Fw: 2 deaths; few other surprises; bup-combo vs clonidine for 'detox'.

Preston Peet ptpeet at nyc.rr.com
Fri Aug 19 08:33:42 EDT 2005


Hi all,
    Here's more from Andrew Byrne.
    While I don't always agree with him, I always appreciate his posts and 
the information he provides us in his extremely detailed and comprehensive 
postings.


Peace and love,
Preston Peet

"Madness is not enlightenment, but the search for enlightenment is often 
mistaken for madness"
Richard Davenport-Hines

ptpeet at nyc.rr.com
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Etc.

----- Original Message ----- 
From: Andrew Byrne
To: ajbyrne at ozemail.com.au
Sent: Friday, August 19, 2005 1:22 AM
Subject: 2 deaths; few other surprises; bup-combo vs clonidine for 'detox'.


Ling W, Amass L, Shoptaw S, et al. A multi-center randomized trial of 
buprenorphine-naloxone versus clonidine for opioid detoxification: findings 
from the National Institute on Drug Abuse Clinical Trials Network. Addiction 
(2005) 100: 1090-1100

Dear Readers,
This 14 day trial showed buprenorphine-naloxone prescribed patients 
significantly more likely to stay in treatment and stop using street drugs 
than those taking clonidine.  It also found much better completion rates for 
in-patients (77%; 22%; n = 77; 36) compared with out-patients (29%; 5%; n = 
157; 74) prescribed the opioid versus clonidine.  Considering the 
buprenorphine was given in therapeutic doses of 2mg daily up to the last 
day, these results are not surprising.

However, it is intriguing that there are so many inconsistencies in this 
report from such highly respected authors.  Most useful randomised trials 
compare an intervention of known utility with a protocol of promising but 
uncertain benefit - using parallel protocols and clearly defined, positive 
end points regarding the subjects' health.  There are usually equal numbers 
of participants but it appears this trial was halted early by a 
pre-determined protocol due to the poor outcomes of the clonidine group. 
Unusual for 'Addiction', this multi-centre trial does not appear to have an 
ethics statement concerning the protocols, the many authors and funding. 
Nor could I see a statement on conflict of interest.  In-patients and 
out-patients are included but selection criteria are not given, nor are they 
randomised.  Also unusual for Addiction, there is more than half a page of 
acknowledgements containing 85 names and up to 20 institutions.  Several 
aspects of the article remind me of the sort of item contained in sponsored 
journal supplements.  One wonders if the normal peer-review process 
occurred, so numerous are the inconsistencies, omissions and questions 
concerning a lack of specific clinical aims/focus in the piece.

As above, most of the findings are predictable from the literature.  The 
study involved a comparison of two non-evidence based 'treatments', being 
clonidine for detoxification and buprenorphine combination for 
'detoxification'.  Both 'treatments' have been shown to be ineffective in 
trials with over 90% failure rates on conservative criteria at medium term 
follow-up (1 to 3 months).  Thus this study, whatever its findings, is 
unlikely to add to the scientific literature or knowledge base.  We know 
that prescribing buprenorphine in standard doses to heroin addicts attracts 
and retains subjects while also reducing heroin use.  We also know that 
clonidine does not do any of the above to any measurable or consistent 
extent although its use still has supporters and there is some promise of 
its chemical cousin, lofexidine (Brit-Lofex) for withdrawal symptoms.  As 
yet, we still do not know whether the buprenorphine combination (bup-combo) 
drug is as effective as pure buprenorphine.  There are indications that it 
is less efficacious (Bell) although another paper (Strain) showed 
contrary-wise that the combination drug caused consistently higher blood 
levels of 10-40% and thus might be expected to yield a better response. 
Thus readers may ask why use a combination drug rather than the pure drug, 
especially when the combination drug is not approved for commencement of 
treatment.  The combination drug's only claimed benefit is reduced 
attractiveness to the street market.  Yet dose diversion would not seem to 
be an issue here, being largely supervised and only short-term.

Unsurprisingly, the authors find that a higher proportion of bup-combo 
opioid dependent patients remained in 14 days of prescribed "detox" than 
those given no opioids.  Also, and most importantly, they found that 
in-patients fared much better than out-patients in all respects (apart from 
hapless pair who perished in the in-patient group).

The authors fail to clearly define 'opioid detoxification'.  Some might find 
the prescribing of opioids during 'detoxification' incongruous.  Opioid 
detoxification cannot really commence until the patient ceases all 
significant intake of opioids.  Even on day 13, these patients were offered 
2mg of buprenorphine, still ten times the standard analgesic dose of 0.2mg 
sublingual (the maximum dose given - on day 3 - was 16mg).  A further period 
of 14 days follow-up for the bup group might have allowed a fairer 
comparison of the two approaches in this case.

