This letter was published in response to Luty's interesting item about the UK decision to ban methadone maintenance and insist that all treatment be abstinence directed (!). http://www.bmj.com/content/346/bmj.f1481
Dear Editor,
Luty is unduly pessimistic about long term abstinence after opioid maintenance treatment.1 About 4% of addicted people become abstinent each year, regardless of treatment.2 By 10 years, over a third are abstinent. The remainder are mostly on maintenance treatment, a small, efficient part of any health system, which often needs little more than an experienced GP and pharmacist. This saves lives and reduces many negative aspects of addiction.3
Those denied appropriate treatment have death rates up to seven times higher than those treated.4 This is especially important on prison release, where access to treatment should be the dual responsibility of the health and custodial systems.
Politically inspired rule changes by the NHS cannot alter what is sound medical practice. Opioid pharmacotherapy is fundamentally no different from treating other chronic conditions but is better researched than most. New and unstable patients need frequent reviews, whereas others can be seen less often to check dose levels, progress, ancillary services, and so on.
Another disadvantage in the UK is that buprenorphine, the only evidence based alternative to methadone, is sometimes not available because of its high cost.
Opioid maintenance is not rocket science, yet for decades the UK had the twin problems of inadequate dose levels and almost non-existent formal dose supervision.5 These factors so limited success that many now doubt the benefits of the treatment as used in the UK. Current and past leaders in the dependency field must take responsibility for those deficiencies, which are currently causing politicians to dismantle an essential intervention implemented in most Western countries, and now even in China.
http://bmj.com/cgi/content/full/bmj.f2773?ijkey=uHddzXVTUeNSHsy&keytype=ref
1 May 2013
‘Something old and something new’: naloxone studies.
Effects of sublingually given naloxone in opioid-dependent human volunteers. Preston KL, Bigelow GE, Liebson IE. Drug Alcohol Dependence 1990 25:27-34
Dear Colleagues,
This old publication was sent to me after some discussions about the use of naloxone in combination with other opioids as an attempt to prevent or deter injecting. My own feeling has always been that the evidence favouring this attractive theory was weak and that its continued abuse in practice was predictable. I still recommend pure buprenorphine (Subutex) as a result.
In this small but well constructed study sublingual (SL) naloxone was found to precipitate a withdrawal reaction in two of six heroin users and in all three methadone subjects who were given graduated doses of naloxone (2-8mg) sublingually. The authors concluded that ‘naloxone doses up to 1–2mg can be administered sublingually to opioid abusers/addicts without precipitating withdrawal’. The conventional wisdom from many quarters is that naloxone is not absorbed sublingually in clinically significant amounts. This study, by prominent authors, showed quite the reverse over 20 years ago.
A new study from Finland (2013* see below) looks at urine levels of naloxone and buprenorphine to check compliance, showing that the concept of adding naloxone is still being worked on. The study of 40 subjects in three groups, new entrants, stable and ‘unstable’, suggests that measuring drug ratios on urine may help to check compliance. Those who were ‘unstable’ had slightly higher naloxone levels. Yet the most logical thing to do with unstable buprenorphine patients would be to consider methadone. This study also seems to confirm that most patients were using buprenorphine before they came into treatment and, like New Zealand 20 years earlier, pharmaceutical buprenorphine was the most popular illicit injected opioid in Finland.
Regarding the combination product with naloxone, even the most basic comparison test of therapeutic equivalence has still not been performed to my best knowledge. Thus evidence needed for its general use is still deficient in my view. In fact some observational and anecdotal reports indicate those changed to the combination drug needed significantly higher buprenorphine doses (over 50% in Bell’s Sydney pilot study#). Others reported that the need for such increases was short lived (other refs on request). These results need clarification and the work would be relatively simple.
Higher doses of buprenorphine mean (1) higher doses of naloxone, (2) higher costs for the health system and (3) bigger profits for manufacturers. Despite the great success of the marketing of the combination drug in some countries, abuse reports are now commonplace and history is repeating itself. A pure drug will always be more desirable to the dependent person. A combination or mixture with anything else, eg. water, juice, chalk, vitamin D, paracetamol or butterscotch, will probably reduce its abuse potential - but may also have other adverse effects. Whether naloxone has any specific benefits to outweigh its costs and potential side effects is still unknown. It is no surprise that neither the manufacturers nor the authorities in most countries endorse the use of the combination drug in pregnancy nor in initiating treatment - despite this advice being widely ignored in both Australia and America.
There is still no doubt that buprenorphine is an excellent opioid maintenance drug for patients unwilling or unable to take methadone, and also in whom methadone is unavailable or unsatisfactory for other reasons. The introduction of a second option has made our professional lives much easier, allowing a choice for some long-suffering patients where previously there was none (apart from detox, which is still always a choice for dependent patients).
* Urine naloxone concentration at different phases of buprenorphine maintenance treatment. Heikman P, Häkkinen M, Gergov M, Ojanperä I. Drug Test Anal. 2013 Mar 19. doi: 10.1002/dta.1464
# 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
Notes by Andrew Byrne ..
Medical blog: http://methadone-research.blogspot.com.au/
Full comments on the Preston study: http://methadone-research.blogspot.com.au/2013/04/old-study-on-withdrawals-induced-by.html
7 April 2013
New York medical musings from Andrew Byrne
As over the past ten years or so, early spring in New York is simultaneously a pleasure and a challenge.
Tues 12th March 2013
My arrival coincided with the monthly meeting of Drugs in Society at Columbia University so even on my first day I was in the company of colleagues discussing dependency issues, in this case, alcohol in the older age group. Dr Alexis Kuerbis’ topic was “Brief Treatments for Older Problem Drinkers”. She spoke well about the consumption of alcohol in the older population, possible complications and co-morbid conditions, along with the benefits of reductions. A Columbia University local, she spoke about the range of interventions and the limited research which has been done (some in Australia). There was only one RCT and it was small and limited relevance. Motivational interviewing, brief interventions, CBT and other measures were discussed in detail. There was an assumption by everyone in the room (except myself) that reductions and abstinence are necessarily desirable. Not everyone in America considers it appropriate to have a good time … or if you do, not to admit as much. Mixing alcohol with prescription drugs is obviously a concern yet consumption of small quantities (these subjects did not reach most criteria for dependency but drank more than some health recommended levels.
My next stop was the Drug Policy Alliance on 33rd Street where I saw five or six colleagues who are working on law reform, medical cannabis, harm reduction and related issues. They have advocates who write letters to the editor, lobby law makers, commence citizen referendum proposals and international work as well. They have a researcher who has been working on buprenorphine and I was asked to give a talk up-dating the situation with an Australian aspect.
Despite a snow storm there was a large attendance and full lecture room for the evening event on Mon 18th March. A member of the audience who was a physician in the Bronx informed us that generic combined buprenorphine / naloxone was first made available in local pharmacies just a few weeks ago. The price was said to be about half of the named item. It is a very important piece of information since the original manufacturer has announced that they are voluntarily withdrawing their traditional product which changed the world of dependency in 2005. Commerce often seems bizarre yet there is always a reason behind every decision, usually based on money and markets. This may explain the absence of a formulation less then 2mg in America and there was a consensus in the room that a 0.4mg tablet and/or a bisectable tablets would assist with tapering doses, a critical time for many patients.
Ira Marion Memorial Service Thursday 28th March.
The death of senior and unique colleague Ira Marion in the Bronx will be felt far beyond that Borough. Dr Joyce Lowinson was chief editor of the worlds largest and longest running text on dependency and she was the one to organize the event with Ira’s family. People came from far and wide, having found out by word of mouth, email or twitters – researchers call this the ‘snowball’ method of recruitment. This saw a crowd of perhaps 150 attend the Robbins Hall on the main campus of Albert Einstein University in the Bronx. I was amazed at just how many leaders of our field were in attendance and appropriately, a contingent of patient representatives headed by Joycelyn Woods who, along with 30 other patients, founded the NAMA group. Robert Millman, John Langrod were co-editors of the big text book with Joyce. Others present included Mike Rizzi and Mark Parrino of AATOD attended. Bob Newman of the Beth Israel, St Lukes and Rothschild Institutes, Icro Maremmani, the professor from Pisa in Italy attended with his wife. Dr Stine and his wife. Veterans Sy Demsky, Herman Joseph and Dr Benny Primm attended, along with Randy Seewald, Dr Ken Levy, Edwin Salsitz and many others.
Two others expressed to me their dismay at not having known about the event. Mary Jeanne Kreek and Ernie Drucker would both have attended if things had been otherwise. I know Elizabeth Khuri would also have liked to attend had circumstances been otherwise.
I attended an evening ‘Colloquium’ in the cinema at Columbia University campus on March 27 to examine ‘Molly’, apparently a local name for MDMA or ecstasy.
Those on the panel were: Jag Davies from The Drug Policy Alliance (Stephanie Jones pulled out due to a house fire); Dr R L'Heureux Lewis-McCoy, (Professor at City College of New York who wrote an article about Molly Madness in Ebony Magazine); Brittany Lewis, music critic from ‘Global Grind’; Ingmar Gorman, Doctoral Student at the New School for Social Research who is studying the therapeutic alliance in MDMA-assisted psychotherapy.
A great new quote was given: “The only difference between a cure and a poison is the dose”. Never a truer word spake. Friendly responses inform me that this is a paraphrase of Paracelus, one of the founding fathers of toxicology. In 1530 he reportedly wrote: "All things are poison, and nothing is without poison; only the dose permits something not to be poisonous."
A preliminary video clip was showed entitled: “Molly in urban culture”. We heard some basic pharmacology and history of MDMA, invented by Merck in 1912 and ‘reinvented’ in California in the 1970s and banned in 1985 in the US. The hip-hop music critic showed excerpts from about a dozen popular songs in which the name and effects of MDMA were mentioned. Then we saw some interviews by the singers responsible, some of whom had never even tried the drug.
In the Q&A section at the end I said that apart from some enquiries from concerned parents, I had never been referred a patient with a problem with MDMA … and (tongue-in-cheek) that regarding the popular culture aggrandising a particular drug, that Falstaff’s character by Shakespeare was so gross that the play should be banned. My comment raised small laughter and modest applause.
Luminaries who I recognised in the audience included Ethan Nadelman, Carl Hart, Scott Kellogg plus lots of others who knew that field of psychodelics much better than me. Dr Carl Hart, Professor at Columbia University is featured in the film "The House I Live In" according to the literature.
Rockefeller University visit Wed 27th March.
I was with Dr Mary Jeanne Kreek from 11am to 3.30pm at Rockefeller University as we discussed many aspects of OTP. She belaboured the need for proper science in our field, yet many have their views informed by anecdotes. Professor Kreek describes herself as ‘tough as nails’ which she is. She will not use trade names for drugs, saying that it is akin to prostitution (as if there is something wrong with the world’s oldest profession). Rockefeller reportedly also refuses funding from drug companies, unlike many of our colleagues, some of whom do not always declare the extent of their subsidies when speaking publicly about the drugs involved. Two more of our senior colleagues and experts in the field have gone onto salary at maintenance drug manufacturers, further depleting the ranks of independent experts: Dr Mark Anns in Australia and Nicholas Reuter in America.
Along with David Eddie, PhD student from Rutger's University, I was taken on a tour of the Rockefeller ‘hospital’ which is a clinical research day-only ward downstairs and a full-service staffed ward upstairs. It was in this upstairs ward that the first methadone patients were housed and examined, one side looking out at the East River, Roosevelt Island and Queensborough while the other side gives onto the beautiful Rockefeller University gardens with its azaleas, perennials, bulbs and blossom trees all behind the white near-spherical structure on York Avenue which serves as a lecture hall.
Dependency Grand Rounds at Bellevue Hospital Wed 3 April was highly instructive with Dr Marc Galanter, one of the giants of our field, introducing a detailed talk on the use of meditation in addiction treatments. The Divisional Grand Rounds discussed research on the application of meditation technique to addiction treatment. The speaker was Dr Zoran Josipovic PhD from NYU, Washington Square. I go back to spend an afternoon with the registrars on Dr Galanter’s ward on the 20th floor of the main “H” building that was so affected by cyclone Sandy. Even their security office on the ground floor is still not open again. Even light-hearted jokes were made about the electrical equipment fusing out with water penetration. There is a HUGE canvas sign in the front foyer: “WELLCOME BACK TO BELLEVUE” (Yes, ‘back’ from the brink as it was flooded out). Details in due course for anyone who is interested.
I was staggered at the numbers of people who come and go in that enormous entrance. While it is the entire front of the old building with three grand entrances, it is now all indoors with a full size semi-circular sky-light and an odd shaped modern building about the same height (?5 storeys) facing it and incorporating a new covered hospital entrance almost the full width of the old building right on First Avenue itself. It was a sign of technology that most mobile phones would not work within the hospital and part of the congestion in the entrance was people exiting in order to make calls. Those on Verizon had better coverage but AT&T was apparently lacking.
