the
>> medical literature of epileptics having difficult withdrawals and I've
>> been unable to find even one case of "Protracted Withdrawal Syndrome."
>> Yet typical anti seizure benzo doses are much higher than those
>> usually needed to control anxiety, 10mg Klonopin being about average,
>> but 20mg/day or higher is not unusual.
>>
>> It should also be noted that many medications and supplements can
>> produce dependency, even some over the counter ones like vitamin C.
>> This may produce rebound scurvy if stopped suddenly after long term
>> use at high doses (1,000mg+/day). Symptoms may include bleeding gums
>> and nails. Extreme reactions may cause both tooth and hair loss.
>>
>> Other commonly used drugs that can induce dependence include:
>> antibiotics, most heart medications (beta-blockers, ACE inhibitors
>> etc), some cholesterol lowering drugs, antidepressants, most
>> painkillers - including OTC, some cancer drugs, valerian, and St
>> John's Wort.
>>
>>
>>> Addiction vs. Dependency:
>>> Benzodiazepines & Anxiety Disorders
>>>
>>>
>>> RESEARCH
>>> "In patients without histories of substance abuse, who are prescribed
>>> benzodiazepines under medical supervision . . . benzodiazepines almost
>>> never induce behavior that satisfies any reasonable definition of
>>> addiction" (Piper, Jr., A. "Addiction to Benzodiazepines -- How
>>> Common?" Archives of Family Medicine 4.11 (1995): 964-970).
>>>
>>> "Long-term users of alprazolam/lorazepam . . . used a constant or
>>> decreasing dose of medication . . . Persistant use of
>>> alprazolam/lorazepam for therapeutic purposes did not represent abuse
>>> or addiction as the terms are usually understood" (Romach, M., et.
>>> al. "Clinical Aspects of Chronic Use of Alprazolam and Lorazepam."
>>> American Journal of Psychiatry 152.8 (1995): 1161-1170).
>>>
>>> "The vast majority of the use of benzodiazepines is appropriate.
>>> Problems of nonmedical use arise nearly exclusively among people who
>>> abuse other drugs" (Woods, J.H. and G. Winger. "Current Benzodiazepine
>>> Issues." Psychopharmacology 118.2 (1995): 107-115).
>>>
>>> "With panic/agoraphobia patients there is no evidence of abuse.
Chronic
>>> use is justified in these patients; risk must be weighed against
>>> benefit, dependence against relief . . . Potential abusers are those
>>> with personality disorders, dysphoria (mood disturbance) and current
or
>>> previous substance abuse . . . there is no epidemic of misuse. Abuse
>>> seems to be limited to substance abusers . . . chronic use is
justified
>>> in chronic anxiety patients. Chronic use does not usually lead to
>>> abuse" (American Psychiatric Association. Benzodiazepine Task Force on
>>> Use, Dependence, Toxicity and Abuse. May 1990).
>>>
>>>
>>> The Definitions
>>>
>>> The term addiction is often equated with abuse. Addiction is generally
>>> marked by tolerance and/or psychological dependence. With tolerance, a
>>> person needs to increase the dosage of a medication over time in order
>>> to receive the same therapeutic benefits. Studies show that the
>>> majority of people with anxiety disorders do not increase their
>>> benzodiazepine dosages over time; in fact, most lower their dosages.
>>>
>>> When we think of addiction we are often thinking of psychological
>>> dependence. With psychological dependence, a person continues to take
a
>>> medication no matter what the consequences. The person will also seek
>>> out the medication no matter what the consequences. Again, as with
>>> tolerance, most studies show that people with anxiety disorders do not
>>> become psychologically dependent on benzodiazepines.
>>>
>>> The exceptions to the studies mentioned above are people who have a
>>> history of addiction to other drugs. People with such a history are
>>> possibly at risk for becoming addicted to benzodiazepines, too.
>>>
>>> A condition which does occur with long-term, regular use of
>>> benzodiazepines is physical dependence. After using benzodiazepines
>>> regularly for a few months (and the time varies for each individual),
a
>>> person's body will usually adapt to the drug. If the medication is
>>> stopped abruptly, the person will experience withdrawal symptoms.
These
>>> symptoms may be lessened (or even eliminated) by slowly tapering off
>>> the medication, if one chooses to stop taking it. Benzodiazepines
>>> should be discontinued only with the supervision of a qualified
>>> physician.
>>>
>>> People who are on medication for an illness for a long time are not
>>> addicted to the medication; they are medically dependent on it. They
>>> need to keep taking the medication in order to keep the symptoms of
the
>>> illness away. The majority of anxiety disorders patients who take
>>> benzodiazepines over the long term fall into the category of medical
>>> dependence.
>>>
>>> The rest of the article is at
>>>
>>>
http://panicdisorder.about.com/health/panicdisorder/library/weekly/aa031
>>> 997.htm
>>>
>>
>>
>> J Clin Psychiatry. 2005;66 Suppl 2:28-33.
>>
>> "Benzodiazepine use, abuse, and dependence"
>>
>> O'brien CP. Department of Psychiatry, University of Pennsylvania,
>> Philadelphia, PA 19104, USA. obrien@[EMAIL PROTECTED]
>>
>>
>> Although *benzodiazepines are invaluable in the treatment of anxiety
>> disorders*, they have some potential for abuse and may cause dependence
or
>> addiction.
>>
>> It is im****tant to distinguish between addiction to and normal physical
>> dependence on benzodiazepines.
>>
>> Intentional abusers of benzodiazepines usually have other substance
abuse
>> problems. Benzodiazepines are usually a secondary drug of abuse-used
>> mainly
>> to augment the high received from another drug or to offset the adverse
>> effects of other drugs.
>>
>> *Few cases of addiction arise from legitimate use of benzodiazepines*
>>
>> Pharmacologic dependence, a predictable and natural adaptation of a
body
>> system long accustomed to the presence of a drug, may occur in patients
>> taking therapeutic doses of benzodiazepines. However, this dependence,
>> which
>> generally manifests itself in withdrawal symptoms upon the abrupt
>> discontinuation of the medication, may be controlled and ended through
>> dose
>> tapering, medication switching, and/or medication augmentation.
>>
>> Due to the *chronic nature of anxiety, long-term low-dose
benzodiazepine
>> treatment may be necessary* for some patients; this continuation of
>> treatment should not be considered abuse or addiction.
>>
>>
>> PMID: 15762817 [PubMed - indexed for MEDLINE]
>>
>>
>>
>>
>> "The controversy surrounding benzodiazepine administration and
potential
>> abuse or addiction in routine patient use is generally not sup****ted by
>> the
>> available scientific evidence.
>>
>> In a large community study of long-term alprazolam users, Romach and
>> colleagues (1992) found that dosage did not escalate over prolonged use
>> and
>> that most patients used the benzodiazepines as prescribed. In fact, if
>> deviations occured, it was generally that a patient took less than the
>> prescribed dosage."
>>
>> from: "The American Psychiatric Press Textbook of Psychopharmacology"
by
>> Schatzberg and Nemeroff, 2nd Edition (1998)
>>
>> ---------------------------------------------------------------------
>>
>> J Clin Psychopharmacol 1992 Oct;12(5):316-21
>>
>> Characteristics of long-term alprazolam users in the community.
>>
>> Romach MK, Somer GR, Sobell LC, Sobell MB, Kaplan HL, Sellers EM.
>>
>> Department of Psychiatry, University of Toronto, Ontario, Canada.
>>
>> The widespread use of benzodiazepines remains a source of concern to
the
>> medical profession and the general public, especially as newer
compounds
>> come on the market. Our goal was to characterize long-term alprazolam
>> users
>> in the community and to determine whether such use represented abuse or
>> behavioural dependence. We conducted three community surveys to learn
>> about
>> the natural history of long-term alprazolam use. Current long-term
>> alprazolam users (those using the drug for 3 months or longer) were
>> recruited on three separate occasions 1 year apart by identical
newspaper
>> advertisements in the metropolitan Toronto area. All respondents were
>> mailed
>> a questionnaire with a stamped, addressed return envelope.
>>
>> Our data from 312 respondents show that:
>>
>> (1) the majority of patients have a substantial history of prior
>> medication
>> use for symptom control (65%),
>>
>> (2) dose escalation is not a characteristic of long-term use,
>>
>> (3) patients change their initial pattern of regular use to one of
symptom
>> control only when required,
>>
>> (4) most physicians do not discuss discontinuation of the drug with
their
>> patients,
>>
>> (5) patients frequently try to stop their drug use (with a median of 2
>> attempts) and often re****t symptoms upon discontinuation, and
>>
>> (6) patients perceive a need for medication use and indicate that
>> alprazolam
>> is effective (75%).
