“Clinical Advances in the management of opiate dependence”
Friday 11th March & Saturday 12th March, 2011. Intercontinental Hotel, Sydney.
“Suboxone Sublingual Film - the US Experience”
Organised by the Reckitt Benckiser company.
While this conference had been billed initially as an update in opioid pharmacotherapies, there were rumours around that it was actually a product launch. Indeed, the first power-point slide stated: "Suboxone Sublingual Film - the US Experience". Professor Eric Strain’s presentation kicked off the first of two papers on the Friday afternoon after a delightful luncheon in the Café Opera provided by the company. I first heard about a mooted wafer version of buprenorphine numerous years ago and was surprised to find that it is now being approved in Australia.
Drug research guru Eric Strain from Johns Hopkins in Baltimore spoke to an audience of about 80 doctors from around Australia and overseas who were welcomed by meeting chair Dr Sue Ballantyne from Brisbane. Unlike most such national and international meetings, I understand that the entire event, travel, meals, transfers and accommodation were all funded by the manufacturer. Indeed, one had the feeling that this was closer to advertising a new product than a balanced educational session.
Dr Strain said that in response to reports of childhood poisonings, slow dissolution, diversion, (*see stop-press below) and other problems with Suboxone sub-lingual tablets, the film version was developed. There were three main pieces of evidence supporting the ‘film’ (or wafer) … initially there were trials in volunteers of the film with pharmacological data measuring absorption - these were part of the registration process but have not been published. We were shown graphs of detailed blood levels, where the films were substantially better absorbed than the buprenorphine tablets with which they were compared. From the graphs we were shown, the levels in the hours after administration appeared to be consistently 20 - 28% higher in subjects given the films versus tablets. Then we were told of some strangely contradictory clinical research work showing that patients who were transferred to the ‘film’ version noted less effect from the film formulation, despite the higher levels in the parallel studies on non-addict volunteers. This was just one of numerous worrying inconsistencies in the field revealed on the day.
We were told that the combination version with naloxone has been approved in the US for about six months and I recall Dr Strain saying that it has now taken a large market share (50% or more in some areas, if I heard correctly).
The speaker then described his own trial in some detail, including the rationale for performing it, something which is not made clear in the article itself. It examined withdrawal symptom indices during the initiation period in two groups taking (1) pure buprenorphine films and the (2) combination film. Performed in volunteers, it showed no difference, although of course this does not prove that they are equivalent. Dr Strain explained that the need for the trial was the [allegedly unfair and inappropriate] FDA requirement under the long-standing US treatment guidelines that patients should be stabilised on pure buprenorphine and only transferred to the combination product later if appropriate (and never in pregnant or potentially pregnant women). He told the audience that few American doctors actually followed this rule and that the Reckitt company was actively fighting to have the provision removed by the FDA. To my mind the use of pure buprenorphine in new patients is just logical, just as with insulin, warfarin, cortisone or lithium. There may be other commercial implications but these should be secondary to good therapeutics. His study in essence showed what he wanted: that there was no significant difference in induction withdrawals between pure and combination product, something one could have predicted.
[Comment by AB: I can see why the company might be pressing for this sort of research to be done, yet it would seem to be a low priority clinically when there are so many unknowns in the field. It seems odd that an august institution like Johns Hopkins Medical Center would follow commercial considerations to this extent. As just one example, to date there has still been no simple ‘head to head’ comparison of the combination product against pure buprenorphine despite strong but unsubstantiated contentions from some quarters that they are the same. One non-blinded trial showed that stable patients sought 50% higher doses when transferred to the combination product (Bell et al.). The work that Dr Strain discussed at this very conference indicates that absorption is also affected by other constituents. Nor has there been any research to my knowledge on the important matter of patient matching, except by ‘trial and error’ which is hardly scientific.
Equally, there has been no persuasive community evidence produced to suggest that the combination product is any less likely to be abused or diverted than the pure product. Its parallel (pure) product for analgesia was widely abused in New Zealand according to Robinson’s report in D&A Dependence in 1991 (ref below). After nation-wide replacement of pure buprenorphine with the combination version (but with three times as much naloxone per mg) the subjects attending an addiction clinic who used/abused buprenorphine had dropped from 81% to 64%. This is a modest reduction indeed, especially considering the claims by some that naloxone inclusion reduces injecting substantially. At the same time Robinson reported that pharmaceutical morphine use increased from 68% to 86% (and morphine is a much more dangerous drug when used without supervision). Buprenorphine was subsequently withdrawn altogether in New Zealand and not reintroduced for almost 20 years. End of ‘editorial’!]
Dr Strain told the audience that the new formulation came in individual packs which were peeled open to reveal their contents which was a square or rectangle of gel-film which was then inserted by the patient under their tongue. It was hard to remove manually as it quickly merged with the buccal mucosa. Dr Strain went into some detail about why pink/orange was chosen to match the Suboxone tablets (he was surprised to learn from a delegate sitting nearby that in Australia Suboxone is not orange but white). The company may not know that in Australia the drug is often supervised (the only places I know where this does NOT occur by regulation are France and the US). Thus pink/orange may be the most difficult to detect in a patient’s mouth. Also, rather than a peel-pack, an applicator or inserter might be more practical, especially the custodial setting where large numbers of patients need to be given doses in a short space of time. A bright and contrasting colour would seem more sensible … so more effective consultation before introduction might have served the manufacturer and consumers better. This may also explain the fact that the company does not market a formulation smaller than 2mg. Many patients on Subutex are taking reducing (or sometimes increasing) increments of 0.4mg. In my experience most patients who successfully withdraw from the drug nearly always do so from such doses which are well under 2mg daily. It is a mystery to me why the company do not make smaller sized buprenorphine SL tablets available more widely. A sceptical reader might think that the company is more interested in patients remaining on treatment indefinitely!
Apart from reports of diversion (which Dr Strain said “where there’s a will there’s a way” or words to that effect), another part of the development rationale included worrying reports of children and even babies involved in Suboxone toxicity incidents in American emergency rooms. While Dr Strain initially raised this issue, when he was asked for details by an audience member at the end he said that he did not know any more about such events. I note that he writes in his recently published article (page 1) “unintentional exposure to B tablets in children under the age of 6 years has increased from 53 reported exposures in 2004 to 907 in 2008; from 2000 to 2008 there were 1,786 child-hood exposures to B”. This would seem to have answered the delegate’s enquiry to a tee.
Strain claimed that the use of the new “films” would be likely to reduce such occurrences … and one can only hope that he is right. Apparently Suboxone is sold as loose tablets in a bottle in America whereas elsewhere it is supplied in sealed blister packs. Further, the colour and flavour of Suboxone in America could make them much more interesting to young children than Subutex without the orange colouring and citrus flavouring. The pure formulation is indeed disgusting and children who tasted it would be most likely to quickly spit it out. Some Australian observers may think that we are being sold an American solution to an American problem.
We were told that there were about 300,000 taking buprenorphine in America on any one day. The total taking methadone maintenance in America was probably about 200,000 - and by law these were all restricted to registered clinics giving ‘comprehensive treatment’ under close supervision.
In answer to another question Dr Strain said that officially the next step in someone who was doing well on 2mg reductions was to go to second daily. Although second daily dosing can work well for maintenance patients, since reducing-dose patients are usually in withdrawals by the end of 24 hours the prospect of second daily dosing is just inappropriate when there is an option of reduction to 1.6mg. Unofficially, however, he said that the logical thing to do was to cut the tablet or patch in half. He said that Reckitts had said that they could not guarantee that the drug was evenly distributed amongst the dry tablet or the patch … yet Dr Strain said that this was not really tenable when the company seemed happy that the rectangle, cut from a large sheet of spray-dried film, was the same strength as the same sized rectangle next to it. This is another inconsistency of the presentation where the obvious answer was to use 0.4mg tablets which are commonly available in Australia at least.
Dr Strain’s conflict statement was given and I presume is the same as in his recent publication: “Dr Strain is a consultant to and paid member of the Scientific Advisory Board of Reckitt Benckiser Pharmaceuticals. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.”
Refs: Robinson GM, Dukes PD, Robinson BJ, Cooke RR, Mahoney GN. The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand. Drug Alcohol Dependence (1993) 33;1:81-6
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
* Stop press report sent from NDRI: “Eleven charged in "Operation Postage Stamp;" Drugs smuggled into Carbon County Prison under stamps”. http://www.attorneygeneral.gov/press.aspx?id=6035
Comments by Andrew Byrne .. Part II John Mendelson on prescription drug abuse summary.
10 April 2011
9 April 2011
“Prescription Opiate Dependence” - John Mendelson
“Clinical Advances in the management of opiate dependence” (Part II)
Fri 11th March & Sat 12th March, 2011. Intercontinental Hotel, Sydney. Organised by the Reckitt Benckiser company.
[“Suboxone Sublingual Film - the US Experience” Eric Strain Part I]
“Prescription Opiate Dependence”
In the second plenary Professor John Mendelson from San Francisco spoke in detail about the epidemic of abuse of prescribed opioids in the USA. He pointed out the extent of this abuse, depending upon the definition, whereby a huge proportion of the population was involved in America. Most had originally obtained the drug from the family medicine cabinet. Vicodin was the most popular with 200 million prescriptions being issued in the past year. Methadone tablets for pain had increased 10 fold in just seven years. Oxycontin, we were reminded, was so abused now that it almost had the bad name of Heroin (which was also originally a trade name of the Bayer company). When the company recently reformulated their oxycodone product to be more long acting (it had previously been long acting in name only, he said) its popularity dropped proportionately. But we were reminded that the users who no longer chose Oxycontin may well have gone back to street heroin with its major complications of injecting, infections and overdose.
On no less than three occasions Mendelson mentioned the unpleasant and unpalatable possibility that Suboxone could end up being the next maligned drug like Xanax, Rohypnol, Normison capsules, LAAM, ‘Heroin’ and Oxycontin. Each of these has either been banned or else seriously restricted due to concerns, both real and constructed. On the positive side he pointed out that to date reports of misuse of buprenorphine was miniscule when compared with the other opiates (morphine, codeine, hydrocodone, oxycodone, methadone, etc). But like Dr Strain he implied that it was impossible to avoid diversion altogether.
Dr Mendelson stressed that a large proportion of respondents to a large survey had obtained the medication legally from medical sources and many of these were from one single doctor who was treating the patient (and sometimes supplying more than one end-user due to on-selling).
We were reminded that at least with prescribed drugs the patients ‘knew what they were getting’ and the risks were lower. He then did an infomercial for Big Pharma, saying how bad it was the drug companies made so much money out of all this when farmers in Afghanistan or Burma were being put out of business along with all those value-added industries all the way to the (American) consumers. While this was apparently not meant to be ‘tongue-in-cheek’, it did little to address the obvious problem of the chronic shortage of treatment facilities for those who need them most in both the US and Australia. It is not hard to estimate how many drug addicts could be treated for the earnings of the head of Reckitt Benckiser (reported to be thirty six million pounds in 2009 - see Wikipedia). This may place Professor Mendelson’s facetious comments into better perspective. I spoke to him collegially afterwards, pointing out that in our Medically Supervised Injecting Centre, the overdose rate for those injecting pharmaceuticals was a fraction of those using street drugs, nearing zero. Some Americans have trouble coming to terms with harm reduction measures like this (see my comments on subjects at risk below). On this subject, Dr Mendelson mentioned that he was in favour of the use of variable amounts of antagonists to deter and distract injectors as they would not know exactly what they were getting. This is rather contrary to our approach in Australia where the official policy is one of harm reduction.
