11 January 2022

4. Microdose transfers from methadone to buprenorphine – 5. Will this spell the end of the methadone clinic?

Part the third: Harm reduction and supervised benzodiazepine prescribing in opiate programs.  [See my old summary Dr. Andrew's Opinions: Benzodiazepines in psychiatry and addiction medicine - do they still have a place in chronic care? (methadone-research.blogspot.com) New summary to follow later when time permits.] 

Part the fourth: Microdose’ transfers from methadone to buprenorphine. Will this spell less need for methadone clinics with more patients benefitting from buprenorphine in community practice? 

4. Due to precipitated withdrawal, transfer of high dose methadone patients to buprenorphine was generally considered impossible.  Gradual reductions to 40mg have enabled some to transition successfully.  However for many others such reductions have proven untenable. 

But things have changed.  We now know that many patients can be transitioned using an overlapping dosing regimen starting with full dose methadone along with ‘micro-doses’ of buprenorphine (eg. 0.4-0.8mg SL) then reducing doses of methadone and increasing doses of buprenorphine after 3 days of the priming doses. 

While this is novel in Australia it was first described in 2010 by Dr Robert Haemmig in Berne, Switzerland and has been recently taken up by a number of centres in Canada (see references below from London, Ontario and Vancouver, BC).  Despite minor differences in protocols the essence is the same.  Seven cases were described by Brar and colleagues in July 2020 using a type of ‘Bernese’ protocol.  

The NSW Health Department first approved a "Bernese" protocol in November 2020 and a major hospital has performed a substantial number of trial cases with ethics committee approval, initially as in-patients, then as out-patients.  In our practice we have performed three initial transfer patients with singular satisfaction from the patients involved and minimal input from staff.  Now we have a wait-list for further candidates to try this innovation.  

Extended unsupervised doses of buprenorphine can often be given as it is far safer than methadone.  There is also the prospect of long acting, depot buprenorphine injections up to monthly intervals. It is known that buprenorphine has less propensity to alter the endocrine system and it is hoped that osteoporosis will be rarer in long-term use compared with methadone.  

The microdosing method staggers the cessation of methadone and simultaneously introduces ‘micro-doses’ of buprenorphine (eg. 0.4mg, 0.8mg, 2mg) to ‘prime’ the mu receptors and thus prevent the withdrawal cascade which can be precipitated when they are saturated with partial agonist.  So, rather than a sudden switch which can risk a precipitated withdrawal reaction the process is smoother and associated with high patient tolerability.  Dr Nolan's group in Vancouver has performed over 200 such transfers on patients taking up to 200mg methadone and she reports zero incidence of precipitated withdrawal and a 95% satisfaction with buprenorphine with just 5% returning to methadone (pers comm.). Furthermore, she emphasises that flexibility is the key, allowing slightly longer cross-over periods when necessary, sedatives and analgesics for those with minor symptoms in the transition period.  

 5. So, is this the end of the ‘methadone clinic’ as we knew it with most patients moving on to buprenorphine?  Our five recent transfer patients (including 2 direct low dose transfers) have reported a variety of benefits such as less sweating, less constipation, ‘clearer head’, less stigma, better mood, better sleep, easier storage and more. Do I sound like a commercial?  The only regret from some was that they did not do this transfer long ago!  

Over the years I have visited methadone clinics across the world including Brighton, England, San Francisco, Honolulu, Maui, Manhattan, Brooklyn, Bronx, Chicago, Beijing, Hong Kong and beyond.  None could be mistaken for a resort hotel and some were scruffy and uninviting dens.  In the past methadone clinics were necessary … a time when heroin addiction was spreading widely, HIV threatened, overdoses were increasing when neither traditional hospital, pharmacy, medical or psychiatry clinics were able to deliver the necessary treatment in sufficient numbers. And methadone was the only opiate maintenance drug available.  While buprenorphine has changed the field in most countries, sadly in the USA the price of buprenorphine is beyond the reach of many who need treatment. 

Now in many countries GPs and community pharmacies can be involved in delivering quality opiate maintenance using buprenorphine.  They may need back-up support and assistance from addiction specialists for new and complex cases.  Time will tell but I predict less need for OTP clinics and the expansion of addiction referral centres.  These should support GPs and other community services and need to be comprehensive, involving smoking cessation, vaping information, alcohol detox services, medical cannabis, harm reduction information, hepatitis monitoring, stimulant programs and associated mental health assistance.  And good coffee! 

