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]
*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 this chapter was sup****ted, in part, by USPHS Research
Grant MHO-8957.
published 2000
International study of expert judgment on therapeutic use of
benzodiazepines
and other psychotherapeutic medications: IV. Therapeutic dose dependence
and
abuse liability of benzodiazepines in the long-term treatment of anxiety
disorders.
J Clin Psychopharmacol. 1999 Dec; 19 (6 Suppl 2): 23S-29S
Uhlenhuth EH, Balter MB, Ban TA, Yang K.
Department of Psychiatry, University of New Mexico School of Medicine,
Albuquerque 87131, USA. uhli@[EMAIL PROTECTED]
last paragraph:
"The experts' judgment seems to sup****t the widespread use of
benzodiazepines for the treatment of bona fide anxiety disorders, even
over
long periods. The experts generally viewed dependence and abuse liability
as
clinical issues amenable to appropriate management, as for other adverse
events related to therapy. However, more definitive clinical research on
the
remaining controversial issues is urgently needed to promote optimal
patient
care."
10587281 [PubMed - indexed for Medline]
Attitudes toward benzodiazepines over the years.
Rosenbaum JF.
Department of Psychiatry, Massachusetts General Hospital, Boston, MA
02114,
USA. jrosenbaum@[EMAIL PROTECTED]
have been used extensively for the treatment of anxiety
and
related disorders since the 1960s. Although they have been proven to be
effective as first-line treatment for anxiety disorders, during the 1980s
public perception and concern for abuse liability and physical dependence
with long-term use gave rise to a great deal of controversy. ***Negative
perceptions toward the use of benzodiazepines for treating anxiety not
only
caused severely ill patients to go untreated or under-treated but also
called into question whether the illness itself was worthy of treatment.
Although new pharmacologic and psychological treatments for anxiety are
available, psychopharmacologists continue to endorse benzodiazepines as
primary or adjunct treatment for anxiety disorders.*** The intent of this
article is to provide a historic overview of these issues and to offer
some
general clinical principles to help minimize the risk of abuse and
dependence with benzodiazepine use.
PMID: 15762813 [PubMed - indexed for MEDLINE]
The group at MGH which Rosenbaum heads apparently do a lot of Clonazepam
research with PD and find favourable outcomes, stressing that there is
little tolerance in long-term treatment and few problems with
discontinuation.
Some links to studies about clonazepam:
http://www.ncbi.nlm.nih.gov/pubmed/15078111?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The development of clonazepam as a psychotropic: the Massachusetts General
Hospital experience (JF Rosenbaum et al., 2004)PMID: 15078111 [PubMed -
indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/10520979?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
PMID: 10520979 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/9641001?ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
9641001 [PubMed - indexed for MEDLINE]
Title: International study of expert judgement on therapeutic use of
benzodiazepines and other psychotherapeutic medications: II.
Pharmacotherapy of
anxiety disorders. Title Abreviation: J Affect Disord
Date of Pub: 1995 Dec 18 Author: Uhlenhuth EH; Balter MB; Ban TA; Yang K;
Issue/Part/Supplement: 4 Volume Issue: 35 Pagination: 153-62
Journal Title Code: H3V Publication Type: JOURNAL ARTICLE
Date of Entry: 960926N Entry Month: 9611 Country: NETHERLANDS
Index Priority: 2 Language: Eng Unique Identifier: 96360231 ISSN:
0165-0327
Abstract: OBJECTIVE: To assemble expert clinical experience and
judgement in the
treatment of anxiety and related disorders in a systematic, quantitative
manner.
METHODS: A panel of internationally recognized Experts in treating
anxiety and
depression was constituted by multistage peer nomination. 90% completed a
questionnaire. This re****t focuses on case vignettes of 7 anxiety
disorders
followed by questions about relevant therapeutic options. RESULTS:
Panelists
usually recommended both psychological and pharmacological
interventions. Most
favored antidepressants, usually tricyclic, for agoraphobia, panic and
OCD;
beta-blockers for specific social phobia; and benzodiazepines for GAD and
adjustment disorder. Some Experts favored polypharmacy, usually an
antidepressant and a benzodiazepine. The majority usually advocated
pharmacotherapy for 6 months or more. They recommended the same duration
of
treatment with benzodiazepines and other medications, except for GAD.
CONCLUSIONS: The responses of the Expert Panel imply that; (1) most
anxiety
disorders are serious and merit vigorous, prolonged pharmacotherapy; and
(2)
antidepressants and benzodiazepines are effective and safe for long-term
treatment of these conditions. This outcome contrasts with the widespread
apprehension about long-term pharmacotherapy, especially with
benzodiazepines,
and some regulatory views.
