26 December 2018

Christmas 'post-card' from Andrew Byrne in Redfern ...

Accreditation albatross; Honour role; ‘Ice’ age; Successful OTP patients; Hep C; rat research using cannabinoids and amphetamine. 

Dear friends, neighbours and colleagues,

It has been a mixed year, but we seem to have survived more-or-less intact at the surgery in Redfern.  Accreditation has been the great bug-bear and I believe it is high time for health professions to reject what masquerades as a motherhood safety net but which I firmly believe is strangling health care in Australia.   More of that later. 

It has been my privilege on annual trips to New York City to meet top people in our field, some of whom have become close friends.  These soldiers, saints and scholars include Vincent P. Dole (RIP), Don Des Jarlais, Charles O’Brien, Joyce Lowinson, Ethan Nadelmann, Herman Joseph, Ernie Drucker, Mary-Jeanne Kreek, Jerome Jaffe and Herb Kleber (RIP).  But none was as close to sainthood as Dr Robert G. Newman who died this year after a car accident in The Bronx.  His loss will be felt in many countries where he advocated for opiate maintenance treatment, harm reduction and ethical medical treatment for drug addiction in parallel with other medical conditions.  Sympathies to his wife Seiko and their children on their huge loss.  And ours. 

It has been a challenging year but with many rewards as we watch our patients achieve their goals, major and minor.  As I approach retiring age I can provide more customised treatment for those with opiate, benzodiazepine and alcohol problems.  Specifically we use split doses, high doses, low doses, frequent swaps between methadone and buprenorphine along with adjuvant therapy using anti-depressants, mood stabilisers, disulfiram, fluvoxamine, propranalol and propantheline.  Yet we are frustrated on a daily basis by the use of ‘crystal’ methamphetamine ('ice').  Previously stable, pleasant methadone maintenance patients have become unpredictable and unreasonable.  There have been frequent admissions to psychiatric wards where nothing much can be done after assessment and possibly antipsychotic medication.  We have tried prescribing dexamphetamine for some consenting trial cases but without success at eliminating the use of ‘ice’ (methamphetamine), even for short periods.  We await a positive strategy, perhaps from one of the younger members of the addiction Chapter (RACP). 

We continue to address the widespread use of benzodiazepine tranquillizers in our patient population (18-50% dependency among OTP patients according to AATOD).  We have started performing differential urine toxicology which can determine the diazepam-temazepam-oxazepam group from the more potent and dangerous alprazolam, clonazepam and flunitrazepam preparations.  We supervise detoxifying doses in new or unstable patients with some receiving ‘staged supply’ dispensing of diazepam for limited periods for anxiety and/or dependency using either 2mg or 5mg tablets.  The supply of diazepam is contingent on the usual stability criteria for take-home doses of methadone or buprenorphine (sober presentation, housing, vocation, family, finances, attendance, psychiatric, toxicology, etc).  ‘Doctor shopper’ information is now available on line.  More will be said on these matters following a seminar at Sydney University (RPAH) in November by Prof Starcevic, Prof Haber and a brief appearance by myself, chaired by Dr Richard Hallinan of our practice. 

We have also had numerous patients leave opiate maintenance successfully in the past 12 months with many others achieving vocational, family and other goals, far from uncontrolled illicit drug or alcohol use.  A fork-lift licence, university degree, new baby, paid off debts, smoking cessation and new housing can all be life changing benefits for those involved.   For others such goals are still at some distance. 

The new oral treatments for hepatitis C have allowed us to almost eradicate the disease from our patient group after sometimes frustrating times with interferon-based treatments in the past.  This has been enormously gratifying for patients, their families and our staff as a very positive outcome.  Congratulations are due to Dr Hallinan for most of this important public health work which is subject of continuing publications. 

My niece Gracie Hay has spent a couple of sessions in the practice after completing her psychology honours year at Macquarie University.  She has published a fascinating paper on her work with Professor Cornish using cannabinoids to diminish behavioural symptoms of withdrawal and relapse in amphetamine-primed rats (see citation below).  Gracie is now a medical student at Notre Dame University and has some busy years ahead of her.  [Hay GL, Baracz SJ, Everett NA, Roberts J, Costa PA, Arnold JC, McGregor IS, Cornish JL. Cannabidiol treatment reduces the motivation to self-administer methamphetamine and methamphetamine-primed relapse in rats. Journal of Psychopharmacology 2018 1 –10. Link below to free publication on-line] 

Merry Christmas and Happy New Year to all from the Byrne Surgery staff, hoping 2019 is a good one for all.

Andrew Byrne ..

13 June 2018

Portuguese drug policy changes save lives wholesale. Sydney meeting.