Like a good lecturer, Mendelson went back to the origins by pointing out that there is nothing new in the world … drunkenness is mentioned in the first chapter of the Bible (Noah goes on a bender after landing the ark on Mount Ararat in Turkey - I am not making this up, you know!). Poppy seeds were found in graves in Mesopotamia where agricultural civilization had begun about seven millennia ago. The name for opium in Latin was Thebacium after Thebes where King Tut was buried and where the poppy was cultivated and its products used and revered. We were reminded that this was also the origin of the name for the alkaloid thebaine from which buprenorphine was originally derived by John Lewis in the 1960s in Bristol, working for Reckitt and Coleman in the quest for an opioid analgesic which did not cause constipation.
We then returned to Michelangelo’s impression of the drunkenness of Noah from the ceiling of the Sistine Chapel. We were then shown two views of a Renaissance architectural corner-piece showing Noah’s pot belly supposedly with veins representing the caput medusae of advanced liver failure. At this point I think he was using some licence with his audience – yet it was a nice cultural/historical foray in an action-packed presentation.
Dr Mendelson dealt with various means of overcoming the diversion problems including addition of antagonists, physical alterations to the product, etc but conceded that where there’s a will there’s a way regarding drug abuse (** see ‘operation postage stamp’ below).
He mentioned the early work of Mary Jeanne Kreek, when she was still a gastroenterologist, giving large doses of naloxone to patients orally to prevent constipation. One new formulation is claiming to do the same, yet another of the ‘me-too’ combination drugs with opiates. Of course mixing opiates with peanut butter will make them less interesting to addicts and one wonders what all this supposedly scientific approach is all about unless it is to do with patents and finance which mere doctors like me would know little about. I was reminded by Dr Robert Graham that when asked about this subject at the Suboxone tablet launch in 2006 the subject of ‘evergreening’ was carefully deflected and only confirmed in direct questioning after the session regarding some ‘exclusive marketing agreement’.
Professor Mendelson has a singular speaking style which leaves little room for oxygen. With a tilt at Cambridge syncopation, his rapid fire delivery is almost alarming as he shoots slide after slide in his compendium of topics to deal with. To start, he performed a spontaneous comedy session as the Apple computer serially froze, flat-lined and rebooted his power point presentation. He showed no hint of nerves despite the uncertainty of the moment.
We heard him initially in answer to the final question to Professor Strain’s talk, pointing out, amongst other things, that the only groups “at risk” for Suboxone injecting were (1) naïve users, (2) those who were in withdrawals and (3) those who were regular buprenorphine recipients. But he did not explain what he meant by “at risk”. I turned to my neighbours and said that they were only “at risk” of having a good time! (He agreed with this when I brought it up in the break).
He had insisted to a concerned questioner whose patients had asked for higher doses that the amount of naloxone absorbed was clinically insignificant and while it may look like there are substantial amounts for 4 to 8 hours after dosing on the graphs shown by Professor Strain, these were measured in picograms per 100ml and could not have had any clinical effect. Others may disagree. Comparative trial have still not been published.
We heard an anecdote about the taste of opiates, all of which are very bitter (hence a “taste” of heroin). However, we were informed that naloxone was the worst which Dr Mendelson once proved by passing it out at a high level meeting including Dr Alan Leishner who was so disgusted that he never gave out another research grant to the San Francisco team (!).
At this point the speaker introduced the famous pie chart of the costs of drug and alcohol abuse. But he pointed out that it had a difference as it was calculated from NEW hospital presentations compared with appendicitis (for instance) which may just occur and cause no more financial burdens beyond the immediate treatment period. On the other hand, most hospitals have about the same number of (new) drug related presentations as appendicitis … but because of the “frequent flyer” nature of dependency patients, the costs to society are vastly greater and were measured to nearly 400 billion dollars in the US alone. He rather seemed to simplify the input of prohibition, forgetting that without it the medical consequences would be very different and almost certainly a fraction of what they are currently. With just a modicum of harm reduction, HIV might be a rarity in his country as it is in Australia, New Zealand and Hong Kong where addicts share needles about as often and the rest of us share tooth brushes (yuck!).
Dr Mendelson went to some trouble to detail the measures which could be taken to reduce the misuse of drugs. He pointed out that ‘fear and fright’ campaigns like the DARE program in America did not work. He said that the effect of education campaigns was unknown. [He failed to mention the work of McBride from Perth and the companion trial in Ireland showed significant benefits in drug/alcohol use from high school education modules.] He would appear to be naturally moved towards pharmaceutical approaches to reduce abuse yet he pointed out many of the failures of this in the past and that it is a constant battle. On the other hand he may have been referring to public media education (and ‘scare’) campaigns which are very hard to prove an effect one way or another, even though they may sound perfectly logical. What is ‘education’ to one may be advertising, indoctrination or lobbying to others.
Pain and addiction treatments, he contended, could be considered one continuum with a grey area in the middle which may be larger than some of us had previously thought. In such a model, features of dependency would invoke additional supervision while stability and progress would permit more liberties with treatment. He did not mention the originators of this approach, Gourlay and Heit (at least that is my understanding) nor their use of the principles of “universal precautions” as adapted for our field. In concluding and looking to the future, he then mentioned something rather worrying to my mind. With digital and phone technology and high sensitivity urine testing some interventions would be possible which could not have been dreamed about before. I hate to think what he was referring to but he did not allow time for any more questions and insisted that we all repair for the dinner arranged at Luna Park’s Crystal Palace dining room. [I repaired elsewhere for a whisky, end-of-week devotions and a sing-along.]
As if a post-script, he said that the Purdue Company (who make Oxycontin I believe) should be sent a huge thank-you card from the Reckitt company. This seemed to be yet more ‘in house’ commercial references which may have gone over the heads of some in the audience.
** “Eleven charged in "Operation Postage Stamp
;" Drugs smuggled into Carbon County Prison under stamps”.
Reckitt’s seminar’s third talk was on Saturday morning: “Hepatitis C and Opiate Dependence” by Prof Paul Haber of Royal Prince Alfred Hospital, Sydney.
Paul Haber spoke about hepatitis C in the opioid pharmacotherapy setting. I arrived late and so cannot comment on the bulk of his presentation. Near to 10am Prof Haber was still discussing the need for regular assessments, treatment and follow-up for such patients. Despite being short of time, he craved the indulgence of the audience to say a few words about acute hepatitis C for which treatment could be very successful, preventing the onset of chronic hepatitis in a high proportion of cases. He also spoke about the seeming quandary regarding the costs of treatments into the future versus doing so at current prices, earlier in the course of the disease.
In question time I brought up the matter of Waizmann’s remarkable outcomes using some variations on the standard anti-viral regimen (ref #). By using double dose ribavirin once daily, supervised dosing and added citalopram ‘cover’ for all patients they reported nearly 100% sustained viral response in what sounds to be an average to difficult treatment group all taking maintenance therapies. The 49 subjects had a mix of genotypes and all but one of them achieved a sustained viral response.
Comments by Andrew Byrne ..
# Waizmann M, Ackermann G. High rates of sustained virological response in hepatitis C virus-infected injection drug users receiving directly observed therapy with peginterferon alpha-2a (40KD) (PEGASYS) and once-daily ribavirin. Journal of Substance Abuse Treatment 2010 38:338-345
Fourth talk Reckitt’s seminar was on “Polysubstance dependence” by Dr Mark Montebello of the Langton Centre in Sydney.
Following Dr Haber we heard psychiatrist Mark Montebello who looks like a tenor but sounds like a bass-baritone. He spoke about his publicity photo for the conference, not having one to hand, and the need to take unusual poses to prevent those self-conscious looks.
Dr Montebello’s erudite speech was on the difficult subject of polysubstance abuse in which he included amphetamine type stimulants, inhalants, cocaine, benzodiazepines and cannabis. For some reason he called the latter ‘marijuana’ (perhaps for the benefit of the American visitors). We were told of the complex nature of categorising these patients, not to mention dealing with the problem clinically.
In question time several doctors announced that they had used various benzodiazepines in reduction and maintenance in opiate patients. Dr Montebello said that he favoured the use of clobazam which could be detected in the urine specifically from most other ‘street’ and prescribed sedatives. One well meaning doctor insisted that alprazolam (Xanax) was his drug of choice for such prescriptions while this raised many eyebrows in others.
Dr Strain said that he had forgotten when he had last prescribed alprazolam (Xanax) for a private psychiatry patient. Nevertheless, he had recently started prescribing ‘longer acting benzodiazepines, especially oxazepam’, to certain pharmacotherapy patients with anxiety symptoms, finding useful outcomes and little abuse.
I raised the issue of benzodiazepine maintenance for a select group who had tried every alternative, utilising more supervision for new and unstable subjects with more liberties for long-term stable folk. Our practice had used the “say no to drugs” philosophy for a decade with little to show for it as about 50% of our patients, like other reports, continued to use benzodiazepines on urine testing. Having started to prescribe diazepam under supervision, we noted anecdotally a high degree of stability with patients largely avoiding alcohol, cocaine, amphetamine and heroin/opiates. We use diazepam doses between 5 and 25mg daily under supervision along with the usual opioid pharmacotherapy, either (pure) buprenorphine or methadone. My final comment was that the use of diazepam in this way had about as much evidence as methadone did in 1990, before the seminal controlled studies of Dr Strain’s group at Johns Hopkins.
I was interested to find that the audience lacked the usual academic, research and ‘admin’ people from our field but mostly clinicians like myself. I met three doctors from Melbourne, several from Queensland and one from WA. There were apparently over 80 attending from all over Australia plus some doctors from Malaysia, Indonesia, Taiwan and South Africa. The Reckitt company budget must be substantial indeed.
Comments by Dr Andrew Byrne ..
Fri 11th March & Sat 12th March, 2011. Intercontinental Hotel, Sydney. Organised by the Reckitt Benckiser company.
[“Suboxone Sublingual Film - the US Experience” Eric Strain Part I]
“Prescription Opiate Dependence”
In the second plenary Professor John Mendelson from San Francisco spoke in detail about the epidemic of abuse of prescribed opioids in the USA. He pointed out the extent of this abuse, depending upon the definition, whereby a huge proportion of the population was involved in America. Most had originally obtained the drug from the family medicine cabinet. Vicodin was the most popular with 200 million prescriptions being issued in the past year. Methadone tablets for pain had increased 10 fold in just seven years. Oxycontin, we were reminded, was so abused now that it almost had the bad name of Heroin (which was also originally a trade name of the Bayer company). When the company recently reformulated their oxycodone product to be more long acting (it had previously been long acting in name only, he said) its popularity dropped proportionately. But we were reminded that the users who no longer chose Oxycontin may well have gone back to street heroin with its major complications of injecting, infections and overdose.
On no less than three occasions Mendelson mentioned the unpleasant and unpalatable possibility that Suboxone could end up being the next maligned drug like Xanax, Rohypnol, Normison capsules, LAAM, ‘Heroin’ and Oxycontin. Each of these has either been banned or else seriously restricted due to concerns, both real and constructed. On the positive side he pointed out that to date reports of misuse of buprenorphine was miniscule when compared with the other opiates (morphine, codeine, hydrocodone, oxycodone, methadone, etc). But like Dr Strain he implied that it was impossible to avoid diversion altogether.