With best regards to my faithful readers.  

Disclaimer: the Bernese method is still not a standard treatment and should only be done under close supervision with experienced staff and Health Department approval.  

 

 References:

Insight - WOWS Lite - Dr Ken Lee - The Bernese Method of buprenorphine micro-dosing

2. Reconsidering the usefulness of adding naloxone to buprenorphine.

Part the second, Dr Byrne’s blog notes (abbreviated due to two articles I have found which have done most of the work I set out to do). 

2. As I prepared my references about the addition of naloxone I happened upon a recent scholarly review paper by Blazes and Morrow from U Michigan at Ann Arbor (see link below which I highly recommend).  Their review of the literature and clinical history of the combination product finds little evidence for the addition of naloxone.  They emphasise the current opioid overdose crisis and the underutilization of buprenorphine in America. 

These authors avoid mention of commercial, marketing and patent factors but state: “…we cannot unambiguously conclude that naloxone is an effective deterrent to parenteral misuse of buprenorphine. At best, naloxone may reduce or delay the subjective “high” users experience, but in the absence of any dramatic effect on abuse liability, this partial blockade of subjective euphoric effects is of dubious clinical value.”

To cast further doubts on the combination product one should consider the substantially higher post-treatment mortality found in combination-treated patients in WA when compared with those prescribed the pure drug (n=3455) over a nine year period.  I could only find two comparative clinical trials, one a pilot study reporting significantly higher doses needed when transferring from the pure drug to combination (not blinded: see Bell below).  The other was a large RCT reporting more withdrawal syndrome in those given combination buprenorphine versus the pure drug (25% vs 18% of subjects: see Fudala below). 

I leave the reader to consider the evidence and decide what is best for their own patients. 

Written by Andrew Byrne .. Regards for a safe New Year for 2022 for all my readers. 

 

Frontiers | Reconsidering the Usefulness of Adding Naloxone to Buprenorphine | Psychiatry (frontiersin.org)  Blazes and Morrow 2020


Buprenorphine alone or with naloxone: Which is safer? - PubMed (nih.gov)


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



12 December 2021

1. Changes to opiate treatment programs during Covid – benefits for some, harms for others.

 1 Changes to opiate treatment programs during Covid – benefits for some, harms for others. 

2 Pure versus combination buprenorphine – drug company tactics, ‘smoke and mirrors’. 

3 Harm reduction and diazepam prescribing in opiate programs. 

4 Microdose transfers from methadone to buprenorphine – the ‘Bernese’ method measures up. 

 5 Are we seeing the end of the ‘methadone clinic’? 

6.   The role of OTP clinics in Covid vaccination, diagnosis, prevention, quarantine, home dosing, etc.  

Part the First: Covid changes. 

Covid has taught us many things about many things, including opiate maintenance treatments.  From early in the Covid pandemic most patients were given extra take-home or dispensed doses.  For about a month due to the delta crisis in New South Wales our practice gave no supervised doses but just doses for home consumption from the practice window.  Although substantial numbers of our patients benefited greatly from increased liberties with take-away or dispensed doses of methadone and buprenorphine, a minority have got into trouble, some in a small way, others seriously.  

In our practice we detected about ten percent of our patients, mostly ‘doubling up’ on doses and thus running out before normal return dates.  Others were injecting the medication, selling it or just saving amounts ‘for a rainy day’ (in case the clinic were closed down).  One patient developed serious septic thrombosis from regular inguinal injecting, requiring in-patient treatment for an extended period.  Yet another was reported to be selling doses to others in the practice. 

Daily supervised dosing has been the usual practice in nearly all opiate maintenance research and practice, at least initially.  However, the place of continued supervised dosing has never been systematically investigated to my knowledge.  We found no distinguishing factors in those who ‘stumbled’ when given extra dispensed doses during Covid lock-down periods.  Some were stable, employed, long term patients while others were known to use other drugs including alcohol and had less stable lives generally. 

Detection of irregularities with adherence was made by self-report, venipunctures, requests for supplements or hospitalisations.  Such patients often dictated their own safety measures such as more regular attendance, increased dose supervision and for some, dose adjustments.  Transfer from methadone to buprenorphine was also considered in some cases. 