Big turn-out on rainy Sydney evening for drug law reform meeting.  Tuesday 5th June 2018. St Stephen’s Church, Macquarie Street, Sydney.
“An evening with Manuel Cardoso the man who helped reform Portugal’s drug policy”. 
Take-home message to get through to our politicians: decriminalisation is now proven to save lives, money and much more. 
The most impressive part of this evening was actually the audience, all like me, frustrated supporters of drug law reform, some for up to 40 years.  And I estimate that there were over 1000 in attendance on a cold wet winter evening.  An email blitz had offered a free umbrella for the first 250 to attend. 
The evening consisted of a fireside chat type presentation – no power-point slides, etc.  Will Tregoning PhD was a whippy and knowledgeable compere with his three guests on a couch up front with microphones and cameras for live-stream on FaceBook.  
Dr Manuel Cardoso said that he was an optimist and did not recall anything bad, just the good.  So when people asked what were the triggers for the move to decriminalization in 2001 in his country he said he could not recall that far back.  His CV seems to indicate that he was not involved in the drug field in 2001 so the title of the evening’s talk seems a little odd.  He explained that he was the deputy and was modest about the dramatic changes in his country following decriminalisation. 
Other information indicates very serious drug-related events in his country with some of the worst stats in Europe for a number of major outcomes such as overdose deaths, HIV transmission, incarceration, etc.  Also the economy was in the doldrums.  I understand that there was a coming together of three great minds being a politician, a radio host and a law professor.  And an opposition in parliament which was also on-side or at least on the same page, partly due to so many overdose deaths, some children of prominent citizens.  The entire story is carefully described in an excellent report by the CATO Institute (G. Greenwald, 2009) as quoted by one speaker (see links below). 
Dr Cardoso was also giving talks in Hong Kong, Argentina, Luxembourg, Norway and elsewhere on this trip, seemingly in great demand.  We were told that only Norway is in any political place to introduce decriminalisation, in great distinction from Sweden which has long had a zero tolerance approach despite their poor outcomes of drug related morbidities in such an environment.  Only America has a worse system and even the current unprecedented overdose crisis seems unable to move the prohibition monster. 
During the talk I realised that decriminalization brings out those who really DO have problems with drugs as distinct from those who like using their drugs, finding they can get on with their lives, work, raise families, pay tax, etc without problems.  This became clear as Dr Cardoso was talking about alcohol which some people use quite seriously but without apparent harm while others get into trouble with excess use and serious social/medical consequences.  This latter group needs help in numerous ways, just like others with disabilities or illness.  Indeed, the evening has taught me to be more tolerant of illicit drug use in my methadone patients when it is clearly low-risk and in some cases may even be quasi-therapeutic. 
Three of the best comments of the night came from the floor after the main interviews were over.  Marion Mc’Connell who co-founded Family and Friends for Drug Law Reform spoke about her frustration at seeing so little progress since the death of her son over 20 years ago.  This was then reflected by Rev Bill Crewes who dated his first meeting on the subject to the 1970s.  He also mourned the lack of serious moves away from the failed policies of prohibition and harm maximization.  Then an articulate young lady introduced herself as the new Labor candidate for Balmain in State Parliament, saying much work needed to be done by and within political parties.  She promised to push the issue as best she could but added that politicians can only act when they know what their constituents want and/or what expert opinion is suggesting.  Why are we still locking up drug users? 
This latter was taken up by ex-Premier Geoff Gallop whose government in WA virtually decriminalised cannabis.  He pointed out that two factors were crucial to successful change: bipartisan support as well as public forums with expert evidence pointing to a need for change.  Even some of his own (Labor) government’s easing of cannabis restrictions in WA were rolled back by a subsequent (Liberal coalition) government. 
Dr Marianne Jauncey spoke briefly about her experience as director of the Medically Supervised Injecting Centre in Kings Cross.  This is the only place in Australia where it is legal to possess illicit drugs.  Despite its success clinically over 17 years (no deaths after up to a million injecting episodes) and public acceptance, it has not been duplicated by the NSW Health Department, which is regrettable.  After numerous false starts it appears that Melbourne may soon have an injecting centre. 
Others had particular questions for Dr Cardoso about the situation in Portugal and how that might be relevant to other jurisdictions.  His answers while direct were generic.  I asked him if there were any moves in Portugal to return to old policies such as from the Catholic Church, older citizens or conservative forces.  He replied that he knew of no such moves and would be surprised if there were any.  The Church, he said, was wholly supportive.  It seems that the benefits have been so widespread and so obvious that the entire population, not just drug users, can see the benefits.  There may be similarities to the lifting of alcohol prohibitions in America 90 years ago. 
There was a great deal of camaraderie in the foyers afterward with nice mingling over savouries and drinks with many old colleagues, some I had not seen for ages.  It was also nice to see a younger generation of health professionals, advocates, researchers, etc in attendance at such a gathering. 
My summation of the event was that there is a groundswell of keen support for total decriminalisation of personal drug use and that the Portuguese experience was one of the largest social experiments of our time … and every indication is that it has proven beyond any doubt that prohibition has failed and removing it along with increasing access to treatment and harm reduction is successful.  This ‘experiment’ (my colleagues say I should not call it an experiment) was so large and so successful in a country with many similarities to our own that it places our system of prohibitions of drugs as being out-dated, counter-productive, wasteful and inhumane. 
If everyone at this meeting made an appointment to see their local member of parliament with their views we may see the start of something big.  It took the ‘Mothers of America’ to start the moves against prohibition in that country … maybe we need a similar movement here.  The rationale is compelling … and in America with the overdose crisis the case is overwhelming. 
Written by Andrew Byrne, Redfern Addiction Physician. 
References: Greenwald G. Drug Decriminalization in Portugal: Lessons for Creating Fair and Successful Drug Policies. Cato Institute. 2009  https://www.cato.org/publications/white-paper/drug-decriminalization-portugal-lessons-creating-fair-successful-drug-policies

13 May 2018

Dr Kandel on memory loss in the elderly.