Dr Mendelson stressed that a large proportion of respondents to a large survey had obtained the medication legally from medical sources and many of these were from one single doctor who was treating the patient (and sometimes supplying more than one end-user due to on-selling).
We were reminded that at least with prescribed drugs the patients ‘knew what they were getting’ and the risks were lower. He then did an infomercial for Big Pharma, saying how bad it was the drug companies made so much money out of all this when farmers in Afghanistan or Burma were being put out of business along with all those value-added industries all the way to the (American) consumers. While this was apparently not meant to be ‘tongue-in-cheek’, it did little to address the obvious problem of the chronic shortage of treatment facilities for those who need them most in both the US and Australia. It is not hard to estimate how many drug addicts could be treated for the earnings of the head of Reckitt Benckiser (reported to be thirty six million pounds in 2009 - see Wikipedia). This may place Professor Mendelson’s facetious comments into better perspective. I spoke to him collegially afterwards, pointing out that in our Medically Supervised Injecting Centre, the overdose rate for those injecting pharmaceuticals was a fraction of those using street drugs, nearing zero. Some Americans have trouble coming to terms with harm reduction measures like this (see my comments on subjects at risk below). On this subject, Dr Mendelson mentioned that he was in favour of the use of variable amounts of antagonists to deter and distract injectors as they would not know exactly what they were getting. This is rather contrary to our approach in Australia where the official policy is one of harm reduction.
Like a good lecturer, Mendelson went back to the origins by pointing out that there is nothing new in the world … drunkenness is mentioned in the first chapter of the Bible (Noah goes on a bender after landing the ark on Mount Ararat in Turkey - I am not making this up, you know!). Poppy seeds were found in graves in Mesopotamia where agricultural civilization had begun about seven millennia ago. The name for opium in Latin was Thebacium after Thebes where King Tut was buried and where the poppy was cultivated and its products used and revered. We were reminded that this was also the origin of the name for the alkaloid thebaine from which buprenorphine was originally derived by John Lewis in the 1960s in Bristol, working for Reckitt and Coleman in the quest for an opioid analgesic which did not cause constipation.
We then returned to Michelangelo’s impression of the drunkenness of Noah from the ceiling of the Sistine Chapel. We were then shown two views of a Renaissance architectural corner-piece showing Noah’s pot belly supposedly with veins representing the caput medusae of advanced liver failure. At this point I think he was using some licence with his audience – yet it was a nice cultural/historical foray in an action-packed presentation.
Dr Mendelson dealt with various means of overcoming the diversion problems including addition of antagonists, physical alterations to the product, etc but conceded that where there’s a will there’s a way regarding drug abuse (** see ‘operation postage stamp’ below).
He mentioned the early work of Mary Jeanne Kreek, when she was still a gastroenterologist, giving large doses of naloxone to patients orally to prevent constipation. One new formulation is claiming to do the same, yet another of the ‘me-too’ combination drugs with opiates. Of course mixing opiates with peanut butter will make them less interesting to addicts and one wonders what all this supposedly scientific approach is all about unless it is to do with patents and finance which mere doctors like me would know little about. I was reminded by Dr Robert Graham that when asked about this subject at the Suboxone tablet launch in 2006 the subject of ‘evergreening’ was carefully deflected and only confirmed in direct questioning after the session regarding some ‘exclusive marketing agreement’.
Professor Mendelson has a singular speaking style which leaves little room for oxygen. With a tilt at Cambridge syncopation, his rapid fire delivery is almost alarming as he shoots slide after slide in his compendium of topics to deal with. To start, he performed a spontaneous comedy session as the Apple computer serially froze, flat-lined and rebooted his power point presentation. He showed no hint of nerves despite the uncertainty of the moment.
We heard him initially in answer to the final question to Professor Strain’s talk, pointing out, amongst other things, that the only groups “at risk” for Suboxone injecting were (1) naïve users, (2) those who were in withdrawals and (3) those who were regular buprenorphine recipients. But he did not explain what he meant by “at risk”. I turned to my neighbours and said that they were only “at risk” of having a good time! (He agreed with this when I brought it up in the break).
He had insisted to a concerned questioner whose patients had asked for higher doses that the amount of naloxone absorbed was clinically insignificant and while it may look like there are substantial amounts for 4 to 8 hours after dosing on the graphs shown by Professor Strain, these were measured in picograms per 100ml and could not have had any clinical effect. Others may disagree. Comparative trial have still not been published.
We heard an anecdote about the taste of opiates, all of which are very bitter (hence a “taste” of heroin). However, we were informed that naloxone was the worst which Dr Mendelson once proved by passing it out at a high level meeting including Dr Alan Leishner who was so disgusted that he never gave out another research grant to the San Francisco team (!).
At this point the speaker introduced the famous pie chart of the costs of drug and alcohol abuse. But he pointed out that it had a difference as it was calculated from NEW hospital presentations compared with appendicitis (for instance) which may just occur and cause no more financial burdens beyond the immediate treatment period. On the other hand, most hospitals have about the same number of (new) drug related presentations as appendicitis … but because of the “frequent flyer” nature of dependency patients, the costs to society are vastly greater and were measured to nearly 400 billion dollars in the US alone. He rather seemed to simplify the input of prohibition, forgetting that without it the medical consequences would be very different and almost certainly a fraction of what they are currently. With just a modicum of harm reduction, HIV might be a rarity in his country as it is in Australia, New Zealand and Hong Kong where addicts share needles about as often and the rest of us share tooth brushes (yuck!).
Dr Mendelson went to some trouble to detail the measures which could be taken to reduce the misuse of drugs. He pointed out that ‘fear and fright’ campaigns like the DARE program in America did not work. He said that the effect of education campaigns was unknown. [He failed to mention the work of McBride from Perth and the companion trial in Ireland showed significant benefits in drug/alcohol use from high school education modules.] He would appear to be naturally moved towards pharmaceutical approaches to reduce abuse yet he pointed out many of the failures of this in the past and that it is a constant battle. On the other hand he may have been referring to public media education (and ‘scare’) campaigns which are very hard to prove an effect one way or another, even though they may sound perfectly logical. What is ‘education’ to one may be advertising, indoctrination or lobbying to others.
Pain and addiction treatments, he contended, could be considered one continuum with a grey area in the middle which may be larger than some of us had previously thought. In such a model, features of dependency would invoke additional supervision while stability and progress would permit more liberties with treatment. He did not mention the originators of this approach, Gourlay and Heit (at least that is my understanding) nor their use of the principles of “universal precautions” as adapted for our field. In concluding and looking to the future, he then mentioned something rather worrying to my mind. With digital and phone technology and high sensitivity urine testing some interventions would be possible which could not have been dreamed about before. I hate to think what he was referring to but he did not allow time for any more questions and insisted that we all repair for the dinner arranged at Luna Park’s Crystal Palace dining room. [I repaired elsewhere for a whisky, end-of-week devotions and a sing-along.]
As if a post-script, he said that the Purdue Company (who make Oxycontin I believe) should be sent a huge thank-you card from the Reckitt company. This seemed to be yet more ‘in house’ commercial references which may have gone over the heads of some in the audience.
** “Eleven charged in "Operation Postage Stamp
;" Drugs smuggled into Carbon County Prison under stamps”.
Reckitt’s seminar’s third talk was on Saturday morning: “Hepatitis C and Opiate Dependence” by Prof Paul Haber of Royal Prince Alfred Hospital, Sydney.
Paul Haber spoke about hepatitis C in the opioid pharmacotherapy setting. I arrived late and so cannot comment on the bulk of his presentation. Near to 10am Prof Haber was still discussing the need for regular assessments, treatment and follow-up for such patients. Despite being short of time, he craved the indulgence of the audience to say a few words about acute hepatitis C for which treatment could be very successful, preventing the onset of chronic hepatitis in a high proportion of cases. He also spoke about the seeming quandary regarding the costs of treatments into the future versus doing so at current prices, earlier in the course of the disease.
In question time I brought up the matter of Waizmann’s remarkable outcomes using some variations on the standard anti-viral regimen (ref #). By using double dose ribavirin once daily, supervised dosing and added citalopram ‘cover’ for all patients they reported nearly 100% sustained viral response in what sounds to be an average to difficult treatment group all taking maintenance therapies. The 49 subjects had a mix of genotypes and all but one of them achieved a sustained viral response.
Comments by Andrew Byrne ..
# Waizmann M, Ackermann G. High rates of sustained virological response in hepatitis C virus-infected injection drug users receiving directly observed therapy with peginterferon alpha-2a (40KD) (PEGASYS) and once-daily ribavirin. Journal of Substance Abuse Treatment 2010 38:338-345
Fourth talk Reckitt’s seminar was on “Polysubstance dependence” by Dr Mark Montebello of the Langton Centre in Sydney.
Following Dr Haber we heard psychiatrist Mark Montebello who looks like a tenor but sounds like a bass-baritone. He spoke about his publicity photo for the conference, not having one to hand, and the need to take unusual poses to prevent those self-conscious looks.
Dr Montebello’s erudite speech was on the difficult subject of polysubstance abuse in which he included amphetamine type stimulants, inhalants, cocaine, benzodiazepines and cannabis. For some reason he called the latter ‘marijuana’ (perhaps for the benefit of the American visitors). We were told of the complex nature of categorising these patients, not to mention dealing with the problem clinically.
In question time several doctors announced that they had used various benzodiazepines in reduction and maintenance in opiate patients. Dr Montebello said that he favoured the use of clobazam which could be detected in the urine specifically from most other ‘street’ and prescribed sedatives. One well meaning doctor insisted that alprazolam (Xanax) was his drug of choice for such prescriptions while this raised many eyebrows in others.
Dr Strain said that he had forgotten when he had last prescribed alprazolam (Xanax) for a private psychiatry patient. Nevertheless, he had recently started prescribing ‘longer acting benzodiazepines, especially oxazepam’, to certain pharmacotherapy patients with anxiety symptoms, finding useful outcomes and little abuse.
I raised the issue of benzodiazepine maintenance for a select group who had tried every alternative, utilising more supervision for new and unstable subjects with more liberties for long-term stable folk. Our practice had used the “say no to drugs” philosophy for a decade with little to show for it as about 50% of our patients, like other reports, continued to use benzodiazepines on urine testing. Having started to prescribe diazepam under supervision, we noted anecdotally a high degree of stability with patients largely avoiding alcohol, cocaine, amphetamine and heroin/opiates. We use diazepam doses between 5 and 25mg daily under supervision along with the usual opioid pharmacotherapy, either (pure) buprenorphine or methadone. My final comment was that the use of diazepam in this way had about as much evidence as methadone did in 1990, before the seminal controlled studies of Dr Strain’s group at Johns Hopkins.
I was interested to find that the audience lacked the usual academic, research and ‘admin’ people from our field but mostly clinicians like myself. I met three doctors from Melbourne, several from Queensland and one from WA. There were apparently over 80 attending from all over Australia plus some doctors from Malaysia, Indonesia, Taiwan and South Africa. The Reckitt company budget must be substantial indeed.
Comments by Dr Andrew Byrne ..
8 April 2011
'MOTHER' study was really looking at babies, not mothers.
“Treatment for Pregnant Opioid Abuse Dependent Women”
Karol Kaltenbach, PhD
Clinical Associate Professor, Thomas Jefferson University, Jefferson Medical College
“Live at St Lukes”. Psychiatry Grand Rounds Wednesday 23rd March 2011.
This presentation was a well constructed description of the MOTHER study in a context somewhat removed from the science in my view.