During the period of zero supervision, several of our patients started taking split doses, finding the benefit of less sedation and longer duration of action.  They were disappointed when dose supervision resumed once the clinic re-opened for regular operation.  The most obvious solution for this is transfer to buprenorphine which is longer acting and usually non-sedating.  This can now be accomplished, even in those on high doses of methadone, using the ‘Bernese’ microdosing technique without the need to reduce methadone doses at all (more about that in a future posting). 

Several groups have tried to measure changes from the Covid provisions in opiate maintenance yet there is still no systematic examination of the outcomes of dose supervision and regular attendance for medication.  A Yale University group headed by addiction psychiatrist Ayana Jordan was working on the subject during the early months of Covid in mid-2020.  A press release waxes about the benefits of increased dispensed doses in American methadone programs (see first reference below).  However, I have read little about the ‘down side’ which we have noted above. Evidence based treatment will always be safest even though it may be inconvenient. 

How COVID pandemic changed methadone treatment for addiction - ABC News (go.com)

Did drug use increase following COVID-19 relaxation of methadone take-out regulations? 2020 was a complicated year - ScienceDirect

Opioid agonist treatment and patient outcomes during the COVID‐19 pandemic in south east Sydney, Australia - Lintzeris - - Drug and Alcohol Review - Wiley Online Library

The impact of COVID-19 on opioid treatment programs in the United States - PubMed (nih.gov)

A pilot randomised controlled trial of brief versus twice weekly versus standard supervised consumption in patients on opiate maintenance treatment - HOLLAND - 2012 - Drug and Alcohol Review - Wiley Online Library

 

 


Written by Andrew Byrne ..


4 July 2021

Benzodiazepines in psychiatry and addiction medicine - do they still have a place in chronic care?

Sydney Addiction Seminar

Wednesday 28th November, 2018

“Benzodiazepines in psychiatry and addiction medicine - do they still have a place in chronic care?”

Vladan Starcevic, Paul Haber, Andrew Byrne. Moderator Dr Richard Hallinan.

 

Psychiatrist and Associate Professor Vladan Starcevic spoke about the safety and effectiveness of diazepam and related drugs for anxiety.  He stressed the poor results from almost every treatment tried since the time of Hippocrates for this common and disabling condition.  This changed dramatically with the introduction of benzodiazepines starting with chordiazepoxide (Librium) in 1959.  We were shown numerous trials which included comparisons with tricyclic antidepressants, SSRI’s, SNRI’s and non-drug alternatives (talking therapies, yoga, acupuncture, etc).  The benzodiazepines came out as more effective nearly every time.  The speaker emphasised the low rates of side effects (‘almost none’) as well as the low rates of dependence on the drugs (around 2% in most studies).  It seems that sedation is not considered a side effect of sedatives but a dose related effect, sometimes wanted, as for insomnia, or unwanted for daytime anxiety patients. 

Some myths were busted such as the canard that antidepressants are not habit forming, do not develop tolerance and do not have any withdrawals (further supportive studies were cited).  The saga of the use and alleged abuse of fluoxetine (Prozac) was quoted.  Professor Starcevic almost sounded like an advertisement for benzodiazepines yet he is clearly expert in the field and quoted rigorous studies to support his views.  He also serves on a number of international committees on the treatment of anxiety and related disorders.  We have all seen the pendulum swing from Valium and related drugs being the panacea to the pariah.  Despite this prescribers all know the great benefits which can be had by using careful assessments, judicious prescribing with psychosocial supports for stress cases who can be very vulnerable and for whom there are few effective alternatives. 

 

This led into a talk by Prof Haber of some aspects of pharmacology of GABA receptors and the respective places in the neurone where barbiturates, alcohol, benzodiazepines, etc, were thought to act … and how flumazanil can block the process of hyper-polarisation when chloride ions are allowed into the cell making it less likely to depolarise.  Then Prof Haber reminded us of the origin of the suffix ‘PAM’ attached to so many of the benzodiazepines - and said it might be the only thing some audience members might remember from the whole evening.  Positive Allosteric Modulators (PAM) of the neurone.  We were shown slides from PBS to demonstrate the enormous popularity of sedatives in Australia since the benzodiazepines replaced the barbiturates from about 1960 onwards. 

