Pilot RCT points to reduced retention, increase abstinence from illicits and alcohol with more supervision.

A pilot randomised controlled trial of brief versus twice weekly versus standard supervised consumption in patients on opiate maintenance treatment. Holland R, Matheson C, Anthony G, Roberts K, Priyardarshi S, Macrae A, Whitelaw E, Appavoo S, Bond C. D&A Rev 2012 6:483-91


Dear Colleagues,

My old professor held that it was nice to learn of controlled research supporting one’s long-held clinical beliefs. This pilot study by a Scottish group fit’s the bill in my book.

There were 60 stable methadone maintenance patients randomised to daily supervised doses (existing treatment), twice weekly supervised doses and daily unsupervised (dispensed) dosing in community pharmacies with surveys and urine tests over a three month study period. The unsupervised patients were still required to collect their medication bottles at the pharmacy daily (this seems to be a uniquely British practice).

The authors state: “This small study was not statistically powered to estimate the effectiveness of different forms of supervision. Nevertheless, our findings are of interest as results suggest that increasing levels of supervision decreased retention (a negative finding), while reducing illicit heroin and alcohol use (a positive finding). This was not statistically significant (with the exception of the alcohol result) and should be treated with caution.” [alcohol problems were reduced from 47 to 33%, a significant reduction, only in the supervised group - other groups showed the same or worse figures].

In their introduction the authors state: “..there is no evidence base for deciding the optimal period of supervision”. In fact there is some controlled research for observed dosing (ref 1) but in opiate treatment the common practice has been of early supervision and the use of take-away doses later in treatment (as also followed by this service in Scotland). This regimen is used in a large proportion of research reports, virtually all with successful outcomes compared with controls - and with few adverse reports. This is the research basis for all opioid maintenance treatments used around the world today. It also parallels what we do with unstable mental patients or diabetics who are commencing treatment. They are usually given supervised treatment for days, weeks or sometimes months rather than bottles of pills, syringes or other therapies to take home for self administration. This is just sound therapeutics utilising available resources.

Controlled research over days, weeks and a few short months has also been done on dose supervision for patients with malaria, HIV, tuberculosis, HCV and renal tract infections with demonstrated benefits, sometimes dramatic ones. The uncharted territory is in long-term treatment since most formal research is of limited duration. Hence the crucial importance of this type of study in longer-term patients. With the authors’ positive and negative findings above, they appear to be supporting the need for initial supervision with early introduction of take-away doses in appropriate cases.

A substantial black market price for any drug and/or a shortage of the treatment availability (such as HIV meds in the third world or America) can yield a strong incentive to sell or divert medication. New patients and those in difficulties may benefit from on-going observation of their dosing (called ‘DOT’ in some work: Directly Observed Therapy) regardless of what they are being treated for.

In the UK uniquely, addicted patients who are new to treatment are often given doses to consume at home despite no controlled research base for this. Indeed, in some countries this would be considered unethical and dangerous, like the criticism of ‘giving alcohol to alcoholics’ (also debateable - see below Toronto experience ref 3).

New York Mayor Giuliani and Senator John McCain have joined a small number of high profile people with serious attempts to restrict the US methadone program, (which is largely *supervised*). Methadone treatment was called “disgusting and immoral” and “an Orwellian drug swap.” It would be even easier to criticise the UK program which is largely unsupervised. While there are calls for methadone maintenance to be curtailed (Ref 2) there are still UK experts trying to defend the use of unsupervised methadone treatments despite its unproven nature. Such moves to restrict opiate programs have naturally caused disquiet amongst this most vulnerable and stigmatised group.

Supervision using adequate methadone doses and graduated take-home provisions for suitable patients - an approach which is evidence-based and time honoured. And in the UK, even those on official government funded treatment, many receive treatment which is sub-optimal and ineffective (Ref 4). As well as ensuring compliance and protecting the patient/family, dose supervision also protects this treatment from needless controversy. In an exhaustive email exchange with one of the most respected addiction writers in England recently the only concession on this matter I received was: “Andrew, on one thing at least we agree - that supervision may be needed to allay public and political concern. Another is of course that done well it eliminates diversion. And these two facts are of course related.”

I say no more.

Comments by Andrew Byrne ..

Citation: Holland R, Matheson C, Anthony G, Roberts K, Priyardarshi S, Macrae A, Whitelaw E, Appavoo S, Bond C. A pilot randomised controlled trial of brief versus twice weekly versus standard supervised consumption in patients on opiate maintenance treatment. D&A Rev 2012 6:483-91

Ref 1. Rhoades HM, Creson D, Elk R, Schmitz J, Grabowski J. Retention, HIV Risk, and Illicit Drug Use uring Treatment: Methadone Dose and Visit Frequency. 1998 Am J Public Health 88:34-39

Ref 2. Methadone to be dumped in Scotland as treatment for heroin addiction. http://www.news-medical.net/news/2008/05/27/38661.aspx

Ref 3. Podymow T, Turnbull J, Coyle D, Yetisir E, Wells G. Shelter-based managed alcohol administration to chronically homeless people addicted to alcohol. CMAJ 2006 174;1:45-49

Ref 4. The prescribing of methadone and other opioids to addicts: national survey of GPs in England and Wales. Strang J, Sheridan J, Hunt C, Kerr B, Gerada C, Pringle M. Brit J General Practice (2005) 55 (June 2005); 515: 444-451


Disclosure: Dr Byrne owns a clinic which, like addiction clinics in most countries supervises methadone, buprenorphine, diazepam, antabuse and other medications for a fee.

Postcard from New York. Tuesday, 8 May 2012.

Dear Colleagues,

I have been in New York City for three weeks and will try to summarize some of my activities relating to dependency issues (opera blog below for those interested).  I will give more detailed accounts of some of these meetings in the future but wanted readers to know what issues were being looked at currently in the dependency field at the four or more centers of learning here in New York. 

It has been a terrible time for public funding of research in our field and some of the most well endowed and well known organisations have been threatened with closure over a lack of continuing funding from NIDA under current austerity measures as well as increasingly strict guidelines and requirements for such funding.  I noted a lack of enthusiasm across the board in the development and research areas but continued optimism in those involved in the clinical side of dependency medicine and what Americans often refer to as ‘recovery’, a word seldom used by Australian patients and clinicians in my experience.  It may be partly due to the lack of public funds that drug company sponsorship is also eagerly sought, despite it ensuring that research is almost always slanted towards the use of big-profit drugs and avoidance of ‘bread and butter’ medications (see many references for this and work of Marcia Angell, previous NEJM editor). 

My trip began with a 3 hour seminar/dinner at Columbia University in which Dr Deborah Hasin told us that the essential change to DSM-V is that the new classification will lose the distinction between abuse and dependency so that there will only be one diagnosis based on 11 criteria.  Substance Use Disorder (SUD) will be ‘moderate’ if 2 or 3 are present and severe SUD if there are 4 or more.  Patients with just one of the criteria will have no DSM diagnosis and will not be considered to have SUD.  The old criterion of involvement in frequent legal issues has been removed while 'cravings' has been added this time.  The time frame for such reports needs to be within 12 months apart in general.  The concept of 'dependence' now only refers to the physiological states of tolerance and withdrawal.  I cannot help thinking that the new definition will have no benefits and may cause confusion in the 'dependency' field for years to come.  It is slated for introduction in May 2013. 

Grand rounds at Bellevue Hospital were chaired by Dr Marc Galanter: three addiction medicine registrars discussed literature reviews on three topics: ADHD in SUD (and vice versa); Acupuncture in dependency treatments; Ketamine in the treatment of severe depression.  These were each comprehensive and equally fascinating - more anon. 

