--
Carey Gregory

   >Newsgroups: sci.med,sci.med.pharmacy,sci.med.psychobiology
   >X-Mailer: Mozilla 4.03 [en] (WinNT; I)
   >Xref: news.cetlink.net sci.med:229177 sci.med.pharmacy:58962 sci.
   >med.psychobiology:17903 X-Cache: nntpcache 2.3.3b4 (see http://www.

   >> How many people with severe depression or anxiety would be saved
   >>if they could  take opiates freely?
   >Giving potentially lethal, judgement-altering {*filter*} to the suicidal
   >is an excellent idea.  I wonder why no one thought of that before?
   >--
   >Carey Gregory
GOSH AND FLUPHENAZINE AND IT'S MATES ARE NOT POTENTIALLY MIND {*filter*}S ?.
BABYMASH.

Check out my new CD "Out Of It" New Zealand Music needs your support
as do I so I can continue to grow as a recording artist,reply 4 info.

Net-Tamer V 1.10 Beta  - Test Drive

Next up: fast moving metal boxes as a means of transportation --
recipe for disaster?

Below is an article on Buprenorphine treatment of depression, which mentions that
opiates were used until the mid-1950s for this purpose, followed by short Usenet
post on the same subject.

             Buprenorphine Treatment of Refractory Depression

  J. Alexander Bodkin, MD, Gwen L. Zornberg, MD, Scott E. Lukas, PhD, and
                           Jonathan O. Cole, MD.
  (McLean Hospital, Consolidated Department of Psychiatry, Harvard Medical
                                 School).
        Journal of Clinical Psychopharmacology , 1995, 15, pp. 49-57

---------------------------------------------------------------------------
                                  Abstract

Opiates were used to treat major depression until the mid-1950s. The advent
of opioids with mixed agonist-antagonist or partial agonist activity, with
reduced dependence and abuse liabilities, has made possible the
reevaluation of opioids for this indication. This is of potential
importance for the population of depressed patients who are unresponsive to
or intolerant of conventional antidepressant agents. Ten subjects with
treatment-refractory, unipolar, non-psychotic, major depression were
treated with the opioid partial agonist buprenorphine in an open-label
study. Three subjects were unable to tolerate more than two doses because
of side-effects including malaise, nausea and dysphoria. The remaining
seven completed 4 to 6 weeks of treatment and as a group showed clinically
striking improvement in both subjective and objective measures of
depression. Much of this improvement was observed by the end of 1 week of
treatment and persisted throughout the trial. Four subjects achieved
complete remission of symptoms by the end of the trial (Hamilton Rating
Scale for Depression scores < 6), two were moderately improved, and one
deteriorated. These findings suggest a possible role for buprenorphine in
treating refractory depression.

---------------------------------------------------------------------------
                                Introduction

Throughout history, {*filter*} and its derivatives have had an important role in
the pharmacologic treatment of various behavi{*filter*}disorders and by 1850
were considered to be specific treatments for melancholia (1). At the turn
of the century, the eminent authority Emil Kraepelin recommended tincture
of {*filter*} for the acute treatment of agitated depression(2). This use of
{*filter*} and its derivatives continued to be recommended in psychiatric
textbooks until as recently as 1956(3). However, before the development of
modern methods of treatment evaluation, opiate treatment was replaced by
somatic treatments such as electroconvulsive therapy and later by monoamine
oxidase inhibitors and tricyclic antidepressants. These proved to be
effective treatments that lacked the opiates' potential for abuse...Thus,
the historically recognized antidepressant properties of the opiates have,
with a few exceptions(4-8), received little empirical evaluation.

Currently used antidepressants, all of which act on monoaminergic systems,
are neither universally effective nor free from adverse effects of their
own(9). For the benefit of patients unresponsive to or intolerant of these
agents, who may constitute 10 to 30% of the population of patients with
major depression(10), alternative drug treatments need to be evaluated.
Now, with the development of opioid partial agonist and mixed
agonist-antagonist {*filter*} exhibiting much reduced abuse and dependence
liabilities,(11) it has become possible to safely evaluate the
antidepressant efficacy of opioids.