Dr Kaltenbach began by saying that "Families I speak to are all real worried about babies withdrawing from drugs when they are born to mothers on methadone". She said that this was the main purpose of their study: to examine paediatric outcomes from pregnancies randomised to methadone or buprenorphine. We were reminded how little formal research has been done on opiate addicted mothers and their offspring even though tens of thousands of cases have been treated in the case of methadone which is considered the ‘gold standard’. While technically neither drug is approved in pregnancy, methadone treatment is considered a priority option for opioid dependent pregnant women in most health systems (and waiting lists are often dispensed with). Further, and reassuringly, to date several hundred babies have been reported born to mothers on buprenorphine. So the best ‘research’ has actually been field experience with this matter as well as scores of observational reports from Finnegan, Kandell and others. There have been no consistent problems reported from either group apart from the occurrence of neonatal abstinence syndrome (NAS). It is my belief that such concerns over NAS can be addressed by reassurance that existing treatments are satisfactory but may delay baby’s discharge by a few days in some cases.
To her credit Dr Kaltenbach stressed at the outset that from their findings and others’, NAS is no more or less likely with either drug, about half the babies exhibiting symptoms in both groups. We were then given an overview of the trial, initial 1074 screened candidates from seven sites (US, Canada, Austria) , 175 randomised to methadone (89) or buprenorphine (86) on double blind, double dummy bases and with 58 buprenorphine and 73 methadone subjects completing the study. We were briefly shown data supporting no substantive differences between the groups in the usual relevant demographic details including drug use (those dependent on sedatives or alcohol had been excluded at initial assessment). Then we saw numerous tables of primary outcomes and secondary outcomes of the study (all fetal results, including mostly non-significant differences - eg. NAS score, birth weight, head circumference, gestational age, etc). It was emphasised by the speaker that three fetal characteristics were significantly better in the buprenorphine group. These were (1) total amount of morphine used (2) infant’s hospital stay and (3) duration of NAS (I noted that these are all derivatives of the same thing, viz: the severity of NAS as perceived by the treating doctors). My feeling is that it is an overstatement to say that these are three (separate) beneficial findings.
To my mind this trial, for the first time, proved that methadone is the drug of choice for opioid dependency in pregnancy … it also showed that the 58 mothers who finally had a baby on buprenorphine (almost 1000 original applicants didn't) had babies with slightly less protracted and/or severe withdrawal syndromes. And this is no surprise since buprenorphine is the weaker agonist drug and thus mothers with more severe dependencies may be more likely to have dropped out. While the authors provided some comparative evidence against this, on the other hand it would appear to be supported by their finding that ten times as many of the buprenorphine drop-outs stated that they were 'dissatisfied with the medication' (20 versus 2 in the methadone drop-outs).
Dr Kaltenbach did emphasise the health care budget and the issue of hospital stays for treatment of NAS. More important than concerns over NAS in my experience is that most expectant parents want to know: 'will our baby grow up healthy?' NAS can be managed relatively simply and its occurrence is not known to be associated with any negative long term outcomes (Finnegan, personal communication). Most important are the proven negative outcomes known for pregnancies of opioid dependent women who are denied adequate treatment. The costs of such complications to the health system, insurance companies, managed care organisations and society generally are substantial and would be vastly more than even the most comprehensive opioid dependency treatment program.
Despite the modest benefits to the offspring and disastrous consequences to the retention rates, we were told that the researchers believed that their data supported a conclusion that buprenorphine is now a ‘first line option’ in pregnancy. Their institution’s press office went further, stating that that buprenorphine is ‘superior to methadone’ in pregnancy, something which I believe is patently untrue and highly misleading.
If indeed this trial were intended to fairly determine outcomes of the respective drugs then the analysis should have included the patients who ‘failed to comply with the protocols’ and were discharged from treatment. In my clinical experience involuntary 'discharges' are exceedingly rare and in most cases would be involuntary ‘transfers’ so treatment would not be curtailed under any circumstances against the wishes of the patient.
My impression from this presentation was that one of the main goals of this study was to support buprenorphine treatment in the community in America where methadone is often not available. Indeed the very title MOTHER would seem to indicate that fetal outcomes were secondary rather than primary. This is intriguing since buprenorphine is already being used widely in pregnancy with excellent results in those women who can tolerate it. In fact the main conclusion from this study is that both drugs are needed for such women since neither has sufficiently high retention rates. As Dr Kaltenbach implied early in her talk, such research during pregnancy has serious ethical limitations (and my feeling is that without a safety net this trial was in the same category).
A doctor in England tried to do a trial of this nature in non-pregnant patients and over a two year period in their busy treatment clinic she reported that she could not recruit one single patient to randomise (Pinto). It is of concern that in the ‘MOTHER’ study that subjects stood to earn up to $5800 in incentives for compliance and so this may explain why they were able to recruit the women, many of whom had been in stable methadone treatment at the time of joining the study (although this detail was not given in the paper or presentation but in a parallel publication by the group). Thus approximately half such stable patients had their prescribed medication altered during the trial. Such an incentive for a pregnant woman in stable treatment seems to me to be unfair and unbalanced. That such women consented to altered treatment is little justification or consolation for the excess number who dropped out of treatment in my view. Dr Kaltenbach implied that the incentives were used as a ‘normal’ part of high quality treatment, ensuring that there would be no criticism that the women were denied state-of-the-art medical attention. I have never heard of incentives of this degree being used or recommended as “contingency” management (the ‘rewards’ for ‘good behaviour’ are usually modest compared to these sums and sometimes the equivalent of bubble gum or lottery tickets). It appears inescapable, however, that this trial could not have gone ahead without some such strong incentives.
Another detail was that daily attendance, including weekends is an onerous task, especially during pregnancy and is hardly consistent with high quality treatment claimed by the researchers. Yet this is just one more deficiency in a very troublesome trial protocol.
At her talk Dr Kaltenbach seemed uncertain of the Canadian site situation (which ended up providing no subjects at all for the trial, rather like Dr Pinto in England). Initially she said that the patients had the opportunity to get pharmacy pick-ups and daily attendance was no longer acceptable to them. Later in response to my comments she said that there were problems getting the Subutex, Suboxone and placebos to the hospital in Canada.
Dr Kaltenbach stated that the researchers originally wanted to recruit 350 candidates but since the numbers were only about half that they changed their alpha significance level to 0.03 … something I confess I find bizarre and unconvincing. In my view a difference in outcomes is either significant or it isn’t using traditional p values for group comparisons. Even just looking at the raw figures on drop-outs I believe most concerned parties would be able to decide which group they would liked their family member or patient to be in.
Dr Kaltenbach described the excess drop-outs in the buprenorphine group as ‘pretty dramatic’. Yet there is a claim in the paper that this difference is not significantly different! We then had some speculation about the reasons behind the poor buprenorphine results, including inadequate induction doses or inadequate withdrawals before starting (and I wonder if it is ethical to induce withdrawals in pregnant women at all). The reader should note that this trial used pure buprenorphine (Subutex) which is the agent used in nearly all the quality research while the combination drug (Suboxone) has still not been subjected to much if any comparative research to my reading.
While Dr Kaltenbach said that there was no reason to do so, it seemed traditional nowadays to put up a disclosure notice. She said that there were no declarations of interest as she did no consultancies for drug companies.
Comments by Andrew Byrne ..
Karol Kaltenbach, PhD
Clinical Associate Professor, Thomas Jefferson University, Jefferson Medical College
“Live at St Lukes”. Psychiatry Grand Rounds Wednesday 23rd March 2011.
This presentation was a well constructed description of the MOTHER study in a context somewhat removed from the science in my view.
Dr Kaltenbach began by saying that "Families I speak to are all real worried about babies withdrawing from drugs when they are born to mothers on methadone". She said that this was the main purpose of their study: to examine paediatric outcomes from pregnancies randomised to methadone or buprenorphine. We were reminded how little formal research has been done on opiate addicted mothers and their offspring even though tens of thousands of cases have been treated in the case of methadone which is considered the ‘gold standard’. While technically neither drug is approved in pregnancy, methadone treatment is considered a priority option for opioid dependent pregnant women in most health systems (and waiting lists are often dispensed with). Further, and reassuringly, to date several hundred babies have been reported born to mothers on buprenorphine. So the best ‘research’ has actually been field experience with this matter as well as scores of observational reports from Finnegan, Kandell and others. There have been no consistent problems reported from either group apart from the occurrence of neonatal abstinence syndrome (NAS). It is my belief that such concerns over NAS can be addressed by reassurance that existing treatments are satisfactory but may delay baby’s discharge by a few days in some cases.
To her credit Dr Kaltenbach stressed at the outset that from their findings and others’, NAS is no more or less likely with either drug, about half the babies exhibiting symptoms in both groups. We were then given an overview of the trial, initial 1074 screened candidates from seven sites (US, Canada, Austria) , 175 randomised to methadone (89) or buprenorphine (86) on double blind, double dummy bases and with 58 buprenorphine and 73 methadone subjects completing the study. We were briefly shown data supporting no substantive differences between the groups in the usual relevant demographic details including drug use (those dependent on sedatives or alcohol had been excluded at initial assessment). Then we saw numerous tables of primary outcomes and secondary outcomes of the study (all fetal results, including mostly non-significant differences - eg. NAS score, birth weight, head circumference, gestational age, etc). It was emphasised by the speaker that three fetal characteristics were significantly better in the buprenorphine group. These were (1) total amount of morphine used (2) infant’s hospital stay and (3) duration of NAS (I noted that these are all derivatives of the same thing, viz: the severity of NAS as perceived by the treating doctors). My feeling is that it is an overstatement to say that these are three (separate) beneficial findings.
To my mind this trial, for the first time, proved that methadone is the drug of choice for opioid dependency in pregnancy … it also showed that the 58 mothers who finally had a baby on buprenorphine (almost 1000 original applicants didn't) had babies with slightly less protracted and/or severe withdrawal syndromes. And this is no surprise since buprenorphine is the weaker agonist drug and thus mothers with more severe dependencies may be more likely to have dropped out. While the authors provided some comparative evidence against this, on the other hand it would appear to be supported by their finding that ten times as many of the buprenorphine drop-outs stated that they were 'dissatisfied with the medication' (20 versus 2 in the methadone drop-outs).
Dr Kaltenbach did emphasise the health care budget and the issue of hospital stays for treatment of NAS. More important than concerns over NAS in my experience is that most expectant parents want to know: 'will our baby grow up healthy?' NAS can be managed relatively simply and its occurrence is not known to be associated with any negative long term outcomes (Finnegan, personal communication). Most important are the proven negative outcomes known for pregnancies of opioid dependent women who are denied adequate treatment. The costs of such complications to the health system, insurance companies, managed care organisations and society generally are substantial and would be vastly more than even the most comprehensive opioid dependency treatment program.
Despite the modest benefits to the offspring and disastrous consequences to the retention rates, we were told that the researchers believed that their data supported a conclusion that buprenorphine is now a ‘first line option’ in pregnancy. Their institution’s press office went further, stating that that buprenorphine is ‘superior to methadone’ in pregnancy, something which I believe is patently untrue and highly misleading.
If indeed this trial were intended to fairly determine outcomes of the respective drugs then the analysis should have included the patients who ‘failed to comply with the protocols’ and were discharged from treatment. In my clinical experience involuntary 'discharges' are exceedingly rare and in most cases would be involuntary ‘transfers’ so treatment would not be curtailed under any circumstances against the wishes of the patient.