Fort Hamilton, Brooklyn, is where the Guantanamo Bay trials were televised for New York journalists, family members and others.  I was asked to give Grand Rounds on methadone maintenance treatments in Australia there and was paired with one of their experienced doctors, Lucas Dreamer who spoke about buprenorphine.  It was intriguing that most American doctors who routinely prescribe buprenorphine in their practices (on in this case the Veterans Administration) have never prescribed methadone for addiction cases (and vice versa for many doctors in methadone clinics).  There was a lively discussion about maintenance, detox, psychosocial service, induction and transfer from one agonist to the other. 

I also gave a talk at Beth Israel Medical Center only a stone’s throw from the institution where methadone was first used in addiction treatment.  The department ‘Leaders’ seemed pleased to hear about treatment down-under.  There were discussions about hepatitis C, diazepam ‘maintenance’, needle provision and injecting centres. 

I had a brief discussion with a colleague from NDRI who is investigating drug courts in America.  These vary in the way they operate in different states with methadone and buprenorphine available as a treatment option in only a minority of cases (30-40%).  Reasons for a lack of maintenance treatments included court bans, financial factors, lack of prescriber and sometimes that the person was already detoxified by the time of reaching the court. 

The Drug Policy Alliance gave me their usual 'open arms' welcome at their new offices in 33rd Street.  Boss Ethan Nadelmann and his capable staff are working on a series of initiatives from ‘medical marijuana’ (cannabis to Australians), chronic pain medications, buprenorphine and much, much more. 

Today would have been the 99th birthday of Dr Vincent P. Dole who died in 2006.  Dr Dole, who was a great friend, colleague and mentor to me and lots of others, changed the lives of many people during his long career.  In fact he pioneered blood ion measurement (sodium/potassium, etc) and cholesterol aggregation research years before they became commonplace, prior to his ground-breaking work on drug addiction treatments at Rockefeller University in 1964. 

I was interviewed by a senior anthropologist who is doing an in-depth study on the history and implementation of buprenorphine treatment.  Her group is only too aware of the commercial factors involved in each aspect, some very positive and in the interests of dependency patients while other moves by the manufacturer or distributor may have in fact denied substantial numbers of dependent patients receiving any opioid maintenance treatment at all, both in America and elsewhere.  It is by no means unique for drug companies to endeavour to 'evergreen' their profitable products using numerous well known means.  However, in this case it may be unique that a drug developed over 30 years ago remains in the high-profit bracket. 

Dr Tom Haines brought me up to date with the situation in Portugal as well as the history of how their government brought in decriminalisation of all personal drug use 12 years ago … stemming amazingly from the persistent use of derogatory humour by a popular radio personality and whose views were then supported by the Law Faculty at Lisbon University and both political parties numerous early public forums on the subject.  While it has not eliminated drug use, the Portuguese ‘experiment’ has been a success in every other way according to reports which have been published in reputable places.  In a way, the implementation of interdiction of drugs from the 1950s was in fact a world-wide, uncontrolled experiment, only to compare with the American experiment with alcohol in the 1920s.  We never learn from history!

My last evening in the city is back to where I started with a panel discussion including Dr Jerome Carroll, Herman Joseph, Charles Winick and George De Leon on the past, present and future of dependency interventions starting from the 1950s.  This is the final meeting for Dr Carroll who has run these meetings for over ten years. 

I hope these brief notes are of interest to readers. 

Andrew Byrne .. (back to Australia next weekend). 

Clinic web page: http://methadone-research.blogspot.com/  

Opera blog: http://andrewsopera.blogspot.com/

DSM - V drops 'dependency' forever!

Drugs and Society meeting at Columbia University. 7.30pm Tuesday 17th April 2012.

I have just had the privilege of attending a presentation of the newly proposed DSM-V criteria for substance use disorders (SUD) which is due for implementation in May 2013. The talk was to have been given by Charles 'Chuck' O'Brien who was apparently entwined in 'grants' and was replaced by Deborah Hasin who is also on the committee devising the new DSM standards.

Dr Hasin is an epidemiologist who has done work with adolescent drug use, HIV, alcohol, household surveys, natural history, etc. She was at home at Columbia University where the meeting was held at their Faculty House in Amsterdam Avenue near 110th Street in Manhattan (West Harlem). Deborah is one of about fifteen members of the DSM-V committee looking as substance use disorders, chaired by Dr O'Brien from U Penn. There is also international representation from Australia (John Saunders), Holland (Wim van der Brink) and elsewhere. We were told some details of the process being followed with consensus and unanimity being attempted rather than confrontation and disagreement. In fact, we were told that there was agreement on most of the issues, often after extensive reviews of the research and discussion.

The DSM-IV was implemented in 1994, replacing the DSM-III and “IIIR”. There was also a 'text review' to DSM IV in 2000. Dr Hasin told us that this very meeting was one of many in the review process and she assured us that our views would be reported back to her committee members.

Dr Hasin gave us a splendid talk about the process being undertaken by the DSM review committee and the brief they were given to redefine the diagnostic categories for drug use disorders.

The committee had discussed changing 'abuse' to 'misuse' but opted to remove any 'loaded' terminology, remaining completely scientific with 'substance use disorder' (SUD). Likewise, 'pathological' gambling was rejected since any diagnosis in the manual was obviously 'pathological' so it became a redundancy and will be called something like ‘gambling disorder’.

The essential change, now virtually concluded, is that the new classification will lose the distinction between abuse and dependency so that there will only be one diagnosis based on 11 criteria. The diagnosis will be moderate SUD if 2 or 3 are present and severe SUD if there are 4 or more. The old criterion of involvement in frequent legal issues has been removed while 'cravings' has been added this time. The time frame for such reports needs to be within 12 months apart from cravings which can last for many years after drug use has ceased, causing an immediate anomaly.

The concept of 'dependence' now only refers to the physiological states of tolerance and withdrawal, something which I predict will cause confusion in the 'dependency' literature for years to come. I worry that the entire process may end up like accreditation, forming an unproductive bureaucracy, language and series of steps to nowhere.

Shopping, sex, eating and internet/gaming disorders have been put into the too hard basket while gambling itself has been taken on board with the same criteria but with minor differences as above.

The criteria for inclusion for 'Substance use disorder' ('SUD') are (simplified):

1. Repeated use with negative consequences

2. Repeated use in hazardous situations

3. Repeated use despite interpersonal issues

4. Tolerance

5. Withdrawals

6. Repeated use for longer or in larger quantities than intended

7. Unsuccessful desire and/or attempts to cut down drug use

8. Long periods taken to obtain drugs or recover from the effects

9. Repeated use causes neglect of other important activities

10. Repeated use despite known continuing adverse consequences on health

11. Cravings

1 criterion = no DSM diagnosis

2-3 criteria positive = Moderate diagnosis of SUD

4 or more criteria positive = Severe diagnosis SUD


Under the existing DSM-IV the first three (plus repeated legal problems) were used to define substance "abuse" (one or more) while 'dependency' required three or more of the remaining criteria (excluding cravings which were not included until DSM-V).

In the ‘case’ to justify the changes Dr Hasin quoted numerous published papers which examined the ‘discrimination’ of individual criteria against an overall diagnostic measure. Various rather complex graphs were shown, each with a flattened ‘S’ curve purportedly showing the effect of up to 15 chosen criteria upon the "latent trait" for problem severity measured in some non-linear manner. Each tracing was coded with its criterion below and each formed a flattened 'S' curve starting from a flat take-off on the X axis, ending similarly on a possible maximum parallel above. I noted that Dr Hasin herself was co-author of some of these papers. She has done extensive public health research in Israel where we were told that American surveys had been translated into Russian and Hebrew (but apparently not Arabic).

We were told that the close approximation of these curves showed the degree of contribution concordance each had with the overall occurrence of problematic drug use in the various (population) samples (none were clinic or patient samples). While the overall impression was that each of the criteria had a similar contribution, the value of the process in population studies was questioned by some delegates so we were then shown some curves of clinic / dependency populations (oops, should not use the term ‘dependency’ any more!).

