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”.