More in due course … New York is certainly a most phenomenal city – as my own grandfather wrote that in his post-cards from here in 1924!! (see http://bpresent.com/harry/code/09n_new-york.php ). So I am grateful to have the opportunity to share in it all and maybe even contribute in a small way.
Notes from Andrew Byrne .. (back to Sydney on Sunday).
Clinic web page: http://methadone-research.blogspot.com/
Tues 12th March 2013
My arrival coincided with the monthly meeting of Drugs in Society at Columbia University so even on my first day I was in the company of colleagues discussing dependency issues, in this case, alcohol in the older age group. Dr Alexis Kuerbis’ topic was “Brief Treatments for Older Problem Drinkers”. She spoke well about the consumption of alcohol in the older population, possible complications and co-morbid conditions, along with the benefits of reductions. A Columbia University local, she spoke about the range of interventions and the limited research which has been done (some in Australia). There was only one RCT and it was small and limited relevance. Motivational interviewing, brief interventions, CBT and other measures were discussed in detail. There was an assumption by everyone in the room (except myself) that reductions and abstinence are necessarily desirable. Not everyone in America considers it appropriate to have a good time … or if you do, not to admit as much. Mixing alcohol with prescription drugs is obviously a concern yet consumption of small quantities (these subjects did not reach most criteria for dependency but drank more than some health recommended levels.
My next stop was the Drug Policy Alliance on 33rd Street where I saw five or six colleagues who are working on law reform, medical cannabis, harm reduction and related issues. They have advocates who write letters to the editor, lobby law makers, commence citizen referendum proposals and international work as well. They have a researcher who has been working on buprenorphine and I was asked to give a talk up-dating the situation with an Australian aspect.
Despite a snow storm there was a large attendance and full lecture room for the evening event on Mon 18th March. A member of the audience who was a physician in the Bronx informed us that generic combined buprenorphine / naloxone was first made available in local pharmacies just a few weeks ago. The price was said to be about half of the named item. It is a very important piece of information since the original manufacturer has announced that they are voluntarily withdrawing their traditional product which changed the world of dependency in 2005. Commerce often seems bizarre yet there is always a reason behind every decision, usually based on money and markets. This may explain the absence of a formulation less then 2mg in America and there was a consensus in the room that a 0.4mg tablet and/or a bisectable tablets would assist with tapering doses, a critical time for many patients.
Ira Marion Memorial Service Thursday 28th March.
The death of senior and unique colleague Ira Marion in the Bronx will be felt far beyond that Borough. Dr Joyce Lowinson was chief editor of the worlds largest and longest running text on dependency and she was the one to organize the event with Ira’s family. People came from far and wide, having found out by word of mouth, email or twitters – researchers call this the ‘snowball’ method of recruitment. This saw a crowd of perhaps 150 attend the Robbins Hall on the main campus of Albert Einstein University in the Bronx. I was amazed at just how many leaders of our field were in attendance and appropriately, a contingent of patient representatives headed by Joycelyn Woods who, along with 30 other patients, founded the NAMA group. Robert Millman, John Langrod were co-editors of the big text book with Joyce. Others present included Mike Rizzi and Mark Parrino of AATOD attended. Bob Newman of the Beth Israel, St Lukes and Rothschild Institutes, Icro Maremmani, the professor from Pisa in Italy attended with his wife. Dr Stine and his wife. Veterans Sy Demsky, Herman Joseph and Dr Benny Primm attended, along with Randy Seewald, Dr Ken Levy, Edwin Salsitz and many others.
Two others expressed to me their dismay at not having known about the event. Mary Jeanne Kreek and Ernie Drucker would both have attended if things had been otherwise. I know Elizabeth Khuri would also have liked to attend had circumstances been otherwise.
I attended an evening ‘Colloquium’ in the cinema at Columbia University campus on March 27 to examine ‘Molly’, apparently a local name for MDMA or ecstasy.
Those on the panel were: Jag Davies from The Drug Policy Alliance (Stephanie Jones pulled out due to a house fire); Dr R L'Heureux Lewis-McCoy, (Professor at City College of New York who wrote an article about Molly Madness in Ebony Magazine); Brittany Lewis, music critic from ‘Global Grind’; Ingmar Gorman, Doctoral Student at the New School for Social Research who is studying the therapeutic alliance in MDMA-assisted psychotherapy.
A great new quote was given: “The only difference between a cure and a poison is the dose”. Never a truer word spake. Friendly responses inform me that this is a paraphrase of Paracelus, one of the founding fathers of toxicology. In 1530 he reportedly wrote: "All things are poison, and nothing is without poison; only the dose permits something not to be poisonous."
A preliminary video clip was showed entitled: “Molly in urban culture”. We heard some basic pharmacology and history of MDMA, invented by Merck in 1912 and ‘reinvented’ in California in the 1970s and banned in 1985 in the US. The hip-hop music critic showed excerpts from about a dozen popular songs in which the name and effects of MDMA were mentioned. Then we saw some interviews by the singers responsible, some of whom had never even tried the drug.
In the Q&A section at the end I said that apart from some enquiries from concerned parents, I had never been referred a patient with a problem with MDMA … and (tongue-in-cheek) that regarding the popular culture aggrandising a particular drug, that Falstaff’s character by Shakespeare was so gross that the play should be banned. My comment raised small laughter and modest applause.
Luminaries who I recognised in the audience included Ethan Nadelman, Carl Hart, Scott Kellogg plus lots of others who knew that field of psychodelics much better than me. Dr Carl Hart, Professor at Columbia University is featured in the film "The House I Live In" according to the literature.
Rockefeller University visit Wed 27th March.
I was with Dr Mary Jeanne Kreek from 11am to 3.30pm at Rockefeller University as we discussed many aspects of OTP. She belaboured the need for proper science in our field, yet many have their views informed by anecdotes. Professor Kreek describes herself as ‘tough as nails’ which she is. She will not use trade names for drugs, saying that it is akin to prostitution (as if there is something wrong with the world’s oldest profession). Rockefeller reportedly also refuses funding from drug companies, unlike many of our colleagues, some of whom do not always declare the extent of their subsidies when speaking publicly about the drugs involved. Two more of our senior colleagues and experts in the field have gone onto salary at maintenance drug manufacturers, further depleting the ranks of independent experts: Dr Mark Anns in Australia and Nicholas Reuter in America.
Along with David Eddie, PhD student from Rutger's University, I was taken on a tour of the Rockefeller ‘hospital’ which is a clinical research day-only ward downstairs and a full-service staffed ward upstairs. It was in this upstairs ward that the first methadone patients were housed and examined, one side looking out at the East River, Roosevelt Island and Queensborough while the other side gives onto the beautiful Rockefeller University gardens with its azaleas, perennials, bulbs and blossom trees all behind the white near-spherical structure on York Avenue which serves as a lecture hall.
Dependency Grand Rounds at Bellevue Hospital Wed 3 April was highly instructive with Dr Marc Galanter, one of the giants of our field, introducing a detailed talk on the use of meditation in addiction treatments. The Divisional Grand Rounds discussed research on the application of meditation technique to addiction treatment. The speaker was Dr Zoran Josipovic PhD from NYU, Washington Square. I go back to spend an afternoon with the registrars on Dr Galanter’s ward on the 20th floor of the main “H” building that was so affected by cyclone Sandy. Even their security office on the ground floor is still not open again. Even light-hearted jokes were made about the electrical equipment fusing out with water penetration. There is a HUGE canvas sign in the front foyer: “WELLCOME BACK TO BELLEVUE” (Yes, ‘back’ from the brink as it was flooded out). Details in due course for anyone who is interested.
I was staggered at the numbers of people who come and go in that enormous entrance. While it is the entire front of the old building with three grand entrances, it is now all indoors with a full size semi-circular sky-light and an odd shaped modern building about the same height (?5 storeys) facing it and incorporating a new covered hospital entrance almost the full width of the old building right on First Avenue itself. It was a sign of technology that most mobile phones would not work within the hospital and part of the congestion in the entrance was people exiting in order to make calls. Those on Verizon had better coverage but AT&T was apparently lacking.
More in due course … New York is certainly a most phenomenal city – as my own grandfather wrote that in his post-cards from here in 1924!! (see http://bpresent.com/harry/code/09n_new-york.php ). So I am grateful to have the opportunity to share in it all and maybe even contribute in a small way.
Notes from Andrew Byrne .. (back to Sydney on Sunday).
Clinic web page: http://methadone-research.blogspot.com/
6 April 2013
Old study on withdrawals induced by sublingual naloxone.
Effects of sublingually given naloxone in opioid-dependent human volunteers. Preston KL, Bigelow GE, Liebson IE. Drug Alcohol Dependence 1990 25:27-34
Dear Colleagues,
This old study was sent to me recently in response to a discussion about the use of naloxone in combination with other opioids in an effort to prevent or deter injecting.
The induction of withdrawals by naloxone (SL or injected) would seem to be academic since buprenorphine alone will precipitate withdrawal in those using heroin, methadone or other pure agonists regularly. For those who already have buprenorphine in the body, neither additional buprenorphine nor naloxone will cause withdrawals if injected. This is because buprenorphine already had the strongest known affinity for the mu receptor. This raises the question of why naloxone would be needed at all (see below). In addition, since naloxone is indeed absorbed, could repeated exposure be harmful? It appears that the regulators did not require evidence on this issue, perhaps believing the misconception that sub-lingual absorption was negligible.
In the 1970s naloxone was combined with methadone yet these early attempts were soon abandoned. Early combinations with buprenorphine around 1990 did not eliminate abuse and the drugs were withdrawn in some countries (Robinson 1993). Yet the attractive sounding concept reappeared around 2003 for a number of reasons, not the least that it ‘sounded attractive’. The pure form was also about to come off patent.
The original abstract (see below) does not indicate, as in the full text, that only 4mg was used in a third of the heroin subjects because that level already caused unpleasant withdrawals and 8mg was not considered acceptable, even in paid volunteers. The authors also use the imprecise expression “up to 1-2mg”, perhaps hoping to give some ‘flexibility’ to their findings. The study was partly funded by Reckitt and Coleman, the company which invented and marketed buprenorphine in that era.
Notes by Andrew Byrne ..
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/2323306
Dear Colleagues,
This old study was sent to me recently in response to a discussion about the use of naloxone in combination with other opioids in an effort to prevent or deter injecting.
In this small but well constructed study sublingual (SL) naloxone precipitated withdrawal in two of six heroin users and in all three methadone subjects who were given graduated doses of naloxone sublingually. This occurred about 30 minutes after administration, about twice as long as when used intramuscularly. The authors concluded that ‘naloxone doses up to 1-2mg can be administered sublingually to opioid abusers/addicts without precipitating withdrawal’. Yet up to 32mg buprenorphine with 8mg naloxone is routinely used in practice. The conventional wisdom from many quarters is that naloxone is not absorbed sublingually in clinically significant amounts. This study, by prominent authors, showed quite the reverse over 20 years ago.
The induction of withdrawals by naloxone (SL or injected) would seem to be academic since buprenorphine alone will precipitate withdrawal in those using heroin, methadone or other pure agonists regularly. For those who already have buprenorphine in the body, neither additional buprenorphine nor naloxone will cause withdrawals if injected. This is because buprenorphine already had the strongest known affinity for the mu receptor. This raises the question of why naloxone would be needed at all (see below). In addition, since naloxone is indeed absorbed, could repeated exposure be harmful? It appears that the regulators did not require evidence on this issue, perhaps believing the misconception that sub-lingual absorption was negligible.
In the 1970s naloxone was combined with methadone yet these early attempts were soon abandoned. Early combinations with buprenorphine around 1990 did not eliminate abuse and the drugs were withdrawn in some countries (Robinson 1993). Yet the attractive sounding concept reappeared around 2003 for a number of reasons, not the least that it ‘sounded attractive’. The pure form was also about to come off patent.
The original abstract (see below) does not indicate, as in the full text, that only 4mg was used in a third of the heroin subjects because that level already caused unpleasant withdrawals and 8mg was not considered acceptable, even in paid volunteers. The authors also use the imprecise expression “up to 1-2mg”, perhaps hoping to give some ‘flexibility’ to their findings. The study was partly funded by Reckitt and Coleman, the company which invented and marketed buprenorphine in that era.
Notes by Andrew Byrne ..
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/2323306
28 March 2013
Some Australian stats on opioid maintenance treatments.
A government report released recently* states that there are 46,446 people receiving opioid pharmacotheraphy treatment in Australia [this is probably about half the number of patients who have ever received such therapy]. There were 69% receiving methadone, 14% pure buprenorphine, and 17% buprenorphine-naloxone combinations.
There are 1,444 doctors licensed to prescribe maintenance opioids. There are 5,270 pharmacies across Australia, one third of whom 1,981 currently supervise opioid pharmacotheraphy dosing. Including hospitals, clinics, prisons, pharmacies, (and 2 doctors offices) the total number of dispensaries Australia-wide is 2,264.