>>
>> We conclude that some patients persistently use alprazolam but that
this
>> use
>> does not represent abuse or behavioral dependence.
>>
>> PMID: 1479048 [PubMed - indexed for MEDLINE]
>>
>>
----------------------------------------------------------------------------
>> ----
>>
>> Addiction.....Dependence........Withdrawal
>>
>> "Addiction and dependence are frequently confused. 'Addiction' is hard
to
>> define, with little consensus on what it means, and in fact is not even
>> defined as a condition in the DSM-IV.
>>
>> 'Addiction' usually refers to a behavioral pattern of drug abuse
>> characterized by overwhelming involvement with use of a drug
(compulsive
>> use) and with the securing of its supply and by a high tendency to
relapse
>> after discontinuation.
>>
>> The term 'addiction' is frequently employed by those who are not
experts
>> in
>> psychopharmacology when 'dependence' is what they mean.
>>
>> 'Dependence' is a physiological state of neuroadaptation produced by
>> repeated administration of a drug, necessitating continued
administration
>> to
>> prevent the appearance of a 'withdrawal syndrome'.
>>
>> 'Dependence' is a term that is not frequently used outside of
>> psychopharmacology but in fact is a key feature of many
antihypertensive
>> medications, hormones, and other treatments throughout medicine. Thus
>> several antihypertensives can produce 'rebound' hyptertension, worse
than
>> the original blood pressure elevation, when suddenly discontinued.
These
>> patients are not 'addicted' to the blood pressure medications although
>> they
>> are 'dependent' on them.
>>
>> 'Withdrawal' is the term for the adverse psychological and
physiological
>> reactions to abrupt cessation of a dependence-producing drug."
>>
>>
>> from: Essential Psychopharmacology, 2nd Edition (2000), Stephen M.
Stahl,
>> published by Cambridge University Press
>>
>> (Dr. Stahl is a PhD and MD, and is a Professor of Psychiatry at the
>> University of California, San Diego. He has conducted numerous research
>> projects awarded by the National Institute of Mental Health, the
Veterans
>> Administration, and the pharmaceutical industry. Dr. Stahl is an
>> internationally recognized clinician, researcher, and teacher in
>> psychiatry
>> with subspecialty expertise in psychopharmacology.)
>>
>>
--------------------------------------------------------------------------
>>
>> "Although it is wise to avoid prolonged hypnotic use, prolonged use of
a
>> benzodiazepine hypnotic may be less harmful than is often said and may,
in
>> fact, provide some benefit. The available evidence from sleep
laboratories
>> suggests that hypnotics improve sleep measurably for only a few weeks,
>> though placebo-controlled studies have shown no diminution in the
efficacy
>> of hypnotics for up to 24 weeks, and single-blind studies show efficacy
up
>> to a year. So far, no studies have clearly established a treatment
>> duration
>> after which benzodiazepine hypnotics fail to work. Many confirmed users
of
>> hypnotics swear that the hypnotics are always helpful and even vitally
>> necessarry for years."
>>
>> from "Manual of Clinical Psychopharmacology", Edition 2003, Schatzberg,
>> Cole, and DeBattista
>>
>>
----------------------------------------------------------------------------
>> --------------
>>
>> Quoted from "Panic Disorder: The Medical Point of View", by William
>> Kernodle, M.D.
>>
>> "Our society appears to have a phobia concerning benzodiazepines. I
>> believe this fear started many years ago when Valium was prescribed for
>> minor anxiety and patients were not made aware of the potential for
>> developing physical dependence. It is physical addiction that most
>> patients worry about with a benzodiazepine. I believe *addiction*
>> refers to a severe form of drug abuse in which the individual craves a
>> substance despite negative consequences and needs more and more for the
>> same effect. I do not think that patients with panic disorder crave
the
>> benzodiazepines for their effect or frequently develop physical
>> tolerance (with the possible exception of substance abusers). It is
>> possible for patients to develop *physical dependence* on the
>> benzodiazepines when used at moderate to high doses over months or
>> years. However, this simply means that the benzodiazepine has to be
>> tapered slowly rather than stopped abruptly to avoid having a
withdrawal
>> symptom" (p 115).
>>
>>
>>
>> Title: Maintenance drug therapy of panic disorder.
>> Title Abreviation: J Psychiatr Res Date of Pub: 1993
>> Author: Curtis GC; Massana J; Udina C; Ayuso JL; Cassano GB; Perugi G;
>> Issue/Part/Supplement: Volume Issue: 27 Suppl 1 Pagination: 127-42
>> Journal Title Code: JTJ Publication Type: CLINICAL TRIAL
>> Date of Entry: 940505N Entry Month: 9407 Country: ENGLAND Index
Priority:
>> 2
>> Language: Eng Unique Identifier: 94194428 ISSN: 0022-3956
>>
>> Abstract: The efficacy of tricyclics and benzodiazepines in the short
term
>> (approximately 2-4 months) treatment of panic disorder is well
>> demonstrated, but
>> efficacy over the longer term is not considered established. The
present
>> study
>> provided systematic data from a double blind comparison of maintenance
>> therapy
>> (up to 8 months) of panic disorder with or without agoraphobia with
>> alprazolam,
>> imipramine, or placebo in 181 patients who had responded to the same
>> regimen in
>> a randomized 8-week treatment trial. All three groups had improved
during
>> the
>> first 2 months (active treatments more than placebo and about equal to
>> each
>> other), and all maintained or extended their improvement over the next
6
>> months
>> without any significant change in dose. More than twice as many
alprazolam
>> and
>> imipramine than placebo patients (15%) remained in treatment for the
full
>> 8
>> months and did slightly better on symptom measures than the remaining
>> placebo
>> patients. Both medications were well tolerated during the maintenance
>> period.
>> The data suggest sustained efficacy and safety of imipramine and
>> alprazolam over
>> an extended period. More specifically, they suggest that tolerance does
>> not
>> develop to the therapeutic effects of either drug.
>> Abstract By: Author
>> Address: University of Michigan, Ann Arbor.
>>
>>
>>
>>
>> Some links:
>>
>>
>>
>> http://www.biopsychiatry.com/clonazepam.html
>>
>>
>> http://www.ncbi.nlm.nih.gov/pubmed/7298586?dopt=Abstract
>>
>>
http://www.ncbi.nlm.nih.gov/pubmed/17881433?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
>>
>>
>>
http://www.ncbi.nlm.nih.gov/pubmed/16103667?ordinalpos=17&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
>>
>>
>>
http://www.ncbi.nlm.nih.gov/pubmed/15907150?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus
>>
>>
>>
>> Tolerance to the anxiolytic effects has been shown in
>> various animal studies [94,95], although not by all authors
>> [9,96], and when detected it appears to occur at a slower rate
>> than that of sedative tolerance [88]. Further, it has been
>> difficult to demonstrate tolerance to the anxiolytic [8] or antipanic
>> effects of benzodiazepines [97,98] in man. In fact, when
>> treated for generalised anxiety disorder patients develop
>> tolerance to the sedative effects without there being a re****ted
>> decrease in anxiolytic efficacy [8].
>>
http://www.ingentaconnect.com/content/ben/cpd/2002/00000008/00000001/art00002
>>
>>
>>
>> Benzodiazepine derivatives--side effects and dangers.Lader MH,
Petursson
>> H.
>> The benzodiazepines are generally safe and effective drugs with usually
>> only
>> minor side effects, dose-related sedation being the most common. A
range
>> of
>> paradoxical effects can occur of which release of aggressive and
hostile
>> feelings has excited most attention. These responses are idiosyncratic
>> however, as most patients re****t decrease of such feelings while taking
>> benzodiazepines. Dependence on benzodiazepines with escalation of
dosage
>> and/or social abuse is uncommon set against their widespread use.
Recently
>> though, evidence has ac***ulated that patients on normal doses for
>> prolonged
>> periods can commonly experience withdrawal symptoms, often unpleasant
and
>> even
>> severe. These drugs should be reserved for patients suffering from
defined
>> clinical anxiety syndromes and not used indiscriminately in patients
with
>> normal stress responses.
>>
>> PMID: 6130800 [PubMed - indexed for MEDLINE]
>>
http://www.ncbi.nlm.nih.gov/pubmed/6130800?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus
>>
>>
>>
>> They may also be regarded as necessary for more severe psychiatric
>> disorders,
>> usually as an adjunct to other therapy. In such instances the
dependence
>> risk
>> is acknowledged but the benefits of treatment are considered to
outweigh
>> them.