 

I spoke next about our negative experience using the zero-tolerance approach.  This had resulted in many patients relapsing after periods of benzodiazepine reductions or abstinence, often associated with high potency products such as alprazolam, clonazepam or flunitrazepam (Xanax, Rivotril, Hypnodorm).  These were sometimes prescribed but most commonly were obtained from the street market.  We selected some long-term patients who were clearly benzodiazepine dependent and allowed a limited daily dose, initially under supervision.  This was most usually diazepam in doses from 2mg to 15mg daily. 

American treatment guidelines point out that just because a patient in on OTP they should not be denied benefits of benzodiazepines for anxiety, panic disorder, insomnia or epilepsy.  And those with dependency need to have this addressed.  Yet this should not simply mean “Valium on demand”. 

I was asked whether I was treating dependence or psychiatric symptoms of stress and anxiety: which is almost like the question of which came first, the chicken or the egg?  Just as methadone maintenance patients may comprise pain management cases as well as some recreational drug users, the matter becomes academic once the patient gets to a certain point in their opiate consumption.  It is now widely agreed that whether one started drug use in a medical setting or the illicit market, opiate dependency treatment should be the same. 

Withdrawal symptoms from both opiates and benzodiazepines usually involve dysaesthesia, anxiety and/or insomnia.  Hence it is not surprising that for some OTP patients, the consumption of opiates and benzodiazepines is closely aligned and equally important to them. 

We have long used the principles of ‘universal precautions’ which assumes that all patients are potentially dependent and should be treated as such, with some dose supervision, some counselling and occasional urine toxicology testing.  Equally, all patients may be genuine anxiety disorder sufferers and thus deserve consideration of pharmacotherapy for that just like any other medical or psychiatric patient. 


10 June 2021

This is my Covid warning email sent to family members on 26th Jan 2020 ...

Subject: Corona virus alert is serious and we should all be taking note.

I have followed this and it is a REAL worry, not only for China but for us as well. 

At this early stage we don’t know that much … but that this disease is a very serious form of respiratory infection which can spread from droplets just like colds and influenza. 

We would be crazy to eat in a busy restaurant in Hurstville just at the moment.  Or to travel to China at all, probably. 

We should all have and wear face masks whenever in public transport or enclosed public spaces.  I have a small supply at the surgery but any chemist should supply (but Gold Cross Pharmacy in Redfern have run out already!!). 

So please take this threat seriously and get take-away food, avoid public transport if possible and WEAR a mask when out of the house. 

In a few more days our entire lives could be changed by both the disease and our authorities’ response to it.  Already China has restricted travel to and from large parts of the country.  Wuhan is at a crossroads in central China and twice in the past has been the capital of China.  Similar things happened with the Great Plague in 1349 … but much slower … see: https://en.wikipedia.org/wiki/Black_Death

I wish I could say, like global warming, that this was all a hoax … but I strongly fear it is for ‘very real’.  AB ..


18 October 2020

Face-masks not only prevent Covid infections but reduce severity in those who contract virus. New UCSF analysis.


An impressive paper from Dr Monica Gandhi and colleagues* has brought together several strands of evidence showing that as well as reducing Covid-19 infections, the wearing of masks substantially reduces the severity of infections. 

Along with a persuasive hamster experiment from Hong Kong, they quote the Diamond Princess in Japan and the Greg Mortimer cruise ship in South America where symptomatic infections were 80% and 20% respectively.  This radical difference is alleged to be largely due to universal wearing of masks on the latter ship, including N95 masks for all crew members.  Several examples are quoted of large Covid clusters in factories which supplied masks with up to 95% of infections being asymptomatic.  The authors use other historical, geographical and basic science evidence to support the conclusion that the quantity of virus exposure (‘inoculum’) is related to infection severity. 

One can understand how climate change denial has a political slant but the politicisation of mask wearing seems beyond explanation.  Older readers may remember a minority who refused to use seat belts when they were introduced.  They were soon silenced by statistics showing reduced injuries and saved lives.  Masks were widely used in the 1918 influenza epidemic – and made compulsory in many jurisdictions.  Yet there were ‘conscientious objectors’ then as now. 