My impression from this presentation was that one of the main goals of this study was to support buprenorphine treatment in the community in America where methadone is often not available. Indeed the very title MOTHER would seem to indicate that fetal outcomes were secondary rather than primary. This is intriguing since buprenorphine is already being used widely in pregnancy with excellent results in those women who can tolerate it. In fact the main conclusion from this study is that both drugs are needed for such women since neither has sufficiently high retention rates. As Dr Kaltenbach implied early in her talk, such research during pregnancy has serious ethical limitations (and my feeling is that without a safety net this trial was in the same category).
A doctor in England tried to do a trial of this nature in non-pregnant patients and over a two year period in their busy treatment clinic she reported that she could not recruit one single patient to randomise (Pinto). It is of concern that in the ‘MOTHER’ study that subjects stood to earn up to $5800 in incentives for compliance and so this may explain why they were able to recruit the women, many of whom had been in stable methadone treatment at the time of joining the study (although this detail was not given in the paper or presentation but in a parallel publication by the group). Thus approximately half such stable patients had their prescribed medication altered during the trial. Such an incentive for a pregnant woman in stable treatment seems to me to be unfair and unbalanced. That such women consented to altered treatment is little justification or consolation for the excess number who dropped out of treatment in my view. Dr Kaltenbach implied that the incentives were used as a ‘normal’ part of high quality treatment, ensuring that there would be no criticism that the women were denied state-of-the-art medical attention. I have never heard of incentives of this degree being used or recommended as “contingency” management (the ‘rewards’ for ‘good behaviour’ are usually modest compared to these sums and sometimes the equivalent of bubble gum or lottery tickets). It appears inescapable, however, that this trial could not have gone ahead without some such strong incentives.
Another detail was that daily attendance, including weekends is an onerous task, especially during pregnancy and is hardly consistent with high quality treatment claimed by the researchers. Yet this is just one more deficiency in a very troublesome trial protocol.
At her talk Dr Kaltenbach seemed uncertain of the Canadian site situation (which ended up providing no subjects at all for the trial, rather like Dr Pinto in England). Initially she said that the patients had the opportunity to get pharmacy pick-ups and daily attendance was no longer acceptable to them. Later in response to my comments she said that there were problems getting the Subutex, Suboxone and placebos to the hospital in Canada.
Dr Kaltenbach stated that the researchers originally wanted to recruit 350 candidates but since the numbers were only about half that they changed their alpha significance level to 0.03 … something I confess I find bizarre and unconvincing. In my view a difference in outcomes is either significant or it isn’t using traditional p values for group comparisons. Even just looking at the raw figures on drop-outs I believe most concerned parties would be able to decide which group they would liked their family member or patient to be in.
Dr Kaltenbach described the excess drop-outs in the buprenorphine group as ‘pretty dramatic’. Yet there is a claim in the paper that this difference is not significantly different! We then had some speculation about the reasons behind the poor buprenorphine results, including inadequate induction doses or inadequate withdrawals before starting (and I wonder if it is ethical to induce withdrawals in pregnant women at all). The reader should note that this trial used pure buprenorphine (Subutex) which is the agent used in nearly all the quality research while the combination drug (Suboxone) has still not been subjected to much if any comparative research to my reading.
While Dr Kaltenbach said that there was no reason to do so, it seemed traditional nowadays to put up a disclosure notice. She said that there were no declarations of interest as she did no consultancies for drug companies.
Comments by Andrew Byrne ..
6 April 2011
Letter from New York ...
Dear Colleagues,
I have had the privilege of spending time in Manhattan meeting up with colleagues, mostly of like minds, on issues of mutual interest.
At the same time, Americans are often also interested in the drug situation in Australia including related viral diseases, public health and the various studies being reported. Of course I was most interested in innovations here in America, including the buprenorphine film/wafer which has been mooted by the manufacturer for quite some years to overcome some of the problems with their SL tablets. See http://www.attorneygeneral.gov/press.aspx?id=6035 It is about ten dollars cheaper than the tablets according to a pharmacist I interviewed here which may account for its popularity currently. It also has some disadvantages it would appear.
Other highlights: ‘MOTHER’ study presentation: http://methadone-research.blogspot.com/2011/04/mother-study-was-really-looking-babies.html This issue became a front page New York Times item last Sunday (links on request).
I visited the Drug Policy Alliance where there is a team of dedicated workers intent on improving harm reduction services in the United States and beyond. They are always keen to hear of progress in Australia, needle programs, injecting facilities, etcetera. Several of their workers have been to the Beirut Harm Reduction Conference earlier this month where they met up with numerous Australians.
Across the road in West 36th Street I met up with Lynn Paltrow at the National Advocates for Pregnant Women. We heard of tragic cases of ignorance in certain states where women on methadone were charged with ‘supplying a drug to a minor’ and being separated from their children as a result. While we all appreciate the great advances undertaken in the United States but it is also clear that there is a Neanderthal side to their approach to drugs and drug use (see warnings on every bottle of alcohol sold in the US but note there is no alcohol percentage noted, even on Fosters!). Their system just seems rigid and less flexible than in other places like Australia.
Grand Rounds at Bellevue Hospital had an interesting presentation on the use of peer mentors for alcohol and drug affected patients. Dr Kathlene Tracy had done two studies, one in the Veterans Administration and one at NYU, looking at attendances for appointments before and after engagement of a mentor (who had been carefully chosen and vetted as being at least 6 months ‘clean’. This ‘buddy’ engagement improved compliance substantially at very modest cost and deserves closer examination, especially for severely disrupted patients with no homes, telephones or other means of support. The staff members at Bellevue were most obliging and invited me to lunch where we had on-going discussions led by Dr Marc Galanter who is their senior D&A specialist.
I give Journal Club at Rockefeller University (Kreek Labs) on Tuesday before returning home for Easter and my father’s birthday on Lord Howe Island (he is 84!).
There is a meeting with the newly formed users’ group here which is lobbying for better access to treatment for hepatitis C. At present the only ‘mandated’ intervention is an antibody test at entry to methadone treatment. For buprenorphine even that can be overlooked.
Best wishes from Manhattan.
Andrew Byrne ..
I have had the privilege of spending time in Manhattan meeting up with colleagues, mostly of like minds, on issues of mutual interest.
At the same time, Americans are often also interested in the drug situation in Australia including related viral diseases, public health and the various studies being reported. Of course I was most interested in innovations here in America, including the buprenorphine film/wafer which has been mooted by the manufacturer for quite some years to overcome some of the problems with their SL tablets. See http://www.attorneygeneral.gov/press.aspx?id=6035 It is about ten dollars cheaper than the tablets according to a pharmacist I interviewed here which may account for its popularity currently. It also has some disadvantages it would appear.
Other highlights: ‘MOTHER’ study presentation: http://methadone-research.blogspot.com/2011/04/mother-study-was-really-looking-babies.html This issue became a front page New York Times item last Sunday (links on request).
I visited the Drug Policy Alliance where there is a team of dedicated workers intent on improving harm reduction services in the United States and beyond. They are always keen to hear of progress in Australia, needle programs, injecting facilities, etcetera. Several of their workers have been to the Beirut Harm Reduction Conference earlier this month where they met up with numerous Australians.
Across the road in West 36th Street I met up with Lynn Paltrow at the National Advocates for Pregnant Women. We heard of tragic cases of ignorance in certain states where women on methadone were charged with ‘supplying a drug to a minor’ and being separated from their children as a result. While we all appreciate the great advances undertaken in the United States but it is also clear that there is a Neanderthal side to their approach to drugs and drug use (see warnings on every bottle of alcohol sold in the US but note there is no alcohol percentage noted, even on Fosters!). Their system just seems rigid and less flexible than in other places like Australia.
Grand Rounds at Bellevue Hospital had an interesting presentation on the use of peer mentors for alcohol and drug affected patients. Dr Kathlene Tracy had done two studies, one in the Veterans Administration and one at NYU, looking at attendances for appointments before and after engagement of a mentor (who had been carefully chosen and vetted as being at least 6 months ‘clean’. This ‘buddy’ engagement improved compliance substantially at very modest cost and deserves closer examination, especially for severely disrupted patients with no homes, telephones or other means of support. The staff members at Bellevue were most obliging and invited me to lunch where we had on-going discussions led by Dr Marc Galanter who is their senior D&A specialist.
I give Journal Club at Rockefeller University (Kreek Labs) on Tuesday before returning home for Easter and my father’s birthday on Lord Howe Island (he is 84!).
There is a meeting with the newly formed users’ group here which is lobbying for better access to treatment for hepatitis C. At present the only ‘mandated’ intervention is an antibody test at entry to methadone treatment. For buprenorphine even that can be overlooked.
Best wishes from Manhattan.
Andrew Byrne ..
11 March 2011
A FEW RECENT JOURNAL ITEMS WHICH MAY INTEREST YOU.
Adding quetiapine (Seroquel) to naltrexone makes no difference to alcohol abstinence rates 61-72% at 4 months (Guardia et al in Barcelona).
No effect demonstrated in a good quality RCT of acamprosate for cocaine dependence (Kampman, O'Brien et al, Philadelphia).
Simojoki, Linzteris and Finland patients: “.. crushing of Subutex tablets does not significantly alter serum .. levels or the drug’s clinical effect ..”. They say crushing has no effect on dissolution time, contrary to our own experience (some chemists, cooks or clients may also disagree).
Cunningham et al compare buprenorphine induction at home with standard daily clinic initiation, finding some advantages in the home strategy … and few problems. This may be just what we need to reduce early treatment drop-outs for this otherwise excellent drug.
Extensive interviews with over 1000 pharmacotherapy patients show bimodal distribution for many aspects of dependency, indicating two categories of patients which are clinically distinct, justifying the DSM categories or levels of opioid dependence.
Strain et al compare cravings at induction of pure buprenorphine films (non-registered) versus buprenorphine/naloxone soluble-films (sometimes called wafers). It is disappointing that only the latter is being marketed because it is contraindicated in pregnancy yet women with young children are a target for measures against diversion and misuse which are claimed benefits of this formulation.
Pharmacist McNamara and colleagues select patients prescribed methadone for pain treatment and then report a (spurious) association with QT prolongation! Their paper has some interesting information but is no scientific treatise. One ‘high risk’ patient is on 5mg daily! One out of 7 patients died - not of torsade de pointes - but of ‘toxic shock’. Like most such papers, there are no cases of torsade. Nearly all (male) patients had QTc > 430ms BEFORE taking methadone(!). This is similar to Reddy’s paper from the Anderson Cancer Center.
The Iguana column in Addiction has rarely been a high point of scientific publication but this month makes no sense at all, at least to this antipodean reader. p685 [Full citations below]
Dear Colleagues,
These items are sent for your interest. I have not read them all fully but it is nice to see that our research colleagues are still working on basic efficacy trials using various combinations and comparisons. Some of these ‘stand up’ (like the superiority of methadone in pregnancy) while others reverse initial encouragement, such as the use of acamprosate for cocaine cravings. Both positive and negative findings are important to clinicians. The possibility of giving one or two initial doses of buprenorphine to candidates to take away and consume WHEN THEY ARE IN WITHDRAWAL may be a safe and beneficial innovation (Cunningham; Lee).
The first three items are high quality scientific comparisons (RCTs) while the last two items are here despite their poverty of content and rigour.
I hope they are of interest to readers.
Andrew Byrne ..