>> There may also be patients who are dependent on benzodiazepines but the
>> alternative of withdrawing the drug may lead to dependence on a more
>> dangerous
>> drug such as alcohol. In such cases it is reasonable to regard
continued
>> prescription of the benzodiazepine as the least dangerous course of
>> action. It
>> is im****tant to maintain a perspective of dependence on minor
>> tranquillizers,
>> particularly as attitudes are in danger of being distorted by excessive
>> media
>> attention. To date there is no evidence that dependence on
benzodiazepines
>> leads to any dangerous long term sequelae although there is concern
over
>> their
>> effects on higher cognitive function. Nevertheless, the dangers of
>> barbiturates, alcohol and nicotine are so much greater that it would be
>> unfortunate if public concern led to excessive restrictions on the use
of
>> benzodiazepines.(ABSTRACT TRUNCATED AT 400 WORDS)
>>
>> PMID: 2894676 [PubMed - indexed for MEDLINE]
>>
http://www.ncbi.nlm.nih.gov/pubmed/2894676?ordinalpos=14&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
>>
>> ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
>>
>>
>>
>> J Psychiatr Res. 1990;24 Suppl 2:81-90.Links
>> A practical approach to benzodiazepine discontinuation.DuPont RL.
>> Department of Psychiatry, Georgetown University School of Medicine,
>> Wa****ngton, D.C.
>>
>> Non-medical use of benzodiazepines is rare among patients with anxiety
>> disorders. Numerous studies have found that non-medical use, or abuse,
of
>> benzodiazepines occurs usually among patients with histories of alcohol
>> and
>> drug abuse--those who use those drugs to get "high". This article
>> distinguishes between medical and non-medical use of benzodiazepines in
>> clinical practice, and offers practical approaches to discontinuation
of
>> benzodiazepine treatment for both medical and non-medical users of
those
>> medicines. The major barrier to clear thinking about the abuse of
>> benzodiazepines is the confusion of "addiction" and "withdrawal".
>> Addiction
>> means high, unstable dosing outside medical and social boundaries for
>> "recreational" purposes, loss of control over use, and continued use
>> despite
>> clear evidence of harm. Alcoholism and heroin addiction are typical
>> examples
>> of addiction (Kalant, 1989). In contrast, withdrawal is a
pharmacological
>> consequence of discontinuation of a substance on which a person has
become
>> dependent. Many drug-addicted people have only minor withdrawal
symptoms
>> when
>> they stop drug use. Many medical patients, with no evidence of
addiction,
>> have
>> withdrawal symptoms when they stop treatment, especially when they stop
>> abruptly (e.g. surgical patients using narcotic analgesics and
epileptics
>> using benzodiazepines or barbiturates in their treatment). Addiction to
>> benzodiazepines, in the sense of loss of control over use and continued
>> despite harm, is virtually limited to people with pre-existing drug or
>> alcohol
>> abuse, while withdrawal symptoms after prolonged daily use are common
>> among
>> medical users of benzodiazepines. The serious nature of both drug abuse
>> and
>> anxiety disorders is not emphasized sufficiently during medical school
or
>> in
>> the professional literature. The distress and disability from which
both
>> groups of patients and their families suffer is profound. Fortunately,
>> both
>> drug abuse and anxiety patients receive tremendous benefit from
successful
>> treatments, both pharmacological and nonpharmacological (DuPont, 1986a;
>> DuPont, 1984). This article discusses the use of benzodiazepines in two
>> distinct populations--drug abusers and patients with anxiety
>> disorders--and
>> helps clinicians distinguish between the use of benzodiazepines in the
two
>> groups. The central distinction made in this article is reflected in
the
>> common use of the words "drugs" and "medicines". The former term often
>> denotes
>> non-medical substance use, while the latter term refers to traditional
>> pharmacotherapy.
>>
>> PMID: 1980703 [PubMed - indexed for MEDLINE]
>>
>>
>> August 01, 2007 Vol. 24 No. 7
>> Risk Versus Benefit of Benzodiazepines
>> Jay M. Pomerantz, MD
>>
>>
>> As Salzman31 pointed out, "dependence" is not necessarily "addiction."
>> Developing dependence is a predictable phenomenon, influenced by
dosage,
>> duration of treatment, and other patient factors. Most often,
dependence
>> is a
>> normal consequence of long-term pharmacological receptor-site activity.
>> Addiction implies not only dependence, but also nonmedical use,
>> pleasure-seeking use, and often polysubstance abuse. Most
benzodiazepine
>> use
>> is not addictive, but appropriate use can sometimes result in
dependence.
>>
http://www.psychiatrictimes.com/topic/Anxiety/showArticle.jhtml?articleID=201201859&pgno=3&topic=Anxiety
>>
>>
>>
>> Issues in the Long-Term Treatment of Anxiety Disorders
>>
>> Edward Schweizer, Karl Rickels, and Eberhard H. Uhlenhuth
>>
>>
>>
>>
>>
>>
>>
>> INTRODUCTION
>>
>>
>> The goal of this chapter is to review issues relating to the long-term
>> treatment of anxiety disorders. The review does not pretend to be
>> exhaustive, but it has been written with the intention of critically
>> addressing clinically im****tant aspects of long-term anxiolytic
>> therapy. The scope of the review is limited to panic disorder with or
>> without agoraphobia, generalized anxiety disorder (GAD), and social
>> phobia. Most of the emphasis is placed on drug therapy. Space
>> limitations, and the limitations of the authors themselves, have
>> dictated that results from psychotherapy studies could only be
>> highlighted. It was felt, though, that the rapidly expanding
>> literature of controlled psychotherapy research simply could not be
>> ignored, because their preliminary results stake a claim to the
>> achievement of sustained efficacy post treatment.
>>
>> The review will first undertake to establish whether there is any need
>> for long-term or maintenance anxiolytic therapy. Long-term therapy can
>> only be justified if there is evidence that the course of illness of
>> panic/agoraphobia, GAD, and social phobia are frequently chronic. The
>> longitudinal nature of these disorders will be evaluated in terms of
>> retrospective re****ts, prospective studies of community samples (ideal
>> but not generally available), and follow-up studies of treated
>> samples. Acute (short-term) treatment studies will also be reviewed:
>> High rates of relapse or recurrence in the months and years following
>> acute treatment suggest that such treatment is inadequate, and that
>> continuation or maintenance treatment may be beneficial. Establi****ng
>> how beneficial leads us to a brief review of recent research on the
>> degree of disability and impairment in quality of life caused by the
>> anxiety disorders. The justification section will conclude with a
>> brief review of the extent to which the natural history of the three
>> anxiety disorders is complicated by Axis I and Axis II comorbidity.
>> Long-term treatment planning cannot be undertaken without considering
>> these high rates of comorbidity.
>>
>> Next will come a brief review of published evidence for the efficacy
>> of long-term treatment of each of the three anxiety disorders.
>> Evidence for long-term efficacy will be reviewed for the various
>> cl***** of antidepressants, as well as for the benzodiazepines and
>> buspirone. Long-term treatment will be conceptualized, in keeping with
>> the terminology employed in the affective disorders literature, as
>> either "continuation" treatment or "maintenance" treatment.
>> Continuation treatment consists of the extension of drug therapy for 6
>> months beyond the acute phase in an attempt to prevent relapse,
>> defined as a return of the current episode of anxiety. Maintenance
>> treatment consists of the long-term use of drugs whose goal is to
>> prevent a recurrence of a subsequent episode of anxiety in a patient
>> who has demonstrated high chronicity, a high rate of recurrence,
>> and/or significant levels of severity or disability associated with
>> previous episodes.
>>
>> The putative benefits of long-term (continuation or maintenance)
>> therapy, insofar as they have been established, will be contrasted
>> with the potential risks attendant upon such therapy. The abuse
>> liability, dependence, and withdrawal risks associated with the
>> benzodiazepines will be especially emphasized. Miscellaneous issues
>> relating to long-term therapy, such as predictors of chronicity,
>> safety and benefits of combination therapy (drug–drug or
>> drug–psychotherapy), compliance, and intermittent medication
>> strategies, will be reviewed next. The chapter will conclude with a
>> review of methodologic issues in studying long-term treatment, suggest
>> some promising research designs, and identify areas for future
>> research.
>>
>> THE EVIDENCE FOR CHRONICITY
>>
>>
>> Only belatedly has it been recognized that the anxiety disorders tend
>> to be chronic and/or recurrent conditions. This recognition has not
>> yet reshaped our basic treatment approach, which still focuses almost
>> exclusively on the acute control of symptoms and only secondarily
>> acknowledges that treatment may need to be either continued or
>> reinitiated. Treatment planning for bipolar disorder, for
>> schizophrenia, and, recently, for unipolar depression is premised on
>> the chronicity of each illness, whether a maintenance or an
>> intermittent drug treatment strategy is ultimately utilized.