Abstract By: Author
Address: Department of Psychiatry, University of New Mexico School of
Medicine,
Albuquerque 87131, USA.
Title: Clinical aspects of chronic use of alprazolam and lorazepam.
Title Abreviation: Am J Psychiatry Date of Pub: 1995 Aug
Author: Romach M; Busto U; Somer G; Kaplan HL; Sellers E;
Issue/Part/Supplement: 8 Volume Issue:152 Pagination: 1161-7
Journal Title Code: 3VG Publication Type: JOURNAL ARTICLE
Date of Entry: 950831N Entry Month: 9511 Country: UNITED STATES
Index Priority: 1 Language: Eng Unique Identifier: 95351392 ISSN:
0002-953X
Abstract: OBJECTIVE: The authors' goal was to determine the clinical
characteristics of persistent users of alprazolam or lorazepam who wished
to
discontinue their medication. METHOD: Long-term users (daily use for
more than 3
months) of alprazolam (N = 34) or lorazepam (N = 97) who entered an
outpatient
treatment program for discontinuation of benzodiazepines were carefully
*****sed. Detailed histories of benzodiazepine use were obtained; a
structured
interview was used to make psychiatric diagnoses based on DSM-III-R
criteria.
RESULTS: The majority of patients were using low therapeutic doses of
medication
(lorazepam: mean = 2.7 mg/day; alprazolam: mean = 1.2 mg/day) and had
either
maintained their initial daily dose over time or decreased it. Individuals
tended to ****ft their use of medication from an as-prescribed to an
as-needed
pattern. Forty-seven percent of the patients were diagnosed with at
least one
current anxiety disorder, most commonly generalized anxiety. At least one
diagnosable personality disorder was found in 45% of the patients, most
commonly
obsessive-compulsive personality disorder. Patterns of benzodiazepine
use were
influenced by age, gender, and past history of alcohol dependence.
CONCLUSIONS:
Long-term users of alprazolam/lorazepam seeking treatment for
discontinuation
had clinically im****tant past and current psychiatric histories. They used
a
constant or decreasing dose of medication and made attempts to stop
their use.
Persistent use of alprazolam/lorazepam for therapeutic purposes did not
represent abuse or addiction as the terms are usually understood. A
substantial
pro****tion of these patients may be receiving appropriate maintenance
therapy
for a chronic psychiatric condition.
Abstract By: Author
Address: Clinical Research and Treatment Institute, Addiction Research
Foundation, Toronto, Ont., Canada.
What Are the Risks of Benzodiazepine Dependence?
We asked Carl Salzman, M.D., Professor of Psychiatry at Harvard
Medical School and Director of Psychopharmacology at the
Massachusetts Mental Health Center, Boston.
The benzodiazepines are a group of chemically related drugs used
by psychiatrists mainly to treat anxiety, insomnia, and panic
disorder. Most benzodiazepines are also prescribed by physicians
who are not psychiatrists, usually for acute stress or as part
of medical or surgical treatment. These drugs are extremely safe
and highly effective, but they may cause physical dependence
leading to a withdrawal reaction, especially when abruptly
discontinued.
The likelihood of becoming dependent on a benzodiazepine varies
with the dose of the drug and the length of the treatment. At
the usual therapeutic doses, dependence can develop after four
to six weeks of regular use. It may develop sooner at high
doses, such as those sometimes used in the treatment of panic
disorder. People who have been previously dependent on a
benzodiazepine, or on alcohol, a barbiturate, or another drug
with sedative-hypnotic properties, are also more likely to
become dependent on therapeutic doses of benzodiazepines, and
they may develop this dependence earlier than most. Physical
dependence does not influence a medication's effectiveness and
does not necessarily imply a need to increase the dose over
time. In fact, people who take benzodiazepines for months or
even years usually maintain the same dose or slightly reduce it.
The cause of dependence is the action of the drugs at nerve
receptors that lie alongside receptors for the inhibitory
neurotransmitter gamma-aminobutyric acid (GABA). With repeated
use, benzodiazepine receptors adapt to the drug's presence and
their sensitivity changes. In this state, abrupt discontinuation
causes withdrawal symptoms. The most common symptoms - anxiety,
insomnia, and agitation - are uncomfortable but not life-
threatening. Other symptoms, potentially more serious but
relatively uncommon, include withdrawal seizures, depression,
and psychotic states.