Dr Hasin's point seemed to be that the inclusion of 'legal issues' added little to the statistical 'mix' for diagnosis. Yet several people in the room pointed out that it was legal issues alone which originally brought some of their most needy patients into treatment. Furthermore, with 10 or more criteria, removing any one would likewise have had little effect on the diagnosis. In practice, the great majority of our patients by the time they get to treatment have not 2 or 3 of these criteria but most of them.

I was a little surprised that there was no patient representative on the committee. Perhaps I should not have been surprised that a majority of delegates contribution to a psychiatry manual were not MD’s or psychiatrists. This is not to question the superb qualifications and need for non-medical input … in fact one member even had two PhD degrees in her credentials (I had thought it was a ‘typo’!).

The new DSM-V definitions remind me of accreditation in a way. The supposed improvements will be of very limited value to my view. The definitions have hazy time-lines with most being 'in the past 12 months have you had …'. As an exception, ‘cravings’, a new criterion, can last for decades after any drugs have been consumed! There is a somewhat closer parallel with smoking, drinking and other medical diagnoses ... but to what end I am not sure. There is absolutely nothing about the quantities of drug used, we were told due to the illicit nature of most of the drugs (now no longer the case with so much prescription drug abuse). However this does not stop every clinician in the field taking such a history, albeit with the inherent difficulties. Hence under the new system $10 per day smoked heroin use on two days per week could be the same under DSM-V as $500 per day if the consequences and reported symptoms were the same. 'Remission' is another problem issue they have decided to avoid altogether. "A lack of symptoms" one delegate said of remission. But for how long? And what of ‘recovery’? Don't ask!

Gambling is ‘in’ the new DSM classification, partly, we were told, because about 20% of substance users have gambling problems and a substantial proportion of gamblers have alcohol/drug troubles too.

But shopperholics and sex addicts and internet habitues don't use enough substances to be included apparently, at least in the SUD section ‘and related disorders’ department. We were told that eating problems and sexual problems had lobby groups of their own and thus were left well alone by this committee. Internet/gaming victims likewise.

Denise Kandel had some most interesting stuff to tell about her mouse experiments ... I am getting the references ... also about adolescent drug use definitions.

Gross and Edwards’ definition of alcoholism in 1960s and is still the basis for all of these modern definitions.

Dr Hasin was thanked for her input and she promised to get feedback working in both directions. True to her word an email mooting a survey appeared only a week after the meeting calling for volunteers to become involved in the process.

Written by Andrew Byrne ..

Concord Seminar on benzodiazepine dependence.

X-Concord Seminar on benzodiazepine dependence: 29 Feb 2012 plus tribute to honour Dr Alex Wodak whose retirement coincided with this seminar.

A panel discussion was given at Royal Prince Alfred Hospital chaired by Dr Richard Hallinan, Staff Specialist in Addiction Medicine. Present were numerous experienced clinicians, some by invitation, others out of habit. Pharmacist Denis Leahy, Nick Lintzeris, director of Langton Centre and a doctor from Redfern. There were over 70 people in the packed audience.

Dr Hallinan gave a short presentation on the ion channel GABA receptor and the difference in its interaction with barbiturates and benzodiazepines and why the latter are so much safer in overdose. We were shown the basic molecular structure involving the fusion of a benzene ring (“benzo”) with a heterocyclic, two-nitrogen (“di-azo”) molecule and various attachments to form the individual characteristics of the different forms of benzodiazepines.

We were then told of the variations in absorption rates, half-lives, metabolic pathways, active and inactive metabolites, blood levels, fat and water solubility and volumes of distribution (initial and steady state) of the common benzodiazepines. These included chlordiazepoxide, diazepam, oxazepam, temazepam, nitrazepam, flunitrazepam, alprazolam, medazolam, clobazam and clonazepam. We learned a little of the history of these drugs which largely replaced the barbiturates in the 1960s. Their effects on convulsive thresholds, anxiety, sedation, muscle relaxation, amnesia, panic disorders and PTSD were canvassed, including mention of a recent comprehensive review by Malcolm Lader, the widely published English benzodiazepine ‘guru’ in the Addiction journal.

Dr Jenny James who is a GP at a western Sydney Aboriginal Medical Service was then asked to present a case. This was an enormously complex case which Dr James and her GP colleagues had looked after for several years, amongst their busy and varied general practice. She pointed out that there are no dedicated staff for counselling, family therapy, case management or other ancillary services which are either carried out by the doctors as a drop-in service or not done at all. There were issues of dual chronic viral infection, doctor shopping, mental illness and intercurrent drug use while on methadone treatment. There followed a question and answer session with response from panel members, including a pharmacist and two drug specialists. It was clear from the history that the difference between general practice and specialist practice is that history and progress can be gleaned over months by the former while the latter cannot afford to get it wrong and thus needs to be more comprehensive and multi-disciplinary … where this is possible considering the ‘urgency’ of our patient group and the lack of resources in the face of large numbers seeking treatment.

The main question of the evening was whether the treating doctors should be prescribing benzodiazepines for patients like this one and if so, with what degree of supervision, quantities and restrictions (alcohol was the big contraindication). It was contended that alprazolam (Xanax) was not an appropriate drug for any definable psychiatric condition and some present felt that like Rohypnol and Normison (capsules) before it, it should be banned from the Australian market. Personally I have not prescribed Xanax (alprazolam) for over a decade and I would be delighted if it were off the market or at least limited to 0.5mg tablets.

The concept of ‘staged supply’ in community pharmacy was mentioned by Dennis Leahy from Stanmore Station Pharmacy. The last federal budget included a small subsidy from the PBS for employing this strategy for those with impulsive and compulsive drug consumption … which means most of our patients, at some of the time.

Dr Jill Roberts said that about 90% of prison inmates on OTP have current benzodiazepine histories on admission, requiring careful diagnosis and management. The Justice Health service has a routine detoxification regimen, using a withdrawal scale. A common starting dose is 20mg diazepam twice daily, especially in those with a history of seizures. This high figure of 90% would seem to be consistent with the extraordinary finding from Malcolm Lader that ‘in the UK about half of all BZD prescriptions were given to patients who are currently in an opioid treatment program’.

Experience has shown that some patients fare well taking substantial quantities of benzodiazepines while others seem to lurch between episodes of varying intoxication which often involve aberrant behaviour, legal diversions and occasionally injuries or even worse.

It was interesting to note from the delegates at this meeting just how much the field has changed. In the past there were significant numbers of doctors who claimed that prescribing sedatives to opiate maintenance patients was never appropriate. At this meeting, however, nobody expressed this sentiment. In fact virtually everyone had been involved with certain dependent patients being prescribed a limited supply of (usually) diazepam for certain periods of time, under supervision, despite the logistic difficulties. In also seemed agreed that there was a certain minority group in whom complete withdrawal was not realistic, just as occurs with opiates, alcohol, tobacco, etc.

So can one use methadone maintenance as a paradigm? Is there a diagnosis of dependence? Have there been reasonable efforts to withdraw? Are there episodes of serious sequelae from the benzodiazepine use? Is there dual or poly drug abuse? Psychiatric diagnosis? Has the patient been compliant with their opiate treatment? Is alcohol a factor? Some of our colleagues are currently asking these very questions regarding stimulants, however for sedatives the response is simpler as diazepam, for instance, is not an S8 (restricted) drug in most states.

What would be the minimum criteria for prescribing diazepam to a dependent patient? Having a good history, physical examination, urine test, experienced dispensary would all be essential in my view. An absence of current alcohol use would also be another safeguard. Given all of these factors, we still need a working diagnosis, goals and review process. Does the patient have anxiety or depression? Some may contend that the diagnosis does not matter too much, just like the reason for which a person allegedly uses heroin. ‘If they are dependent, they are dependent’. And the treatment, or at least the principles, should be the same.