>>
>> But what is the evidence for chronicity for panic disorder (with or
>> without agoraphobia), GAD, and social phobia? The evidence comes
>> mostly from cross-sectional and retrospective *****sments of duration
>> of illness and, much less frequently, from prospective studies. These
>> latter prospective studies are not long-term, but generally consist of
>> patient samples followed naturalistically post treatment, in which
>> case they provide evidence not only for the chronicity of the
>> disorder, but also for the insufficiency of acute therapy alone.
>>
>> Panic Disorder
>>
>> In the ECA community survey (51), the median age of onset was 23, and
>> the mean duration of panic disorder was 7.1 years for the subset of
>> patients whose panic was in remission. The duration of panic in the
>> majority (81%) who continued to re****t panic was apparently not
>> computed, because the illness was still ongoing. Treatment studies
>> find a similar mean duration of illness (ongoing at the time of
>> evaluation) in the range of 5–12 years (4, 56, 59). The
>> retrospectively *****sed age of panic onset in these treatment studies
>> was in the mid-twenties, comparable to the results obtained in the ECA
>> community survey, suggesting that the re****ted duration of illness was
>> long not simply due to a sampling bias with respect to the type of
>> patient applying for treatment in a drug study. Overall, the course of
>> illness of panic disorder appears to be chronic in the majority of
>> patients, but with many re****ting periods of remission lasting 6
>> months or longer.
>>
>> Generalized Anxiety Disorder
>>
>> For GAD, the ECA community survey re****ted a median age of onset in
>> the early twenties (51). For the good outcome cases that had remitted,
>> mean duration was 4.5 years, with 40% re****ting durations of illness
>> of longer than 5 years. For currently active cases of GAD, the mean
>> duration of illness to date was re****ted as 8.5 years. Duration of
>> illness for still-active cases of GAD entering both drug and
>> psychotherapy treatment studies (45, 47) ranges from 5 to 15 years,
>> confirming that GAD has high chronicity. Several researchers (5, 29)
>> have noted that the clinical course of GAD is both more chronic and
>> more unremitting than panic disorder. Noyes et al. (35!popup(ch127),
>> in one of the few prospective studies (of anxiety neurosis), re****ted
>> that 48% of patients continued to have moderate-to-marked symptoms at
>> the 4- to 9-year follow-up.
>>
>> Social Phobia
>>
>> Much less information is available about the course of illness of
>> social phobia, but available data from both community (23, 54) and
>> patient samples (19, 24) suggest an age of onset in the mid to late
>> teens, with a chronicity that is equal to or greater than that of
>> panic disorder, with mean duration of illness exceeding 5 years.
>>
>> AGE OF ONSET: EVIDENCE FROM ADOLESCENT POPULATIONS
>>
>>
>> As has been mentioned, panic/agoraphobia appears to have a mean age of
>> onset, estimated retrospectively, to be in the early to mid twenties,
>> GAD in the early twenties, and social phobia in the mid teens. Because
>> retrospective recollection is prone to bias, in the direction of
>> either over- or underestimation, it would be a useful corrective to
>> study anxiety directly in its early incarnations. This is especially
>> true in light of the lack of reliable course of illness data from
>> prospective community samples followed over time. Fortunately, recent
>> research provides data on the onset of panic, social phobia, and GAD
>> in contem****aneous child and adolescent populations. Structured,
>> prospectively conducted DSM-III-R *****sments of a random community
>> sample of 1710 adolescents found a lifetime prevalence rate, to date,
>> of 1.2% for panic disorder, 0.6% for agoraphobia, 1.5% for social
>> phobia, 4.3% for separation anxiety disorder, and 1.2% for overanxious
>> disorder (23). A similar community survey of adolescents (70) found
>> prevalence rates of 0.6% for panic disorder and 3.7% for GAD. Other
>> community prevalence estimates place the rate of panic attacks post
>> puberty as high as 12–13%. The panic/agoraphobia, GAD, and social
>> phobia prevalence rates for adolescents are in the range of rates
>> re****ted for adults, suggesting that the age of onset and duration of
>> illness estimates gleaned from retrospective re****ts in adults are, if
>> anything, an underestimate.
>>
>> THE ADEQUACY OF SHORT-TERM (ACUTE) TREATMENT
>>
>>
>> Panic Disorder
>>
>> Ac***ulated evidence across multiple controlled trials suggests that
>> the high-potency benzodiazepines (the most studied is alprazolam) are
>> effective drugs for the short-term treatment of panic disorder, either
>> with or without agoraphobia (e.g., see refs. 4, 12, and 58). Similar
>> short-term treatment efficacy has been re****ted for the tricyclic
>> antidepressants (12, 58), the MAOI antidepressants (59), and, in pilot
>> studies, the SSRI antidepressants (8).
>>
>> Only a few studies, though, have examined clinical and drug treatment
>> status after naturalistic follow-up 1–3 years post acute study
>> treatment. Studies re****ting outcome after short-term benzodiazepine
>> therapy find that many patients experience transient rebound anxiety
>> symptoms to a level above their pretreatment baseline (38, 56). By 1–3
>> years, approximately 50% or more of acutely treated patients have had
>> a recurrence (34), and at least 50% have resumed treatment, either
>> with a benzodiazepine or with an antidepressant.
>>
>> Acute treatment with antidepressants appears to have a similar
>> clinical and drug treatment outcome at follow-up, with re****ts of
>> relapse ranging from 25% to 70% (30, 36). Less data are available at
>> follow-up for the MAOI antidepressants, but here again clinical
>> experience suggests that relapse rates are comparable. The similar
>> relapse rates after both antidepressant and benzodiazepine therapy
>> suggest the need for continuation therapy. They also suggest that
>> relapse is not simply an iatrogenic byproduct of benzodiazepine
>> therapy.
>>
>> Generalized Anxiety Disorder
>>
>> We are not aware of any published research that re****ts reliable
>> relapse/recurrence rates for GAD patients treated with
>> antidepressants. With azapirones, however, Rickels and Schweizer (48)
>> found GAD patients treated with buspirone for 6 months to have a lower
>> relapse at 3 years post treatment than did patients treated with
>> clorazepate.
>>
>> A few studies have examined relapse/recurrence rates after acute
>> benzodiazepine therapy. Rickels et al. (42) re****ted an 81% anxiety
>> recurrence rate at 1 year for patients who had received 4 weeks of
>> benzodiazepine therapy. In another study, Rickels et al. (44) treated
>> 138 GAD patients for a minimum of 6 weeks with diazepam. A recurrence
>> rate of 63% was re****ted at 1 year, with 50% of the patients
>> sustaining improvement for at least 3 months. Overall, it appears that
>> 60–80% of GAD patients (at least the ones applying for drug therapy)
>> require additional treatment by 1 year.
>>
>> Another index of the inadequacy of acute benzodiazepine treatment is
>> the percent of patients who relapse in the week or two immediately
>> after discontinuation of acute treatment. In a 4-week treatment study
>> utilizing both a long-and a short-half-life benzodiazepine, 30% of
>> patients had relapsed by 2 weeks (46). In fact, approximately 20%
>> achieved HAM-A scores that were equal to or higher than their
>> pretreatment baseline, indicating a rebound anxiety that, it has been
>> speculated, might be an early precursor of the benzodiazepine
>> withdrawal syndrome. Other studies have re****ted similar rates of
>> rebound anxiety after short-term benzodiazepine therapy, ranging from
>> 25% to 44% (17). It is unclear what percent of patients experience
>> rebound anxiety as a transient and self-limited phenomenon, and in
>> what percent it serves to trigger a recrudescence of the underlying
>> generalized anxiety.
>>
>> Relapse/Recurrence Rates After Psychotherapy
>>
>> The published outcome research for the psychotherapy of GAD is
>> hampered by small sample sizes and low-power, frequently inadequate
>> inclusion/exclusion criteria and characterization of the study
>> populations, as well as a variety of other methodological problems.
>> Therapies that appear to have the most well-established efficacy are
>> cognitive therapy (with various degrees of behavior therapy added in)
>> and anxiety management therapies. Despite poor power, the tentative
>> evidence to date consistently suggests some degree of acute efficacy
>> for the psychotherapies (6, 9, 16, 40). Of special interest is that 3-
>> to 12-month follow-up suggests that GAD treated by cognitive or
>> anxiety management therapy may be unusually effective in sustaining
>> improvement, with less than one-third of patients relapsing in the
>> immediate 6- to 12-month follow-up period. If these results are
>> confirmed, especially in drug versus psychotherapy trials, it would be
>> a significant advance in the long-term management of GAD.
>>
>> Social Phobia
>>
>> Much less treatment research has been conducted on social phobia.
>> Treatment experience with MAOI antidepressants consists of at least
>> two open-label studies (63, 64) and three controlled studies (19, 24),
>> all of which suggest efficacy over 8–16 weeks of acute treatment. Only
>> one of these studies (69) examined efficacy during continuation
>> therapy for up to 1 year. This latter study found efficacy to be
>> sustained. None of the studies examined rates of relapse or recurrence
>> after MAOI discontinuation.