April 12 2018
The Eric Simon Lecture in Basic & Translational Neuroscience
Eric R. Kandel, MD
University Professor and Fred Kavli Professor
Department of Neuroscience
Columbia University
Senior Investigator
Howard Hughes Medical Institute
Smilow Seminar Room
I had been invited by Addiction Textbook editor Dr Joyce Lowinson to a talk by Nobel Laureate Eric Kandel on memory loss in the elderly.  His Nobel Prize in 2002 was for work on snails and the laying down of short and long term memory in brain cells.  I sat in the front row next to a doctor from Bellevue Hospital where some of the rat experiments quoted by Prof Kandel had been done.  The speaker was introduced by Dr Eric Simon who was honoured by this annual address and who was the first to name endogenous endorphins in the human brain.
The initial point of the talk was to emphasise the important differences between Alzheimer’s disease and ‘benign senescent memory loss’.  The latter had first been described (allegedly) by a member of the audience and is a well known syndrome.  A side point was made that despite modern publications needing 20 or more pages plus appendices, Crick and Watson’s paper reporting the double helix was only 3 pages long.  And Sigmund Freud wrote some critical papers of a similar length.  Dr Kandel reported being at James Watson’s 90th birthday the week before.  We were indeed in the presence of greatness!  I might add that Dr McBride’s report of thalidomide consequences was less than half a page in Lancet.   
The most important message of the talk was that rodent experiments had confirmed the difference between modest memory loss due to age and Alzheimer’s Disease with amyloid build-ups, tangles and other typical pathological findings which can be induced in rats.  Dr Kandel’s main finding was that high levels of ‘osteocalcin’ were associated with benefits in retaining memory functions, even into old age (which for rats is 18 to 24 months).  It seems that this hormone is produced in osteoclasts mostly in bone but also in the circulating blood stream.  He also described on a specific haplotype which was apparently associated with low level of osteocalcin and a propensity to significant memory less. 
Over the past five years of research Dr Kandel found that the best way to elevate osteocalcin levels is to exercise to the level of walking about 3 kilometres every day (for a human – most of his experiments so far have been with rats).  There are numerous other benefits of walking for the heart, blood pressure, stress levels, etc, etc. 
There was a wide ranging and lively Q&A session after the presentation. An audience member asked if swimming was as good as walking but we were told that since one is weightless it is probably less effective on the bones producing osteocalcin … also, “one could drown” (a comic interjection from an Israeli colleague in the audience – to which the speaker quipped “you Israelis are always worried about existential threats”).  I asked Dr Kandel if taking exogenous osteocalcin would do the same as exercise.  Some enterprising audience members had already searched for supplies and found some company allegedly selling the chemical already!  This remains to be trialled, it appears. 
My neighbour from Bellevue had done some rat trials and told me quietly that their rats were very keen on exercise, running on their treadmills for hours on end, thus improving their experimental memory scores into ‘old age’ (>18 months for rats).  I wanted to ask whether they were in small cages or ‘rat-park’ enclosures as per Bruce Alexander’s work in Canada but time ran out and I may never know. 
Notes by Andrew Byrne .. visiting addictions physician from Sydney, Australia. 

Summary in brief in talk by Dr Kandel: https://www.youtube.com/watch?v=X15zFT7jyh4
Also brilliant TED talk on neuroscience approach to portraiture: https://www.youtube.com/watch?v=Jyc7FIglkHI


8 May 2018

Medical Postcard from New York: overdose crisis summary from NYU.