We should all wear masks when in buses, trains, elevators, taxis, shops, etc, as currently advised by many health authorities. 

Written by Andrew Byrne, Redfern Addictions Physician.  Usual email ajbyrne@ozemail.com.au


References:

* Gandhi M, Beyrer C, Goosby E. Masks Do More Than Protect Others During COVID-19: Reducing the Inoculum of SARS-CoV-2 to Protect the Wearer. 2020 Journal of General Internal Medicine.   

https://link.springer.com/article/10.1007/s11606-020-06067-8     


One More Reason to Wear a Mask: You’ll Get Less Sick From COVID-19. News Summary from UCSF.                    

https://www.ucsf.edu/news/2020/07/418181/one-more-reason-wear-mask-youll-get-less-sick-covid-19

           

Chronology of COVID-19 Cases on the Diamond Princess Cruise Ship and Ethical Considerations: A Report From Japan.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156812/


COVID-19: in the footsteps of Ernest Shackleton.

https://thorax.bmj.com/content/75/8/693


Surgical Mask Partition Reduces the Risk of Noncontact Transmission in a Golden Syrian Hamster Model for Coronavirus Disease 2019 (COVID-19)

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa644/5848814

29 June 2020

Historical paper on the development of opiate maintenance and links with AA.

'ALCOHOLISM' Clinical and Experimental Research Vol 15/No 5 Sept/Oct 1991

EDITORIAL Addiction as a Public Health Problem: Vincent P. Dole


WHEN I FIRST became involved in studies of addiction 30 years ago, a society dedicated to this topic would have had no place in organized medicine. The subject was not even considered in the curricula of medical schools. Back then we assumed that addiction simply was a sign of psychopathology. Drug abuse and alcoholism were regarded as shameful dependencies on chemical substances, used for illicit gratification and escape from reality. If the subject came up in discussion, a typical physician would say that addicts were morally weak: they needed discipline, not medical treatment and certainly not a medically prescribed drug. This negative attitude still has considerable force today in medical and political circles.

Times are changing, however. The existence of this society bears witness to the official recognition of addicts as sick persons, deserving serious study and medical treatment, when appropriate. I have seen some of the changes that have led us to this point and have had the privilege of learning from persons who are now legends. Let me describe these experiences.

In 1960 I was a laboratory-based investigator at Rockefeller University-busy in specialized work and insulated from the real world. I commuted to New York from a comfortable house with a big lawn and view of the water in Rye, New York. I worked during the day in a laboratory on the University campus, and returned home in the evening, usually reading and editing journal papers in transit. Sometimes I looked out of the window. Occasionally, to save time in the morning, I left the train at the 125th Street Harlem Station and continued the trip to my laboratory on the elevated Third Avenue trolley (now gone). Walking the short distance between stations on 125th Street and then travelling 60 blocks on the elevated trolley-in effect a moving aerial platform-I saw drugs being sold on the sidewalks, drunks sleeping in doorways, young men idling on corners, young women apparently available at a price, shabby buildings, and busy bars.

Of course I had been aware of social problems in the inner city. Then, as now, the media were filled with reports of gang wars, murders, rape, arson, drug abuse, police raids, etc. But being in the neighborhood made the problems real. Society was disintegrating in my own city, not in another world. Something very bad had happened to people in what not long ago had been decent neighborhoods. The community was sick. What should be done?

In the basic sense of the term, this was a public health problem. Young people had grown up in disorder, without adequate education or employment, and many were now addicted to alcohol and drugs. Streets were littered. Buildings had deteriorated. Successful persons had left the area. Drug abuse had made the victims of the process the vectors of further spread. Treatment would have to go beyond hiring more police. By analogy with epidemics of infectious disease, critical interventions were needed to halt transmission of drug abuse without adding to the damage, and do this with limited resources. In public health terms, where were the feasible points of attack on the epidemic of drug abuse?

Obviously, this would be more complicated than dealing with an epidemic of infectious disease, but it seemed reasonable to hope that a comprehensive public health approach could succeed, if backed by consistent political support. Large scale effective treatment programs were needed for persons already addicted, coupled with rational measures for prevention of new cases. However, it soon became apparent that this was too much to expect. A profound disruption of society, then as now, fragments a community into special-interest groups opposing each other. Elected officials become powerless to resist vocal minorities, or to institute needed reforms. And the medical profession, which should have provided leadership, was uninvolved.