>>
>> Clonazepam has also shown pilot evidence of efficacy, but only in
>> open-label studies (13). Fluoxetine and buspirone have both also been
>> used successfully in short-term pilot studies (55). Again, no data
>> were re****ted for post-drug relapse or recurrence rates, so no
>> conclusions can be drawn concerning whether there is a role for
>> continuation therapy. Anecdotal experience, though, with all its
>> shortcomings, does suggest, at least for the MAOIs and clonazepam,
>> that relapse frequently occurs within 3–6 months of discontinuing
>> short-term treatment.
>>
>> LEVEL OF DISTRESS, DISABILITY, AND QUALITY OF LIFE IMPAIRMENT
>> ASSOCIATED WITH ANXIETY DISORDERS
>>
>>
>> It can be concluded with some degree of confidence (albeit with
>> methodological caveats) that the evidence is fairly strong and very
>> consistent and that the three anxiety disorders all have substantial
>> chronicity. But to what extent is this chronicity associated with
>> significant distress, disability, and impairment in functioning and
>> quality of life? In the end, judgments about the benefits and risks of
>> long-term anxiolytic therapy must be placed in this broader context.
>>
>> The evidence regarding disability and quality of life is not
>> substantial, but appears to be fairly consistent as far as it goes.
>> For panic disorder, significant psychosocial impairment appears to be
>> a common feature of the disorder. In the 1979 National Survey of
>> Psychotherapeutic Drug Use, significant pro****tions of respondents
>> with anxiety syndromes re****ted impaired role performance due to
>> psychological and other factors: for panic/agoraphobia, 41% and 25%;
>> for other phobias, 33% and 23%; for general anxiety, 22% and 45% (66).
>> The rates for panic/agoraphobia were comparable to those for major
>> depression in the same study: 47% and 31%. Substantial pro****tions of
>> respondents with anxiety syndromes utilized treatment during the year
>> prior to the survey: panic/agoraphobia, 62%; other phobias, 32%;
>> general anxiety, 50%; compared to 26% of the general population (67).
>>
>> The ECA survey re****ted that approximately 58% of their community
>> sample of persons with panic disorder had some degree of financial
>> disability, whether welfare, disability, or social security payments
>> (28, 51). Massion et al. (29), re****ting on 234 panic patients in an
>> outpatient setting, found approximately 50% to be employed full time
>> and found 27% to be receiving some form of public assistance. In the
>> ECA community survey, 86% had sought medical outpatient evaluation and
>> treatment in the previous 6 months (compared to 8% of persons without
>> panic), and 51% had sought mental health evaluation and treatment. In
>> keeping with these figures, 35% of the community ECA sample rated
>> their physical health as fair to poor, and 38% rated their emotional
>> health as fair to poor (28). In the ECA survey, 7% of panic patients
>> without comorbid depression re****ted a history of suicide attempts,
>> while Massion and colleagues (29) found a rate of 3%. In a large group
>> of high utilizers of medical outpatient care, Katon et al. (20) found
>> a 12% rate of current panic disorder and a 30% rate of lifetime panic.
>> This overrepresentation of panic disorder is especially high in
>> medical subspecialty clinics, where rates of panic range from 20% to
>> 50% for medically unexplained episodes of chest pain, tinnitus,
>> dizziness, irritable bowel, and chronic fatigue (7, 27).
>>
>> For GAD, the best information currently available probably comes from
>> the ECA community survey (51) and from a multisite survey of
>> psychiatric outpatients (29). The overall picture for GAD is one of
>> significant psychosocial impairment (albeit somewhat less severe than
>> is observed with panic disorder), with 38% of ECA subjects and 71% of
>> outpatients characterizing their emotional health as fair to poor; 27%
>> and 25%, respectively, were receiving disability payments, and only
>> about one-half worked full time. Of those who were working, 38% of the
>> patient population had missed at least 1 week of work in the past year
>> due to their anxiety. The ECA survey found a strong correlation
>> between occupational status/income and GAD, with presence of GAD being
>> associated with (a) a threefold greater likelihood of working at a low
>> occupational level and (b) a more than twofold greater likelihood of
>> earning less than $10,000 per year. Medically, 35% of the ECA sample
>> with GAD, and 23% of the patient population of Massion et al. (29),
>> re****ted that their physical health was fair to poor. This latter
>> finding is corroborated in an outpatient medical setting by Katon et
>> al. (20), who found that 24% of all high utilizers of medical
>> outpatient care had a diagnosis of GAD.
>>
>> The early onset and the high degree of chronicity, disability, and
>> medical and psychiatric morbidity associated with GAD have led some
>> researchers to speculate that GAD might not be an independent
>> diagnosis, but instead a trait or vulnerability factor that
>> predisposes to later problems. Whatever its status, the chronicity and
>> disability associated with GAD make it an unlikely candidate for a
>> cure or sustained remission after short-term drug therapy.
>>
>> Quality-of-life issues and the degree of disability associated with
>> social phobia have been much less well studied. Unfortunately, social
>> phobia was not analyzed as a separate part of the ECA survey, so good
>> community-based information is not available.
>>
>> As can be seen, the anxiety disorders are not only chronic in nature,
>> but are often accompanied by a wide range of moderate impairments in
>> both psychosocial functioning and quality of life. The impairment and
>> early onset of these disorders raise questions about what
>> developmental distortions they may produce and what benefits early
>> treatment may provide.
>>
>> THE DEVELOPMENT OF COMORBIDITY DURING THE LONGITUDINAL COURSE OF
>> ANXIETY DISORDERS
>>
>>
>> One of the most im****tant issues in the long-term treatment of the
>> anxiety disorders is the presence of comorbidity. Any long-term
>> anxiolytic treatment strategy must take account of the high rates of
>> comorbidity that appear to develop during the longitudinal course of
>> panic, GAD, and social phobia—and that complicate these disorders, in
>> fact, from their very inception. Comorbidity rates for adolescent
>> anxiety disorders have been re****ted to range from approximately 20%
>> to 60%, with higher rates recorded for patient samples that are under
>> treatment (21).
>>
>> It is well-established that comorbidity is significantly higher for
>> patients seeking treatment than for persons not in treatment in the
>> community. Nonetheless, even community surveys suggest a high rate of
>> comorbidity, especially for GAD. In the ECA survey (51), 1-year
>> prevalence estimates, reflecting current comorbidity, showed that
>> approximately 25% of patients with a diagnosis of GAD also suffered
>> from either panic or major depression, while an additional 30%
>> (approximately) suffered from another Axis I diagnosis, leaving only
>> about 40–45% of patients with "pure" GAD (at least from an Axis I
>> standpoint, though the extent to which social phobia might have been
>> an undetected source of comorbidity is unclear). This figure re****ts
>> only 1-year prevalence rates for comorbidity, and as such is a likely
>> underestimate because anxiety has been shown frequently to evolve into
>> either depression or panic (10) over time.
>>
>> Patient surveys show even higher rates of comorbidity, though the
>> samples studied are obviously much smaller. Massion et al. (29) found
>> that of 123 psychiatric outpatients diagnosed with GAD, 51% had a
>> history of comorbid panic disorder. When these patients were edited
>> out, 46% of the remaining patients had a history of comorbid major
>> depression and 27% had social phobia. Overall, only 1.6% (2 of 123
>> patients in a psychiatric treatment setting) were felt to have "pure"
>> GAD, with no history of comorbid depressive or anxiety disorders.
>> Similarly, Brown and Barlow (10) have re****ted high comorbidity rates
>> for outpatients with a principal diagnosis of GAD. Thirty-six percent
>> suffered from concurrent panic disorder with or without agoraphobia,
>> 29% suffered from concurrent social phobia, and 29% suffered from
>> concurrent major depression or dysthymic disorder. In another study
>> (37) of outpatients who had been recruited through the media, 34% had
>> a history of major depression and 17% had a history of social phobia
>> (a panic disorder diagnosis was a reason for exclusion).
>>
>> The ECA community survey (51), as well as the Zurich cohort of Angst
>> (2), found that 73% of patients with panic disorder had other comorbid
>> conditions. Massion et al. (29), in their outpatient sample of 294,
>> re****ted the following rates of comorbidity, depending on whether the
>> patient was diagnosed with panic alone versus panic with agoraphobia:
>> social phobia, 6% versus 15%; major depression, 27% versus 22%; OCD,
>> 10% versus 7%. Twenty percent of panic patients suffered from comorbid
>> GAD, but these patients were excluded from the previously re****ted
>> comorbidity rates. Brown and Barlow (10), in a sample of 232
>> outpatients with a panic disorder diagnosis (both with and without
>> agoraphobia), re****ted comorbid social phobia ranging from 6% to 36%,
>> comorbid GAD ranging from 20% to 36%, and comorbid major depression
>> ranging from 7% to 36%, largely depending on the presence and severity
>> of the associated agoraphobia. In a sample of patients with panic
>> disorder alone versus panic with agoraphobia who were recruited for a
>> trial of psychotherapeutic medication, substantially higher rates of
>> comorbidity were found; for example, social phobia, 26% versus 64%;
>> GAD, 32% versus 68%; major depression, 26% versus 68% (61).