Dear Colleagues,
During a recent New York visit I had numerous encounters in the medical, public health and dependency fields.  The opioid overdose crisis dominates conversation, media and even the White House has been involved.  Below is a summary of one key lecture I attended followed by some other events which may be of interest. 
Regards from Andrew Byrne .. now back in Sydney, Australia. 
April 19 2018         Stephen Ross, MD
The Opioid Epidemic: How We Got Here and How Do We Fix the Problem?” Associate Professor, Departments of Psychiatry and Child and Adolescent Psychiatry Senior Director, Division of Substance Abuse, Bellevue Hospital. Director, Addiction Psychiatry, Tisch Hospital, NYU.
This was an action-packed talk filled with a vast quantity of detail but with the overall ‘messages’ carefully enunciated by Dr Ross who was introduced by department Chair with a string of accolades from early life in Johannesburg, South Africa to medical school in the US, psychiatry training, teaching awards, research publications and more.  Dr Ross has also authored some interested papers on the therapeutic possibilities of hallucinogens in patients with serious medical disease. 
We were told about the epidemics of opioid use starting early in the 19th century when opium, laudanum and paragoric became very popular.  A series of advertisements for these products while cute and dated also had their same ring of snake oil tactics still used by today’s drug companies who he repeatedly blamed, at least in part, for much of the current problems in America.  Dr Ross reminded us that the lessons of history should be heeded right now since overdose problems have happened in several surges of opiate popularity over the 20th century and the circumstances can almost be predicted, or should have been. 
The present epidemic seems to have started after an air of confidence in medically prescribed opioids with a low risk of addiction.  These were started by two brief communications published as letter to the editor, one from Russell Portenoy and colleagues in NYC Sloane Kettering.  Both brief letters which Dr Ross showed on the screen pointed out the low rate of dependency they found following medical prescription of opioids for pain.  Neither was a RCT nor even a prospective study and yet they were given a significance well beyond their actual scientific value by some well meaning doctors and avaricious drug companies.  Dr Ross also pointed out that prescribing by experienced pain management teams with multi-disciplinary measures is very different from a dentist or ‘orthopedist’ writing up a month of opioid pain killers for post operative cases as some do routinely to this day (we were given examples). 
I read elsewhere that about 15 years ago the Joint Commission for Medicare and Medicaid Services (CMS) had required reporting of pain in therapeutic outcomes after numerous parties had pushed a well meaning but fundamentally flawed and dishonest campaign of : “Pain as the Fifth Vital Sign” (after pulse, temp, BP and respirations).  Of course pain is a symptom and not a sign at all yet for marketing purposes this was highly effective.  And furthermore there was very limited evidence that opioids were effective for chronic non-cancer pain. 
Dr Ross divided the recent overdose epidemic into three parts starting in about 2001: (1) prescribed opioids, (2) heroin then (3) fentanyl additives.  The last has been the most deadly as his graph showing yearly deaths had three lines of increasing slope, ending at the terrible annual toll of 60,000 for ~2016/7.  It seems that there is general agreement that aggressive marketing and lax regulations from 2002 to about 2009 led to the initial dramatic increase in opiate problems in America based on the assertions (1) that addiction rarely follows medical prescription and (2) the claim that chronic pain was widely undertreated.  Opponents at the time were accused of ‘opiophobia’ (Dr Ross quipped that this would become a new DSM diagnostic category!). 
The predictable and protracted reaction against this over-prescribing by the states was to restrict opiate prescription in numerous ways: triplicate prescription requirements, limited quantities, and refills, reduced insurance rebates, and (supposedly) less abusable formulations.  These knee-jerk restrictions caused many who were unwittingly addicted to move to illicit heroin which flooded the market from Mexico.  Only a very small proportion could take advantage of addiction treatments due to high cost as well as limited availability in many areas, thus there was a second wave of drug use and consequent deaths. 
Then we were told about a third and most worrying phase of the overdose crisis being the unprecedented increase in deaths in the past 3 years which has been associated with replacement with and contamination by some of the opiates using fentanyl and carfentanil, mostly manufactured in China.  Because these drugs are hundreds to thousands of times more potent than heroin they can be imported in small packets undetected.  Also we were told that innovations of the dark web, bitcoin and ‘pill presses’ have added further to the difficulties.  Two pills which look identical may have vastly different potencies. 
Dr Ross was extremely critical of drug regulation authorities, criminal justice, customs, drug companies, medical insurers, medical schools and health practitioners all of whom he said had played a role in the current disaster which leads to an overdose death every 12 minutes in America.  The number of deaths has now exceeded all casualties of war including both world wars for the US.  The annual death rate has topped cancer, suicide, road deaths and is now the leading cause of death in 20-50 year age group (I think I got that right).  We were shown age at death tables to show that this is affecting all age groups but that younger people are now involved.  The number of drug overdose deaths in the USA was estimated to have been over 60,000 per year by 2017.
Dr Ross put up a table of the types of practitioners most involved in the current prescribing and I was surprised to see the orthopaedic surgeons and dentists were high on the list along with family physicians, psychiatrists, gastroenterologists, etc. 
It appears that many minor procedures such as arthroscopy are routinely prescriber 30 or even 90 days of opiate pain killers and that there is a significant financial incentive to do so under some payment ‘plans’.  In my discussions during my time in New York I heard of a 15 year old boy who returned to school after a knee arthroscopy as a day procedure with a bottle of 90 Vicodin tablets (containing paracetamol plus hydrocodone).  I saw a TV interview with a mother who had found both of her late-teenage sons dead after a family celebration.  It was chokingly tragic but is being repeated all over the country every single day. 
Naloxone programs were mentioned and commended briefly but the obvious fact that they are of no assistance when the overdose victim is alone. 