References:
Guardia J, Roncero C, Galan, J, Gonzalvo B, Burguete T, Casas M. A double-blind, placebo-controlled, randomized pilot study comparing quetiapine with placebo, associated to naltrexone, in the treatment of alcohol-dependent patients. Addictive Behaviors 2011 36;3:265-269
Kampman KM, Dackis C, Pettinati HM, Lynch KG, Sparkman T, O'Brien CP. A double-blind, placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence. Addictive Behaviors 2011 36;3:217-221
Simojoki K, Lillsunde P, Linzteris N, Alho H. Bioavailability of buprenorphine from crushed and whole buprenorphine (Subutex) tablets. Euro Addiction Res 2010 16;2:85-90
Cunningham CO, Giovanniello A, Li X, Kunins HV, Roose RJ, Sohler NL. A comparison of buprenorphine induction strategies: Patient-centered home-based inductions versus standard-of-care office-based inductions. Journal of Substance Abuse Treatment 2011
Lee JD, Grossman E, DiRocco D, Gourevitch MN. Home buprenorphine/naloxone induction in primary care. Journal of General Internal Medicine 2009 24:226-232
Shand FL, Slade T, Degenhardt L, Baillie A, Nelson EC. Opioid dependence latent structure: two classes with differing severity? Addiction 2011 106:590-598 http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03217.x/abstract
Strain EC, Harrison JA, Bigelow GE. Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films. Clinical Pharmacology and Therapeutics 26th Jan 2011 published on line ahead of print.
McNamara JK, Shinkazh N, Rim F, Zunga R, Cristian A. Methadone-Associated Prolongation of the QTc Interval at Doses Used for Chronic Pain. P&T February 2011 36;2:78-82 [references and conclusion on p107] http://www.nxtbook.com/nxtbooks/medimedia/pt_201102/#/28
News and Notes. Addiction 2011 p685
No effect demonstrated in a good quality RCT of acamprosate for cocaine dependence (Kampman, O'Brien et al, Philadelphia).
Simojoki, Linzteris and Finland patients: “.. crushing of Subutex tablets does not significantly alter serum .. levels or the drug’s clinical effect ..”. They say crushing has no effect on dissolution time, contrary to our own experience (some chemists, cooks or clients may also disagree).
Cunningham et al compare buprenorphine induction at home with standard daily clinic initiation, finding some advantages in the home strategy … and few problems. This may be just what we need to reduce early treatment drop-outs for this otherwise excellent drug.
Extensive interviews with over 1000 pharmacotherapy patients show bimodal distribution for many aspects of dependency, indicating two categories of patients which are clinically distinct, justifying the DSM categories or levels of opioid dependence.
Strain et al compare cravings at induction of pure buprenorphine films (non-registered) versus buprenorphine/naloxone soluble-films (sometimes called wafers). It is disappointing that only the latter is being marketed because it is contraindicated in pregnancy yet women with young children are a target for measures against diversion and misuse which are claimed benefits of this formulation.
Pharmacist McNamara and colleagues select patients prescribed methadone for pain treatment and then report a (spurious) association with QT prolongation! Their paper has some interesting information but is no scientific treatise. One ‘high risk’ patient is on 5mg daily! One out of 7 patients died - not of torsade de pointes - but of ‘toxic shock’. Like most such papers, there are no cases of torsade. Nearly all (male) patients had QTc > 430ms BEFORE taking methadone(!). This is similar to Reddy’s paper from the Anderson Cancer Center.
The Iguana column in Addiction has rarely been a high point of scientific publication but this month makes no sense at all, at least to this antipodean reader. p685 [Full citations below]
Dear Colleagues,
These items are sent for your interest. I have not read them all fully but it is nice to see that our research colleagues are still working on basic efficacy trials using various combinations and comparisons. Some of these ‘stand up’ (like the superiority of methadone in pregnancy) while others reverse initial encouragement, such as the use of acamprosate for cocaine cravings. Both positive and negative findings are important to clinicians. The possibility of giving one or two initial doses of buprenorphine to candidates to take away and consume WHEN THEY ARE IN WITHDRAWAL may be a safe and beneficial innovation (Cunningham; Lee).
The first three items are high quality scientific comparisons (RCTs) while the last two items are here despite their poverty of content and rigour.
I hope they are of interest to readers.
Andrew Byrne ..
References:
Guardia J, Roncero C, Galan, J, Gonzalvo B, Burguete T, Casas M. A double-blind, placebo-controlled, randomized pilot study comparing quetiapine with placebo, associated to naltrexone, in the treatment of alcohol-dependent patients. Addictive Behaviors 2011 36;3:265-269
Kampman KM, Dackis C, Pettinati HM, Lynch KG, Sparkman T, O'Brien CP. A double-blind, placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence. Addictive Behaviors 2011 36;3:217-221
Simojoki K, Lillsunde P, Linzteris N, Alho H. Bioavailability of buprenorphine from crushed and whole buprenorphine (Subutex) tablets. Euro Addiction Res 2010 16;2:85-90
Cunningham CO, Giovanniello A, Li X, Kunins HV, Roose RJ, Sohler NL. A comparison of buprenorphine induction strategies: Patient-centered home-based inductions versus standard-of-care office-based inductions. Journal of Substance Abuse Treatment 2011
Lee JD, Grossman E, DiRocco D, Gourevitch MN. Home buprenorphine/naloxone induction in primary care. Journal of General Internal Medicine 2009 24:226-232
Shand FL, Slade T, Degenhardt L, Baillie A, Nelson EC. Opioid dependence latent structure: two classes with differing severity? Addiction 2011 106:590-598 http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03217.x/abstract
Strain EC, Harrison JA, Bigelow GE. Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films. Clinical Pharmacology and Therapeutics 26th Jan 2011 published on line ahead of print.
McNamara JK, Shinkazh N, Rim F, Zunga R, Cristian A. Methadone-Associated Prolongation of the QTc Interval at Doses Used for Chronic Pain. P&T February 2011 36;2:78-82 [references and conclusion on p107] http://www.nxtbook.com/nxtbooks/medimedia/pt_201102/#/28
News and Notes. Addiction 2011 p685
22 February 2011
Possibly the last case report of torsade in a methadone patient. Now, how to treat it?
Torsade de Pointes due to Methadone Use in a Patient with HIV and Hepatitis C Coinfection. John J, Amley X, Bombino G, Gitelis C, Topi B, Hollander G, Ghosh J. Cardiol Res Pract. 2010; 2010: 524764
Dear Colleagues,
This case history is instructive although it is not novel. To call this torsade "due to methadone" in the title is highly misleading and contrary to the paper’s data.
The daily methadone dose was low at 40mg (and ‘recently increased’); the patient was aged 50 and was also prescribed three antiviral agents and two antibiotics for HIV. These factors made the patient easily identifiable as a high risk case for numerous medical complications including torsade de pointes tachycardia. Importantly, one of the HIV drugs used has been reported elsewhere to cause torsade (atazanavir, as reported by Dabiesingh; Ly and others). Hence older age, atazanavir and HIV are thus all known to be specific risk factors for developing QT problems. There is also some evidence that HCV may be an independent risk factor for QT prolongation (Norden). From the literature I have searched it seems that most HIV subjects with torsade de pointes are not taking methadone.
Unfortunately, details of this patient’s dependency management are scanty and it seems that there was limited if any addiction specialty input. Note that the patient survived and even 23 days after the methadone was ceased still had QT prolongation and was considered to be in need of a pacemaker (ICD). The reader is not informed, but methadone may have been substituted by another drug, such as morphine. Either way, it would seem to indicate that the methadone was NOT the cause of the electrical perturbations in this patient, despite the alarmist title.
The authors concede that a dose level of 40mg (increased two months before the episode following two years of no illicit drug use) is very unlikely to be a significant causative factor for QT prolongation. The methadone may even have delayed the onset of torsade, for example, by keeping the patient from other cardio-toxic drugs including alcohol, cocaine and amphetamine. It is paradoxical that this very patient was administered another QT prolonging drug, the anti-arrhythmic amiodarone during resuscitation. This drug is similar to methadone in that it can reportedly cause QT prolongation but rarely induces torsade.
These authors cite Adelaide author Athanasos but do so rather selectively. While he does indeed describe U-waves, of uncertain clinical significance, his study found no cardiologic consequences of low to medium doses of methadone, the latter findings appear to be ignored in the current paper. It is intriguing that these authors would repeat Krantz and colleagues’ controversial and unproven advice (Ann Int Med) about performing annual ECGs on methadone patients (see responses in Annals, 4 against, none in favour). This very case report is yet another example in which such serial ECGs were performed and yet torsade occurred regardless. It seems that in America performing a test is sometimes seen as a defence regardless of its utility or otherwise.
That this patient is alive at 50 after having such serious complications of IV drug use as HCV, HIV and hepatoma is indeed a credit to the methadone and medical care received at this institution bearing the name of one of the most innovative doctors of all time, Maimonides (see his treatises on haemorrhoids, digestion, chicken soup and cohabitation).
Reports of torsade in methadone patients are not usually published any more, probably because the details are similar to over 100 other such reports - it would be like describing a 'routine' case of appendicitis. Furthermore, there have apparently been no fatalities from confirmed torsade to date to my best knowledge, at least in the past 15 years (an American text states that it should have a mortality of zero). According to the Journal's web site these authors would have paid over US$500 to have this vignette made public.
If nothing more, the report should be a wake-up call to all who treat middle aged opioid dependent patients and remind us to take greatest care when anti-virals, anti-fungals, antibiotics, etc are being prescribed, especially by others who may not be familiar with the dependency side of their patient’s treatment. The size of the methadone dose appears to be of little relevance (Krantz’s original series had 6 of 9 subjects taking between 65mg and 125mg, mean 96mg daily; Pearson reports one case at 29mg daily).
Comments by Andrew Byrne ..
Link to article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021856/
Correction for Jones article summary: I stated in an early draft that there was no fetal loss but in fact there were two such events, both in the methadone group. This was promptly corrected on the web site and I apologise for the mistake. Dr Jones has also pointed out that the trend for greater attrition in the buprenorphine group did not reach statistical significance. To my mind the authors have still not justified their comment that buprenorphine is now a ‘first line option’. Just because they showed no difference in retention/attrition, this does not prove that the two treatments are equivalent therapeutically. I believe that both drugs are extremely useful in opioid dependency and that methadone remains the gold standard (O’Connor 2010 JAMA) although it does not suit everyone or every situation.
Dear Colleagues,
This case history is instructive although it is not novel. To call this torsade "due to methadone" in the title is highly misleading and contrary to the paper’s data.
The daily methadone dose was low at 40mg (and ‘recently increased’); the patient was aged 50 and was also prescribed three antiviral agents and two antibiotics for HIV. These factors made the patient easily identifiable as a high risk case for numerous medical complications including torsade de pointes tachycardia. Importantly, one of the HIV drugs used has been reported elsewhere to cause torsade (atazanavir, as reported by Dabiesingh; Ly and others). Hence older age, atazanavir and HIV are thus all known to be specific risk factors for developing QT problems. There is also some evidence that HCV may be an independent risk factor for QT prolongation (Norden). From the literature I have searched it seems that most HIV subjects with torsade de pointes are not taking methadone.