Conversations with experts over the next several months showed confusion at all levels, from the technical details of treatment to the feasibility of social rehabilitation. However, by then I had become too deeply concerned with the problem to quit. At least I could examine one detail of the problem, namely the pharmacology of heroin addiction, to see if an effective large-scale treatment could be developed. Having no experience in the field, I needed help.

The event that changed my life was finding Marie Nyswander. I had read her book entitled “The Drug Addict as a Patient”, and it made sense. Moreover, I heard that she was the only doctor in New York who was willing to treat drug addicts outside of an institution. Other doctors were uninterested, or feared harassment by the Federal Bureau of Narcotics. I invited her to lunch at Rockefeller, expecting to meet a formidable lady.

To my surprise the lady who arrived was a gentle person, vibrantly alert but small in stature, soft spoken, shy in manner. What I remember most vividly about our first meeting is how tired she looked. Later I learned why. She was supporting herself as a practicing psychiatrist on Park Avenue while also counseling addicts in Spanish Harlem and fending off the bullies of the Federal Bureau of Narcotics. At that time even psychiatric treatment of addicts without prescription of any medication (she had surrendered her narcotic license to avoid entrapment) was considered suspicious by the Bureau. Nevertheless she persisted. Although she had had little long-term success in treating heroin users with psychotherapy, psychoanalysis (she was also a certified analyst), group therapy, and social services, she was determined to continue her work and find a better treatment. On the positive side, she had found the addicts to be cooperative patients who were desperately in need of help. What had sustained her during a decade of lonely struggle was a sense of injustice-sick people asking for help and being rejected-and the gratitude of the patients even when her efforts failed. She expressed the conviction that narcotic addiction is basically a medical problem, an organic disease needing an effective medicine to abolish the pathological craving for narcotic drugs before social and psychological help could be effective on a large scale. Coming from an experienced psychiatrist who had been trained at the Federal Treatment Center in Lexington, Ky, and subsequently had devoted 10 years of her life to the problem, this was persuasive. I invited her to join me in setting up a physiological study of heroin addicts in Rockefeller Hospital. She accepted. Three years later we were married and remained inseparable companions until her death from cancer 5 years ago.

During the first year of this work we had the good fortune to recruit a talented young clinician, Dr. Mary Jeanne Kreek, to participate in the testing program. We started where previous studies had stopped. Research on narcotic pharmacology in the Public Health Hospital (Lexington, Ky), although carefully conducted, had been incomplete. Short-term, toxic, and analgesic effects of various narcotic drugs had been well documented, but long-term behavioral pharmacology (which for narcotic drugs is quite different from the acute effects because of the development of tolerance and physical dependence) had not been adequately studied outside of a prison environment. In particular, the possibility of using a narcotic drug for maintenance of intractable addicts had been dismissed because earlier attempts to maintain addicts with morphine had failed. Knowing that the term “narcotic” comprises a wide range of drugs with significantly different properties, we decided to look further, testing other pharmacological agents in the narcotic category on addicted volunteers.

To our surprise we found that one of the tested drugs, methadone (but not any of several other narcotics that we tested), had a normalizing, rather than narcotic, effect on long-term administration at a constant dose. This paradoxical finding of a narcotic drug having a normalizing effect was not understood until some years later when the pharmacokinetic studies of Dr. Kreek showed that the blood level of methadone is stabilized by first pass removal of about 98% of an oral dose, thus in effect creating a slow-release depot. As the circulating drug is removed from blood by metabolism, it is replaced by dissociation of molecules absorbed in the depot. The nervous system adapts to the steady level of methadone in the blood, thus abolishing its depressant effects. The medication thereafter acts as a normal neuromodulator, apparently substituting for dysfunctional components. Repeated testing by many independent observers during the past 25 years has verified this functional normalization. A patient who is stabilized on an adequate, constant daily dose of methadone is alert, healthy, and responds normally to painful stimuli.