Dr Ross alluded briefly to the Portuguese drug law reform implemented in 2001 which involved removal of all sanctions for persons found in possession of quantities of drugs (defined) consistent with only personal use.  He emphasised that drug dealers were still arrested but that there were no legal sanctions against drug users apart from being introduced to treatment services (de-addiction committees … which the subject could take-or-leave referrals to treatment services).  Funds saved in the criminal justice sector were put into treatment which had been substantially expanded and improved.  From having the worst statistics in Europe for consequences of drug use most improved year by year to be some of the most envious.  These included reduced overdose rates, HIV and Hep C transmission, crime, etc. 
Dr Ross pointed out that the most effective form of treatment for opiate dependence included Medication Assisted Treatment (MAT) with buprenorphine and methadone. In the USA extended release injectable naltrexone is also included in MAT despite the small and largely unimpressive evidence for effectiveness, safety and cost effectiveness compared to methadone and buprenorphine.   While treatment availability in American cities is quite limited, in rural areas such services were often completely absent.  We were shown various colour-coded maps of the country showing the paucity of approved physicians for buprenorphine and even worse availability of methadone clinics (methadone is not available in American pharmacies unlike other western countries).  The ratios of drug users to treatment facilities were as unfortunate as they could be.  [see NY Times interactive map with opioid overdose rates for every county: https://www.nytimes.com/interactive/2017/12/22/upshot/opioid-deaths-are-spreading-rapidly-into-black-america.html ] The expansion and improvement of maintenance treatments is the most important part of the package of measures needed in the USA to reduce the number of opioid overdose deaths.
Unlike many Americans, our speaker was happy to mention prevention, treatment and harm reduction in the one breath.  The common reticence was partly due to a White House edict some years ago that any grant application which mentioned ‘harm reduction’ was to be refused.  This is despite its complete compatibility with good public health polices as first exemplified in the Broad Street Pump reports of cholera in London in the 19th century.  Some facetious comments even refer to inappropriate interventions such a blanket prohibition as being ‘harm maximization’.  
There were a few Q&A’s at the end after a major applause showing the audience appreciation.  Prof Ernie Drucker brought up the issue of cannabis and mentioned that he had discussed with Lester Grinspoon about heroin users modulating their opioid use with cannabis products which may explain the lower overdose rates being reported in states which have legalised cannabis. 
Notes by Andrew Byrne .. visiting addictions physician from Sydney, Australia.  http://methadone-research.blogspot.com/
** Lecture by Dr Steve Ross on the opioid crisis and what to do about it (summary/link above). 
** Lecture by Nobel Laureate Dr Eric Kandel on memory loss in the elderly (exercise more!)
** Opening address at ASAM meeting at San Diego (seen on web-stream) by Dr Ellinore McCance-Katz, after a statistical run-down and promise of research funding, then started to sound more political than like the caring physician I know her to be.  Second speaker was Michael Charness, Boston VA, on alcohol interventions in 50 years time.  Surprisingly, popular singer Judy Collins had equal time in the third plenary (and sang her songs rather too often), giving her profound story of long-term sobriety and lessons for others. It was also in honour of Dr Stuart Gitlow who had been instrumental in Ms Collins' success.   
** Subsequent web-stream ASAM talks of interest: https://www.youtube.com/watch?v=a8IcJXdwKbE&feature=youtu.be
** Harm reduction still a long way to go in America.  American Society of Addiction Medicine (ASAM). 

** New guidelines in US on prescribing for opiate maintenance TIP63 but there is still no “connect” between buprenorphine and methadone even though they should obviously be complimentary, both being licensed for opiate dependence.  Yet they are rarely if ever given in the same institution by the same staff thus transfers are complex and sometimes impossible.
** Meeting with Dr Mary Jeanne Kreek at Rockefeller University wide ranging discussions including high dose methadone and methadone for pain. 
** I gave a talk on optimising outcomes in opiate maintenance treatment at Columbia University (more info on request). 
** Meetings also with Dr Joyce Lowinson, Dr Robert G. Newman, Prof Ernie Drucker, Dr Herman Joseph, Dr Doug Kramer, Ethan Nadelmann and many others. 
** Recommended TED talk J. Hari: https://www.youtube.com/watch?v=PY9DcIMGxMs “Everything you think you know about addiction is wrong”. 