Among these "second-generation" opioids, buprenorphine has pharmacologic
properties that make it particularly attractive as a potential
antidepressant drug. Buprenorphine, an oripavine derivative of thebaine, is
a partial agonist of the opioid mu receptor with kappa receptor antagonist
activity(12). It has undergone considerable recent clinical investigation
as a potential therapeutic agent for drug {*filter*}ion(13-15). It is safe even
in extreme overdosage(16), despite being 30 to 40 times more potent than
morphine as an analgesic. This lack of toxicity is attributed to the its
partial agonist activity at the mu receptor which results in a "ceiling
effect" on respiratory depression, because it acts primarily as a mu
receptor antagonist at high doses(17). It has a longer duration of action
than do conventional opioids, having been studied with alternate-day dosage
regimens as a maintenance drug in opiate {*filter*}s(18).The drug has modest
mood-elevating effects in humans, which actually decline with increasing
dose, and is devoid of the dysphoric effects seen with increasing doses of
cyclazocine-like compounds(17,19). Former {*filter*} {*filter*}s report that
buprenorphine causes feelings of generalized contentment, but not the
"rush" induced by {*filter*}(20) Even after prolonged administration of high
daily doses of the drug, the withdrawal syndrome has been found to be mild
and quite delayed(17,19,21), although {*filter*}s aware of the absence of the
drug almost immediately(21). One study that found more marked and less
delayed withdrawal effects than prior investigations still noted that the
peak withdrawal was only 59% of the mean previously reported over the first
10 days of the discontinuation of a significantly lower equivalent dosage
of morphine(22). Furthermore, chronic treatment with buprenorphine has been
shown to decrease the self-administration of {*filter*} in primates(23) and in
humans(24).

Buprenorphine has an electroencephalographic profile in the rat similar to
that of cyclazocine(25) [Figure 1], an opioid mixed agonist-antagonist with
mu antagonist and kappa agonist properties. Cyclazocine was studied as an
antidepressant because its encephalographic profile was similar to that of
imipramine(26). It was shown in that study to have antidepressant
properties in both acute and chronic depression in a mixed psychiatric
population. However, it is not clear that cyclazocine has clinical
properties that can be equated with buprenorphine, because the {*filter*} have
opposite actions at the mu and kappa receptors and because cyclazocine does
not share its imipramine-like electroencephalographic profile with
buprenorphine in humans(21). In any case, the utility of cyclazocine came
into question when it was found to have psychotomimetic properties,(27) a
feature that buprenorphine does not have, and it was removed from clinical
use.

---------------------------------------------------------------------------
FIGURE 1. Cyclazocine and buprenorphine: molecular structures.
                                  [Image]
---------------------------------------------------------------------------
Motivated by recent evidence that buprenorphine appeared to be safer
clinically that conventional opiates, as well as by a historical literature
describing the antidepressant efficacy of opiates and more recent
investigations of antidepressant properties of endogenous opiates, Emrich
and colleagues(2) undertook the first published study of buprenorphine as
an antidepressant. This double-blind, placebo-controlled study used an
A1-B-A2 design and found that there was a robust mean improvement in
depressive symptoms over 5 to 8 days of low-dose sublingual buprenorphine
administration in a group of 10 depressed patients, most of whom were
unresponsive to standard treatments.

Some additional evidence has accumulated subsequently that buprenorphine
may have useful antidepressant properties. The drug was associated with
reduced depressive symptomatology when substituted for methadone in a
population of opiate dependent patients undergoing methadone
maintenance(28). Buprenorphine was also successful in reducing depressive
symptoms in patients with borderline personality disorder(29). Finally, in
a placebo-controlled challenge study using 11 non-drug-dependent
psychiatric inpatients, (8 with depression) buprenorphine induced a marked
improvement mood and behavior in 73% of subjects (and 75% of those with
depression); one dysphoric response was observed in a single nondepressed
control subject(30)

This study was conducted to characterize more fully the nature of
buprenorphine's potential antidepressant effects, including whether these
are persistent beyond the 5- to 8-day period previously studied and whether
the drug is effective in depression specifically found to be refractory to
current standard medication therapies.
...

read more »

Perhaps some forms of depression do respond well to opiates, as history and
the article you attached suggest. But the problems and risks that go with it
are very real.  Treatment would have to be carefully monitored.  And while it
might help some, it would undoubtedly prove deadly for many others if
dispensed without tight controls. And then there's the problem of tolerance.
The effective dose continuously increases with chronic use, but the lethal
dose remains largely unchanged.

Perhaps these problems could be overcome with attentive medical attention, but
there is one last problem that is almost insurmountable, at least in the US at
this time.  The so-called "War on {*filter*}" has made it virtually impossible for
any doctor to use opiates in this manner and continue practicing.  As it is US
doctors have a difficult enough time using them for their usual purpose
without ending up in serious trouble with the ignorant, self-serving,
self-righteous, but very powerful idiots who run this country along with the
equally clueless voters who support them.

But you do raise an interesting question after all....

--
Carey Gregory

: 0

That's not true.  For a small percentage of people, opiates are the only
thing which does resolve their depression.  The only real practical
alternative for these few people is to get on long-term methadone
maintenance.  Tell the people at the clinic how difficult it is to stop.  
That's why maintenance treatment exists, it's for people like this.  The
chances a doctor prescribing pk's for this reason are close to zero.

Another article I had saved on my PC related to this, which appears to be a condensed version of the
earlier article I posted.  First I'm reproducing a Usenet post on this subject.