That is enough to say about the pharmacology of methadone in the present discussion, but before leaving the topic I must acknowledge the essential contributions made by many hundreds of dedicated physicians, counsellors, nurses, social workers, administrators, lawyers, volunteers, and ex-addicts who in their collective efforts translated a research finding into a treatment program. The original team deserves special recognition: Physicians: Drs. Joyce Lowinson, Robert Newman, Robert Millman, Elizabeth Khuri, Harold Trigg; Administrators: Ray Trussell and Detlev Bronk; Lawyer: Dona1 O’Brien; numerous ex-addicts who will remain anonymous; and the indispensable Herman Joseph, who is too versatile to characterize and too important to omit from this list.

Now to the second topic, alcoholism. In the early 1960’s I was honored (and puzzled) by an invitation to join the Board of Alcoholics Anonymous as a Class A (nonalcoholic) trustee. Under the Constitution of AA only seven nonalcoholic persons could occupy this position, while several hundred thousand regular members of AA had entered the Fellowship the hard way, by being alcoholics. I was afraid that they might have made a mistake, and so before accepting the position, I discussed my research with executives of the Fellowship and raised the question as to whether this appointment might involve a conflict of interest, or at least the appearance of one. Would it embarrass the Fellowship to have an investigator of chemotherapy for narcotic addiction included in the Board of AA? They insisted that they saw no problem since the objectives were parallel-namely providing the best treatment available to sick persons. They also pointed to AA’s Fifth Tradition, which states that the mission of AA is solely to help alcoholics, and firmly rules against taking a position on other issues. They were right. There never has been a problem in my association with AA, and my admiration for Bill Wilson and the dedicated AA members that I came to know has increased over the years.

Needless to say, I have gained far more from AA than the Fellowship did from me. It was my privilege to witness the healing force of personal service, group support and humility, while my only serious responsibility was to serve on a few committees and be an alert observer. As an organization, AA is the purest form of democracy. Major questions are submitted to the membership at the annual meetings of delegates representing all groups. Ultimately, questions of policy are resolved in a statement of the Group Conscience. The headquarters of AA, the General Services Office, is just what the name states. The secret of AA’s strength is service. It is a secret that certainly should be shared with the medical profession.

Throughout most of my time on the Board I continued to be puzzled by the original question: Why had I, specifically, been invited to serve? If a physician experienced in treatment of alcoholics had been needed for professional opinion, there were many persons with better qualifications than I. If an administrative advisor was sought, I would be near the bottom of any search list. My only qualification was caring. One answer gradually became clear: In the early years of AA Bill and the original trustees were acutely sensitive to the danger of the Fellowship being distorted by aggressive persons with dogmatic opinions. During my time on the Board, I never detected any sign of this happening, but perhaps that simply reflected the success of the Traditions in the mature organization, keeping the Fellowship on track. Anyway, I assumed that I had been brought in as sort of a smoke alarm, a canary in the mine.

A more specific answer, however, emerged in the late 1960s, not long before Bill’s death. At the last trustee meeting that we both attended, he spoke to me of his deep concern for the alcoholics who are not reached by AA, and for those who enter and drop out and never return. Always the good shepherd, he was thinking about the many sheep who are lost in the dark world of alcoholism. He suggested that in my future research 1 should look for an analogue of methadone, a medicine that would relieve the alcoholic’s sometimes irresistible craving and enable him to continue his progress in AA toward social and emotional recovery, following the Twelve Steps. I was moved by his concern, and in fact subsequently undertook such a study.

Until its closure this year, my laboratory sought an analogue of alcoholism in mice so as to be able to test potential medicines that could benefit human alcoholics. We failed in this, but the work is only begun. Talented investigators in other laboratories are working on various aspects of the analogue problem. With the rapid advance in neurosciences, I believe that Bill’s vision of adjunctive chemotherapy for alcoholics will be realized in the coming decade.

Now let me describe a coincidence that linked my work with Bill’s in an unexpected way, and perhaps explains my reaction to the scenes on the 125th Street 30 years ago. In Bill’s biography, he recalls a time in the winter of 1940 when the future of AA looked bleak. There was no activity in the newly opened club on 24th Street, and he was resting upstairs. Someone called up that a bum had come in, asking for Bill. Stumping up the steps was a stooped man with a cane who identified himself as a Jesuit priest. He said that he had come to meet Bill because of his admiration for the Twelve Steps. They were, he said, remarkably similar to the precepts of St. Ignatius Loyola, the founder of his religious order. As Bill’s biographer put it, “thus began a conversation that lasted 20 years.”