25 March 2018

Buprenorphine alone or with naloxone: Which is safer? Subutex versus Suboxone

Buprenorphine alone or with naloxone:  Which is safer?  Kelty E, Cumming C, Troeung L, Hulse G. Journal of Psychopharmacology (2018) in press. 1-9
Dear Colleagues,
After a ten year chronological comparison of 3500 patients prescribed either pure buprenorphine or the combination product with naloxone these authors found few differences in hospital admissions or death rates while in treatment.  However there was a significant increase in mortality post-treatment in those who were prescribed the combination product (odds ratio 1.59).  There were also higher all-cause hospital admission rates in those prescribed the combination product but slightly lower rates for those with skin infection diagnosis.  These extended to the post treatment period and the authors conclude that: “The addition of naloxone does not appear to improve the safety profile of buprenorphine”. 
These Western Australian researchers had access to Health Department prescribing records which were then compared with hospital admission rates and mortality over a ten year period, month by month, in 3500 patients starting in 2001.  The combination product was introduced in the middle of the study period and it quickly became about 90% of the market, allowing a useful comparison.  The 90% transition rate was partly because in WA take-away doses of the pure drug were banned coercively.  There may have been an exemption for pregnant women for whom the pure drug remains the recommended product. 
So here finally we have a study comparing pure buprenorphine with the combination product, although not a randomised controlled trial.  To my knowledge, despite the claims for benefit, there has been little rigorous comparative research before widespread replacement of the pure product with the combination.  The opioid antagonist naloxone was added to an existing sub-lingual product with the intention that it would be safer by being less attractive to inject.  As with other approved medicines, there is no obligation to do comparative research before TGA/FDA approval.  Indeed, all of the early research was on the pure product including the MOTHER study in 2009.  The only real support for the combination product meantime has been some indication that it was marginally less desirable on the black market, attracting a slightly lower reported price.  Yet it would seem self evident that a pure drug would be more desirable to drug seekers than a combination, regardless of the constituents.  Two studies indicated the need for higher doses when the combination drug was used (Fudala and Bell). 
In a small pilot study Bell and colleagues found that after transitioning to the combination product most seemed to do quite well on a number of indices.  However, they also found that subjects appeared to require substantially higher doses (>50% on average) when naloxone was added.  Fudala et al. found substantially more cravings in a large multi-centre RCT in the combination group using fixed doses.  There have been no confirmatory studies to my best knowledge. 
Western Australia has always been a good location for serious D&A research, Perth being a wealthy metropolis with good public health facilities in a relatively isolated position.  And with earnest, experienced and one-time well funded researchers. 
Kelty et al. point out that significant amounts of naloxone are in fact absorbed and that this is known to up-regulate the opioid receptors, possibly making some patients more vulnerable to overdose even after ceasing treatment.  It is also possible that this was the cause of the Sydney patients seemingly requiring higher doses in Bell’s old study. 
A good investigative journalist might make a good story over the profit motive, drug ‘evergreening’ and such, but I leave all this to others.  Suffice it to say that currently our government through the PBS is paying high prices whereas in France the pure product has been used since 1994 and is sold to the government suppliers as a cheap generic (and by an Australian company I believe!). 
Notes by Andrew Byrne ..
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
Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN, Jones K, Collins J, Raisch D, Casadonte P, Goldsmith RJ, Ling W, Malkerneker U, McNicholas L, Renner J, Stine S, Tusel D. Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone. NEJM (2003) 349:949-958

2 October 2017

Large study shows torsade risk remote and ECG non-predictive in methadone maintenance.

Methadone and the QTc Interval: Paucity of Clinically Significant Factors in a Retrospective Cohort. Bart G, Wyman Z, Wang Q, Hodges JS, Karim R, Bart BA. J Addiction Medicine pre-publication 2017. 
Dear Colleagues,
Dr Bart and co-authors have examined the medical records of around 1000 admissions to methadone maintenance nearly all of whom had at least one ECG on or off methadone (or both).  They then compared clinical cardiac events and mortality over 7000 patient years from the major health facility in Minneapolis.  There was an average increase in QTc of 13 milliseconds in those on methadone at the time of the ECG, consistent with other studies.  This was associated with a very low rate of cardiac events of 2.5 per 1000 and QTc intervals were not predictive.  Sudden cardiac death (SCD) rate was lower than age-adjusted community rates (0.4 versus 1.75 per 1000 based on CDC state statistics).  This parallels numerous other reports attesting to the general protective value of being on methadone treatment (see Krantz ref below on cardiac protection).  No case of torsade des pointes was identified by the present authors over 15 years.
This study gives great reassurance in the cardiac safety of methadone maintenance treatment.  The authors also suggest that the requirement for ECG in methadone patients should be reviewed since it does not appear to serve any practical purpose.  A Cochrane review also found no evidence to support QTc screening. 
Concerns over the supposed dangers of QTc prolongation have been over-played, partly by commercial factors favouring the only licensed alternative to methadone maintenance.  Of about 150 torsades cases reported in the literature since 2002 only one was fatal to my best knowledge. 
A paper by Mori Krantz from Denver in 2002 claimed to have found an extraordinary number of tachycardia cases from Colorado methadone clinics and a pain management service in Canada.  Torsade des pointes was reported as a side effect of methadone yet Krantz’s findings have never been replicated elsewhere, even in large samples of closely studied patients over 30 years of research literature.  In the present series by Bart and colleagues not one case was identified in 7000 patient-years.  About 150 anecdotal reports in the literature since 2002 shows this rare event occurs mostly in high-dose, complex methadone patients who were taking other medications, were over 40 years of age and with a higher rate in female patients.  My own practice with approximately 3000 patient-years has identified one single torsade case (non-fatal).  Alcohol and pre-existing heart disease were also associations in this aging population.  Krantz’s claim that methadone was associated with large numbers of otherwise unexplained deaths has also never been supported by the literature (Byrne, Stimmel. Lancet 2009*). 
Notes FYI by Andrew Byrne, Sydney, Australia.  http://methadone-research.blogspot.com/
Krantz on cardiac concerns from the following year (no mention of the balancing protections above): Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, D. Robertson AD, Mehler PS. Torsade de Pointes Associated with Very-High-Dose Methadone. Ann Intern Med. 2002 137:501-504 http://www.annals.org/cgi/reprint/137/6/501
*Byrne A, Stimmel B. Methadone and QTc prolongation. Lancet 2007 369:366  http://www.thelancet.com/journals/lancet/article/PIIS0140673607601810/fulltext