Unfortunately, details of this patient’s dependency management are scanty and it seems that there was limited if any addiction specialty input. Note that the patient survived and even 23 days after the methadone was ceased still had QT prolongation and was considered to be in need of a pacemaker (ICD). The reader is not informed, but methadone may have been substituted by another drug, such as morphine. Either way, it would seem to indicate that the methadone was NOT the cause of the electrical perturbations in this patient, despite the alarmist title.
The authors concede that a dose level of 40mg (increased two months before the episode following two years of no illicit drug use) is very unlikely to be a significant causative factor for QT prolongation. The methadone may even have delayed the onset of torsade, for example, by keeping the patient from other cardio-toxic drugs including alcohol, cocaine and amphetamine. It is paradoxical that this very patient was administered another QT prolonging drug, the anti-arrhythmic amiodarone during resuscitation. This drug is similar to methadone in that it can reportedly cause QT prolongation but rarely induces torsade.
These authors cite Adelaide author Athanasos but do so rather selectively. While he does indeed describe U-waves, of uncertain clinical significance, his study found no cardiologic consequences of low to medium doses of methadone, the latter findings appear to be ignored in the current paper. It is intriguing that these authors would repeat Krantz and colleagues’ controversial and unproven advice (Ann Int Med) about performing annual ECGs on methadone patients (see responses in Annals, 4 against, none in favour). This very case report is yet another example in which such serial ECGs were performed and yet torsade occurred regardless. It seems that in America performing a test is sometimes seen as a defence regardless of its utility or otherwise.
That this patient is alive at 50 after having such serious complications of IV drug use as HCV, HIV and hepatoma is indeed a credit to the methadone and medical care received at this institution bearing the name of one of the most innovative doctors of all time, Maimonides (see his treatises on haemorrhoids, digestion, chicken soup and cohabitation).
Reports of torsade in methadone patients are not usually published any more, probably because the details are similar to over 100 other such reports - it would be like describing a 'routine' case of appendicitis. Furthermore, there have apparently been no fatalities from confirmed torsade to date to my best knowledge, at least in the past 15 years (an American text states that it should have a mortality of zero). According to the Journal's web site these authors would have paid over US$500 to have this vignette made public.
If nothing more, the report should be a wake-up call to all who treat middle aged opioid dependent patients and remind us to take greatest care when anti-virals, anti-fungals, antibiotics, etc are being prescribed, especially by others who may not be familiar with the dependency side of their patient’s treatment. The size of the methadone dose appears to be of little relevance (Krantz’s original series had 6 of 9 subjects taking between 65mg and 125mg, mean 96mg daily; Pearson reports one case at 29mg daily).
Comments by Andrew Byrne ..
Link to article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021856/
Correction for Jones article summary: I stated in an early draft that there was no fetal loss but in fact there were two such events, both in the methadone group. This was promptly corrected on the web site and I apologise for the mistake. Dr Jones has also pointed out that the trend for greater attrition in the buprenorphine group did not reach statistical significance. To my mind the authors have still not justified their comment that buprenorphine is now a ‘first line option’. Just because they showed no difference in retention/attrition, this does not prove that the two treatments are equivalent therapeutically. I believe that both drugs are extremely useful in opioid dependency and that methadone remains the gold standard (O’Connor 2010 JAMA) although it does not suit everyone or every situation.
15 February 2011
Like randomised trials, patient choosing methadone also have much better retention.
The SUMMIT Trial: A field comparison of buprenorphine versus methadone maintenance treatment. Pinto H, Maskrey V, Swift L, Rumball D, Wagle A, Holland R. Journal of Substance Abuse Treatment, 2010 39;4:340-352
Dear Reader,
This naturalistic description and follow up study from a drug service in England shows comparative retention rates in opiate maintenance patients with exhaustive comparisons between the two groups. The current study followed a previous abortive attempt at randomisation of the groups which failed to attract any subjects, so determined were they all on their preferred medication.
These authors enrolled 361 eligible applicants for opioid maintenance of whom 227 (63%) chose methadone with the rest opting for (pure) buprenorphine (37%).
Despite the methadone patients having ‘more severe substance abuse and psychiatric and physical problems’ their retention rate was substantially higher than the buprenorphine patients (70% vs. 43% at 6 months).
Only seven of 134 patients swapped from buprenorphine to methadone early in the trial (apparently none swapped the other way around). Of the remaining buprenorphine drop-outs 10 were planned detox episodes; 40 failed to attend; 13 were detained by police; 10 were involuntary discharges. Relating to buprenorphine retention the authors report that the only significant difference on multivariate analysis in the many features/opinions solicited from the subjects was a ‘belief as to whether buprenorphine blocked the effect of heroin’. While this belief is not soundly based, it might be a helpful street myth, keeping some patients away from dangerous drugs. However, it could also give some users a false sense of security in a high risk overdose situation.
The trial patients were prescribed a mean maximum daily dose for buprenorphine of 12mg (r 4-20mg); and for methadone of 73mg (r 10-170mg). There were two deaths in the methadone group, one in the induction period and another while on a stable dose of methadone caused by overdose of multiple depressants.
As in most such longitudinal studies the proportion of subjects successfully reducing their dose to zero was low - around 7% for buprenorphine and under 1% for those choosing methadone during a six month period. This is consistent with other research showing about 4% of opioid dependent people become abstinent each year (and this is regardless of the type of treatment - see Thorley’s seminal work from the UK).
Crucial to the results of this trial was the finding that 10% of the total said that they would not have attended if methadone were the only drug available. The derived figure of buprenorphine patients who stated that they would not have attended for methadone in the absence of an alternative was 28%. This is a novel finding to my knowledge but fits with clinical experience in other areas that greater choice yields greater patient acceptance, better enrolments, compliance (adherence) and retention. Apparently English health authorities are required to justify the expense of each medication and so this provides strong evidence in that regard which was one of the aims of the authors (see their previous paper).
Since these authors used pure buprenorphine SL tablets readers should be cautious about extrapolating these findings to buprenorphine-naloxone (Suboxone) … it may or may not be the case that buprenorphine-naloxone would have achieved similar results to pure buprenorphine on which most of the fundamental research has been performed to date (RCT, safety, etc). Another reason to favour pure buprenorphine is that it is available in 0.4mg tablets (in Australia). In our own practice we have at least a quarter of our patients taking increments requiring 0.4mg tablets.
While there must be end-points to any research trial, it would be instructive to know how many of the drop-outs had re-registered in treatment (if any). While the group was not able to examine this issue, other research would indicate largely negative results including a high mortality. Dr Bell investigated this from official enrolment statistics in New South Wales some years ago [Bell J, Burrell T, Indig D, Gilmour S. Cycling in and out of treatment; participation in methadone treatment in NSW, 1990–2002. Drug and Alcohol Dependence 2006 81; 1: 55-61]. Such research, as well as clinical experience with buprenorphine shows that there is indeed a ‘revolving door’ or ‘frequent flyer’ syndrome with this treatment, at least in comparison to methadone.
Because there was no randomisation to the intervention, this study does not give us scientific information about the different drugs. However, it does inform us for the first time I believe that the most seriously dependent patients are more likely to choose methadone and that they have a better retention rate in so doing. Less seriously dependent patients are more likely to choose buprenorphine and are more likely to drop out of treatment (and some successfully withdraw from treatment). So unsurprisingly, outcomes are a function of both the patient group and the treatment chosen. While this information is not a major benefit in individual clinical decision making, this study at the very least provides an excellent “barometer” by which we might measure our own practices regarding the proportion taking each drug and the dose ranges used.
Comments by Andrew Byrne ..
Dear Reader,
This naturalistic description and follow up study from a drug service in England shows comparative retention rates in opiate maintenance patients with exhaustive comparisons between the two groups. The current study followed a previous abortive attempt at randomisation of the groups which failed to attract any subjects, so determined were they all on their preferred medication.
These authors enrolled 361 eligible applicants for opioid maintenance of whom 227 (63%) chose methadone with the rest opting for (pure) buprenorphine (37%).
Despite the methadone patients having ‘more severe substance abuse and psychiatric and physical problems’ their retention rate was substantially higher than the buprenorphine patients (70% vs. 43% at 6 months).
Only seven of 134 patients swapped from buprenorphine to methadone early in the trial (apparently none swapped the other way around). Of the remaining buprenorphine drop-outs 10 were planned detox episodes; 40 failed to attend; 13 were detained by police; 10 were involuntary discharges. Relating to buprenorphine retention the authors report that the only significant difference on multivariate analysis in the many features/opinions solicited from the subjects was a ‘belief as to whether buprenorphine blocked the effect of heroin’. While this belief is not soundly based, it might be a helpful street myth, keeping some patients away from dangerous drugs. However, it could also give some users a false sense of security in a high risk overdose situation.
The trial patients were prescribed a mean maximum daily dose for buprenorphine of 12mg (r 4-20mg); and for methadone of 73mg (r 10-170mg). There were two deaths in the methadone group, one in the induction period and another while on a stable dose of methadone caused by overdose of multiple depressants.
As in most such longitudinal studies the proportion of subjects successfully reducing their dose to zero was low - around 7% for buprenorphine and under 1% for those choosing methadone during a six month period. This is consistent with other research showing about 4% of opioid dependent people become abstinent each year (and this is regardless of the type of treatment - see Thorley’s seminal work from the UK).
Crucial to the results of this trial was the finding that 10% of the total said that they would not have attended if methadone were the only drug available. The derived figure of buprenorphine patients who stated that they would not have attended for methadone in the absence of an alternative was 28%. This is a novel finding to my knowledge but fits with clinical experience in other areas that greater choice yields greater patient acceptance, better enrolments, compliance (adherence) and retention. Apparently English health authorities are required to justify the expense of each medication and so this provides strong evidence in that regard which was one of the aims of the authors (see their previous paper).
Since these authors used pure buprenorphine SL tablets readers should be cautious about extrapolating these findings to buprenorphine-naloxone (Suboxone) … it may or may not be the case that buprenorphine-naloxone would have achieved similar results to pure buprenorphine on which most of the fundamental research has been performed to date (RCT, safety, etc). Another reason to favour pure buprenorphine is that it is available in 0.4mg tablets (in Australia). In our own practice we have at least a quarter of our patients taking increments requiring 0.4mg tablets.
While there must be end-points to any research trial, it would be instructive to know how many of the drop-outs had re-registered in treatment (if any). While the group was not able to examine this issue, other research would indicate largely negative results including a high mortality. Dr Bell investigated this from official enrolment statistics in New South Wales some years ago [Bell J, Burrell T, Indig D, Gilmour S. Cycling in and out of treatment; participation in methadone treatment in NSW, 1990–2002. Drug and Alcohol Dependence 2006 81; 1: 55-61]. Such research, as well as clinical experience with buprenorphine shows that there is indeed a ‘revolving door’ or ‘frequent flyer’ syndrome with this treatment, at least in comparison to methadone.
Because there was no randomisation to the intervention, this study does not give us scientific information about the different drugs. However, it does inform us for the first time I believe that the most seriously dependent patients are more likely to choose methadone and that they have a better retention rate in so doing. Less seriously dependent patients are more likely to choose buprenorphine and are more likely to drop out of treatment (and some successfully withdraw from treatment). So unsurprisingly, outcomes are a function of both the patient group and the treatment chosen. While this information is not a major benefit in individual clinical decision making, this study at the very least provides an excellent “barometer” by which we might measure our own practices regarding the proportion taking each drug and the dose ranges used.
Comments by Andrew Byrne ..
21 December 2010
Say no to "just say no"! Give in, with therapeutic strings.
Article printed in "OF SUBSTANCE".