>>
>> Comorbidity patterns for social phobia are less well-studied. The ECA
>> community survey offers no data on social phobia. Brown and Barlow
>> (10) re****ted the following comorbidity rates among 76 outpatients
>> with a principal diagnosis of social phobia: panic disorder, 9%; GAD,
>> 17%; major depression, 11%; and dysthymic disorder, 13%.
>>
>> Substance abuse and Axis II personality disorders constitute two other
>> im****tant, but often neglected, categories of comorbidity which may
>> complicate the natural history of the anxiety disorders and which must
>> be taken into account when planning treatment interventions over time
>> (39, 62). Studies of alcoholic patients suggest a range of 25–45% for
>> comorbid anxiety disorders, with social phobia and panic/agoraphobia
>> being the most prevalent (60). Conversely, prevalence rates of
>> alcoholism in anxiety disorder populations range from 15% to 40% (29,
>> 37, 61, 63). The ECA community survey found, not surprisingly, much
>> lower rates of alcohol dependence/abuse. Van Ameringen et al. (68)
>> have re****ted a 28% rate of alcoholism in a group of outpatient social
>> phobics.
>>
>> Comorbidity rates for substance abuse are lower for all three anxiety
>> disorders, ranging from about 10% to 36% in patient samples (29, 37,
>> 61). Again, these rates are much lower in the ECA community survey
>> (51).
>>
>> Multiple studies have re****ted rates of comorbidity for the anxiety
>> disorders and Axis II disorders, most commonly the anxious "Cluster C"
>> type. Axis II comorbidity rates for panic/agoraphobia generally range
>> from about 30% to 60% (18, 37), with more severe agoraphobia being
>> associated with increased rates (18). Axis II comorbidity rates for
>> GAD have been re****ted in the same 30–60% range (37, 53).
>>
>> As can be seen from the above review, comorbidity is the rule and not
>> the exception in the clinical picture of the anxiety disorders.
>> Long-term treatment planning cannot be undertaken except on the
>> assumption that the majority of patients suffering from a principal
>> anxiety disorder diagnosis also suffer from another disorder, or will
>> suffer from one in the near future. This clinical reality makes it
>> im****tant to maintain an index of suspicion concerning the development
>> of other disorders, and to carefully reevaluate the patient at
>> intervals. This is especially true if patients fail to respond fully
>> to a course of drug therapy or if an initial good response is lost. In
>> both instances, unsuspected comorbidity is frequently the culprit.
>>
>> The high rates of comorbidity among anxiety and depressive disorders
>> also raise serious questions about the true independence of these
>> disorders. An alternative way of conceptualizing comorbidity, with
>> depression for example, is to view the two disorders as varying
>> manifestations of one underlying diathesis—that is, two phenotypic
>> expressions of a common underlying "genotype." Such a view has been
>> proposed by Tyrer et al. (65), who speak of a "general neurotic
>> syndrome." Recent genetic analyses of women suffering from major
>> depression and GAD (22) provide some confirmation for this
>> perspective, with results suggesting that the genetic vulnerability
>> for both disorders is largely shared.
>>
>> EVIDENCE FOR SUSTAINED EFFICACY (PREVENTION OF RELAPSE AND RECURRENCE)
>> DURING CONTINUATION AND MAINTENANCE THERAPY
>>
>>
>> Previous sections of this chapter have established that the anxiety
>> disorders are frequently chronic conditions associated with (a) a high
>> degree of comorbidity and (b) impairment in both psychosocial
>> functioning and quality of life. Furthermore, evidence has been
>> presented that acute (4–12 weeks) drug therapy frequently results in
>> early return of symptoms (relapse) or subsequent episodes (recurrence)
>> when treatment is discontinued. What is the evidence, though, that
>> continuation therapy is effective in preventing relapse, or that
>> maintenance therapy is effective in preventing recurrences?
>>
>> Unfortunately, there is little controlled research addressing these
>> issues for panic/agoraphobia or GAD, and none for social phobia. The
>> evidence for the efficacy of continuation and/or maintenance therapy
>> of panic disorder is currently being studied in an NIMH-funded
>> multicenter trial that compares imipramine to a form of
>> cognitive-behavioral therapy.
>>
>> Schweizer et al. (58) have conducted an 8-month, placebo-controlled
>> study of continuation therapy for panic disorder with alprazolam and
>> imipramine that found sustained efficacy for both compounds with no
>> dose escalation, suggesting an absence of tolerance to the therapeutic
>> effect. When drug was discontinued after 8 months of maintenance
>> therapy, at 3 weeks post discontinuation, approximately 25% of
>> patients had experienced a return of their panic attacks. At 1 year
>> follow-up, 30% of patients had a recurrence of their panic, and 49%
>> had restarted or never stopped their medication (50). Of course, the
>> selection bias that was likely operating in the choice of patients for
>> the initial study, as well as the naturalistic nature of the
>> follow-up, makes this only a suggestive pilot study.
>>
>> Preliminary evidence for the efficacy of continuation therapy of GAD
>> comes from two studies (43, 47). In both studies the benzodiazepine
>> therapy achieved sustained remission of anxious symptomatology with no
>> tolerance and no dose escalation over a 6-month period. In the second
>> study, buspirone also achieved a comparable sustained remission of
>> anxious symptoms, though the significantly higher attrition rate by
>> patients treated with buspirone complicates the interpretation of
>> results. In both studies, about 25% of the patients experienced a
>> return of their initial anxiety within 4 weeks of drug
>> discontinuation.
>>
>> There is no good published evidence for the sustained efficacy of
>> either antidepressants or the benzodiazepines in the continuation or
>> maintenance treatment of social phobia. The only published re****ts
>> found both tranylcypromine (69) and clonazepam (13) to sustain
>> efficacy over an 11- to 12-month period of treatment.
>>
>> The 1979 National Survey of Psychotherapeutic Drug Use (67) indicates
>> that a small fraction of patients with anxiety syndromes take
>> psychotherapeutic medications for a year or more (panic/agoraphobia,
>> 25%; other phobias, 6%; general anxiety, 6%). On the other hand,
>> experts in the pharmacotherapy of these disorders, aware that they are
>> chronic, severe, and disabling, generally recommend vigorous,
>> long-term treatment. Here, as is so often the case, clinicians have
>> had to use their best judgment in addressing clinical problems that
>> lie beyond the scope of existing empirical evidence. Whether long-term
>> drug treatment represents effective continuation or maintenance
>> therapy, or patients continue to take medication because it elicits
>> only a partial response, is uncertain. Two of the present authors have
>> re****ted HAM-A scores of 16 in anxious patients with a mean of 6 years
>> of benzodiazepine therapy, suggesting that long-term drug therapy, at
>> least in this population, may have been continued even though (and
>> perhaps because!) it was less than effective. The public health
>> interest urgently requires clinical research to address these
>> long-term issues of efficacy.
>>
>>
>> RISKS OF LONG-TERM MEDICATION TREATMENT
>>
>>
>> The efficacy obtained from drug therapy must always be weighed
>> carefully against the potential adverse effects of the drug. This is
>> especially true when it comes to long-term or maintenance drug
>> therapy. What is considered tolerable, and even safe, during acute
>> treatment may be neither of the above during chronic administration.
>> This section will focus most intensively on the safety of long-term
>> administration of the benzodiazepines. Not only have they been the
>> object of intense scrutiny and concern, both publicly and
>> scientifically, over the past 10–15 years (see ref. 71 for an
>> excellent review), but they continue to be widely prescribed,
>> sometimes for long-term therapy. The most recent survey data indicate
>> that 1.6% of the adult population in 1980 took benzodiazepine for 12
>> months or longer in the previous re****ting year (32). Some decline in
>> long-term usage appears to have occurred since then, but it is still
>> estimated that approximately 1% of the adult population has currently
>> or recently received long-term benzodiazepine therapy.
>>
>> Benzodiazepines
>>
>> Discussion of the safety of the benzodiazepines during chronic use can
>> be usefully reviewed under two headings: (i) the psychological and
>> behavioral effects and (ii) the medical or physiological effects.