23 May 2017

Medical post-card from New York in April 2017

Butler Library, Columbia University
Dear Colleagues,
New York has had an early spring but all talk is about the new President and his almost daily tweets.  In medical circles, however the opioid overdose crisis across America is top news yet solutions are hard to find and some (like methadone in general practice) are unmentionable.  After three years of investigations I believe I now know why methamphetamine is less of a problem on the US East Coast and it seems to be due to cocaine being so cheap being less than five dollars per cap in some areas.  For the same financial reasons benzodiazepines are less of a problem due to their high price in America.  With national health schemes Valium and other stronger sedatives are relatively easy to obtain at low cost in France, Israel, Australia, etc.  Ergo a larger abuse problem. 
Safer injecting facilities are now being pushed for in public health forums but by few in authority in America.  Naloxone without prescription is now commonplace which is gratifying ... yet by definition it requires the presence of another person at the scene of the overdose to save a life.  Opioid maintenance TREATMENT can ensure a way to stabilize the opioid epidemic yet such treatment is very hard or impossible to access in much of the United States due to the restrictions on methadone programs and the high cost of buprenorphine.  It is a mystery to me why methadone is not available from private American physicians, nor why American pharmacists are banned from administering methadone in addiction programs.  In a meeting at Rockefeller University I was told the reason was the lack of a profit motive as the drug is old and out of patent in its pure form (about 50 cents per dose). I was pleased to be able to get a world authority on buprenorphine, Dr Doug Kramer into the Journal Club of a world authority on methadone, Professor Mary Jeanne Kreek for a lively discussion including the history of FDA approvals and initial dose recommendations. 
A new publication in the British Medical Journal (including an American editorial) attests to the dramatic reduction in mortality, both overdose and all-cause mortality, in those taking opioid maintenance treatment when compared with opioid dependent citizens who are out of treatment.  The metanalysis across several countries shows substantial reductions in deaths, something which has been shown in smaller studies for over 20 years.  See: http://www.bmj.com/content/357/bmj.j1947 (free access for both editorial and article on the subject).  The acute need for action is talked about daily in the US media yet nobody seems to talk about the elephant(s) in the room which are a lack of treatment availability and drug company culpability for pushing profitable opioid analgesics for so long.  As a maintenance treatment, buprenorphine is excellent for those who can afford it and those with lesser habits and the ability to tolerate the induction requirements (being in or near withdrawal before starting).  The lack of a community methadone program is costing America dearly.  One recent report quoted 50,000 deaths in one single year which out-numbers victims or war, cancer, accidents and suicides. 
An interesting side issue is that American states which legalised 'medicinal' cannabis in recent years have significantly lower overdose rates and the initial figures are now being confirmed in longer term statistics.  While one can speculate on the reasons, the 'normalisation' and decriminalisation of cannabis which has been spearheaded by the Drug Policy Alliance, funded by George Soros must now be given credit for saving hundreds or even thousands of lives.  This organisation has been directed by Ethan Nadelmann who stepped down in April after 20 years at the helm.  His send-off was a moving event with supporters, colleagues and friends including Ira Glasser, Stanton Peele, Joyce Lowinson, Ernie Drucker, Clovis Thorn, asha bandele, Chris Soda, Ellen Flenniken, Dr Robert Newman, Tony Newman, Tony Pappa, and many others including Chief Prosecutor from Albany, David Soares and his wife.  I was happy to be able to represent Australia at such an auspicious gathering in Chelsea overlooking the Hudson River. 
Hepatitis C remains a festering issue between outrageous drug prices and limited funding.  The New York based activist group V.O.C.A.L. has long been advocating strongly for State and Federal subsidies for such treatments to be more widely available.  We are very fortunate in Australia that our PBS struck a very favourable deal with the suppliers, allowing universal access to five new direct acting anti-viral (DAA) drugs (the maximum yearly outlay was capped regardless of the number of prescriptions written).  After just over twelve months, an estimated 38,000 patients have been treated ... which is 15% or more of all the cases in Australia.  This makes hepatitis C eradication possible within the next several years.  Only tiny Iceland has done a similar effort, with its reported 1200 HCV cases.
I had very fruitful discussions with senior colleagues at Columbia University and at Rockefeller University regarding the possible safe use of benzodiazepines in stable OTP patients as well as our own recent experience with treating hepatitis C.  It appears that cirrhosis based on viral hepatitis may be partly reversible, contrary to the popular wisdom and I was able to give some examples from Australia.  We have had ~30 viral clearances out of ~30 patients on Direct Acting Antivirals (DAA) over the past 14  months.  This compares with about 45 out of 55 successful treatments on interferon and ribavirin (plus protease inhibitors more recently) over about 9 years (and it was NOT all easy going). 
My last days in Manhattan included some touristy things such as Katz's Deli (a disappointment), Barney Greengrass Deli (a high point), Hello Dolly with Bette Midler ($59 seats in back row sold on day of performance only) and the 50th Anniversary concert at the Metropolitan Opera House.  Details and photos on request (or on my other blogs soon). 
With best regards,
Andrew Byrne ..  