So in our own service we use diazepam 5mg - 25mg according to history, initially daily or second daily from the dispensary along with the methadone (or buprenorphine in the few such cases who are taking the ‘weaker’ maintenance drug). Some patients state that they prefer to take some of their dose in the evening and we try to accommodate this where possible. If they state they are sedated on 5 to 10mg Valium we question the diagnosis of dependence and ask to examine the patient 3 hours after such a dose. Others seem to be able to take much higher doses and show no signs of intoxication (on gross testing).

Our goals and follow-up review are the same as for any other behavioural treatment: housing, social, financial, drug-use and general medical parameters are reviewed before further ‘dispensed’ doses are permitted up to a week’s supply at a time (one day supervised) which seems to suit a large proportion of long-term dependent patients. Even without active prompting, doses have generally reduced and a small number have withdrawn, some long-term. A proportion can be expected to relapse to sedative use, just as happens with every other chemical addiction. Better luck next time!

The use of diazepam and other tranquillisers for ‘maintenance’ therapy may be off-label in some cases yet in many there will be a diagnosis of panic disorder, anxiety or insomnia (where benzodiazepines have been shown to be effective) or PTSD, convulsions or depression where such drugs do not have an established evidence base.

Dr Nick Lintzeris gave a heart-felt sentiment of sadness but gratitude regarding the retirement that very day of Dr Alex Wodak to whom so much is due for making the D&A field what it is today in Australia. His influence on policy and practice here and overseas has been unsurpassed, even by Griffith Edwards in the UK … and we all remain in his debt.

Commentary by Andrew Byrne ..
Clinic web page: http://methadone-research.blogspot.com/

Ref: Lader M. Benzodiazepines revisited - will we ever learn? Addiction 2011 106:2086-2109

Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution-a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction 2010 105;11:1870–1874

Byrne A. Benzodiazepines: the end of a dream. Aust Fam Physician 1994 Aug; 23(8):1584-1585

Tranquillizer use rife amongst OTP subjects world-wide, most legally prescribed.

Prolonged use of benzodiazepines is associated with childhood trauma in opioid-maintained patients. Vogel M, Dürsteler-MacFarland KM, Walter M, Strasser J, Fehr S, Prieto L, Wiesbeck GA. Drug & Alcohol Dependence 2011 119:93-98

Dear Colleagues,

While these authors have emphasised an association between childhood trauma and benzodiazepine (BZD) use, their study tells us much more about opioid dependent patients in treatment in Switzerland and beyond. Their bibliography is also exemplary and it clearly demonstrates that the current approach, zero tolerance in the main, is simply not working. As the authors state: “if abstinence from BZD is conveyed as primary treatment aim, as has generally been the norm in the past, this finding illustrates the limits of current therapeutic management and therapeutic options”.

We are told that ‘point’ and ‘lifetime’ BZD use reportedly occurs in 18-55% and 35-94% of OTP patients from numerous reports including from Australia. The current surveys were taken in two large opioid maintenance programs in Basel, Switzerland. These provided a variety of medications, including prescribed heroin, both oral and injected, methadone, morphine, buprenorphine and codeine.

Of 315 patients approached, 193 (61%) responded to a survey including childhood trauma (a validated instrument ‘CTQ’ was used), drug use and other clinical and demographic characteristics. Reports of drug use were confirmed with urinalysis showing a high degree of concordance. Psychiatric diagnoses were obtained from the detailed medical files which were updated regularly.

The rate of reported benzodiazepine use in the current sample was 61%, 47% being ‘prolonged’ (>2 months duration) while lifetime use was 85%. Thus almost half of the cohort had prolonged use at some time in the previous five years.

There was at least one childhood trauma sub-score of moderate to severe level in 67% of the subjects who completed the survey. As well as BZD use, the degree of trauma was significantly related to methadone dose (or equivalent for other opioids).

After multivariate analysis the authors found that there was an association between prolonged benzodiazepine use and (1) excessive childhood trauma, (2) hepatitis C, (3) psychiatric family history and (4) methadone dose in milligrams. The odds ratios were 1.5, 4.0, 2.3 and 1.01

Rather than using the loaded (British) term ‘misuse’, these authors wisely stick to ‘use’. They also categorise sedative use into (1) ‘hedonistic’ or ‘recreational’ use, (2) self-medication to counteract or amplify the effects of primary drugs of abuse (eg. to ‘come down’ from stimulants), (3) prescription use for anxiety, insomnia, PTSD, panic disorders, etc, and (4) ‘off-label’ prescription as benzodiazepine ‘maintenance’. The great majority of patients obtained their BZD from legal prescription (84% of those with ‘prolonged use’).

The authors point out that none of these associations can prove causality. This will always be difficult to determine when so many overlapping issues occur in OTP patients such as childhood abuse, PTSD and self medication. However, the authors seem persuaded that ‘zero tolerance’ is no longer tenable as a policy, just as it did not work for opioids (or alcohol in a different era). They support the measured prescription of benzodiazepines in research trials as advanced by Liebrenz in Addiction.

In our own practice we provide diazepam under close supervision and in limited quantities to those who are unwilling or unable to cease the use of benzodiazepines, and who agree to alcohol abstinence, in the context of OTP.

Summary written by Andrew Byrne ..

Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution-a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction 2010 105;11:1870–1874

First publication on Suboxone film gives little clinical information.

Clinical Pharmacology and Therapeutics ‘Perspectives’, Letter to the Editor.

Advance online publication 28 September 2011. [see response by Strain et al.]

Commercial Factors Override Science in Combination Addiction Drug Trial

A Byrne [1]

To the Editor:

Strain et al. have performed a detailed and thorough treatment induction trial of a novel sublingual buprenorphine “film” or “wafer” in their article “Induction of
Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films.”1 However, the appropriate test for any new medication is a randomized, blinded comparison using accepted protocols against existing effective interventions, with outcome measures such as retention, drug-use parameters, and toxicology.

Instead, these authors compare a newly introduced formulation of an old drug (buprenorphine/naloxone film) with a nonapproved and unvalidated medication (buprenorphine film). In going to great lengths to show complex documentation on the differences in withdrawal characteristics between the two treatments (by means of
multifarious, complex graphs), the authors appear to believe that it is important to determine whether such differences exist, even though neither of the treatments involves any known “quantity” and that these differences are of little relevance to clinical practice.

It is a false premise that the apparent absence of differences between two treatments indicates their equivalence. Strain et al. do not make such a claim, but others may misinterpret such results in this way, just as has happened with Suboxone (combination with naloxone) and Subutex (pure), which, remarkably, have still not been subjected to equivalence testing except in a small pilot study.2. Strain et al. do not make it clear what they were trying to demonstrate in their paper, which is one of the first reports of buprenorphine in a more soluble sublingual film/wafer preparation.

I am not aware of evidence that withdrawal symptoms during induction are linked to retention, an outcome that is known to be strongly associated with benefits to drug-dependent patients. In my experience, some recipients of successful buprenorphine and methadone treatment have experienced unpleasant withdrawal symptoms during
the induction period. Furthermore, Strain and colleagues’ study involved the use of multiple induction doses of buprenorphine over many hours, an induction regimen that is not used in clinical practice to the best of my knowledge. It would probably also be costly and difficult to implement in actual practice.