Either way, the authors have not clearly defined what they mean by 
detoxification, nor have they explained their statement in the abstract that 
'success' involved an 'opioid-free urine sample on the last day of clinic 
attendance'.  Perhaps their pathologist was unable to detect buprenorphine. 
Later in the article they state this must be free of *illicit* opioids, 
without defining *illicit*.  Buprenorphine, like methadone, morphine or 
codeine can be licit or illicit.  Indeed, it was to address the issue of 
diversion that the combination drug was introduced into the USA.  Yet we now 
know that it can be abused, and that there is little if any evidence of less 
diversion than for other prescribed opioids.

In several countries now, even heroin can be legally prescribed and it is 
possible that, prescribed in decreasing doses, it might have comparable or 
better results than buprenorphine reductions.  The very next item in 
Addiction is, in fact, a favourable comparison of oral morphine with 
methadone from experienced researchers in Austria.

Adverse events:
The section on side effects starts out with a long, confusing, 'de 
Quincey-esque' sentence of 62 words.  In the following 57 lines comes a 
tedious and confusing 'lecture' to the reader on the technical difference 
between 'serious adverse events' and 'adverse events'.  Only at line 37, and 
after the reassuring statement 'Few serious adverse events occurred in 
either protocol' do we first learn of two deaths in this 14 day, 344-subject 
study.  This implies a very high average mortality and requires some 
detailed explanation.  All we are told is that one death (in the bup-combo 
group) was due to 'respiratory failure' (could this be 'code' for drug 
overdose?) and one was from the clonidine treated group ('bacterial 
endocarditis' - usually a slow or sub-acute disease in drug addicts).  We 
are told (without coronial references) that 'neither death was attributed to 
study medication'.  However, we are also told that patients in both groups 
took an average of three other medications during the trial, including 'OTC' 
acetaminophen (paracetamol), ibuprofen, loperamide and diphenhydramine as 
well as prescribed oxazepam, lorazepam, phenobarbital, hydroxyzine, 
methocarbamol, trimethobenzamide, Donnatal (containing phenobarb), zolpidem, 
trazadone and doxepin.

I have never heard of a patient dying whilst undergoing supervised 
detoxification from opioids, so these mortality reports need to be taken 
very seriously, especially when the patients were in a NIDA approved 
treatment protocol in registered and (presumably) accredited medical 
facilities.  I can only speculate (as the authors do not) that this was a 
trial which attracted the most severely ill American addicts and/or may not 
have provided the best means to rehabilitation for their condition.  Neither 
trial protocol is an 'evidence based' or proven modality for heroin 
addiction, even though both may be reasonable choices for subjects as long 
as they also have the option of more effective avenues such as traditional 
methadone maintenance.  In many American (and Australian) cities there are 
still long waiting lists and/or methadone is beyond the financial reach of 
many addicts.

The authors state "In the out-patient group, 18 serious events occurred, 
with 14 in the bup-nx group and four in the clonidine group."  Equal numbers 
of serious events occurred in the in-patient groups, including two with 
suicidal behaviour and one with persistent vomiting in those receiving 
bup-nx.  I am mystified how an in-patient can have a 'motor accident' whilst 
under treatment, yet, along with 'spine surgery' we are offered this as an 
'adverse event' without further explanation.  It is also hard to understand 
how a patient who was assessed as suitable for detoxification could have 
died so quickly of sub-acute bacterial endocarditis.  Detoxification is 
highly unwise in those with active septicaemia.  One patient dropped out due 
to 'sensitivity to a study medication' (unspecified).  This 'unfortunate' 
omission becomes a 'serious' one if buprenorphine were implicated.

The most important finding of this trial is probably that in-patient 
detoxification was so much more efficacious than community treatment 
(despite there being no randomisation).  The differences were dramatic and 
they point up the inappropriate decisions made by successive administrations 
to close down drug and alcohol detoxification wards in New South Wales and 
elsewhere.  Much of this was based on claims by so-called experts of their 
services not being 'cost-effective' or 'evidence based'.  This trial shows 
that by using counselling and the Californian "Matrix" protocols and a 
'placebo' such as clonidine, excellent in-patient detox results can be 
obtained in selected patients.

Comments by Andrew Byrne ..

Conflict of interest: Dr Byrne earns a proportion of his income dispensing 
methadone and buprenorphine to registered dependency patients.

Please note that Professor Charles O'Brien has written an excellent 
editorial in this 'Addiction' pointing out many of the above problems.  Were 
he or I a reviewer, this month's edition might have been thinner.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
   Dr Andrew Byrne MB BS (Syd) FAChAM (RACP)
   Dependency Medicine,
   75 Redfern Street, Redfern,
   New South Wales, 2016, Australia
   Email - ajbyrneATozemail.com.au
   Tel (61 - 2) 9319 5524  Fax 9318 0631
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
http://www.abc.net.au/7.30/content/2005/s1418817.htm

 




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