*Ref: Medication-Assisted Treatment for Opioid Dependence (MATOD). 1st Canberra Roundtable Report. August 2012 Australian National Council on Drugs.
Cost of buprenorphine tablets.
My local pharmacist was unable to ascertain the price for private purchase, nor the price the PBS pays on behalf of approved recipients under the S100 system. Nor could the distributor give me the price and their staff were unwilling or unable to make further enquiries on my behalf.
Cutting through this seeming conspiracy, a senior insider informed me that 28 x 8mg buprenorphine tablets cost about A$130 (~US$130). Thus the maximum dose of 32mg would come in at $520 per month exclusive of dose supervision. This is about half the American price for the brand product I was quoted but comparable to or slight more than a US generic quote. I am not aware that the manufacturing cost of this drug is greatly different from other opioids and it seems to be the current marketing structure, substitute formulations and lack of competition which keep this 40 year old drug at a premium price. Other medications of the same generation such as diazepam and doxycycline are in the ‘bread and butter’ class, costing less than ten dollars for an average prescription. Likewise, methadone costs between 50 cents and a dollar per day on usual doses (excluding dispensing).
I hope this information is of interest to readers … and I would value any comparative feedback on its accuracy as my sources are still verbal for some of the above.
Andrew Byrne .. [presently in New York City, waiting for the spring]
Since writing this I have been informed that the PBS listed prices are indeed available on-line.
There are 1,444 doctors licensed to prescribe maintenance opioids. There are 5,270 pharmacies across Australia, one third of whom 1,981 currently supervise opioid pharmacotheraphy dosing. Including hospitals, clinics, prisons, pharmacies, (and 2 doctors offices) the total number of dispensaries Australia-wide is 2,264.
*Ref: Medication-Assisted Treatment for Opioid Dependence (MATOD). 1st Canberra Roundtable Report. August 2012 Australian National Council on Drugs.
Cost of buprenorphine tablets.
My local pharmacist was unable to ascertain the price for private purchase, nor the price the PBS pays on behalf of approved recipients under the S100 system. Nor could the distributor give me the price and their staff were unwilling or unable to make further enquiries on my behalf.
Cutting through this seeming conspiracy, a senior insider informed me that 28 x 8mg buprenorphine tablets cost about A$130 (~US$130). Thus the maximum dose of 32mg would come in at $520 per month exclusive of dose supervision. This is about half the American price for the brand product I was quoted but comparable to or slight more than a US generic quote. I am not aware that the manufacturing cost of this drug is greatly different from other opioids and it seems to be the current marketing structure, substitute formulations and lack of competition which keep this 40 year old drug at a premium price. Other medications of the same generation such as diazepam and doxycycline are in the ‘bread and butter’ class, costing less than ten dollars for an average prescription. Likewise, methadone costs between 50 cents and a dollar per day on usual doses (excluding dispensing).
I hope this information is of interest to readers … and I would value any comparative feedback on its accuracy as my sources are still verbal for some of the above.
Andrew Byrne .. [presently in New York City, waiting for the spring]
Since writing this I have been informed that the PBS listed prices are indeed available on-line.
7 January 2013
New Year's wishes for 2013
Andrew Byrne’s greeting: busy with family matters; less time for journal summaries; depressed by ‘big pharma’ tactics; occupied with mosque and synagogue events; look forward with gusto to 2013.
Dear Colleagues,
The year 2012 was one I did not expect to get to, being my eighth whole year after treatment for advanced lymphoma. This year my partner Allan and I have relocated to the charming Southern Highlands town of Bowral. I still live in Sydney Wed to Sat as I continue to work at the Redfern surgery. My father John died in May aged 85 following an operation. As executor I have been busy dealing with a lot of material and emotional things. With my four wonderful sibs (one temporarily in New York) we have still enjoyed another festive season relatively intact.
Some of you will know that I have been despondent at the widespread acceptance of drug company advertising that a certain combination drug is preferable to the pure form and that a new and largely untested (in the field) film formulation is ‘better’ than the tablets. Neither combination form has been made available in the smallest size (0.4mg) which is the modality most useful for those on final reductions to abstinence. A cynic might think that the company is not interested in that market. Neither combination form is suitable for pregnant women (or those who may become pregnant in my view) yet there is talk of the pure drug being withdrawn altogether even before generics have been approved. It is indeed depressing but these marketing tactics do not just affect our field but are to be found across the medical spectrum where less effective but far more costly products are pushed only as long as they are profitable.
My continuing involvement in comparative religions has almost become a recreation after several years. Yet each time I think I have cracked a ‘secret Semitic code’ I invariably find that I am up another blind alley and need to start again. Arabic and Hebrew are quite difficult, making Cantonese seem easy in my book (clue: the latter is musical).
Some of my greatest joys during 2012 have been re-reading The Merchant of Venice and listening to Gotterdamerung (Wagner's final Ring opera). While I have still not encompassed the details of either, I adore delving at random into the beauty of either work, marvelling at the genius involved in their geneses. Apart from their complex character interactions and racial overtones, there is also a court-room drama, concealed identities, double crossing and a murder on stage. Interestingly, both plots revolve around the default of a sub-prime mortgage of sorts (over Valhalla and Antonio’s merchant ships respectively).
Wishing you all a happy and prosperous 2013 from Andrew Byrne ..
My first summary for the New Year is a guide for clinical urine toxicology testing aimed at general practitioners (see home page).
Dear Colleagues,
The year 2012 was one I did not expect to get to, being my eighth whole year after treatment for advanced lymphoma. This year my partner Allan and I have relocated to the charming Southern Highlands town of Bowral. I still live in Sydney Wed to Sat as I continue to work at the Redfern surgery. My father John died in May aged 85 following an operation. As executor I have been busy dealing with a lot of material and emotional things. With my four wonderful sibs (one temporarily in New York) we have still enjoyed another festive season relatively intact.
Some of you will know that I have been despondent at the widespread acceptance of drug company advertising that a certain combination drug is preferable to the pure form and that a new and largely untested (in the field) film formulation is ‘better’ than the tablets. Neither combination form has been made available in the smallest size (0.4mg) which is the modality most useful for those on final reductions to abstinence. A cynic might think that the company is not interested in that market. Neither combination form is suitable for pregnant women (or those who may become pregnant in my view) yet there is talk of the pure drug being withdrawn altogether even before generics have been approved. It is indeed depressing but these marketing tactics do not just affect our field but are to be found across the medical spectrum where less effective but far more costly products are pushed only as long as they are profitable.
My continuing involvement in comparative religions has almost become a recreation after several years. Yet each time I think I have cracked a ‘secret Semitic code’ I invariably find that I am up another blind alley and need to start again. Arabic and Hebrew are quite difficult, making Cantonese seem easy in my book (clue: the latter is musical).
Some of my greatest joys during 2012 have been re-reading The Merchant of Venice and listening to Gotterdamerung (Wagner's final Ring opera). While I have still not encompassed the details of either, I adore delving at random into the beauty of either work, marvelling at the genius involved in their geneses. Apart from their complex character interactions and racial overtones, there is also a court-room drama, concealed identities, double crossing and a murder on stage. Interestingly, both plots revolve around the default of a sub-prime mortgage of sorts (over Valhalla and Antonio’s merchant ships respectively).
Wishing you all a happy and prosperous 2013 from Andrew Byrne ..
My first summary for the New Year is a guide for clinical urine toxicology testing aimed at general practitioners (see home page).
18 December 2012
A practical approach to clincal urine drug testing.
THE STATUS OF URINE DRUG TESTING:
A near ‘holy grail’ status in the eyes of the community has partially eclipsed the useful place of urine drug testing when performed appropriately in the therapeutic milieu. Like DNA testing, the perception of urine toxicology has sometimes moved ahead of its technology.
There is a widely held belief that toxicology results can convict or exonerate, create or dissolve a family union as well as cause a worker to be employed or to be sacked. Doctors who are familiar with toxicology testing may help avert crisis points by using a balanced approach tempered by the usual medical safeguards. It is a conundrum that tests may be ordered by court officials, police, employers and even schools, yet such people are not generally qualified to interpret results and can therefore be prone to serious errors.
The first urine tests to prove clinically useful were probably in Vincent Dole’s classic study on methadone treatment in 1964 [ref 1]. Along with numerous other seemingly obsessive measures, Dole performed daily, witnessed urine tests on his in-patient subjects, proving beyond any criticism that the treatment resulted in favourable drug use outcomes. Paradoxically, at the time opiates could not be detected but instead they tested for quinine, an almost ubiquitous contaminant of street heroin in New York at the time (because its bitterness balanced the sugar used for ‘cutting’ the illicit heroin).
WHEN SHOULD YOU ORDER A URINE DRUG TEST?
Whenever questions are raised about drug or alcohol use affecting a patient’s life, work or family a ‘spot urine’ test can be very useful. It can be done in the same way as a urine culture, and by the same lab under normal Medicare billing. The usual rules of informed consent should apply and patients should be reminded of the possible consequences, positive and negative in their own circumstances. If one is considering treatment or referral for a drug or alcohol issue a urine test is essential as a base-line. Like other blood tests or X rays, one sometimes orders them just because of some clinical doubt, again with consent. “I think that a urine drug screen might look good for the records … what do you think about that?” This question and any response can be a useful clinical exercise in itself. “What do you think a toxicology test would show right now?” “Well, actually Doc I was going to tell you …”.
Urine testing can be crucial in cases where child custody is involved. Likewise with driving, work safety or sports competition, a urine test or series of tests in the course of normal clinical practice can sometimes influence matters very significantly in the patient’s interests.
Patients who are taking quantities of opioid analgesics for chronic pain should have urine screening performed occasionally [ref 2]. This is a safeguard for both patient and doctor and is described as a part of ‘universal precautions’.
WHAT DRUGS CAN BE TESTED FOR? ARE THE TESTS VALID?
Attempts to make urine testing forensically rigorous include: (1) ID checking and witnessing the sample being produced; (2) ‘chain of custody’ procedures for transporting the sample to the laboratory; (3) parallel second sample for checking (either to the patient or a third party); (4) tests for adulteration. These procedures are only needed for ‘life and death’ or ‘safety critical’ situations. Doctors are familiar with such procedures in the case of blood transfusion cross-matching, for example, where mistakes could be life threatening. So for child custody cases, drug court convictions or employment dismissals such rigour is also required. However, as an aid to clinical medicine it is perfectly satisfactory to perform a ‘spot’ urine test at the surgery or clinic. A degree of supervision and a degree of ‘randomness’ can make the results more ‘dependable’ but neither is necessary on every occasion. Tests for adulteration are now routinely performed including creatinine levels to detect dilution. Low measured levels of a drug may become undetectable on a more dilute specimen. Some vitamins or other chemicals such as soap have been tried to inhibit certain assays.
Laboratory procedures vary widely and one should be familiar with what is offered locally. Most labs have a standard battery of immunoassays for common drugs of abuse such as opiates, cocaine, benzodiazepines and stimulants. Where necessary a confirmation may be performed, generally by ‘GCMS’ (gas chromatography mass spectrometry). In our service we have stopped testing for cannabis except in specific cases of cannabis dependency.
REDUCING FALSE POSITIVES TO AVOID ADVERSE CONSEQUENCES … WITHOUT INCREASING FALSE NEGATIVES.
The common qualitative immunoassay for opiates is highly sensitive but not very specific. Hence we usually expect a confirmation for positives using more specific assays for codeine and morphine at least. Morphine can and is metabolised from codeine and yet it may also come from common analgesic combinations and even poppy seeds. Recent use of quantitative measures can help distinguish over-the-counter codeine from heroin/morphine. However, there are traps for the unwary since codeine ‘recovery’ from the usual glucuronide metabolite is highly variable. In addition, people may have taken codeine as well as morphine or heroin (di-acetyl morphine), complicating matters still further. Specific stimulants can usually be detected using modern testing, including amphetamine, metamphetamine (also known as methamphetamine) and MDMA (ecstasy).
By far the most useful result is a negative one. This indicates that the patient was highly unlikely to have used any drugs of abuse in the previous 4 to 6 days. This almost excludes drug dependence but does not exclude casual or binge drug use.
WHO ELSE ORDERS SUCH TESTS? POLICE, SCHOOLS, EMPLOYERS AND SPORTS BODIES. INTERPRETING THE RESULTS.
Some may find it surprising that people with no medical training are able to order pathology tests. The matter was raised again recently when an American college introduced mandatory urine testing for all students [ref 3]. While the request may be simple, the interpretation is rarely a simple matter, as shown by media exposés of anomalies, mistakes and sometimes even fraud. Furthermore, it remains to be proven whether there are more benefits or harms resulting in such groups. Should the medical profession become involved? Nobody is better qualified yet many of us may still feel uneasy about such interpretations. Yet interpretation is just a matter of fundamental pharmacology and chemical toxicology so that we should not need to second-guess the outcomes. Where there is any doubt, guilt should not be assumed. Yet in some situations the onus is put onto citizens to ‘prove’ that they are drug-free (as if a single test could prove that). As with the hangman of old, it should never be a doctor’s role to ‘convict’ a patient: if we cannot speak in their defence we should be silent in my view.