It is of concern that the authors raise the issue of drug packaging because this was not tested in their protocols. Indeed, their subjects were administered doses as in most addiction research and were apparently not given doses to take home as occurs in the field. In the abstract and twice again in the text, the reader is told about new individual packaging that is alleged to be safer than that for the existing product, which is marketed by the same manufacturer (which also supported the research). Rather than the blister packs used elsewhere, in the United States buprenorphine tablets are apparently dispensed loose in packs of 30. While the film or wafer preparation reportedly comes in an individual unit-dose format with child-resistant packaging, this could just as easily be used for existing preparations if the latter are considered by the company to be unsafe due to incidents with accidental childhood poisonings. 3

Hence, it is a liberty to introduce such discussions into the report of a study that ostensibly examined the physiological effects of introducing two buprenorphine products to dependent patients and in which most medication was given under supervision. It is also claimed that serial numbers will allow tracking for drugs that may be diverted onto the black market. This would depend on chain-of-custody supply as well a new layer of detailed record keeping, the cost of which is unknown—nor is it known whether this type of measure can be effective. Such research is awaited, and speculation by these authors is unhelpful in my view, especially in a study funded by the manufacturer.

Conflict of interest.
The author operates a private addiction clinic in which buprenorphine and methadone are used in opioid maintenance treatments. He does not consider this to constitute an actual or potential conflict with respect to the study discussed but includes the information for completeness and transparency.

© 2011 ASCPT
1. Strain, E.C., Harrison, J.A. & Bigelow, G.E. Induction of opioid-dependent individuals onto buprenorphine and buprenorphine/naloxone soluble-films. Clin. Pharmacol. Ther. 89, 443–449 (2011).
2. Bell, J., Byron, G., Gibson, A. & Morris, A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone) in treatment of opioid dependence. Drug Alcohol Rev. 23, 311–317 (2004).
3. Boyer, E.W., McCance-Katz, E.F. & Marcus, S. Methadone and buprenorphine toxicity in children. Am. J. Addict. 19, 89–95 (2010).

1Private practice, Redfern, Australia.
Correspondence: A Byrne (ajbyrne@ozemail.com.au)

Advance online publication 28 September 2011.

doi: 10.1038/clpt.2011.166

See also this blog: Click here

The response letter does not address most of the above nor does it do credit to its renowned authors due to its patronising invective. Copy on request.

Launch of Suboxone Film - Sydney Olympic Site - August 2011

Product launch by Reckitt Benckiser - Suboxone Film 2mg and 8mg for opioid maintenance. Sydney Olympic site - Novotel 7pm Tuesday 23rd Aug 2011

Dramatis personae: Dr Mark Hardy (Chair); Mr Ruari Macdonald (Reckitt Benckiser); Prof Nicholas Lintzeris (Langton Centre); Mr Peter Muhleisen (Hunter NE area pharmacist); Ms Simone Cass (Consumer Representative).

Headings: Is combination buprenorphine best practice? Why is the film being marketed now? Is it bio-equivalent? No childhood poisonings in Oz. Prison diversion under postage stamps, etc. Pharmacists: unsung heroes of dependency treatments. Is dosing ‘films’ really faster? Were consumers consulted adequately?

## This was a rather unedifying event, proving, sadly, how much our field of medicine is now influenced by the pharmaceutical industry. It seemed as though not one person in the large assembly questioned the wisdom of swapping from one unproven mixed drug to another on the appointed day. And the recent appearance of a half-price ‘generic’ buprenorphine (at least in America) was not raised.

I personally do not prescribe combination buprenorphine at all so this launch was largely hypothetical in my case. I spoke to Dr Alex Wodak earlier in the day and was reassured to learn that he and his colleagues at St Vincent’s Hospital currently prefer to prescribe buprenorphine without naloxone and for the same reasons: a lack of good research evidence on equivalence, safety and effectiveness. My advice to doctors and pharmacists is to demand this evidence before prescribing any new drug. Products approved by the TGA and promoted by State health authorities are not automatically ‘best practice’ in the field.

The dinner guests were told that the new Suboxone SL ‘film’ was approved from September on condition that the tablets were withdrawn within two years because they are not bio-equivalent, the film being more highly soluble. It would be helpful to know what proven advantage the PBS committee found in this product that justifies the switch from the existing sublingual tablet. This is particularly the case since the ‘film’ formulation has been used as a vehicle to smuggle buprenorphine into prisons in the US on writing paper, under postage stamps and envelopes. It is important to justify any known disadvantages of a new formulation with the potential benefits, especially when a new drug effectively locks out generic competition. A more highly soluble product which dissolves more rapidly may also have a greater potential for intravenous use. An internet search can quickly confirm some of these harmful concerns, most notably injecting.

Even if one were to accept that naloxone reduces some diversion, the pure product is certainly the preferred medication during pregnancy … and probably also in women who may become pregnant … and also for inductions of new patients onto the drug.  The pure medication was used in the controlled research which supported buprenorphine treatment for addiction.  It was also the pure product which is used in France where widespread buprenorphine treatment started in 1995.  There are no serious moves, I understand, to use the combination drug in France, although it is a registered therapeutic product in the EU generally.  One wonders what the French know that we do not (or does ‘market saturation’ solve many of the problems found elsewhere?).  I cannot understand why, with its purported advantages, the company is not marketing a film version of the pure drug, even if just for pregnant patients. Such a form was supplied by the company to Strain et al. for their induction trial. The promise of unique identifiers on each sachet of the film as a means to detect and prevent diversion seems to have lapsed so ‘pill-counts’ and diversion tracing cannot be done. Yet another disappointment.

The evidence supporting reduced diversion with the combination tablets/films is scant anyway and lacks scientific rigour in my view.  Reports of the widespread injection use of the combination drug are legion and go back 20 years (‘The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand’. See below.).  If there is a disincentive to inject the combination drug, it is modest in degree and it can be little greater than that of buprenorphine alone in current users of heroin, morphine or methadone due to its well known ability to induce the extremely unpleasant ‘precipitated withdrawal reaction’. On the other hand, there is little or no aversive effect in those currently taking buprenorphine nor in those without a current tolerance, so these groups can inject either preparation with impunity. The latter may include some patients in detoxification facilities or prisons as well as opiate naïve individuals.  Furthermore, the evidence that is available indicates that the deterrent effects in persons who are actively using opioids may be associated with less safe injection practices (‘Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market’. See below.). 

Despite these disadvantages, I remain a great supporter of buprenorphine as a dependency treatment option. I first prescribed it (exceptionally) over 20 years ago ‘off-label’ to dependent patients.  The original combination product buprenorphine and naloxone was approved for maintenance prescription about 6 years ago in Australia.  We were strongly encouraged to prescribe it by each State and Territory Health Department.  There were also guidelines for unsupervised use in certain circumstances, based, we were told, on a single overseas study. However, close reading shows it mostly used supervised dosing and is of limited relevance to Australia (Fudala et al. 2003).  Apart from better results than with placebo (only in America or Russia could placebo be used in this context) this study showed a trend for better abstinence outcomes in those taking 16mg of pure buprenorphine compared with those taking the combination product (sixteen percent more clear urine tests in those on pure buprenorphine).  The trial was not sufficiently ‘powered’ to make this difference statistically significant.  Paradoxically, if pure buprenorphine had shown significant superiority, buprenorphine might have had a very different story in America. 

In the scramble to develop new guidelines for unsupervised use in 2006 (and contrary to its own long standing practice) the Royal Australasian College of Physicians accepted a six figure sum from the manufacturer/distributor to help ‘educate’ the profession. And this was using a combination drug which their chief dependency education officer Dr James Bell stated at the time was “therapeutically identical” to the pure product.  It was a shame such funds were not made available when the original product appeared on the market five years earlier when the original drug was introduced. 