>>
>> A variety of psychological and behavioral effects have been attributed
>> to the benzodiazepines when chronically administered. These include:
>> persistent attentional, psychomotor, cognitive, and memory-impairing
>> effects; abuse liability; physical dependence and withdrawal;
>> post-withdrawal craving; and effects on coping and stress response
>> capabilities. A brief review of each of these potential safety
>> concerns is necessary in order to obtain a more complete picture of
>> the benefit–risk equation regarding long-term therapy.
>>
>> Attentional, Psychomotor, Cognitive, and Memory Effects
>>
>> Substantial tolerance appears to develop to the attentional and
>> psychomotor effects of benzodiazepines, beginning after the first few
>> weeks of acute administration. The actual clinical significance (e.g.,
>> effects on driving ability) of subtle residual impairments, or the
>> potentiation of these impairments by low levels of alcohol consumption
>> that otherwise would pose no problem, is uncertain. Results of
>> laboratory *****sments, including driving simulation, have had very
>> variable and contradictory results (see refs. 1 and 71 for reviews).
>> But there appears to be some persistent attentional and psychomotor
>> impairment that may be relevant to the execution of complex real-world
>> tasks.
>>
>> Preliminary research suggests that cognitive tasks and (especially)
>> short-term memory tasks continue to be impaired even after long-term
>> (5–10 years) daily administration of benzodiazepines (25), apparently
>> exhibiting less tolerance than psychomotor function. The existence of
>> differential rates of tolerance development is an intriguing
>> phenomenon, and may depend on subtle regional differences in the
>> monomeric constituents of the benzodiazepine receptor. The amnestic
>> effect of benzodiazepines, which appears to be relatively resistant to
>> tolerance in humans, probably has a hippocampal substrate. It should
>> be cautioned that statistically "significant" amnestic findings
>> ascertained, for example, using meaningless word lists may have little
>> generalizability to life situations. Furthermore, since
>> moderate-to-severe anxiety frequently has been noted to impair
>> performance, the net effect of benzodiazepine treatment may be an
>> enhancement of performance. Nonetheless, the subtle effects on
>> learning and motivation of chronic, mild benzodiazepine-induced
>> amnesia have not been well-studied.
>>
>> A final behavioral effect for which there is no good evidence that
>> tolerance does, or does not, develop with long-term benzodiazepine
>> administration is irritability and hostility.
>>
>> Abuse Liability
>>
>> Benzodiazepines have a potential for recreational abuse (1, 71). But
>> actual recreational abuse appears to occur principally in persons who
>> abuse other drugs (see ref. 71 for review).
>>
>> The abuse liability of the benzodiazepines in drug and alcohol abusers
>> appears to stem in large part from marked individual differences in
>> the euphoriant effects of benzodiazepines. Drug addicts, alcoholics,
>> and even the nonalcoholic sons of alcoholics appear to be much more
>> susceptible to the euphorigenic properties of the benzodiazepines
>> (11). In most other populations, even among anxious persons (14),
>> benzodiazepines do not appear to have much of a euphoric effect. In
>> fact, the reinforcing properties of the benzodiazepines appear to be
>> relatively low compared to every other drug of abuse (71). The
>> reinforcing property of a drug appears to be an im****tant behavioral
>> correlate of abuse liability that tends to be fairly consistent across
>> primate species. Even when one corrects for availability, diazepam and
>> alprazolam are more widely abused in at-risk populations. It is
>> unknown whether this re****ted effect is due to methodological problems
>> with the adjustment for availability or to the rapidity of onset of
>> action (lipophilicity, etc), or to differences in the intrinsic
>> efficacy of the benzodiazepine at the receptor.
>>
>> Another indicator of abuse liability that has been identified is drug
>> liking or preference in normal human subjects. Here, again, the
>> benzodiazepines appear to elicit much less drug liking than do
>> traditional drugs of abuse (14, 31).
>>
>> Physical Dependence and Withdrawal
>>
>> An ineluctable consequence of chronic benzodiazepine therapy is
>> physical dependence, along with the likelihood of developing a
>> withdrawal syndrome upon drug discontinuation. The clinical picture of
>> benzodiazepine withdrawal is not always easy to distinguish from
>> anxiety, though the tem****al pattern of onset is of some help. Further
>> confounding the clinical picture is that the experience of
>> benzodiazepine withdrawal may serve, in turn, to trigger a
>> recrudescence of the patient's underlying anxiety. Common symptoms of
>> the benzodiazepine withdrawal syndrome consist of increased anxious
>> mood and nervousness, insomnia, restlessness, tension, irritability,
>> lethargy, nausea, depression, hyperacusis, and tinnitus. There appear
>> to be no pathognomonic symptoms that are unique to the withdrawal
>> syndrome and that do not commonly occur in anxiety disorders. After
>> abrupt discontinuation of a short half-life benzodiazepine (e.g.,
>> alprazolam or lorazepam), withdrawal symptoms begin to appear within
>> 6–12 hr, with a peak severity generally at 2–4 days. Symptoms usually
>> subside within 1–3 weeks. After abrupt discontinuation of a long
>> half-life benzodiazepine (e.g., diazepam or clorazepate), withdrawal
>> symptoms begin to appear within 24–36 hr, peak at 4–7 days, and
>> subside within 2–4 weeks. The benzodiazepine withdrawal syndrome,
>> unless complicated by other medical or psychiatric illness or by other
>> drug or alcohol problems, can be managed in an outpatient setting.
>>
>> Several factors have been identified that appear to contribute to the
>> development of benzodiazepine withdrawal and that add to its severity.
>> The first of these is duration of therapy. Rebound anxiety (to a level
>> above pretreatment baseline) has been observed after as little as 4
>> weeks of benzodiazepine treatment (46). Such transient rebound
>> reactions are thought to be the prodromal signs of a developing
>> pattern of dependence and withdrawal. By 3–4 months, physical
>> dependence is likely to have been established, and a withdrawal
>> syndrome upon benzodiazepine discontinuation can clearly be observed
>> in a significant number of patients. There is no good evidence that
>> longer durations of maintenance therapy beyond 12 months contributes
>> to greater dependence and withdrawal liability (49, 57).
>>
>> A second factor that contributes to dependence and withdrawal is the
>> daily dose of the drug. It is im****tant to note, though, that
>> dependence and withdrawal do not require aggressive dosing. Patients
>> treated with as low as 5–10 mg of diazepam or its equivalent have been
>> noted to experience withdrawal reactions upon drug discontinuation.
>> The clinical implications of the dose and duration of treatment
>> factors is that only the most short-term treatment is without risk of
>> physical dependence and withdrawal. The medical–legal implication of
>> this situation is that information on dependence and withdrawal
>> effects should probably be a routine part of the educational
>> introduction of all patients to the benefits and risks of
>> benzodiazepine therapy.
>>
>> Several other factors contribute to the severity of benzodiazepine
>> withdrawal. These include the rate of taper (obviously abrupt
>> discontinuation poses a greater problem than a gradual taper over 4–8
>> weeks) and the presence of Axis I and II disorders. Residual anxiety,
>> panic, and depressive symptoms also predict greater difficulty with
>> withdrawal.
>>
>> One unresolved issue is whether the benzodiazepine withdrawal syndrome
>> may persist, in some form and in some patients, for many months, or
>> even years. A subset of patients subjectively re****ted ongoing
>> symptoms and complaints (3), and a "post-withdrawal syndrome" has even
>> been proposed (64). The pharmacologic mechanism of this proposed state
>> of persistent withdrawal is unclear, though a putative "receptor
>> ****ft" has been suggested. It is, of course, difficult to disentangle
>> persistent symptoms of withdrawal from a recrudescence of anxiety. The
>> fact that the symptoms differ from a patient's previous experience of
>> anxiety is no guarantee that an iatrogenic state has been triggered,
>> because symptoms of anxiety can change over time. It is also of
>> interest that two of the authors (Rickels and Schweizer) have noted an
>> absence of any re****ts of persistent withdrawal states in abstinent
>> patients with a history of benzodiazepine dependence, but in whom
>> benzodiazepines were not prescribed for anxiety. In most cases, such
>> post-benzodiazepine discontinuation symptoms are most likely related
>> to the patient's Axis I and Axis II disorders. Still, it is a topic of
>> concern, and deserves further research, whether chronic administration
>> of benzodiazepines may in some way permanently alter the
>> benzodiazepine-GABAergic system.
>>
>> Post-withdrawal Craving of Drug and Restarting Benzodiazepine
>>
>> It is an almost universal feature of drugs of abuse that they
>> intermittently evoke craving in the user long after the withdrawal
>> syndrome has subsided. Alcohol, tobacco, cocaine, amphetamines,
>> opiates, and even coffee engender cravings in the months and years
>> after drug discontinuation. Preliminary research (26) suggests that
>> there is little or no craving associated with long-term dependence on
>> benzodiazepines. Certainly former benzodiazepine-dependent patients do
>> restart their benzodiazepine, but resumption of benzodiazepine use is
>> almost exclusively caused by a recurrence of symptoms of anxiety.