As with other pathology ‘group tests’ each lab will do a certain number of agreed tests with or without confirmation. There will be ‘cut-off’ levels quoted for each drug tested with a positive or negative result given. These may change over time and it is important to keep up to date with testing procedures to avoid errors, especially when comparing results from different labs.
SPECIAL CASES - POPPY SEEDS, ANTI-TUSSIVES, OTC ANALGESICS.
A common scenario is a positive test for opiates and amphetamine-type stimulants in a person who claims to have taken no such drugs at all. On closer questioning over-the-counter cold and ‘flu medicines or even poppy seeds can and do cause positive tests. While selective confirmatory testing can sometimes distinguish these, doubts may remain about the origin of, say, morphine. Such doubts must never be allowed to disadvantage a worker, driver, parent or (especially) a school child.
The science of driver testing for alcohol has taken 20 years to get to its present state so it is not surprising that there are still anomalies and ignorance regarding testing for other drugs. In contrast to the close direct relation between alcohol levels and clinical intoxication, cannabis and diazepam, for example, are detectable many days after exposure and levels may bear little relation to ‘sobriety’. Hence a positive test for these drugs is of little relevance to driving or work performance and may just be a needless invasion of the person’s privacy.
Other special cases might be pethidine, buprenorphine and growth hormone. These are difficult to detect using normal techniques although they are of limited relevance in the normal clinical setting. Research for pharmaceutical compliance/adherence often depends upon urine testing although saliva and hair can also be used, the latter with its own ‘time capsule’ drug history.
SUMMARY OF URING DRUG TESTING.
We must not lose sight of the fact that this is just another pathology test, subject to all the same familiar faults, flaws and limitations. Thus if used selectively with appropriate interpretation, such testing can have a valuable place but should never be seen as a panacea.
Written by Andrew Byrne, Redfern GP specialising in dependency medicine.
References:
1. Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. JAMA 1965 193:646-50
2. Heit HA, Gourlay DL. Urine drug testing in pain medicine. J Pain Symptom Management. 2004 27;3:260-7
3. http://www.nytimes.com/2011/10/11/us/at-linn-state-technical-a-fight-over-required-drug-tests.html?hpw New York Times 11/10/11
Reading list:
Clinical Drug Testing in Primary Care. Technical Assistance Publication Series TAP32. SAMHSA 2012 http://kap.samhsa.gov/products/manuals/pdfs/TAP32.pdf
Tenore PL. Advanced urine Toxicology testing. Journal of Addictive Diseases 2010 29:436-448
Chermack ST, Roll J, Reilly M, Davis L, Kilaru U, Grabowski J. Comparison of patient self-report and urinalysis results obtained under naturalistic methadone maintenance conditions. D&A Dependence 2000 59:43-49
Fellous J, Lowenstein W, Gourarier L, Bonan B, et al. Relevance of urinalysis monitoring of methadone maintenance patients: a clinical-biological agreement on 41 patients. Addiction Biology 2000 5:313-318
Cone EJ, Lange R, Darwin WD. In vivo adulteration: excess fluid ingestion causes false-negative marijuana and cocaine urine test results. J Anal Toxicol. 1998 22;6:460-73
Goldstein A, Brown BW. Urine testing in methadone maintenance treatment: applications and limitations. J Substance Abuse Treatment 2003 25;2:61-63
This article on urine testing in clinical practice was commissioned by Australian Prescriber (NPS) but rejected by their editorial team for unspecified reasons. The present article has some minor changes since the original submission.
Written by Andrew Byrne, General Practitioner and Dependency Specialist.
A colleague in England has suggested that we should broach the area of hair testing as well so I am grateful to Dr Colin Brewer for the following observations:
It may be useful to consider the testing of other body fluids (eg. saliva) and also hair.
For people on amphetamine maintenance, it is possible to tell by analysis of the isomers on hair testing whether the patient is also using street amphetamine.
‘Doctor addicts’ are sometimes very cunning about using alternative or ‘custom’ opiates that don't show up in conventional screening, including pethidine, buprenorphine and fentanyl.
Hair testing has two big advantages. It can reveal occasional use, eg at weekends between regular testing or when patients have to be away for a while such as overseas workers, military folk or airline staff. Also, and uniquely, if there is doubt about a sample, the test can usually be retrospectively repeated on a second sample unless the subject has had a recent and very short haircut. Conversely, for a patient who normally has visible hair suddenly to become a skinhead when hair testing is mentioned is deeply suspicious, especially if they shave their armpits and private regions as well (although the eyelashes usually remain in such cases).
Due to the time frame involved, a mooted hair test can be helpful in the scenario of: 'well, actually doctor, I was going to tell you...'. Furthermore, the increased likelihood of detection can also act as a deterrent to illicit or irregular use when hair testing is being used at some frequency.
For alcohol, hair can now be used to detect occasional use by measuring ethyl glucuronide and similar compounds. This, too, has a strong deterrent effect against occasional use - as with other drugs - thus making such testing therapeutic as well as diagnostic.
In practical terms only one Australian centre can do this test commercially at present (in Adelaide) and it costs about $600 per test, regardless of the length of hair (1-3cm = 1-3 months approx). There is no Medicare rebate for this test so it is usually only useful for proving abstinence where important family court, road traffic or employment matters may hinge on such evidence.
[latter on hair testing written by regular BMJ columnist and London psychiatric consultant Dr Colin Brewer]
A near ‘holy grail’ status in the eyes of the community has partially eclipsed the useful place of urine drug testing when performed appropriately in the therapeutic milieu. Like DNA testing, the perception of urine toxicology has sometimes moved ahead of its technology.
There is a widely held belief that toxicology results can convict or exonerate, create or dissolve a family union as well as cause a worker to be employed or to be sacked. Doctors who are familiar with toxicology testing may help avert crisis points by using a balanced approach tempered by the usual medical safeguards. It is a conundrum that tests may be ordered by court officials, police, employers and even schools, yet such people are not generally qualified to interpret results and can therefore be prone to serious errors.
The first urine tests to prove clinically useful were probably in Vincent Dole’s classic study on methadone treatment in 1964 [ref 1]. Along with numerous other seemingly obsessive measures, Dole performed daily, witnessed urine tests on his in-patient subjects, proving beyond any criticism that the treatment resulted in favourable drug use outcomes. Paradoxically, at the time opiates could not be detected but instead they tested for quinine, an almost ubiquitous contaminant of street heroin in New York at the time (because its bitterness balanced the sugar used for ‘cutting’ the illicit heroin).
WHEN SHOULD YOU ORDER A URINE DRUG TEST?
Whenever questions are raised about drug or alcohol use affecting a patient’s life, work or family a ‘spot urine’ test can be very useful. It can be done in the same way as a urine culture, and by the same lab under normal Medicare billing. The usual rules of informed consent should apply and patients should be reminded of the possible consequences, positive and negative in their own circumstances. If one is considering treatment or referral for a drug or alcohol issue a urine test is essential as a base-line. Like other blood tests or X rays, one sometimes orders them just because of some clinical doubt, again with consent. “I think that a urine drug screen might look good for the records … what do you think about that?” This question and any response can be a useful clinical exercise in itself. “What do you think a toxicology test would show right now?” “Well, actually Doc I was going to tell you …”.
Urine testing can be crucial in cases where child custody is involved. Likewise with driving, work safety or sports competition, a urine test or series of tests in the course of normal clinical practice can sometimes influence matters very significantly in the patient’s interests.
Patients who are taking quantities of opioid analgesics for chronic pain should have urine screening performed occasionally [ref 2]. This is a safeguard for both patient and doctor and is described as a part of ‘universal precautions’.
WHAT DRUGS CAN BE TESTED FOR? ARE THE TESTS VALID?
Attempts to make urine testing forensically rigorous include: (1) ID checking and witnessing the sample being produced; (2) ‘chain of custody’ procedures for transporting the sample to the laboratory; (3) parallel second sample for checking (either to the patient or a third party); (4) tests for adulteration. These procedures are only needed for ‘life and death’ or ‘safety critical’ situations. Doctors are familiar with such procedures in the case of blood transfusion cross-matching, for example, where mistakes could be life threatening. So for child custody cases, drug court convictions or employment dismissals such rigour is also required. However, as an aid to clinical medicine it is perfectly satisfactory to perform a ‘spot’ urine test at the surgery or clinic. A degree of supervision and a degree of ‘randomness’ can make the results more ‘dependable’ but neither is necessary on every occasion. Tests for adulteration are now routinely performed including creatinine levels to detect dilution. Low measured levels of a drug may become undetectable on a more dilute specimen. Some vitamins or other chemicals such as soap have been tried to inhibit certain assays.
Laboratory procedures vary widely and one should be familiar with what is offered locally. Most labs have a standard battery of immunoassays for common drugs of abuse such as opiates, cocaine, benzodiazepines and stimulants. Where necessary a confirmation may be performed, generally by ‘GCMS’ (gas chromatography mass spectrometry). In our service we have stopped testing for cannabis except in specific cases of cannabis dependency.
REDUCING FALSE POSITIVES TO AVOID ADVERSE CONSEQUENCES … WITHOUT INCREASING FALSE NEGATIVES.
The common qualitative immunoassay for opiates is highly sensitive but not very specific. Hence we usually expect a confirmation for positives using more specific assays for codeine and morphine at least. Morphine can and is metabolised from codeine and yet it may also come from common analgesic combinations and even poppy seeds. Recent use of quantitative measures can help distinguish over-the-counter codeine from heroin/morphine. However, there are traps for the unwary since codeine ‘recovery’ from the usual glucuronide metabolite is highly variable. In addition, people may have taken codeine as well as morphine or heroin (di-acetyl morphine), complicating matters still further. Specific stimulants can usually be detected using modern testing, including amphetamine, metamphetamine (also known as methamphetamine) and MDMA (ecstasy).
By far the most useful result is a negative one. This indicates that the patient was highly unlikely to have used any drugs of abuse in the previous 4 to 6 days. This almost excludes drug dependence but does not exclude casual or binge drug use.
WHO ELSE ORDERS SUCH TESTS? POLICE, SCHOOLS, EMPLOYERS AND SPORTS BODIES. INTERPRETING THE RESULTS.
Some may find it surprising that people with no medical training are able to order pathology tests. The matter was raised again recently when an American college introduced mandatory urine testing for all students [ref 3]. While the request may be simple, the interpretation is rarely a simple matter, as shown by media exposés of anomalies, mistakes and sometimes even fraud. Furthermore, it remains to be proven whether there are more benefits or harms resulting in such groups. Should the medical profession become involved? Nobody is better qualified yet many of us may still feel uneasy about such interpretations. Yet interpretation is just a matter of fundamental pharmacology and chemical toxicology so that we should not need to second-guess the outcomes. Where there is any doubt, guilt should not be assumed. Yet in some situations the onus is put onto citizens to ‘prove’ that they are drug-free (as if a single test could prove that). As with the hangman of old, it should never be a doctor’s role to ‘convict’ a patient: if we cannot speak in their defence we should be silent in my view.
As with other pathology ‘group tests’ each lab will do a certain number of agreed tests with or without confirmation. There will be ‘cut-off’ levels quoted for each drug tested with a positive or negative result given. These may change over time and it is important to keep up to date with testing procedures to avoid errors, especially when comparing results from different labs.
SPECIAL CASES - POPPY SEEDS, ANTI-TUSSIVES, OTC ANALGESICS.
A common scenario is a positive test for opiates and amphetamine-type stimulants in a person who claims to have taken no such drugs at all. On closer questioning over-the-counter cold and ‘flu medicines or even poppy seeds can and do cause positive tests. While selective confirmatory testing can sometimes distinguish these, doubts may remain about the origin of, say, morphine. Such doubts must never be allowed to disadvantage a worker, driver, parent or (especially) a school child.
The science of driver testing for alcohol has taken 20 years to get to its present state so it is not surprising that there are still anomalies and ignorance regarding testing for other drugs. In contrast to the close direct relation between alcohol levels and clinical intoxication, cannabis and diazepam, for example, are detectable many days after exposure and levels may bear little relation to ‘sobriety’. Hence a positive test for these drugs is of little relevance to driving or work performance and may just be a needless invasion of the person’s privacy.
Other special cases might be pethidine, buprenorphine and growth hormone. These are difficult to detect using normal techniques although they are of limited relevance in the normal clinical setting. Research for pharmaceutical compliance/adherence often depends upon urine testing although saliva and hair can also be used, the latter with its own ‘time capsule’ drug history.
SUMMARY OF URING DRUG TESTING.
We must not lose sight of the fact that this is just another pathology test, subject to all the same familiar faults, flaws and limitations. Thus if used selectively with appropriate interpretation, such testing can have a valuable place but should never be seen as a panacea.