We were told that in Australia the major complaint about Suboxone tablets was that they took too long to be absorbed.  Hence the company had developed the new film preparation as a response to this.  By contrast, Americans were told last year that the main reason for the company introducing the new ‘film’ preparation was the issue of childhood poisonings from Suboxone tablets (see Strain et al 2011, almost 1000 such reports annually by 2008 in America).  I was surprised to learn that despite these worrying statistics, buprenorphine is still sold by American pharmacies as loose tablets in regular pill bottles (albeit with child-resistant caps). Even paracetamol/acetaminophen is sold in blister packs in Australia and elsewhere to avoid this problem.

At the drug launch dinner the childhood poisonings were mentioned numerous times yet there have apparently been no cases in Australia to date.  Of itself, this would seem to be a lesson in public health safety. It would seem wrong-headed to address the dangers of existing tablets by introducing a new patented product rather than by promptly changing the loose packaging to blister packs. 

There was a warning from Professor Lintzeris that although he believed that most diversion of buprenorphine was of limited clinical significance, the treatment (Subutex) had been banned in Singapore and Finland after reported diversion and misuse.  He emphasised also that the use of unsupervised buprenorphine treatment could be at risk if patients were seen to divert medication.  Such treatment was introduced into France and America, and in a limited manner here in Australia, with almost no research base (see above).  The study which is quoted in the literature, Fudala et al., did not examine supervision in any rigorous way. Regarding diversion, the panel members seemed unaware of the New Zealand experience the early 1990s with Temgesic NX (buprenorphine 0.2mg plus naloxone 0.17 mg). This was another major lesson in public health policy which was published in D&A Dependence (Robinson et al, 1993).  In succession over a short period of time the pure drug and then combination buprenorphine were each withdrawn from the New Zealand market due to the wholesale abuse (the company states it was for ‘purely commercial reasons’).  

In question time Professor Kate Conigrave of Sydney University asked if the company proposed to make Suboxone in a 0.4mg size for patients who are detoxing or for finer dose titration.  Product manager Ruari McDonald answered in the negative.  He stated further that few if any other countries had 0.4mg Subutex and that Australian doctors were “lucky” that it was available.  To this Professor Lintzeris volunteered that he hardly ever finds the need for doses smaller than 2mg.  He told his fellow professorial colleague that at Langton Centre they did not use 0.4mg tablets much at all (meaning that they did use it, at least occasionally, I presume).  He said that one should not draw a false parallel between small reductions on methadone as this was just not necessary with buprenorphine – yet he did not explain this assertion or give any supporting references.  Furthermore, he contended that such a low-dose preparation would not have enough naloxone to deter injecting … although it was unclear how much naloxone he was referring to, 0.1, 0.17 or 0.34mg or other. Robinson reported that Temgesic NX, with over three times the proportion of naloxone than Suboxone, was nevertheless the most commonly injected drug by more than half of those applying for methadone treatment in Wellington in 1991.  This was one of the first reports of widespread injecting of a prescribed analgesic (see Quigley 1984; Strang 1985 for incident cases). 

The Reckitt Benckiser company earned my highest admiration ten years ago when, against the odds, it managed to have Subutex approved in Australia despite the unfortunate New Zealand experience. Happily for the manufacturer’s shareholders since 2000 they have managed to “evergreen” the exclusive market for the product on two further occasions. First this was done by using the naloxone combination and more recently with the ‘film’. In this way the company has turned a relatively cheap drug into a high profit line. I note that the Wikipedia entry reveals numerous commercial feats as well as some disturbing findings against the company along the way. I was interested to note that associates of this company have contributed to publications and conference events relating to supposed cardiac complications of methadone. Some of these omitted appropriate conflict statements (details on request). Large studies in France and Norway have now shown the reported cardiac complications of methadone to be vanishingly rare while at the same time highlighting the aging and complex nature of the medical problems faced by our patient population.

It is worrying that neither the manufacturer nor anyone else has performed controlled studies on the equivalence of Subutex and Suboxone. It is hard to understand why this was not required by the TGA before approval of the combination product. Evidence for the safety and effectiveness of combination buprenorphine cannot necessarily be extrapolated from the pure product. The need for more than 50% higher doses in an open-label study changing to the combination product by Bell and colleagues has never been corroborated (nor refuted).

A front page New York Times article recently reported the smuggling of Suboxone films into American jails (link below). When I asked about this none of the panel members admitted to knowing about it, despite its obvious relevance to the evening’s proceedings. Professor Lintzeris said that he recalled reading something about ‘crushed up tablets’ (not films at all, apparently) being made into paint in children's pictorial offerings to ‘daddy in jail’. According to the report, since the introduction of Suboxone film, prisoners’ mail in America is now vetted, delayed and in many cases, shredded. Envelopes and stamps are removed, and reportedly due to the widespread reported practice of smuggling buprenorphine films into jails. One prison governor was quoted saying the situation was a ‘crisis’. Lintzeris then changed the subject to advocating buprenorphine treatment in prison. This was a good point but only limited practical relevance to the serious problems described in the report. Professor Lintzeris then also told us that we needed to make a distinction between ‘true’ diversion where the drug was used by another party and the situation where the drug was used by the intended recipient which was ‘not really diversion’. These matters remain for debate. The film’s introduction into the US a year ago should be considered a research trial of sorts, and one which is already showing worrying outcomes from my reading (see also Pennsylvania Attorney General report below).

I wondered if I was the only one in the room to be questioning the use of Suboxone films in future. Two large Sydney clinics I contacted at the time did not generally dispense the combination drug at all. I will continue to prescribe pure buprenorphine in my practice and when necessary, in order to hasten dissolution and/or reduce diversion we will continue to ‘scrunch’ the tablets. It has not been explained why the company is not marketing a film version of the pure product, something the company has tested, see Strain et al below.

On the night nobody mentioned the need for pharmacists to keep yet more drug books (at least for the next two years). To my mind the community pharmacists remain the unsung heroes of dependency treatment in Australia. These caring professionals still mostly charge the same as they did in the 1980s for a service which is now more complex and in some ways hazardous. Instead of just one drug book (for methadone), they will now need up to nine such books!

We were all handed a glossy brochure on the new buprenorphine combination “film” stating: “Clinically Interchangeable with the Suboxone Tablet”. The text included a graph of a single dose comparison with a 6 day run-off axis. The first day (the only one that matters to those taking daily doses) blood levels were substantially higher in the film subjects (eg. 3.0 versus 2.25 ng/ml for peak). This single-dose study finding may be augmented in daily maintenance dosing, showing quite clearly that the film and tablet forms are not interchangeable at all with a very substantial 33% higher blood level for film when compared to the tablet (presumably not crushed). The prominent title statement would seem to be directly countered by the graph provided on the same page, showing (or, better expressed, almost concealing) a substantially higher area under the curve (AUC) in the first 16 hours. Knowledge of the raised blood levels may make a prudent doctor consider a lower dose for those changing to the film product, despite advice to keep the dose constant and only reduce it where necessary. The variability in response was stressed by all speakers at the launch. I invite Reckitt Benckiser to submit a comment to my blog explaining this and will gladly post the response as a service to readers.

This same glossy hand-out states that “Suboxone Film dissolves faster than Suboxone Tablet”. It was disappointing that the company provided evidence for slightly faster dissolution times but omitted to state just how much longer it takes for the staff to open the tough little packets to reveal and then administer the flimsy films. I tried with the placebo and took 35 seconds to open one while the experienced nurse who ran one of the trials told me that she had got it down to about 15 seconds. And the pack does not always open as designed, sometimes needing scissors and therefore taking even longer. Most patients will need more than one pack and someone taking 22mg, for example, would need 5 (2x8mg and 3x2mg). One example quoted was that 2mg dissolved one minute faster (6 versus 7 minutes), yet to open the packs needed before administration could mean little is gained in staff and patient time. Advice that one does not need to observe the patient for so long due to adherence of the film is not based on evidence and remains to be demonstrated to be safe and effective, just like the preparation itself (at least in comparison to pure buprenorphine). Crushing tablets may be just as useful when time is limited or when dealing with challenging circumstances such as in the prison system.