My association with AA came much later, but my contact with Edward Dowling, the priest in this story, antedated Bill’s meeting with him by 15 years. He was my classroom teacher in first year high school at Loyola Academy in Chicago in the mid 1920’s. At that time he was a slim and vigorous young novitiate with jet black Irish hair and an intense manner. Among other subjects he discussed ethical conduct, not as an abstract thesis, but as a practical obligation toward others, and as a service that brings its own reward.

In his subsequent busy career as a priest Father Dowling lived what he had taught, friend and advisor to people in trouble, to young families, to students, to alcoholics. I saw him only infrequently in later years, but remember most clearly the contrast between his continued intellectual force and his deteriorating health. Medically, he had severe rheumatoid spondylitis. He became progressively more stooped, white haired, limited in travel. Yet he did not even seem to be aware of his disability. He was too occupied with the problems of others.

Marie Nyswander, Bill Wilson, and Edward Dowling are no longer with us, but their inspiration remains. For each, life was a continuing Twelve Step. They cared for people who suffered and especially those with the double jeopardy of being sick and being rejected. They left a positive record of success in dealing with these problems.

It is my privilege, as their student, to greet the Society for Addiction Medicine, and transmit the expectations that they surely would have had for its future. They would have welcomed the strength and scientific discipline that you bring to the field. They would expect you to study and debate the technical details of treatment while being united in compassion for addicts. They would look to you for leadership that rises above special interests and prejudice. They would hope that you could lead the way to rational measures of prevention, and a variety of effective, nonpunitive treatments for various addictions. Certainly they would expect you to be concerned with the enormous public health problem of addiction: tens of thousands of drug addicts and hundreds of thousands of alcoholics who still remain untreated. It would be their fervent hope that you succeed.

From The Rockefeller University, New York, New York. Receivedfor publication May 8, 1991; accepted May 24. 1991 The Distinguished Science Lecture presented at the Annual Meeting of the American Society of Addiction Medicine, Boston, MA, April 19, 1991. Reprint requests: Vincent P. Dole, The Rockefeller University. I230 York Avenue, New York, NY 10021-6399. Copyright 0 I991 by The Research Society on Alcoholism. Alcohol Clin E.xp Re.\. Vol 15, No 5. 199 I; pp 749-752

2 February 2020

Fentanyl manufacturer and top executives jailed for unlawful marketing.

Fentanyl manufacturer and top executives jailed for unlawful marketing. Financial Times 24 January 2020


John Kapoor, who founded Insys Therapeutics, was sentenced to 5½ years in prison for Big Pharma crimes including the marketing of fentanyl, a product only approved in the USA for cancer break-through pain.  See news item on https://www.ft.com/content/a27bbc80-3d35-11ea-a01a-bae547046735

 “Opioid executive admits to ‘no morals’ ahead of prison term”

‘US pharmaceutical executives have been put on notice that they could be held criminally liable for fuelling America’s epidemic of opioid addiction, after the founder of the drugmaker Insys was sentenced on Thursday to five-and-a-half years in prison for masterminding a scheme to bribe doctors to prescribe a dangerous painkiller.’

Despite causing great satisfaction in some quarters, such prosecutions are unlikely to make much difference to opioid deaths currently.  In America, where addiction to prohibition is endemic, opioid use has now moved from prescription drugs back to the black market where we know regulation has no effect on price and little effect on availability. 

Comment by Andrew Byrne .. any replies best to ajbyrne@ozemail.com.au

Along the same line, relating to Mundipharma in Australia: Wall St Journal article.
“OxyContin Made The Sacklers Rich. Now It’s Tearing Them Apart.” https://www.wsj.com/articles/oxycontin-made-the-sacklers-rich-now-its-tearing-them-apart-11562990475  

And further: alleged actions denying life-saving buprenorphine treatment by hiking costs to patients and insurers. 
“Federal prosecutors said that starting in 2010, Indivior falsely marketed its film as being safer and less prone to abuse than cheaper tablet forms, illegally earning billions of dollars in a "nationwide scheme" to bill healthcare providers and insurers including Medicaid.”
https://www.npr.org/2019/07/11/740856948/reckitt-benckiser-agrees-to-pay-1-4-billion-in-opioid-settlement

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