Written by Andrew Byrne, Redfern GP specialising in dependency medicine.
References:
1. Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. JAMA 1965 193:646-50
2. Heit HA, Gourlay DL. Urine drug testing in pain medicine. J Pain Symptom Management. 2004 27;3:260-7
3. http://www.nytimes.com/2011/10/11/us/at-linn-state-technical-a-fight-over-required-drug-tests.html?hpw New York Times 11/10/11
Reading list:
Clinical Drug Testing in Primary Care. Technical Assistance Publication Series TAP32. SAMHSA 2012 http://kap.samhsa.gov/products/manuals/pdfs/TAP32.pdf
Tenore PL. Advanced urine Toxicology testing. Journal of Addictive Diseases 2010 29:436-448
Chermack ST, Roll J, Reilly M, Davis L, Kilaru U, Grabowski J. Comparison of patient self-report and urinalysis results obtained under naturalistic methadone maintenance conditions. D&A Dependence 2000 59:43-49
Fellous J, Lowenstein W, Gourarier L, Bonan B, et al. Relevance of urinalysis monitoring of methadone maintenance patients: a clinical-biological agreement on 41 patients. Addiction Biology 2000 5:313-318
Cone EJ, Lange R, Darwin WD. In vivo adulteration: excess fluid ingestion causes false-negative marijuana and cocaine urine test results. J Anal Toxicol. 1998 22;6:460-73
Goldstein A, Brown BW. Urine testing in methadone maintenance treatment: applications and limitations. J Substance Abuse Treatment 2003 25;2:61-63
This article on urine testing in clinical practice was commissioned by Australian Prescriber (NPS) but rejected by their editorial team for unspecified reasons. The present article has some minor changes since the original submission.
Written by Andrew Byrne, General Practitioner and Dependency Specialist.
A colleague in England has suggested that we should broach the area of hair testing as well so I am grateful to Dr Colin Brewer for the following observations:
It may be useful to consider the testing of other body fluids (eg. saliva) and also hair.
For people on amphetamine maintenance, it is possible to tell by analysis of the isomers on hair testing whether the patient is also using street amphetamine.
‘Doctor addicts’ are sometimes very cunning about using alternative or ‘custom’ opiates that don't show up in conventional screening, including pethidine, buprenorphine and fentanyl.
Hair testing has two big advantages. It can reveal occasional use, eg at weekends between regular testing or when patients have to be away for a while such as overseas workers, military folk or airline staff. Also, and uniquely, if there is doubt about a sample, the test can usually be retrospectively repeated on a second sample unless the subject has had a recent and very short haircut. Conversely, for a patient who normally has visible hair suddenly to become a skinhead when hair testing is mentioned is deeply suspicious, especially if they shave their armpits and private regions as well (although the eyelashes usually remain in such cases).
Due to the time frame involved, a mooted hair test can be helpful in the scenario of: 'well, actually doctor, I was going to tell you...'. Furthermore, the increased likelihood of detection can also act as a deterrent to illicit or irregular use when hair testing is being used at some frequency.
For alcohol, hair can now be used to detect occasional use by measuring ethyl glucuronide and similar compounds. This, too, has a strong deterrent effect against occasional use - as with other drugs - thus making such testing therapeutic as well as diagnostic.
In practical terms only one Australian centre can do this test commercially at present (in Adelaide) and it costs about $600 per test, regardless of the length of hair (1-3cm = 1-3 months approx). There is no Medicare rebate for this test so it is usually only useful for proving abstinence where important family court, road traffic or employment matters may hinge on such evidence.
[latter on hair testing written by regular BMJ columnist and London psychiatric consultant Dr Colin Brewer]
27 September 2012
New York Grand Rounds: ADHD and dependency; acupunture in addiction syndromes; ketamine in severe depression.
Wednesday, 2 May 2012 10.30am Grand Rounds.
I was privileged to hear three registrars at Bellevue Hospital in Manhattan discuss literature reviews on three interesting topics.
Dr Erin Zerbo spoke on ‘ADHD and Co-Morbid Substance Abuse’
Dr Crystal Tholany dealt with ‘Acupuncture in dependency practice’
Dr Joseph Kwon addressed ‘Ketamine for Treatment of Depression’
1. ADHD & Co: Dr Zerbo.
We learned that ADHD was extremely prevalent, affecting 6-9% of children with ½ to 2/3 of cases persisting into adulthood, making ~4.4% of US adult population (~8 million victims).
Since 10-30% of adults have substance use disorder (SUD) there is a very large overlap of these groups. This was shown starkly in The National Comorbidity Survey Replication (n=3000) where prevalence of ADHD in those with a SUD was 11% while in those without SUD it was only 4%. The same survey showed that SUD was present in 15% of those respondents with ADHD but only 5.5% of those not having the ADHD. Four other studies (each 100-300 subjects) showed a high prevalence (10-24%) of DSM diagnosed ADHD in those with alcohol, cocaine and opioid dependency.
This information puts ADHD clearly in the scope of dependency health workers although on the other hand almost 90% of ADHD subjects have no substance use disorder (SUD) at all. It was emphasised by Dr Zerbo that as well as having a more severe and more prolonged course, ADHD subjects with addiction are also less likely to fit in with existing treatments despite such treatments being known to be just as effective in this population group.
I was interested to learn that those with ADHD are likely to use the same spectrum of drugs as others with drug use disorders and no ADHD. However, the drug use is often from a younger age and is more severe with more co-morbid psychiatric and behavioural disturbances.
The criteria for diagnosis of ADHD included six symptoms of inattention, hyperactivity or impulsivity for more than 6 months, dating from before 7 years of age, in two or more settings involving clear impairment and in the absence of other psychiatric reasons for the symptoms. In adults one would expect: low frustration tolerance, chronic conflicts with peers and authorities, stubbornness and impulsivity (which are major obstacles for treatment).
To make the diagnosis in adults one would ideally (but not necessarily) have the substance use disorder stabilised for at least one month before making the diagnosis. Differential diagnoses include thyroid disease, sleep disorders, bipolar disorder, generalised anxiety, chronic drug or withdrawal related syndromes.
Treatment using stimulants, antidepressants, noradrenergic agents, etc can be very effective for ADHD symptoms but rarely does anything for the SUD directly. Hence opiate maintenance or other pharmacotherapy for SUD should be used just as insulin might be used if the patient were diabetic. Dr Zerbo has made the point that appropriate and early treatment of the ADHD will ensure lower drop-out rates from treatment, including opiate maintenance where this is necessary.
A case history given raises issues of polypharmacy as a complex in-patient from the Bellevue Hospital ward was discharged after stabilisation with the following medications: methadone 120mg daily, dextroamphetamine 60mg daily (slow release), gabapentin 300mg tds, hydroxyzine 25mg nocte (sedating antihistamine) and valproic acid 500mg bd. I was told by staff that such cases are not uncommon but reminded that Bellevue tends to attract some of the more difficult cases, being a tertiary referral centre.
A colleague from California tells me that it can be a regulatory nightmare getting permission to prescribe opiate maintenance along with stimulants even though there is obviously a group of patients who need both drugs. He said that only in the Veterans Administration setting was it possible to give comprehensive care in his experience.
Conclusions given by Dr Zerbo:
1. Patients with ADHD are at higher risk for SUD, and have a more severe and prolonged course if they develop SUD.
2. ADHD symptoms can be a significant barrier to effective SUD treatment.
3. Pharmacological treatments for ADHD are effective in patients with SUD; they have not been found to be addictive or to worsen the SUD (even while active).
4. ADHD is often under-prioritized, which can lead to greater morbidity for these patients and a longer time to remission.
My own conclusion is that we must be under-treating some of our dependency patients unless we have a proportion (at least 5% probably) taking prescribed stimulants. If we are not comfortable with that then we are not comfortable with evidence based medicine. I am not proud to say that we only have had three or four such cases in our practice in Sydney over the past decade. The regulatory hurdles are immense.
For more information on this subject: http://dependencyseminars.blogspot.com.au/2008/07/adult-adhd-substance-use-disorders-dr.php4
2. Dr Crystal Tholany spoke next about acupuncture in the treatment of dependency and withdrawal syndromes.
We were given a description of acupuncture and some proposed mechanisms for its apparent effectiveness in various medical settings. We were given the historical context for following thousands of years’ of use in China, its introduction into American medicine and especially in the treatment addiction and withdrawals and the several studies that have been published. There were connections through Japan, Hong Kong and the Bronx. All eyes were on whether it was better than placebo. Many modern settings use electronic as well or instead of mechanical stimulation to the fine needles inserted into the body.
It was found that acupuncture could lessen withdrawal symptoms dramatically. However, this was not evidence based and the effect wore off quickly once the acupuncture was ceased.
Trials show no change in symptoms after treatment stops but some changes remained in PET scans and pathology with several proposed mechanisms.
We were also told about ‘HANS Acupoint’ nerve stimulation which has some followers using sticky patches rather than needles at specific anatomical points found on charts. Studies showed much lower doses of methadone or buprenorphine were required to abolish withdrawal symptoms (published in Chinese Journals of addiction and pain): 1mg versus 13mg bup and 50mg methadone vs. 200mg ‘total of doses requested’ over a 14 day period.
There are also some unconvincing but interesting animal studies. In some intriguing para-placebo studies groups were randomised to receive either “sham” acupuncture of the real thing. This was the closest one might get to a RCT, showing that in addiction cases no differences were shown for symptoms yet some changes were noted on MRI scan findings. In fibromyalgia cases, however, there were some significant improvements in those receiving the true acupuncture under the blindfold.
So, like AA, therapeutic communities, ten-day detoxification and numerous other respected interventions, acupuncture remains a folk treatment and non-evidence based to date. After centuries of use it should not be dismissed but likewise it should not be recommended in place of known effective treatments regarding serious outcome measures including morbidity and mortality. Because this treatment has only been used quite recently in addiction it warrants further investigation, according to Dr Tholany. Naturally it must never be advised in preference to proven treatments like opiate maintenance but in those refusing such treatments and consenting to non-evidence based approaches it may a valid alternative.
3. Dr Joseph Kwon spoke about ketamine for treatment of depression.
Dr Kwon was the third of three senior registrars at Bellevue to deliver a brief paper at their Grand Rounds to which I was invited. Dr Kwon had performed a literature search and presented some history, pharmacology and made the case for this option to be investigated further and possibly used now under close supervision for treatment resistant cases of suicidal depression.
The reason this subject was broached was the recent focus on suicide prevention and the delayed onset of most current forms of treatment for depression. There was also a group of treatment resistant individuals who failed to respond to either antidepressants or ECT. These included both endogenous depression and those with histories of bipolar disorder.
Ketamine was discovered as a shorter acting form of phencyclidine in 1962, having dissociative anaesthetic properties as well as uses in local anaesthetics and analgesia. It was found to have sympathomimetic effects, causing a trance like state at high doses and had a low incidence of respiratory depression. The half life was 2 hours.
The drug’s effect is largely on inhibiting the glutamate system and a Wikipedia page indicates that it shares this property with nitrous oxide, alcohol, methadone, propoxyphene, tramadol, PCP, ibogaine and numerous other substances.
There are groups interested in this subject at Mt Sinai Hospital in New York as well as Bethesda Maryland and in the Netherlands (there was also a paper from New Zealand I noted). Numerous publications of small trials were cited to justify further work and even to use this treatment off-label in certain severe cases at the present time. There has been at least one RCT in an add-on trial with other observational studies being reported, largely very positive in their outcomes with low rates of side effects.
We were told by Dr Kwon that research had shown depression to be associated with increased glutamate in the occipital cortex and reduced levels in the anterior cingulate gyrus. Animal experiments with stressed mice showed better coping with shock when pre-treated with ketamine as also seen with other antidepressants (at least that was the inference).
We were informed that ketamine is fifth on a relatively long WHO list of ‘essential drugs’ for medical purposes.
A small number of invivo human trials were cited: infusions in emergency room situation were very effective apparently as promptly reversing many signs and symptoms of depression on validated scales. In cases of suicidality this type of intervention could clearly be life saving if used appropriately.
Small doses of ketamine (1mg/kg) were shown to improve postoperative depression (and also pain in depressed patients). Another three trials were mentioned involving single or repeated infusions, one with placebo control. No patient developed psychotic symptoms (schizophrenic patients were excluded).
Like morphine and other prescription drugs, it is also used as a mind altering drug recreationally. Taken at rave parties, for example, it seems to cause more dissociative symptoms than the much more popular MDMA. I was informed that it has become one of the most popular recreational drugs in Hong Kong in recent years.
I understand that some Australian centres use ketamine for acute analgesia in patients who are taking buprenorphine (presumably due to resistance to morphine from the antagonist properties of the maintenance drug). According to a colleague in London it could also be useful in those taking naltrexone. I note that ketamine is available in Australia as a parenteral anaesthetic/analgesic under the trade name Ketalar, available in vials for injection of 200mg per 2ml liquid. Product information states that doses must be titrated individually but that 150mg injected intravenously can cause ten minutes of surgical anaesthesia.