In an early presentation we were told of the comprehensive post marketing survey published recently by Briony Larance et al. in D&A Dependence (n=440). It was perhaps the most important slide of the night although its significance was not emphasised by the speaker at the time. It demonstrated the enormous misuse of buprenorphine as published when compared to methadone. They showed that no less than one in eight supposedly “supervised” doses of buprenorphine (12%) were taken out of the dispensary compared with 1% for methadone(!). They also showed that buprenorphine patients consistently showed about double the rate of injecting drugs when compared with those on methadone. While there was less injecting of the combination drug, this finding is confounded because at the time it may have been used more widely unsupervised for those who were already more stable patients and therefore may be less likely to inject anyway. Clearly a proportion of these buprenorphine patients would be doing better on methadone … but this was neither the time nor the place.

Ms Cass spoke eloquently from a consumer perspective about communications, involvement with health professionals and ‘vulnerability’. While she and others had made out that consumer representation was a novel endeavour and it was not usual in other fields, my understanding is that it is now much more widespread than it was. Such moves are still inadequate and consumer involvement can always be improved. However, such input made an early start in Australia before many other countries and now there are respected voices from individuals, State and Federal organisations of several persuasions, which is as it should be. One of the earliest and most prominent is Family Drug Support which enjoys widespread respect in the Australian community (there is nothing remotely comparable in the United States according to my sources). NUAA and AVIL representatives were also at this meeting.


Despite the usual modern practice, there were no conflict statements given by the speakers which would seem to be a fault.


Comments by Andrew Byrne ..

Conflict statement: Reckitt Benckiser paid for my dinner but I paid my own train fare to Homebush Bay from Kings Cross. Reckitt Benckiser has sponsored refreshments and data projector for our post-graduate Concord study group.

References:
Strain EC, Harrison JA, Bigelow GE. Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films. Clinical Pharmacology and Therapeutics 2011 89: 443-449

Robinson GM, Dukes PD, Robinson BJ, Cooke RR, Mahoney GN. The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand. Drug Alcohol Dependence (1993) 33;1:81-6

Larance B, Degenhardt L, Lintzeris N, Bell J, Winstock A, Dietze P, Mattick R, Ali R, Horyniak D. Post-marketing surveillance of buprenorphine-naloxone in Australia: Diversion, injection and adherence with supervised dosing. Drug and Alcohol Dependence 2011 In press.

Strain EC, Harrison JA, Bigelow GE. Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films. Clinical Pharmacology and Therapeutics 2011 89: 443-449

Fudala PJ, Bridge TP, Herbert S, et al. Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone. NEJM (2003) 349:949-958

Bell J, Byron G, Gibson A, Morris A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Drug Alcohol Rev 2004 23;3:311-318

Bruce RD, Govindasamy S, Sylla L, Kamarulzaman A, Altice FL. Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market. Am J Drug Alcohol Abuse 2009 Feb 12;1:1-5

Quigley AJ, Bredemeyer DE, Seow SS. A case of buprenorphine abuse. Medical Journal of Australia 1984 140:425-426

Strang J. Abuse of buprenorphine. Lancet. 1985 Sep 28;2(8457):725

Goodnough A. When Children’s Scribbles Hide a Prison Drug. New York Times 27 May 2011 page A1. http://www.nytimes.com/2011/05/27/us/27smuggle.html

Click here Full Pennsylvania report.

HARRISBURG Acting Attorney General Bill Ryan noted that Suboxone, a Schedule III prescription narcotic used to treat heroin addiction, was commonly produced in pill form, but now is being manufactured in thin film like strips very similar to the popular breath freshening strips. … charges [were announced] against eleven suspects, including five inmates, who allegedly smuggled prescription narcotics into the Carbon County Correctional Facility via the inmates’ incoming mail. The investigation, known as ‘Operation Postage Stamp’ began in January 2011 after the Warden at the Carbon County Correctional Facility intercepted three letters containing a Suboxone underneath the letters’ stamps.

http://en.wikipedia.org/wiki/Bart_Becht

http://en.wikipedia.org/wiki/Reckitt_Benckiser

Is levo-methadone the answer to so-called cardiac complications?

McCance-Katz EF. (R)-methadone versus racemic methadone: what is best for patient care? Addiction 2011 106:687-688

Dear Readers,

I need to disagree with my respected colleague Dr Elinore McCance-Katz in her editorial in Addiction proposing the active isomeric formulation of methadone as a viable solution to the supposed problem with cardiac arrhythmias. She states, without any supporting reference: “Methadone confers some risk for cardiac adverse events and sudden death.” The research I have read shows that methadone actually reduces the risk of sudden death. It is also likely that methadone protects against serious cardiac events (Krantz 2001).

Addiction published Justo’s reassuring literature review of QT prolongation and torsade de pointes in methadone prescribed subjects yet now the world’s oldest dependency journal has joined the cardiac cargo cult with this piece. There are no new references for cardiac side effects, nor are we told about the recent reassuring literature from France and Norway showing the vanishing rarity of this arrhythmia in methadone patients (and a lack of reported mortality). Krantz et al 2009 is the Editorial’s main supporting reference yet this piece was so problematic that it was withdrawn and republished with an altered list of contributors, new conflict statement and changed title (see my review Click here).

Dr McCance-Katz cites this latter paper as the CSAT (Centre for Substance Abuse Treatment) consensus guideline which it was not. The terms ‘CSAT’, ‘consensus’ and ‘guideline’ were all expunged from the title in the formally re-published version (and for good reason, it would appear). CSAT’s official advice came later and was quite different from the recommendations in the Annals publication of March 2009. Krantz quotes Ballesteros, Shah, Sorg, Gagajewski as ‘a growing number’ of reports of ‘unexplained methadone-associated deaths’: yet there were none in Ballesteros; one from Sorg; none in Gagajewski; reducing, not increasing NM death rates in Shah. In practice, unexplained deaths in MMT subjects are very rare. Sudden death in the general (‘healthy’) community is reported at about 7 per 10,000 person/years (Ray 2001). It is problematic that this editorial quotes Krantz 2009 as supporting the link between methadone maintenance treatment and torsade de pointes when the evidence cited by Krantz is on shaky epidemiological grounds (Chugh's conclusions are not sustainable; Fanoe’s findings are fanciful (10-30% of OTP subjects allegedly develop unexplained syncope in a year).

Furthermore, Wedam’s RCT findings are quoted by Dr McCance-Katz and Krantz et al, despite their being consistent with the view that there is almost no risk of torsade de pointes, even in those with substantially prolonged QT intervals (>500ms). Wedam showed very high rates of QT prolongation in young patients new to treatment, yet this is the very group which rarely if ever develops torsade de pointes (vide ~100 case reports over 30 years on request).

To support the argument about the probable safety of (R)-methadone the editorial cites two studies which relate to QT intervals but not to arrhythmias. The author seems to have missed the point that QT prolongation is commonplace in methadone patients, having been reported in over 30% of patients in 1973 (Lipski). Yet such electrical observations do not appear to translate into torsade de pointes unless other factors supervene (electrolytes, other drugs, heart disease, alcohol, HIV, old age, etc). Furthermore, many or even most of the actual case reports have had normal QT intervals away from the arrhythmia episode. Justo reported a known intercurrent cause in 85% of cases. Hence these findings show the futility of ECG as a strategy to prevent torsade de pointes … and they emphasise the value of a good history and physical examination.