Subject: Re: Buprenorphine for depression?
Date: 26 Nov 1997 13:55:51 GMT

Organization: Lexis-Nexis
Newsgroups: sci.med.pharmacy

I had the same experience when I started taking Hydrocodone (Vicodin) for
back pain.  My doc explained that it is probably due to the euphoria caused
by opiates.  Of course in our case, it's not euphoria, it just brings us
back
to normal.  I've since started a low dose of amitryptilline in addition to
the Vicodin which helped trememdously, and I'm now weaning from the
Vicodin.

-Mike Dedek

|> Has anyone out there heard of using buprenorphine for depression?  I
|> have tried all the conventional antidepressants and none seem to work.
|> However I have had the pleasant experience of taking percocet recently
|> for a pulled tooth and it made me feel NORMAL.  Not euphoric, just
|> well.  My doctor says that they are using buprenorphine for depression
|> for people who react that way to opiods.  Any input would be more than
|> welcome.

--------------------------------------------------------------------------------------------

The following are exerpts from a recent article in the Journal of Clinical
Pharmacology reporting on a study conducted at McCLean Hospital, Belmont,
Mass.

Buprenorphine Treatment of Refractory Depression
------------------------------------------------
J. Alexander Bodkin, MD, Gwen L. Zornberg, MD, Scott E. Lucas, PhD, and
Jonathan O. Cole, MD. (J Clin Pharmacol 1995;15:49-57)
                       ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

Throughout history, {*filter*} and its derivatives have had an important role
in the pharmacologic treatment of various behavi{*filter*}disorders and by 1850
were considered to be specific treatments for melancholia. At the turn of
the century, the eminent authority Emil Kraepelin recommended tincture of
{*filter*} for the acute treatment of agitated depression. This use of {*filter*}
and its derivatives continued to be recommended in psychiatric textbooks
until as recently as 1956. However, before the development of modern
methods of treatment evaluation, opiate treatment was replaced by somatic
treatments such as electroconvulsive therapy and later by monoamine
oxidase inhibitors and tricyclic antidepressants. These proved to be
effective treatments that lacked the opiates' potential for abuse...Thus,
the historically recognized antidepressant properties of the opiates have,
with a few exceptions, received little empirical evaluation.

Currently used antidepressants, all of which act on monoaminergic systems,
are neither universally effective nor free from adverse effects of their
own. For the benefit of patients unresponsive to or intolerant of these
agents, who may constiture 10 to 30% of the population of patients with
major depression, alternative drug treatments need to be evaluated. Now,
with the development of opioid partial agonist and mixed
agonist-antagonist {*filter*} exhibiting much reduced abuse and and dependence
liabilities, it has become possible to evaluate the antidepressant
efficacy of opioids.

Among these "second generation" opioids, buprenorphine has pharmacologic
properties that make it particularly attractive as a potential
antidepressant drug. Buprenorphine, an oripavine derivative of thebaine,
is a partial agonist of the opioid mu receptor with kappa receptor
antagonist action...It is safe even in extreme overdosage, despite being
30 to 40 times more potent than morphine as an analgesic. This lack of
toxicity is attributed to the its partial agonist activity at the mu
receptor which results in a "ceiling effect" on respiratory
depression...It has a longer duration of action than do conventional
opioids...The drug has modest mood-elevating effects in humans, which
actually decline with increasing dose, and is devoid of the dysphoric
effects seen with increasing doses of cyclazocine-like compounds [e.g.
pentazocine] Former {*filter*} {*filter*}s report that buprenorphine causes
feelings of generalized contentment, but not the "rush" induced by
{*filter*}...

Buprenorphine has an electroencephalographic profile in the rat similar to
that of cyclazocine, an opioid mixed agonist-antagonist...Cyclazocine was
studied as an antidepressant because its encephalographic profile was
similar to that of imipramine...[But] the utility of cyclazocine came into
question when it was found to have psychotomimetic properties, a feature
that buprenorphine does not have, and it was removed from clinical use.

...[In previous studies, buprenorphine] was associated with reduced
depressive symptomatology when substituted for methadone in a population
of opiate dependent patients... Buperenorphine was also successful in
reducing depressive symptoms in patients with borderline personality
disorder. Finally, in a placebo-controlled challenge study using 11
non-drug-dependent psychiatric inpatients,... buprenorphine induced a
marked improvement...in 73% of subjects (and 75% of those with
depression)...

This study was conducted to characterize more fully the nature of
buprenorphine's potential antidepressant effects...

                              Results

Ten subjects...met criteria for inclusion, but three could not tolerate
the drug and dropped out after one or two doses because of nausea,
malaise, or dysphoria...All subjects met DSM-III-R criteria for recurrent
major depression without psychotic features...