It is the writer’s view that ketamine could do with a ‘White Knight’ like Reckitt Benckiser which developed buprenorphine as a treatment for opioid dependence. As an old drug, ketamine is of little interest to drug companies in its present state. However, with some manipulation and focussed research a new patented version could be part of the way to both profits and improved treatment options. With the benefits promised by Dr Kwon’s presentation I would buy stocks in any company working in this direction.
As well as Dr Marc Galanter, head of department, and addiction psychiatrist Dr Phoebus Dhrymes, veteran dependency advocate Charles Winick was in the small audience at Bellevue for this morning session. As it happened, Winick gave a talk I attended at Columbia University the following week outlining some parallel issues with fundamental research on rehabilitation which, like acupuncture and AA, is not easily amenable to controlled trials although some have been attempted with positive outcomes. Yet another coincidence was that we were both due for appointments at the Drug Policy Alliance later that day - let’s share a cab! “Only in New York!” There were more stories on request of security in New York hospitals and other institutions these days … food in New York … ‘coffee’ in New York … and more.
Written by Andrew Byrne ..
Clinic web page: http://methadone-research.blogspot.com/
A month in New York: http://andrewbyrneinnewyork.blogspot.com/
New York in 1922 from grandfather: http://bpresent.com/harry/code/09n_new-york.php
Lord Howe Island story: http://www.redfernclinic.com/c/2007/10/lord-howe-island-naturalists_4153.php4
Our butterfly collection: http://schraderbutterflies.blogspot.com/
Shylock and anti-Semitism: http://cantorialcrossoverculture.blogspot.com/2011/04/shylock-shakespeare-and-jews-anti.html
I was privileged to hear three registrars at Bellevue Hospital in Manhattan discuss literature reviews on three interesting topics.
Dr Erin Zerbo spoke on ‘ADHD and Co-Morbid Substance Abuse’
Dr Crystal Tholany dealt with ‘Acupuncture in dependency practice’
Dr Joseph Kwon addressed ‘Ketamine for Treatment of Depression’
1. ADHD & Co: Dr Zerbo.
We learned that ADHD was extremely prevalent, affecting 6-9% of children with ½ to 2/3 of cases persisting into adulthood, making ~4.4% of US adult population (~8 million victims).
Since 10-30% of adults have substance use disorder (SUD) there is a very large overlap of these groups. This was shown starkly in The National Comorbidity Survey Replication (n=3000) where prevalence of ADHD in those with a SUD was 11% while in those without SUD it was only 4%. The same survey showed that SUD was present in 15% of those respondents with ADHD but only 5.5% of those not having the ADHD. Four other studies (each 100-300 subjects) showed a high prevalence (10-24%) of DSM diagnosed ADHD in those with alcohol, cocaine and opioid dependency.
This information puts ADHD clearly in the scope of dependency health workers although on the other hand almost 90% of ADHD subjects have no substance use disorder (SUD) at all. It was emphasised by Dr Zerbo that as well as having a more severe and more prolonged course, ADHD subjects with addiction are also less likely to fit in with existing treatments despite such treatments being known to be just as effective in this population group.
I was interested to learn that those with ADHD are likely to use the same spectrum of drugs as others with drug use disorders and no ADHD. However, the drug use is often from a younger age and is more severe with more co-morbid psychiatric and behavioural disturbances.
The criteria for diagnosis of ADHD included six symptoms of inattention, hyperactivity or impulsivity for more than 6 months, dating from before 7 years of age, in two or more settings involving clear impairment and in the absence of other psychiatric reasons for the symptoms. In adults one would expect: low frustration tolerance, chronic conflicts with peers and authorities, stubbornness and impulsivity (which are major obstacles for treatment).
To make the diagnosis in adults one would ideally (but not necessarily) have the substance use disorder stabilised for at least one month before making the diagnosis. Differential diagnoses include thyroid disease, sleep disorders, bipolar disorder, generalised anxiety, chronic drug or withdrawal related syndromes.
Treatment using stimulants, antidepressants, noradrenergic agents, etc can be very effective for ADHD symptoms but rarely does anything for the SUD directly. Hence opiate maintenance or other pharmacotherapy for SUD should be used just as insulin might be used if the patient were diabetic. Dr Zerbo has made the point that appropriate and early treatment of the ADHD will ensure lower drop-out rates from treatment, including opiate maintenance where this is necessary.
A case history given raises issues of polypharmacy as a complex in-patient from the Bellevue Hospital ward was discharged after stabilisation with the following medications: methadone 120mg daily, dextroamphetamine 60mg daily (slow release), gabapentin 300mg tds, hydroxyzine 25mg nocte (sedating antihistamine) and valproic acid 500mg bd. I was told by staff that such cases are not uncommon but reminded that Bellevue tends to attract some of the more difficult cases, being a tertiary referral centre.
A colleague from California tells me that it can be a regulatory nightmare getting permission to prescribe opiate maintenance along with stimulants even though there is obviously a group of patients who need both drugs. He said that only in the Veterans Administration setting was it possible to give comprehensive care in his experience.
Conclusions given by Dr Zerbo:
1. Patients with ADHD are at higher risk for SUD, and have a more severe and prolonged course if they develop SUD.
2. ADHD symptoms can be a significant barrier to effective SUD treatment.
3. Pharmacological treatments for ADHD are effective in patients with SUD; they have not been found to be addictive or to worsen the SUD (even while active).
4. ADHD is often under-prioritized, which can lead to greater morbidity for these patients and a longer time to remission.
My own conclusion is that we must be under-treating some of our dependency patients unless we have a proportion (at least 5% probably) taking prescribed stimulants. If we are not comfortable with that then we are not comfortable with evidence based medicine. I am not proud to say that we only have had three or four such cases in our practice in Sydney over the past decade. The regulatory hurdles are immense.
For more information on this subject: http://dependencyseminars.blogspot.com.au/2008/07/adult-adhd-substance-use-disorders-dr.php4
2. Dr Crystal Tholany spoke next about acupuncture in the treatment of dependency and withdrawal syndromes.
We were given a description of acupuncture and some proposed mechanisms for its apparent effectiveness in various medical settings. We were given the historical context for following thousands of years’ of use in China, its introduction into American medicine and especially in the treatment addiction and withdrawals and the several studies that have been published. There were connections through Japan, Hong Kong and the Bronx. All eyes were on whether it was better than placebo. Many modern settings use electronic as well or instead of mechanical stimulation to the fine needles inserted into the body.
It was found that acupuncture could lessen withdrawal symptoms dramatically. However, this was not evidence based and the effect wore off quickly once the acupuncture was ceased.
Trials show no change in symptoms after treatment stops but some changes remained in PET scans and pathology with several proposed mechanisms.
We were also told about ‘HANS Acupoint’ nerve stimulation which has some followers using sticky patches rather than needles at specific anatomical points found on charts. Studies showed much lower doses of methadone or buprenorphine were required to abolish withdrawal symptoms (published in Chinese Journals of addiction and pain): 1mg versus 13mg bup and 50mg methadone vs. 200mg ‘total of doses requested’ over a 14 day period.
There are also some unconvincing but interesting animal studies. In some intriguing para-placebo studies groups were randomised to receive either “sham” acupuncture of the real thing. This was the closest one might get to a RCT, showing that in addiction cases no differences were shown for symptoms yet some changes were noted on MRI scan findings. In fibromyalgia cases, however, there were some significant improvements in those receiving the true acupuncture under the blindfold.
So, like AA, therapeutic communities, ten-day detoxification and numerous other respected interventions, acupuncture remains a folk treatment and non-evidence based to date. After centuries of use it should not be dismissed but likewise it should not be recommended in place of known effective treatments regarding serious outcome measures including morbidity and mortality. Because this treatment has only been used quite recently in addiction it warrants further investigation, according to Dr Tholany. Naturally it must never be advised in preference to proven treatments like opiate maintenance but in those refusing such treatments and consenting to non-evidence based approaches it may a valid alternative.
3. Dr Joseph Kwon spoke about ketamine for treatment of depression.
Dr Kwon was the third of three senior registrars at Bellevue to deliver a brief paper at their Grand Rounds to which I was invited. Dr Kwon had performed a literature search and presented some history, pharmacology and made the case for this option to be investigated further and possibly used now under close supervision for treatment resistant cases of suicidal depression.
The reason this subject was broached was the recent focus on suicide prevention and the delayed onset of most current forms of treatment for depression. There was also a group of treatment resistant individuals who failed to respond to either antidepressants or ECT. These included both endogenous depression and those with histories of bipolar disorder.
Ketamine was discovered as a shorter acting form of phencyclidine in 1962, having dissociative anaesthetic properties as well as uses in local anaesthetics and analgesia. It was found to have sympathomimetic effects, causing a trance like state at high doses and had a low incidence of respiratory depression. The half life was 2 hours.
The drug’s effect is largely on inhibiting the glutamate system and a Wikipedia page indicates that it shares this property with nitrous oxide, alcohol, methadone, propoxyphene, tramadol, PCP, ibogaine and numerous other substances.
There are groups interested in this subject at Mt Sinai Hospital in New York as well as Bethesda Maryland and in the Netherlands (there was also a paper from New Zealand I noted). Numerous publications of small trials were cited to justify further work and even to use this treatment off-label in certain severe cases at the present time. There has been at least one RCT in an add-on trial with other observational studies being reported, largely very positive in their outcomes with low rates of side effects.
We were told by Dr Kwon that research had shown depression to be associated with increased glutamate in the occipital cortex and reduced levels in the anterior cingulate gyrus. Animal experiments with stressed mice showed better coping with shock when pre-treated with ketamine as also seen with other antidepressants (at least that was the inference).
We were informed that ketamine is fifth on a relatively long WHO list of ‘essential drugs’ for medical purposes.
A small number of invivo human trials were cited: infusions in emergency room situation were very effective apparently as promptly reversing many signs and symptoms of depression on validated scales. In cases of suicidality this type of intervention could clearly be life saving if used appropriately.
Small doses of ketamine (1mg/kg) were shown to improve postoperative depression (and also pain in depressed patients). Another three trials were mentioned involving single or repeated infusions, one with placebo control. No patient developed psychotic symptoms (schizophrenic patients were excluded).
Like morphine and other prescription drugs, it is also used as a mind altering drug recreationally. Taken at rave parties, for example, it seems to cause more dissociative symptoms than the much more popular MDMA. I was informed that it has become one of the most popular recreational drugs in Hong Kong in recent years.
I understand that some Australian centres use ketamine for acute analgesia in patients who are taking buprenorphine (presumably due to resistance to morphine from the antagonist properties of the maintenance drug). According to a colleague in London it could also be useful in those taking naltrexone. I note that ketamine is available in Australia as a parenteral anaesthetic/analgesic under the trade name Ketalar, available in vials for injection of 200mg per 2ml liquid. Product information states that doses must be titrated individually but that 150mg injected intravenously can cause ten minutes of surgical anaesthesia.
It is the writer’s view that ketamine could do with a ‘White Knight’ like Reckitt Benckiser which developed buprenorphine as a treatment for opioid dependence. As an old drug, ketamine is of little interest to drug companies in its present state. However, with some manipulation and focussed research a new patented version could be part of the way to both profits and improved treatment options. With the benefits promised by Dr Kwon’s presentation I would buy stocks in any company working in this direction.
As well as Dr Marc Galanter, head of department, and addiction psychiatrist Dr Phoebus Dhrymes, veteran dependency advocate Charles Winick was in the small audience at Bellevue for this morning session. As it happened, Winick gave a talk I attended at Columbia University the following week outlining some parallel issues with fundamental research on rehabilitation which, like acupuncture and AA, is not easily amenable to controlled trials although some have been attempted with positive outcomes. Yet another coincidence was that we were both due for appointments at the Drug Policy Alliance later that day - let’s share a cab! “Only in New York!” There were more stories on request of security in New York hospitals and other institutions these days … food in New York … ‘coffee’ in New York … and more.
Written by Andrew Byrne ..
Clinic web page: http://methadone-research.blogspot.com/
A month in New York: http://andrewbyrneinnewyork.blogspot.com/
New York in 1922 from grandfather: http://bpresent.com/harry/code/09n_new-york.php
Lord Howe Island story: http://www.redfernclinic.com/c/2007/10/lord-howe-island-naturalists_4153.php4
Our butterfly collection: http://schraderbutterflies.blogspot.com/
Shylock and anti-Semitism: http://cantorialcrossoverculture.blogspot.com/2011/04/shylock-shakespeare-and-jews-anti.html
28 August 2012
RPAH Grand Rounds were indeed GRAND!
Grand Rounds at Prince Alfred circa 1975. An institution within an institution.