>> Naturalistic follow-up studies of chronic benzodiazepine users find a
>> clear trend over time toward lower daily doses, and eventual
>> discontinuation. The pharmacoepidemiological data (32) also indicate
>> that the vast majority of regular daily benzodiazepine use continues
>> less than a year (85%) and usually less than a month (67%).
>>
>> Long-Term Medical/Physiological Effects
>>
>> The risk of adverse medical or physiological effects from chronic
>> benzodiazepine therapy has not been systematically studied. Medical
>> evaluations of over 400 benzodiazepine-dependent patients (mean
>> duration of use: >5 years), which included blood chemistries, complete
>> blood count with differential, urinalysis, and electrocardiogram, have
>> yielded no obvious abnormalities (Rickels et al., personal
>> communication). A question has been raised concerning whether chronic
>> benzodiazepine treatment might be associated with increased
>> ventricular–brain ratios on computerized tomography scans. Several
>> studies have yielded conflicting results on this subject, but because
>> a variety of other comorbid medical factors, particularly alcohol use,
>> were not excluded, the issue remains unresolved (1).
>>
>> Several other physiological effects appear to result from chronic
>> benzodiazepine treatment. Preliminary data suggest that chronic
>> treatment alters the functional status of one or more components of
>> the benzodiazepine– GABAergic receptor complex (33). One of the
>> hypothesized mechanisms for benzodiazepine withdrawal suggests that
>> the symptoms can be explained by the "overdrive" of downstream
>> noradrenergic, s*****onergic, and cholinergic receptors that have been
>> released from inhibitory control (that had been previously augmented
>> by the exogenously administered benzodiazepine agonists).
>>
>> Parenthetically, clinical anxiety may be due to a subsensitivity of
>> the benzodiazepine receptors (52). If additional data establish that a
>> functional deficit in benzodiazepine receptors is one of the
>> pathological substrates of anxiety, then the rationale for maintenance
>> therapy with benzodiazepines would be greatly strengthened.
>>
>> Antidepressants and Azapirones
>>
>> Long-term safety *****sments of the tricyclic antidepressants, and of
>> the newer SSRI antidepressants, has long been a routine part of the
>> drug development and FDA approval process. Most safety research on
>> antidepressants has been conducted on depressed populations, but from
>> a behavioral and medical standpoint one might tentatively extrapolate
>> to a population of patients suffering from anxiety disorders. Safety
>> and benefit–risk issues relating to antidepressants as a class are
>> discussed elsewhere in this volume (see In Vivo Structural Brain
>> *****sment, Methodological Issues in the Neuropathology of Mental
>> Illness, and Psychiatric Molecular Genetics). Noyes et al. (36) have
>> re****ted safety data on long-term use of tricyclic antidepressants in
>> a population of panic patients followed-up naturalistically for 1–4
>> years. They found that 35% of these patients were unable to tolerate
>> tricyclic antidepressants (TCAs) and discontinued them. Early
>> discontinuations (in the first 6 weeks) were most commonly for
>> overstimulation, orthostatic reactions, and allergic reactions. Late
>> discontinuations were most commonly for weight gain and persistent
>> anticholinergic effects. Forty percent of long-term patients re****ted
>> weight gain, with the mean weight gained being 22 pounds.
>>
>> Abrupt discontinuation of long-term antidepressants (TCAs, MAOIs, and
>> short half-life SSRIs) has also been re****ted to result in a
>> withdrawal reaction (15). The exact prevalence, or consequences, of
>> such withdrawal reactions has not been systematically studied for
>> panic disorder patients, though it appears to be correlated with the
>> rapidity of the taper schedule. For TCAs, the withdrawal reaction may
>> be related to cholinergic rebound, with common symptoms consisting of
>> insomnia, nausea, headache, and tremor. For the MAOIs, vivid dreams
>> associated with rapid eye movement (REM) rebound are also observed.
>> The extent to which these withdrawal reactions trigger a recrudescence
>> of panic is uncertain.
>>
>> Buspirone appears to be safe in maintenance therapy (41, 47). Unlike
>> the TCAs, no significant side effects were found to emerge with
>> long-term therapy. In general, buspirone was well-tolerated during
>> maintenance treatment. No withdrawal reaction has been re****ted to
>> occur upon discontinuation.
>>
>>
>> BENEFITS AND RISKS OF COMBINED TREATMENTS
>>
>>
>> Combined Drug Therapies
>>
>> Surveys of prescribing practices suggest that perhaps one-quarter to
>> one-third of anxiolytic drug therapy consists of treatment with
>> combinations of drugs. The addition of a second or third drug may be
>> clinically indicated because of the presence of a comorbid
>> condition—most commonly either another anxiety disorder or an
>> affective illness. But virtually no controlled research exists
>> concerning the effectiveness of long-term drug treatment for comorbid
>> conditions with one, not to mention two, drugs.
>>
>> Combined Drug and Psychotherapy
>>
>> Again, it is common clinical practice to combine anxiolytic drug
>> therapy with some form of psychotherapy. Yet there are virtually no
>> controlled studies that establish the clinical indications or additive
>> efficacy of such treatment. Nor can it be confidently predicted that
>> the addition of psychotherapy to a drug regimen, or vice versa, will
>> result in enhanced efficacy. In fact, experienced cognitive therapy
>> researchers (A. T. Beck, personal communication, May 1993) believe
>> that the efficacy of cognitive therapy in panic disorder is reduced by
>> the concomitant administration of benzodiazepines. The reason for
>> this, if it is confirmed, is uncertain. Perhaps the cognitive effects
>> of benzodiazepines hamper psychotherapy, or perhaps learning under the
>> influence of a benzodiazepine does not carry over to the drug-free
>> state (state-dependent learning).
>>
>> NEED FOR FUTURE RESEARCH ON MAINTENANCE TREATMENT
>>
>>
>> The high chronicity and/or recurrence rate of the major anxiety
>> disorders suggest that studies of the safety and efficacy of
>> maintenance therapy should be integral to the *****sment of any drug
>> or psychotherapy. Acute symptom reduction is im****tant to achieve, but
>> is a hollow victory over the distress and disability associated with
>> clinical anxiety if it cannot be sustained.
>>
>> Research questions, largely unanswered, concerning maintenance
>> treatment of GAD, social phobia, and panic disorder are legion and
>> include the following: What constitutes an adequate course of
>> maintenance drug therapy? What are the predictors (e.g., duration,
>> severity, rate of recurrence, comorbidity) that suggest the need for
>> further continuation therapy? What are optimal doses for both
>> maintenance and continuation therapy? When, if ever, are intermittent
>> medication strategies indicated as opposed to maintenance or
>> continuation therapy? Does any further clinical improvement accrue
>> from maintenance therapy compared to what is achieved by acute
>> therapy? Is there any prophylactic benefit, in terms of long-term
>> outcome, from continuation therapy? What is the safety of continuation
>> drug therapy—including withdrawal, rebound, and other behavioral
>> effects? Does tolerance develop during the course of maintenance or
>> continuation drug therapy, or is efficacy maintained? What is the
>> optimal way to discontinue maintenance or continuation drug therapy?
>> How should emergent comorbidity be optimally managed? When are
>> combination drug therapies indicated, and what are the safety and
>> efficacy of such combination therapies? What is the comparative safety
>> and long-term efficacy of drug versus psychotherapy? Can response
>> predictors be identified for choosing drug versus psychotherapy? What
>> are the clinical indications, safety, and efficacy of combined drug
>> and psychotherapy?
>>
>> All of these questions can, and should, be asked, not only for each
>> anxiety diagnosis, but for each treatment modality: benzodiazepine,
>> TCA, MAOI, SSRI, azapirones, cognitive therapy, dynamic therapy, and
>> so on. The investigation of the long-term treatment and outcome of the
>> anxiety disorders is a difficult area of research. It is afflicted
>> with its own methodological problems that daunt even the most seasoned
>> researcher who dares to enter this largely uncharted domain. These
>> problems include: issues of sample size; patient retention over time;
>> the influence of retention strategies on outcome; how to handle a host
>> of potentially significant intervening variables (e.g., non-study
>> medication usage, life events, etc.) that cannot be simply excluded as
>> they can in acute treatment studies; how and when to randomize for
>> maintenance therapy; how to handle emergent comorbidity; how to handle
>> taper and discontinuation of study medication; how to undertake
>> long-term follow-up post study; and how to determine appropriate
>> outcome measures.
>>
>> ACKNOWLEDGMENTS
>>
>>
>> Preparation of th |