When thousands of patients (in Germany) are currently taking the isomeric form of methadone it would appear superfluous to examine theoretical or indirect electrical studies. Out of over 100 case reports in the literature, one single German anecdotal report describes torsade de pointes causing recurrent syncope in a patient taking racemic methadone 120mg, doxepin 100mg and a beta blocker. The patient did well when the beta blocker and doxepin were withdrawn and (R)-methadone (40mg) was substituted (Rademacher 2005). A preliminary communication on these issues from a German colleague was very reassuring, pointing out that some patients preferred the active form for its lower rate of adverse effects (constipation, sweating, sexual disturbance, etc). Swiss toxicologist Dr Chin Eap and colleagues showed that the change from racaemic to (R)-methadone led to only very modest decreases in QT interval (7.8ms two weeks after changing, p=0.06, n=39).

The French and Norwegian studies would appear to satisfy the call by Krantz and others for large national studies due to the relative low prevalence of the syndrome (sic). Norway (Anchersen, 2009) had four unexplained sudden deaths in a six year period. None was a suspected torsade case but these were the only ‘possible’ torsade deaths. Despite 15,000 patients taking methadone maintenance in France only three single torsade cases were reported to the French ‘pharmacovigilence’ department over eleven years along with seven unexplained deaths (Perrin-Terrin 2010). These figures are likely to be under-reported even though there was a nationwide awareness campaign including a ‘Dear Doctor’ letter to prescribers in France. None of the deaths was due to suspected arrhythmia yet even if they had all been due to torsade de pointes the prevalence would still be very low (0.06 per 100 patient years in the case of Norway) and may be comparable with matched subjects who are not taking methadone.

When torsade de pointes is recognised it is almost universally non-fatal. In fact, Salle and colleagues, who Krantz cites in claiming that the torsade mortality is ‘less than 20%’ in fact showed that following their initial group that over eight more years their institution had a torsade mortality of zero. Phibbs’ cardiology primer states: ‘.. torsade can be controlled 100% of the time’ which is consistent with the older French experience.

So where does this leave the baffled clinician? ‘Addiction’ has long had a bias emphasising problems with maintenance treatments in favour of demonstrating their benefits when used in appropriate circumstances (refs on request). ‘Addiction’ once published an item [Curran 1999] purporting to show that increased doses of methadone caused increased cravings (!). Letters from humble Australian and distinguished British authors on the subject were rejected so that its bizarre finding stands uncorrected to this day.

On one point Dr McCance-Katz and I agree: levo-methadone (the active isomer, (R)-methadone) is worth examining regarding its possible benefits in addiction treatments.

Comments by Andrew Byrne ..

References:

Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4

Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006 101:1333-1338

Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 150;6:387-395 [Byrne critique:Click here]

Rademacher S, Dietz R, Haverkamp W. QT prolongation and syncope with methadone, doxepin, and a beta-blocker. Ann Pharmacother 2005 39:1762-3

Ansermot N, Albayrak O, Schlapfer J, *Eap C, et al. Substitution of (R,S)-methadone by (R)-methadone: impact on QTc interval. Arch Intern Med. 2010;170(6):529-536

Perrin-Terrin A, Pathak A, Lapeyre-Mestre M. QT interval prolongation: prevalence, risk factors and pharmacovigilance data among methadone-treated patients in France. Fundam Clin Pharmacol. 2010 Sep 6

Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical relevance of QTc interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction 2009 104;6:993-999

Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT:
Antipsychotics and the risk of sudden death. Arch Gen Psychia-
try 2001 58;12:1161-7

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. American Heart J 1973 86:663-8

Salle P, Rey JL, Bernasconi P, et al. Torsades de pointe. Apropos of 60 cases. Ann Cardiol Angeiol (Paris). Jun 1985;34(6):381-8

Phibbs B. Advanced ECG: boards and beyond. 2006 Elsevier

Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR, Fischer G. Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure. N Engl J Med 2010; 363:2320-2331

Curran HV, Bolton J, Wanigaratne S, Smyth C. Additional methadone increases craving for heroin: a double blind, placebo controlled study of chronic opiate users receiving methadone substitution treatment. Addiction (1999) 94;5:665-674 Byrne’s commentary: Click here

Buprenorphine wafer/film inductions confusing.

Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films. Strain EC, Harrison JA, Bigelow GE. Clinical Pharmacology and Therapeutics 2011 89: 443-449

Dear Colleagues,

I was intrigued when searching for research on the mooted new ‘wafer-film’ form of buprenorphine to find that Dr Strain and his experienced research colleagues have performed a detailed and thorough drug induction trial which nevertheless seems to be of little or no utility to the clinical field. The appropriate test for any new medication is a randomised, blinded comparison with an established intervention using standard outcome measures. In the field of dependency these include retention, drug use parameters, side effects, sero-conversions, mortality, etc.

In this study the authors compare a newly introduced formulation of an old drug (buprenorphine/naloxone ‘film’) with a non-approved and possibly non-validated medication (buprenorphine film). By going to complex lengths to document withdrawal differences (see multifarious bewildering graphs), the authors appear to believe it is important to determine if there is any such difference, despite neither being a known ‘quantity’ to start with.

It is a false premise that finding no difference between two treatments proves their equivalence. Such a conclusion may be a statistical ruse rather than a rubric, as pointed out by Walter Ling many years ago. Strain and colleagues do not make such a claim, yet it is possible that others may misinterpret the work in this way, just as has happened with Suboxone (combination with naloxone) and Subutex (pure) which remarkably have still yet to be subjected to even simple equivalence testing. The reader is still left with the question of what exactly Strain and colleagues were trying to demonstrate in this paper.

[This question was answered in a recent lecture by Dr Strain at a function organised by the manufacturer in Sydney, Australia: see my summary on the subject in which it is state that the manufacturer was fighting to have the FDA recommendation to do inductions only with pure buprenorphine, now a cheap generic drug in some countries.]

While it would be beneficial to avoid or minimise withdrawal symptoms during induction, it is not clear whether this is linked to retention rates. In our experience some of the most successful buprenorphine and methadone recipients had unpleasant periods of withdrawal during the induction period.

Another weakness of their study is that their treatment induction bears little resemblance to normal clinical practice, further limiting relevance to the real world. They gave multiple doses of buprenorphine over many hours, something which is not used routinely either in clinics or community practice to my best knowledge. Furthermore, it would probably be costly and difficult to implement in the field.

It is not at all clear why these authors include the issue of drug packaging. In the abstract and twice again in the text the reader is informed about new individual packaging which is alleged to be safer than the existing product. Yet both are marketed by the same company which also supported this research. Rather than blister packs which are used in most of the world, in America buprenorphine is apparently dispensed as loose tablets (and now wafers). The new wafer formulation reportedly comes as individual unit-dose format with child resistant packaging. This aspect was not tested in any way in the paper and it would appear that the researchers are taking liberties by introducing this matter into a paper which ostensibly examines the physiological effects of introducing two buprenorphine products to dependent patients and in which most medication was given under supervision such that the packaging format was irrelevant to the outcomes. This is quite unlike the manner in which buprenorphine is commonly used in America and France … but not in most other countries which use supervision (evidence based) treatments. The irony is that most of the evidence was from studies performed in the United States where it was apparently overlooked in the Act of Congress which gave a waiver allowing doctors to prescribe it from their offices as a drug to be dispensed like any other drug from the pharmacy.

It is further claimed that serial numbers will allow tracking for buprenorphine films which may be diverted onto the black market. This would depend on chain-of-custody supply as well a new layer of detailed record keeping the cost of which is unknown, nor is it known if this type of measure can be effective. In short, this is a peccadillo and should be tested properly rather than being speculated upon here.

The first lines of the abstract read more like an advertisement than a serious scientific study: “[buprenorphine film product] provides unit-dose, child-resistant packaging amenable to tracking and accountability, offers more rapid dissolution, and has a potentially preferred taste vs. tablets.” Note that inventive drug users have already found ways of exploiting the increased solubility of buprenorphine wafers as described in a front page New York Times article entitled “When Children’s Scribbles Hide a Prison Drug”