Recently I chanced to meet two senior medical colleagues who had participated in the Grand Rounds at Royal Prince Alfred Hospital for the years that I was a student and resident there in the late 70s. These were Friday afternoon sessions in which two cases were presented plus one or two follow-up cases from the senior registrars involved. The two regular attenders were Dr John Hallinan, chief radiologist and Dr John Emder, a senior local GP and probably one of the last GPs ever to be allowed in the doors of the hospital in the great age of the specialist.
Medical Grand Rounds was a long standing venerable tradition at the hospital according to my father who had been a resident there around 1950. The Scot Skirving lecture theatre was a windowless Victorian conclave between A2 medical ward and the small veranda ward used for peritoneal dialysis. There was an element of anticipation each Friday afternoon as hurried last minute pathology results or research papers were incorporated into the presentations, some of which were so notable (or notorious) that some of the audience already met the patient(s) involved in our own ‘rounds’.
Some of the more exotic diagnoses included myasthenia gravis, osteogenesis imperfecta (the only time in my experience that an actual patient was wheeled into the hall), lacunar stroke, dissecting aneurysm, carotid sinus syndrome, hairy cell leukaemia, cerebral lymphoma, mononeuritis multiplex, small bowel leiomyosarcoma, splanchnic claudication, ‘HHH syndrome’ (later called AIDS), methicillin resistant staphylococcus infection, cardiac tamponade, mixed connective tissue disease, idiopathic thrombocytopaenic purpura, systemic lupus erythematosus and narcolepsy/cataplexy.
Dramatis personae: The main characters of this high academic drama included the following: Prof Ruthven Bickerton Blackburn (lord high physician and usual chair person), Prof Tony Basten (immunology), Prof Martin Tattersall (oncology: “I do not treat the relatives”), Prof Anne Woolcock (respiratory medicine … and in real life, wife to Prof Blackburn), John Greenaway (possibly the last physician in Macquarie Street), David Tiller (who could derive a social profile from a biochemical one), John Hassall (rheumatology).
Less often, and sometimes on special occasions, there would be guest appearances from Prof Jim McLeod (neurology and dean of faculty), Harry Kronenberg (haematology), John Allsop (neuro), John Turtle (endocrine), Richard Benn (bacto), Geoff Duggin (renal), Warwick Selby (gastro), John York (rheumatology), Dick Richards (cardio), Lou Bernstein (cardio staff), Rodney Shearman (gynae), John Sands (of the games fame), Frank Harding Burns (notionally drug and alcohol and an advocate for God and moderation), Geoff McDonald (another of the few Catholics), and perhaps a dozen others.
The senior registrars at the time were amongst the most gifted young doctors in the country, including Michael Field, Michael Halmagi, Roger Tuck, Ian Caterson, Bill Bye, Stephen Lee, Sheryl Van Nunen, Geraldine Room, Paul Russell, Ben Friedman and many others.
Classic statements:
“Myaesthenia gravis is called gravis because it IS ‘gravis’”.
“Sjogren’s syndrome does not require the existence of a rash”. Response from up-start registrar: “When I worked with Dr Sjogren in Stockholm he used to say otherwise”.
‘The only five medical causes of abdominal patient are myocardial infarction, diabetes, familial Mediterranean fever, porphyria and tabes dorsalis.’
After a long and tedious discussion about a patient with auto-immune cold agglutinins, cryoprecipitins and acute renal failure Dr Jonathan Leicester, who was not associated with the case, commented in his slow, measured way: “I wonder if the patient just had a chill on the kidney?” (huge laughter from the audience).
Dr John Greenaway (leaning over the wooden railing, frowning sternly): “Mr Chairman, I would take to task the treating team over all these investigations!”
Mr Bruce Leckie (thoracic surgeon invited concerning a chest lump, possibly parathyroid): “Look, Mr Chairman I have been sitting here for 30 minutes listening to all these differential diagnoses, fancy test results, nuclear scans and other learned speculation. In that time, I could have made a small incision in the patient’s side, exposed the lesion and in all probability, cured it. I’m afraid I have to go back to work!”
I have always enjoyed being a fly on the wall but after three years of passive attendance I was finally asked to present a case when working for the neurology team in C1 ward under HMOs McLeod and Allsop. It may have been posterior inferior cerebellar artery (PICA) syndrome and I did not do the case justice.
I had the misfortune to speak French better than John Allsop which put me on the back foot as he looked after the private patients from Noumea who would be brought from the airport by ambulance once weekly for triage. They would have all manner of interesting diseases, mostly strokes, but also myopathies, epilepsy, neuritis, tumours and other differential exotica. John’s speciality was demonstrating gait disturbances, sure to trigger the funny-bone of each new cohort of students as he looked like Quasimodo lurching large.
In attending RPAH Medical Grand Rounds I was immensely privileged to be witness to this magnificent piece of medical history the likes of which have probably not been seen before or since in this country. Who in their right mind would expect a high-powered group of people to muster at 5pm on a Friday these days unless it was for a keg of beer and a music box? In fact the latter occurred slight later on a Friday at the Gross Farm Hotel nearby in Missenden Road.
Written by Andrew Byrne MB BS FAChAM (RACP)
Dependency Physician
75 Redfern St
Redfern 2016
9319 5524
[with thanks to John Byrne, Richard Benn, Martin Tattersall, John Hallinan, John Hassall and John Emder.]
This item was 'politely declined' by MJA as being too Sydney-centric for their Christmas edition. Such is life!
Recently I chanced to meet two senior medical colleagues who had participated in the Grand Rounds at Royal Prince Alfred Hospital for the years that I was a student and resident there in the late 70s. These were Friday afternoon sessions in which two cases were presented plus one or two follow-up cases from the senior registrars involved. The two regular attenders were Dr John Hallinan, chief radiologist and Dr John Emder, a senior local GP and probably one of the last GPs ever to be allowed in the doors of the hospital in the great age of the specialist.
Medical Grand Rounds was a long standing venerable tradition at the hospital according to my father who had been a resident there around 1950. The Scot Skirving lecture theatre was a windowless Victorian conclave between A2 medical ward and the small veranda ward used for peritoneal dialysis. There was an element of anticipation each Friday afternoon as hurried last minute pathology results or research papers were incorporated into the presentations, some of which were so notable (or notorious) that some of the audience already met the patient(s) involved in our own ‘rounds’.
Some of the more exotic diagnoses included myasthenia gravis, osteogenesis imperfecta (the only time in my experience that an actual patient was wheeled into the hall), lacunar stroke, dissecting aneurysm, carotid sinus syndrome, hairy cell leukaemia, cerebral lymphoma, mononeuritis multiplex, small bowel leiomyosarcoma, splanchnic claudication, ‘HHH syndrome’ (later called AIDS), methicillin resistant staphylococcus infection, cardiac tamponade, mixed connective tissue disease, idiopathic thrombocytopaenic purpura, systemic lupus erythematosus and narcolepsy/cataplexy.
Dramatis personae: The main characters of this high academic drama included the following: Prof Ruthven Bickerton Blackburn (lord high physician and usual chair person), Prof Tony Basten (immunology), Prof Martin Tattersall (oncology: “I do not treat the relatives”), Prof Anne Woolcock (respiratory medicine … and in real life, wife to Prof Blackburn), John Greenaway (possibly the last physician in Macquarie Street), David Tiller (who could derive a social profile from a biochemical one), John Hassall (rheumatology).
Less often, and sometimes on special occasions, there would be guest appearances from Prof Jim McLeod (neurology and dean of faculty), Harry Kronenberg (haematology), John Allsop (neuro), John Turtle (endocrine), Richard Benn (bacto), Geoff Duggin (renal), Warwick Selby (gastro), John York (rheumatology), Dick Richards (cardio), Lou Bernstein (cardio staff), Rodney Shearman (gynae), John Sands (of the games fame), Frank Harding Burns (notionally drug and alcohol and an advocate for God and moderation), Geoff McDonald (another of the few Catholics), and perhaps a dozen others.
The senior registrars at the time were amongst the most gifted young doctors in the country, including Michael Field, Michael Halmagi, Roger Tuck, Ian Caterson, Bill Bye, Stephen Lee, Sheryl Van Nunen, Geraldine Room, Paul Russell, Ben Friedman and many others.
Classic statements:
“Myaesthenia gravis is called gravis because it IS ‘gravis’”.
“Sjogren’s syndrome does not require the existence of a rash”. Response from up-start registrar: “When I worked with Dr Sjogren in Stockholm he used to say otherwise”.
‘The only five medical causes of abdominal patient are myocardial infarction, diabetes, familial Mediterranean fever, porphyria and tabes dorsalis.’
After a long and tedious discussion about a patient with auto-immune cold agglutinins, cryoprecipitins and acute renal failure Dr Jonathan Leicester, who was not associated with the case, commented in his slow, measured way: “I wonder if the patient just had a chill on the kidney?” (huge laughter from the audience).
Dr John Greenaway (leaning over the wooden railing, frowning sternly): “Mr Chairman, I would take to task the treating team over all these investigations!”
Mr Bruce Leckie (thoracic surgeon invited concerning a chest lump, possibly parathyroid): “Look, Mr Chairman I have been sitting here for 30 minutes listening to all these differential diagnoses, fancy test results, nuclear scans and other learned speculation. In that time, I could have made a small incision in the patient’s side, exposed the lesion and in all probability, cured it. I’m afraid I have to go back to work!”
I have always enjoyed being a fly on the wall but after three years of passive attendance I was finally asked to present a case when working for the neurology team in C1 ward under HMOs McLeod and Allsop. It may have been posterior inferior cerebellar artery (PICA) syndrome and I did not do the case justice.
I had the misfortune to speak French better than John Allsop which put me on the back foot as he looked after the private patients from Noumea who would be brought from the airport by ambulance once weekly for triage. They would have all manner of interesting diseases, mostly strokes, but also myopathies, epilepsy, neuritis, tumours and other differential exotica. John’s speciality was demonstrating gait disturbances, sure to trigger the funny-bone of each new cohort of students as he looked like Quasimodo lurching large.
In attending RPAH Medical Grand Rounds I was immensely privileged to be witness to this magnificent piece of medical history the likes of which have probably not been seen before or since in this country. Who in their right mind would expect a high-powered group of people to muster at 5pm on a Friday these days unless it was for a keg of beer and a music box? In fact the latter occurred slight later on a Friday at the Gross Farm Hotel nearby in Missenden Road.
Written by Andrew Byrne MB BS FAChAM (RACP)
Dependency Physician
75 Redfern St
Redfern 2016
9319 5524
[with thanks to John Byrne, Richard Benn, Martin Tattersall, John Hallinan, John Hassall and John Emder.]
This item was 'politely declined' by MJA as being too Sydney-centric for their Christmas edition. Such is life!
Rare non-fatal cardiac risk should not discourage the use of adequate supervised methadone doses which save lives.
Increased incidence of QT interval prolongation in a population receiving lower doses of methadone maintenance therapy. Roy A, McCarthy C, Kiernan G, McGorrian C, Keenan E, Mahon N, Sweeney B. Addiction 2012 107;6:1132-9
Dear Readers,
These Irish researchers examine QT intervals in relation to methadone dose, cocaine, opiates and benzodiazepine use in 180 stable maintenance patients (total clinic population 376). They find that 9-11% have ‘drug induced’ QT prolongation despite finding no relation to daily methadone dose (which was a healthy mean of 80mg, SD 27mg) and no control group. Nor was there any relation between QT interval and the presence of cocaine in toxicology tests.
The article’s title makes an implication about the relevance of high versus low dose methadone in relation to QT prolongation. Yet the very first report of nine dependency cases had six taking less than 130mg daily and four taking less than 100mg (ref 1 - but see below why this cannot be gleaned from the paper directly).
QT prolongation has been reported in a high proportion of potential methadone recipients, but who were not actually taking methadone at the time. In hospice patients being considered for methadone treatment Reddy found QT prolongation in 28%. Lipski and her colleagues in 1973 reported 19% of street heroin users had QT prolongation before starting methadone treatment.
It is clear that a population of patients taking a variety of medications and with certain underlying illnesses such as HIV and hepatitis C are at risk of having QT prolongation, quite apart from any methadone treatment. Alcohol is also believed to be a risk factor [ref 4]. With a lack of any reported cases of this arrhythmia in 37 years, one might reasonably infer that this issue was not a major clinical problem in methadone prescribed patients.
Yet in the past decade there have been just over 100 reported cases of torsade in methadone patients. So, as our patients have survived their addiction, viral infections (and especially treatment for those infections), a small proportion have reached an age at which they have become susceptible to a rare clinical entity which most large centres have now seen at least once. Torsade de pointes was so rare amongst methadone recipients in 2002 that it was thought to be a new entity [see ref 13 for an earlier report]. Yet torsade de pointes was delineated and re-branded in the 1960s by a French group (no relation to methadone which was not used in that country at the time) [ref 11]. In 1985 another French group also provided a systematic approach to torsade treatment such that for eight years they had a mortality of zero [ref 12].