12 February 2017

Lower mortality and better retention in OTP patients prescribed benzos.

Bakker A, Streel E. Benzodiazepine maintenance in opiate substitution treatment: Good or bad? A retrospective primary care case-note review. Journal of Psychopharmacology 2016 1-5
Dear Colleagues,
Finally we have some strong evidence that prescribing benzodiazepines for patients on opiate maintenance treatment is not only safe and effective but in some cases may be obligatory, under careful supervision with adequate psychosocial supports. 
Dr Bakker in London has done us the great service of publishing the data he has extracted from his own general practice from over 20 years of caring for drug dependent patients.  His practice is based on sound harm reduction principles, prescribing long acting, low potency benzodiazepines such as diazepam or clonazepam using graduated supervision for dependent patients.  In this he bucked the trend based on what he considered good medical practice, albeit non-evidence based (like much prescribing practice). 
Bakker reports on 278 OTP patients since 1998 (1289 patient/treatment years) comprising a high proportion of socio-economically deprived citizens, two thirds being male.  Regarding prescription for benzodiazepines (bzd) from the practice, patients were classified ‘never prescribed bzd’, ‘occasional prescription bzd’ and ‘maintenance bzd.  Further, he examined those still in treatment against those who had departed (96% still in UK, 4% gone overseas, lost to follow-up).  From comprehensive statistics kept by the British NHS Bakker was able to derive accurate mortality figures for these six groups with surprising results for retention and mortality. 
Never              Occasional       Maintenance
Current pats:   223t/y              301t/y              765t/y  
Mortality:        1.79p100ty      0.33p100ty     1.31p100ty
Retention        34 months       51 months       72 months      
Ex-patients:     267t/y              320t/y              305t/y
Mortality:        2.24 p100t/y    0.63 p100t/y   5.90 p100t/y
Excess mort:    125%               191%               450%
T/y = treatment years
Contrary to some expectations, retention was highest in the group prescribed maintenance benzodiazepines.  Furthermore, mortality was lower than in the group never prescribed sedatives and the lowest mortality was intriguingly in those occasionally prescribed sedatives.  However, the most meaningful, and very worrying statistic is the high mortality in maintenance patients who transferred elsewhere for their treatment (more than 4 fold those remaining in treatment at Dr Bakker’s practice in London).  The authors report that following health authority directives very few maintenance prescribers in the UK allow benzodiazepine prescription in parallel as Dr Bakker’s practice does.  Hence the likely inference that these patients had legal supplies of benzodiazepines curtailed on transferring elsewhere for their OTP treatment. 
Another important finding was that the death rates were lowest, and very significantly lower, in those prescribed benzos occasionally, both in-house patients and in those transferred elsewhere. 
This report is not a randomised controlled trial, nor was it prospective, yet it involves large numbers of patients in a normal medical population over a long period with very few lost to follow-up (4%).  Hence the findings are very meaningful for those involved in comparable practice providing opiate maintenance with methadone and/or buprenorphine in a community setting. 
From this paper is it apparent that withdrawing benzodiazepines may increase mortality substantially.  Hence, official guidelines and clinical recommendations which warn against benzodiazepine prescription may be contributing to excess deaths rather than preventing them.  In my experience most OTP prescribers have a small number of patients who are prescribed benzodiazepines, some long-term.  Yet up to 70% of our patients have had problems with sedatives and so to ignore this and advise: ‘just say no’ may not be the proper approach.  However, prescribing is well beyond the comfort zone for many in our field without formal protocols. 
It is my view that all dependent patients should be able to access benzodiazepines under some clinical framework although this should not be open-ended, just like methadone.  There should be dose supervision initially ranging to normal unsupervised prescription for those who are socially integrated but unable or unwilling to cease sedative use.  Those abusing alcohol should be excluded until they can demonstrate abstinence.  Trial dose reductions should be negotiated periodically, as with methadone.  In our own practice we use diazepam and we aim to a dose of 4-15mg daily which is satisfactory for the great majority after initial reductions. 
Notes by Andrew Byrne ..
Bakker article PDF:
References: Franklyn AM, Eibl JK, Gauthier G, Pellegrini D, Lightfoot NK, Marsh DC. The impact of benzodiazepine use in patients enrolled in opioid agonist therapy in Northern and rural Ontario. Harm Reduction Journal 2017 14:6
Weizman T, Gelkopf M, Melamed Y, Adelson M, Bleich A. 2003 Treatment of benzodiazepine dependence in methadone maintenance treatment patients: A comparison of two therapeutic modalities and the role of psychiatric comorbidity. Aust N Z J Psychiatry 37: 458–463
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