...Six of seven subjects achieved marked clinical improvement by the end
of the trial, and one deteriorated. The final buprenorphine dosage
averaged 1.26 mg/day...The mean endpoint HAM-D score [Hamilton Rating
Scale for Depression, minimum score at start = 20] was 10.7, representing
a 60.7% reduction from baseline...At the endpoint, four subjects (57.1%)
had HAM-D scores of six or less, whereas at 1 week, only one subject had
improved to that extent...

                 Case Reports [Only one excerpted here]

Patient 1

This outpatient was a 45-year-old, married, white academic physician...in
psychotherapy since his late 20s for the treatment of chronically
depressed mood, low energy, social anxiety...In residency training, he had
extensive dental work and was treated with oxycodone...This raised his
energy and his mood and relieved his social anxiety. He subsequently took
opiates whenever he had the opportunity, moving over time to intravenous
use...For the first several weeks of an episode of opiate use, his work
performance was markedly improved, he would then become tolerant...He was
finally discovered at work with a supply of hydromorphone, and was forced
to enter outpatient drug abuse treatment...His depressive symptoms
immediately recurred, and his psychiatrist started him on
amitryptiline...However, he continued to suffer from low energy, easy
fatigue, social anxiety, a pessimistic outlook, and little enjoyment in
life...After 5 years, he again began to abuse opiates intravenously. He
again experienced a marked enhancement of his quality of life. Over a
6-month period, he got married, aquired a new home, and made strides in
his research. He was then discovered by the hospital to be using opiates
and was induced to undergo inpatient treatment...Again he relapsed into
depression. A course of amoxapine [was unsuccessful]. Subsequent trials of
phenelzine, buproprion, and fluoxetine were without effect...He began to
have suicidal thoughts. He withdrew from research activities and rarely
left home. At this point he was referred for a trial of buprenorphine...

...Buprenorphine was rapidly titrated to 0.15 mg intranasally thrice
daily...[After experiencing some improvement] his dosage was pushed
slightly to 0.6 mg/day for the third week. He remained at this dosage for
the remainder of the 6-week study...By that time he had returned to his
research and writing. Over the next few months, his dosage was raised to
0.3 mg thrice daily and 0.45 mg at bedtime...At this dosage, he felt he
had not only recovered from depression, but had achieved a new level of
well-being and hopefulness. He reported...both a lack of acute euphoria
and an absence of tolerance to the mood-elevating effects of the drug...

                           Discussion

The degree of ...

read more »

Subject:      Orphenadrine (Disipal, Norflex) - euphoric and antidepressive effects

Date:         1997/01/11
Newsgroups:   sci.med,sci.med.psychobiology

Orphenadrine (Disipal, Norflex) is a relatively old drug, having being
available for several decades.  Its chemical structure differs only slightly
from that of diphenhydramine (Benadryl), though it is less sedating and may
produce insomnia, and it has only a weak antihistamine action.  Orphenadrine
is an anticholinergic drug with central effects and is used (primarily as
the hydrochloride, Disipal) for the relief of extrapyramidal side-effects of
neuroleptic {*filter*}.  It is also used (primarily as the citrate, Norflex) as a
centrally-acting skeletal muscle relaxant, although its value as such has
been described as uncertain.

For years, orphenadrine has been described in some pharmacopoeias as having
a euphoric effect.  The drug has also been reported to rapidly relieve
mental depression in parkinsonian patients for whom it has been prescribed,
despite physical parkinsonian symptoms being yet only slightly relieved.  A
very old issue of Martindale's Extra Pharmacopoeia stated that because of
its euphoric effect, orphenadrine warranted investigation for use in
depression.  However, this does not appear to have been followed-up in later
issues.

Particularly over the more recent years, misuse of the anticholinergic
antiparkinsonian {*filter*} for euphoric effect has come to light, and this has
been given as one reason for the recommendation that these {*filter*} should be
prescribed after extrapyramidal symptoms arise rather than prophylactically
with neuroleptic {*filter*}.  Anticholinergic antiparkinsonians which are known
to have been misused include benzhexol (trihexiphenidyl, Artane, Pipanol),
benztropine (Cogentin) and procyclidine (Kemadrin).  Orphenadrine has been
stated in the British National Formulary as being more euphoric.  The {*filter*}
in this group seem to have been engineered to enhance central and minimise
peripheral anticholinergic effects.  High doses of these {*filter*} can produce
anticholinergic psychosis.

Recent issues of the New Ethicals Compendium (a New Zealand-published guide
for medical practitioners, giving usually detailed, manufacturer-supplied
information on {*filter*} by trade name) gives "senile and presenile depressions"
as one indication for Disipal (orphenadrine HCl) in doses of 50-150 mg
daily.  However, it does not elaborate any further and my attempts to obtain
further information on this have failed.