One may ask why we do not see more torsade de pointes since QT prolongation has a high prevalence in out treatment population. In a RCT Wedam [ref 8] found ~10% of new methadone recipients in Baltimore had QTc > 500mg (but no torsade cases), yet contrary-wise nearly all of the reports of torsade are in longer-term patients [ref 5 and pers comm].
So QT prolongation, even at the level of greater than 500ms in this population of methadone recipients does not appear to confer a measurable risk of torsade de pointes tachycardia (and numerous torsade cases had normal ECG away from the arrhythmia episode).
While torsade is symptomatically a distressing and unpleasant condition, it is rarely if ever fatal and is “controllable 100% of the time” with modern treatment, according to US cardiologist Phibbs [ref 6].
Suggestions from some quarters that there may be large numbers of unrecognised deaths due to torsade are not credible for two reasons: (1) deaths of patients on methadone programs are reportedly very rare and (2) such deaths are usually rigorously investigated by coroners and positive findings are the rule with only very occasional ‘unknown causes’ which might include a fatal arrhythmia [Anchesen; Perrin-Terrin, refs 9 and 10].
It is regrettable that in his seminal article on the subject Krantz did not delineate pain from addiction subjects [1]. This appears to have caused a decade of confusion about the supposed effect of extremely high doses of methadone (see Annals Editorial comments relating to “very-high-dose methadone”). When the cases were separated for the reader in a follow-up paper [7], it became clear that torsade may occur in those taking average doses as well as with the supra-therapeutic doses cited by Krantz’s group (up to 1000mg daily in the pain cases). Yet only two of nine addiction cases were taking such doses when developing torsade de pointes. Six of the nine were prescribed between 65mg and 125mg (mean 96mg), which are dose levels found commonly in methadone maintenance treatment reports. There were no deaths among these nine MMT patients. Indeed there are no documented torsade deaths in MMT as far as I can find in the entire literature (one suspected death in France has been reported).
Krantz’s finding of nine cases of torsade in a small catchment over a relatively short period remains to be explained as it has never been duplicated anywhere else in the world to my best knowledge. Most reports have been of one or two cases. One wonders if there were other factors at play such as a viral induced cluster, the high altitude in Denver or some other factor unique to Krantz’s area.
It is often instructive to go back to the original sources and while most cite Lipski et al., few seem to have actually read the paper which is elegantly written. Even some major authors on the subject apparently believed that Lipski and colleagues were examining the effect of methadone on the QT interval. They were in fact examining why so many heroin users in New York died of apparent overdose but with relatively low levels of morphine at post-mortem examination, proposing arrhythmia in some such cases (from heroin or other street drugs). As they had no way of testing QT effects from heroin, ECG changes were examined in new entrants to treatment at their methadone program (which closed down recently, to the shame of the otherwise venerable Mt Sinai Medical Center in northern Manhattan).
In short, these early researchers performed 12-lead cardiographs on 75 patients new to methadone treatment. About half had not yet started treatment and had used heroin in the previous 24 hours. The rest were already taking methadone and a range of other drugs as shown by urine testing. The first group had prolonged QT intervals in 19% of subjects while the new patients who had started treatment had a rate of 34%. The latter were reportedly using combinations of heroin, cocaine, methadone and other drugs. So their theory was not confirmed yet their findings indicated a possibility that methadone extended the QT interval despite this being asymptomatic in all cases. Further, there were no reports of arrhythmias in MMT patients for the next 29 years.
This leaves us asking why one would spend time and money highlighting, emphasising and investigating the torsade issue while ignoring the vastly more important issue of standards of treatment. Drop-outs, deaths, overdose, viral infection, unemployment, etc, are all well documented consequences of deficient doses, inadequate supervision and a lack of psychosocial supports which are still sadly common. Each of these factors was clearly delineated in Dole’s first report in 1965 - and which modern prescribers ignore to their patients’ eternal cost.
Notes by Andrew Byrne .. Clinic web page: http://methadone-research.blogspot.com/
REFERENCES:
1. 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
2. Reddy S, Fisch M, Bruera E. Oral methadone for cancer pain: no indication of Q-T interval prolongation or torsades de pointes. Journal of Pain and Symptom Management 2004 28;4:301-303
3. Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. American Heart J 1973 86:663-8
4. Hyslop B. Prolongation of the QT interval on methadone: how important is methadone dose? New Zealand Medical Student Journal 2007 6 Aug
5. Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006 101:1333-1338
6. Phibbs B. Advanced ECG: boards and beyond. 2006 Elsevier
7. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy. 2003;23:802-805
8. Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473
9. Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical relevance of QTc interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction 2009 104;6:993-999
10. Perrin-Terrin A, Pathak A, Lapeyre-Mestre M. QT interval prolongation: prevalence, risk factors and pharmacovigilance data among methadone-treated patients in France. Fundam Clin Pharmacol. 2010 Sep 6
11. Dessertenne PF. La tachycardie ventriculaire a deux foyers opposes variables. Arch Mal Coeur 1966 59:263-72
12. Salle P, Rey JL, Bernasconi P, et al. Torsades de pointe. Apropos of 60 cases. Ann Cardiol Angeiol (Paris). Jun 1985;34(6):381-8
13. Bittar P, Piguet V, Kondo-Oestreicher J et al. Methadone induced long QTc and "torsade de pointe". Swiss Medical Forum 2002 S4;P244:36S
Roy A, McCarthy C, Kiernan G, McGorrian C, Keenan E, Mahon N, Sweeney B. Increased incidence of QT interval prolongation in a population receiving lower doses of methadone maintenance therapy. Addiction. 2012 107;6:1132-9
Dear Readers,
These Irish researchers examine QT intervals in relation to methadone dose, cocaine, opiates and benzodiazepine use in 180 stable maintenance patients (total clinic population 376). They find that 9-11% have ‘drug induced’ QT prolongation despite finding no relation to daily methadone dose (which was a healthy mean of 80mg, SD 27mg) and no control group. Nor was there any relation between QT interval and the presence of cocaine in toxicology tests.
The article’s title makes an implication about the relevance of high versus low dose methadone in relation to QT prolongation. Yet the very first report of nine dependency cases had six taking less than 130mg daily and four taking less than 100mg (ref 1 - but see below why this cannot be gleaned from the paper directly).
QT prolongation has been reported in a high proportion of potential methadone recipients, but who were not actually taking methadone at the time. In hospice patients being considered for methadone treatment Reddy found QT prolongation in 28%. Lipski and her colleagues in 1973 reported 19% of street heroin users had QT prolongation before starting methadone treatment.
It is clear that a population of patients taking a variety of medications and with certain underlying illnesses such as HIV and hepatitis C are at risk of having QT prolongation, quite apart from any methadone treatment. Alcohol is also believed to be a risk factor [ref 4]. With a lack of any reported cases of this arrhythmia in 37 years, one might reasonably infer that this issue was not a major clinical problem in methadone prescribed patients.
Yet in the past decade there have been just over 100 reported cases of torsade in methadone patients. So, as our patients have survived their addiction, viral infections (and especially treatment for those infections), a small proportion have reached an age at which they have become susceptible to a rare clinical entity which most large centres have now seen at least once. Torsade de pointes was so rare amongst methadone recipients in 2002 that it was thought to be a new entity [see ref 13 for an earlier report]. Yet torsade de pointes was delineated and re-branded in the 1960s by a French group (no relation to methadone which was not used in that country at the time) [ref 11]. In 1985 another French group also provided a systematic approach to torsade treatment such that for eight years they had a mortality of zero [ref 12].
One may ask why we do not see more torsade de pointes since QT prolongation has a high prevalence in out treatment population. In a RCT Wedam [ref 8] found ~10% of new methadone recipients in Baltimore had QTc > 500mg (but no torsade cases), yet contrary-wise nearly all of the reports of torsade are in longer-term patients [ref 5 and pers comm].
So QT prolongation, even at the level of greater than 500ms in this population of methadone recipients does not appear to confer a measurable risk of torsade de pointes tachycardia (and numerous torsade cases had normal ECG away from the arrhythmia episode).
While torsade is symptomatically a distressing and unpleasant condition, it is rarely if ever fatal and is “controllable 100% of the time” with modern treatment, according to US cardiologist Phibbs [ref 6].
Suggestions from some quarters that there may be large numbers of unrecognised deaths due to torsade are not credible for two reasons: (1) deaths of patients on methadone programs are reportedly very rare and (2) such deaths are usually rigorously investigated by coroners and positive findings are the rule with only very occasional ‘unknown causes’ which might include a fatal arrhythmia [Anchesen; Perrin-Terrin, refs 9 and 10].
It is regrettable that in his seminal article on the subject Krantz did not delineate pain from addiction subjects [1]. This appears to have caused a decade of confusion about the supposed effect of extremely high doses of methadone (see Annals Editorial comments relating to “very-high-dose methadone”). When the cases were separated for the reader in a follow-up paper [7], it became clear that torsade may occur in those taking average doses as well as with the supra-therapeutic doses cited by Krantz’s group (up to 1000mg daily in the pain cases). Yet only two of nine addiction cases were taking such doses when developing torsade de pointes. Six of the nine were prescribed between 65mg and 125mg (mean 96mg), which are dose levels found commonly in methadone maintenance treatment reports. There were no deaths among these nine MMT patients. Indeed there are no documented torsade deaths in MMT as far as I can find in the entire literature (one suspected death in France has been reported).
Krantz’s finding of nine cases of torsade in a small catchment over a relatively short period remains to be explained as it has never been duplicated anywhere else in the world to my best knowledge. Most reports have been of one or two cases. One wonders if there were other factors at play such as a viral induced cluster, the high altitude in Denver or some other factor unique to Krantz’s area.
It is often instructive to go back to the original sources and while most cite Lipski et al., few seem to have actually read the paper which is elegantly written. Even some major authors on the subject apparently believed that Lipski and colleagues were examining the effect of methadone on the QT interval. They were in fact examining why so many heroin users in New York died of apparent overdose but with relatively low levels of morphine at post-mortem examination, proposing arrhythmia in some such cases (from heroin or other street drugs). As they had no way of testing QT effects from heroin, ECG changes were examined in new entrants to treatment at their methadone program (which closed down recently, to the shame of the otherwise venerable Mt Sinai Medical Center in northern Manhattan).
In short, these early researchers performed 12-lead cardiographs on 75 patients new to methadone treatment. About half had not yet started treatment and had used heroin in the previous 24 hours. The rest were already taking methadone and a range of other drugs as shown by urine testing. The first group had prolonged QT intervals in 19% of subjects while the new patients who had started treatment had a rate of 34%. The latter were reportedly using combinations of heroin, cocaine, methadone and other drugs. So their theory was not confirmed yet their findings indicated a possibility that methadone extended the QT interval despite this being asymptomatic in all cases. Further, there were no reports of arrhythmias in MMT patients for the next 29 years.
This leaves us asking why one would spend time and money highlighting, emphasising and investigating the torsade issue while ignoring the vastly more important issue of standards of treatment. Drop-outs, deaths, overdose, viral infection, unemployment, etc, are all well documented consequences of deficient doses, inadequate supervision and a lack of psychosocial supports which are still sadly common. Each of these factors was clearly delineated in Dole’s first report in 1965 - and which modern prescribers ignore to their patients’ eternal cost.
Notes by Andrew Byrne .. Clinic web page: http://methadone-research.blogspot.com/
REFERENCES:
1. 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
2. Reddy S, Fisch M, Bruera E. Oral methadone for cancer pain: no indication of Q-T interval prolongation or torsades de pointes. Journal of Pain and Symptom Management 2004 28;4:301-303
3. Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. American Heart J 1973 86:663-8
4. Hyslop B. Prolongation of the QT interval on methadone: how important is methadone dose? New Zealand Medical Student Journal 2007 6 Aug
5. Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006 101:1333-1338
6. Phibbs B. Advanced ECG: boards and beyond. 2006 Elsevier
7. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy. 2003;23:802-805
8. Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473
9. Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical relevance of QTc interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction 2009 104;6:993-999
10. Perrin-Terrin A, Pathak A, Lapeyre-Mestre M. QT interval prolongation: prevalence, risk factors and pharmacovigilance data among methadone-treated patients in France. Fundam Clin Pharmacol. 2010 Sep 6
11. Dessertenne PF. La tachycardie ventriculaire a deux foyers opposes variables. Arch Mal Coeur 1966 59:263-72
12. Salle P, Rey JL, Bernasconi P, et al. Torsades de pointe. Apropos of 60 cases. Ann Cardiol Angeiol (Paris). Jun 1985;34(6):381-8
13. Bittar P, Piguet V, Kondo-Oestreicher J et al. Methadone induced long QTc and "torsade de pointe". Swiss Medical Forum 2002 S4;P244:36S
Roy A, McCarthy C, Kiernan G, McGorrian C, Keenan E, Mahon N, Sweeney B. Increased incidence of QT interval prolongation in a population receiving lower doses of methadone maintenance therapy. Addiction. 2012 107;6:1132-9
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