Although there is no proof, many clinicians believe that
benzodiazepine dependence develops faster and the symptoms are
more severe if the drug has a high potency and a short half-life
(is eliminated more quickly from the body). The most im****tant
high-potency, short half-life benzodiazepines used to treat
anxiety are alprazolam (Xanax) and lorazepam (Ativan). Other
familiar benzodiazepines are diazepam (Valium), chlordiazepoxide
(Librium), and oxazepam (Serax).
Patients who express concern about becoming dependent on a
medication may use the term "addiction." Physicians too may fear
that any illegitimate use of benzodiazepines will "addict" their
patients. But it is im****tant to distinguish physiological
dependence from addiction, which implies non-therapeutic,
medically unsupervised use, primarily for pleasure. Dependence
on medications may be undesirable, but sometimes it is the least
of evils. Many patients with medical illnesses are dependent on
medications to survive. Withdrawal reactions and rebound
symptoms, too, are produced by many commonly prescribed drugs,
including pain medications, antidepressants, and antipsychotic
drugs.
There is nothing unique about benzodiazepines in this respect.
Non-medical abuse of these drugs is uncommon. Most of them are
prescribed only for the short-term treatment of anxiety and
insomnia, but even long-term use rarely leads to the kind of
persistent drug-seeking associated with alcohol or heroin
addiction. Benzodiazepines may have been prescribed excessively
in the past, but now there is no evidence of rampant misuse and
abuse. Although mild dependence can be expected with long-term
use, these drugs are safe and effective for continued use in
appropriate clinical settings. Clinicians should not be timid
about prescribing benzodiazepines where appropriate, and
patients should not be afraid to take them because of the
possibility of dependence.
Are benzodiazepines still the medication of choice for patients with panic
disorder with or without agoraphobia?
Am J Psychiatry. 2003 Aug;160(8):1432-8.
Bruce SE, Vasile RG, Goisman RM, Salzman C, Spencer M, Machan JT, Keller
MB.
Brown University, Providence, RI 02906, USA. Bruce_PhD@[EMAIL PROTECTED]
Recently, pharmacological treatment guidelines for panic
disorder
have changed as newer treatment options have become available. The authors
examined how the use of psychotropic drugs has ****fted over the course of
10
years to determine if prescribing patterns have changed to reflect these
revised treatment guidelines.
METHOD: A total of 443 patients with panic disorder were enrolled in the
Harvard/Brown Anxiety Research Project, a prospective longitudinal study
of
anxiety disorders. These patients were interviewed over the course of 10
years to examine their use of psychotropic medications.
RESULTS: **Despite efforts aimed at increasing the use of selective
s*****onin reuptake inhibitors (SSRIs) in patients with panic disorder
(e.g.,
APA's practice guideline for panic disorder, Food and Drug Administration
approval of particular SSRIs for the treatment of panic disorder), only a
modest increase in their use was found**.
Treatment patterns for psychotropic drugs appear to have remained stable
over the past decade, with **benzodiazepines being the most commonly used
medication for panic disorder**.
In comparison, **SSRI use throughout the follow-up period has remained
low**. Patients using an SSRI did not have a more favorable clinical
course
than those using a benzodiazepine, nor were there significantly better
rates
of remission in patients using SSRIs and benzodiazepines concomitantly.
CONCLUSIONS: **These results highlight a gap between pharmacological
treatment guidelines and actual delivery of care in that recommendations
to
use SSRIs to treat panic disorder are not being followed**.
Factors potentially associated with promoting and ignoring treatment
recommendations are discussed.
PMID: 12900305 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12900305&dopt=Abstract
The claim - 1: Benzodiazepines are toxic chemicals foreign to our
bodies.
2: That benzodiazepines are stored in body fat and
when released trigger re-occurrence of withdrawal
symptoms.
The facts: All the food we eat contains a number of naturally occurring
benzodiazepine and benzo like chemicals, including diazepam (Valium) and
lorazepam (Ativan). [1] All life have been subject to benzodiazepines
perhaps for billions of years and has become adapted to them. Indeed,
eating a sustained benzodiazepine free diet would result in
uncontrollable seizures followed by death. Fortunately, that is
impossible.
While the amounts are small (natural plasma levels are about 0.5-1% of
that typically recorded 30 minutes after taking 10-12mg Valium), the
daily intake is much greater than would be released from fat stores.
These daily food derived benzos can become a problem for those with some
types of liver disease who are less able to metabolise them.[2] In some
cases levels become so high that benzo antagonists like flumazenil have
to be given to protect the patient.[3]
(c) 2002 - all rights reserved
**********
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