"View from the coal face" … in Redfern, inner Sydney.
Commentary on Addiction editorial on benzodiazepine maintenance.
After many years of wrestling with the problem of benzodiazepine use in opioid dependency patients it was reassuring to read the prominent paper by Liebrenz and colleagues. Their hypothesis is an approach using what appear to be harm reduction principles, parallel to methadone maintenance. Our original practice policy was to ‘just say no’ but despite our entreaties, about one third of our patients continued to use benzodiazepines on urine testing. A number did succeed at abstinence, only to relapse with significant harms occurring due to disinhibited behaviour, often involving amnesia for the events.
Some patients were able to function almost normally while taking illicit benzodiazepines. Others became disorganised regarding their finances, housing and interpersonal relationships, some even coming to the attention of the police or emergency departments.
Although there appeared to be a number of patters of tranquillizer use, from binge and recreational use to quasi-therapeutic, we treated all such patients the same way initially, using diazepam 5mg tablets supervised at the clinic. Those currently abusing alcohol were excluded. Each patient needed to return at least once, about 3 hours after a witnessed dose for a brief examination to confirm their tolerance and exclude intoxication. All patients also had to agree to random urine testing and regular medical consultations to assess progress.
Our impression has been that when given access to diazepam under close supervision, stability returned to most such patients. A recent audit of our referral dependency practice showed that of 167 pharmacotherapy patients, (80% methadone, 20% buprenorphine) 30% were being prescribed benzodiazepines, mostly under supervision at the practice. The mean dose was 14mg daily (range 2mg - 25mg). One third were gainfully employed.
Thus we can confirm that some of the protocols alluded to in the forward thinking item in Addiction are feasible and are ripe for research. Enquiries showed that many of our colleagues had one or two pharmacotherapy patients taking long-term benzodiazepines and nearly all had organised supervised dosing at least once.
Benzodiazepine use has been the ‘elephant in the room’ in addiction treatment. While many centres still use an abstinence approach, many patients continue to use these drugs. Since benzodiazepines, along with alcohol, constitute a major source of drug-related harm it may be timely to reassess our approach. Severe restrictions on supply alone have historically never solved drug problems. Such restrictions also necessarily reduce access to those who need the drugs therapeutically. As with many other areas of public health, we believe that it is possible to translate the principles of ‘harm reduction’ to benzodiazepine use by utilizing the protocols of ‘universal precautions’ espoused by Dr Gourlay in Canada.
The use of benzodiazepine maintenance is probably at the same stage of ‘evidence’ as methadone treatment was in about 1980. It appears to be acceptable to the patient population; it appears to be safe in practice, yet definitive research is awaited to prove its effects … and to identify optimal dosing, supports and necessary supervision. Likewise oral morphine, injectable methadone and heroin assisted treatments are being trialled in several countries currently. Thus in our own patient group we found that supervised, low dose diazepam was worth offering to those who were unable or unwilling to give up benzodiazepines.
References:
Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution-a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction 2010 105;11:1870–1874
Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med (2005) 6;2:107-112
Darke S, Ross J, Mills K, Teesson M, Williamson A, Harvard A. Benzodiazepine use among heroin users: Baseline use, current use and clinical outcome. D&A Review 2010 29:3:250-255
Byrne A. Benzodiazepines: the end of a dream. Aust Fam Physician 1994 23;8:1584-1585
See article summary by Libby Topp http://www.ofsubstance.org.au/images/archive/pdf/ofsubstance_2010_3.pdf
"View from the coal face" … in Redfern, inner Sydney.
Commentary on Addiction editorial on benzodiazepine maintenance.
After many years of wrestling with the problem of benzodiazepine use in opioid dependency patients it was reassuring to read the prominent paper by Liebrenz and colleagues. Their hypothesis is an approach using what appear to be harm reduction principles, parallel to methadone maintenance. Our original practice policy was to ‘just say no’ but despite our entreaties, about one third of our patients continued to use benzodiazepines on urine testing. A number did succeed at abstinence, only to relapse with significant harms occurring due to disinhibited behaviour, often involving amnesia for the events.
Some patients were able to function almost normally while taking illicit benzodiazepines. Others became disorganised regarding their finances, housing and interpersonal relationships, some even coming to the attention of the police or emergency departments.
Although there appeared to be a number of patters of tranquillizer use, from binge and recreational use to quasi-therapeutic, we treated all such patients the same way initially, using diazepam 5mg tablets supervised at the clinic. Those currently abusing alcohol were excluded. Each patient needed to return at least once, about 3 hours after a witnessed dose for a brief examination to confirm their tolerance and exclude intoxication. All patients also had to agree to random urine testing and regular medical consultations to assess progress.
Our impression has been that when given access to diazepam under close supervision, stability returned to most such patients. A recent audit of our referral dependency practice showed that of 167 pharmacotherapy patients, (80% methadone, 20% buprenorphine) 30% were being prescribed benzodiazepines, mostly under supervision at the practice. The mean dose was 14mg daily (range 2mg - 25mg). One third were gainfully employed.
Thus we can confirm that some of the protocols alluded to in the forward thinking item in Addiction are feasible and are ripe for research. Enquiries showed that many of our colleagues had one or two pharmacotherapy patients taking long-term benzodiazepines and nearly all had organised supervised dosing at least once.
Benzodiazepine use has been the ‘elephant in the room’ in addiction treatment. While many centres still use an abstinence approach, many patients continue to use these drugs. Since benzodiazepines, along with alcohol, constitute a major source of drug-related harm it may be timely to reassess our approach. Severe restrictions on supply alone have historically never solved drug problems. Such restrictions also necessarily reduce access to those who need the drugs therapeutically. As with many other areas of public health, we believe that it is possible to translate the principles of ‘harm reduction’ to benzodiazepine use by utilizing the protocols of ‘universal precautions’ espoused by Dr Gourlay in Canada.
The use of benzodiazepine maintenance is probably at the same stage of ‘evidence’ as methadone treatment was in about 1980. It appears to be acceptable to the patient population; it appears to be safe in practice, yet definitive research is awaited to prove its effects … and to identify optimal dosing, supports and necessary supervision. Likewise oral morphine, injectable methadone and heroin assisted treatments are being trialled in several countries currently. Thus in our own patient group we found that supervised, low dose diazepam was worth offering to those who were unable or unwilling to give up benzodiazepines.
References:
Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution-a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction 2010 105;11:1870–1874
Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med (2005) 6;2:107-112
Darke S, Ross J, Mills K, Teesson M, Williamson A, Harvard A. Benzodiazepine use among heroin users: Baseline use, current use and clinical outcome. D&A Review 2010 29:3:250-255
Byrne A. Benzodiazepines: the end of a dream. Aust Fam Physician 1994 23;8:1584-1585
See article summary by Libby Topp http://www.ofsubstance.org.au/images/archive/pdf/ofsubstance_2010_3.pdf
17 December 2010
More drop-outs with buprenorphine in pregnancy.
Reduced retention makes buprenorphine a poor second to methadone in pregnancy.
Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR, Fischer G. Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure. NEJM 2010; 363:2320-2331
Dear Colleagues,
These authors assessed 1074 pregnant women from clinics in Austria, Canada and the USA for this comparison of methadone and buprenorphine regarding neonatal abstinence syndrome (NAS). There were 250 who declined to participate and another 650 did not fit inclusion criteria (alcohol, benzo use, medical conditions, for example) leaving 175 in the randomised comparison groups, blinded by a morphine wash-out period in hospital and use of ‘double dummy’ placebo. Pure buprenorphine (Subutex) was used to avoid prenatal exposure to naloxone (Suboxone is contraindicated in pregnancy). Over $1000 was available to subjects contingent on clear urine toxicology during the trial.
There were two peri-natal deaths reported from those who remained in the study, one from each group. There were two miscarriages (both in the MMT group). “The percentage of neonates requiring NAS treatment did not differ significantly between groups (P = 0.26), nor did the groups differ significantly with respect to the peak NAS score (P = 0.04) or head circumference (P = 0.04).” However, two other primary outcomes were significantly better in the buprenorphine group: (1) quantities of morphine used for neonatal abstinence syndrome (NAS) and (2): ‘total hospital stay’. The prognostic significance of these outcomes is unknown to my best knowledge.
The numbers of enrolled subjects were not large enough to show anything but very major outcome effects as being statistically significant. Previous experience has consistently shown only modest differences between methadone and buprenorphine regarding neonatal outcomes. Hence this trial was under-powered on the numbers to find minor differences to statistical significance.
Aside from the unsurprising neonatal outcomes, there were some dramatic and remarkable maternal findings which are mentioned but not brought to the prominence they deserve in my view. These differences are so great that they may even invalidate the neonatal findings (for example if those with high tolerance or rapid metabolism were more likely to drop out).
To my mind the two most important findings of the study are as follows:
The methadone group (n=89) had 16 drop-outs (18%) while the buprenorphine group (n=86) had 28 drop-outs (33%) [p=0.02]. Even more dramatic, of the 16 methadone drop-outs, 2 were due to ‘dissatisfaction with the medication’ while the corresponding number for the buprenorphine candidates was 20, a massive difference. These findings are discussed in the text but should probably also be enshrined in the title of the article. There is no point in having favourable neonatal outcomes if a third of the mothers have left treatment before term.
Even with its failings, I believe that this study provides the most persuasive evidence to date showing the safety and effectiveness of methadone in pregnancy. Indeed, it clearly demonstrates that, in the absence of contraindications, methadone should be the first line drug for opiate dependence in pregnancy (as in the non-pregnant). Yet despite their finding that almost twice as many women dropped out in the buprenorphine group, these authors state, somewhat clumsily: “Although there were no significant differences in overall rates of NAS among infants exposed to buprenorphine and those exposed to methadone, the benefits of buprenorphine in reducing the severity of NAS among neonates with this complication suggest that it should be considered a first-line treatment option in pregnancy.”
Rather than an option, “first line” status implies an obligation in my book. Since buprenorphine is the only alternative medication licensed for opioid dependence then it is obviously an ‘option’, if a somewhat less effective one. This RCT confirms that during pregnancy, consistent with the existing body of research evidence, (pure) buprenorphine should be the second line drug and only used when methadone is found to be clinically inappropriate. I believe that it is unethical to prescribe Suboxone (buprenorphine/naloxone).
Comments by Andrew Byrne ..
http://methadone-research.blogspot.com/
Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR, Fischer G. Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure. NEJM 2010; 363:2320-2331
Dear Colleagues,
These authors assessed 1074 pregnant women from clinics in Austria, Canada and the USA for this comparison of methadone and buprenorphine regarding neonatal abstinence syndrome (NAS). There were 250 who declined to participate and another 650 did not fit inclusion criteria (alcohol, benzo use, medical conditions, for example) leaving 175 in the randomised comparison groups, blinded by a morphine wash-out period in hospital and use of ‘double dummy’ placebo. Pure buprenorphine (Subutex) was used to avoid prenatal exposure to naloxone (Suboxone is contraindicated in pregnancy). Over $1000 was available to subjects contingent on clear urine toxicology during the trial.
There were two peri-natal deaths reported from those who remained in the study, one from each group. There were two miscarriages (both in the MMT group). “The percentage of neonates requiring NAS treatment did not differ significantly between groups (P = 0.26), nor did the groups differ significantly with respect to the peak NAS score (P = 0.04) or head circumference (P = 0.04).” However, two other primary outcomes were significantly better in the buprenorphine group: (1) quantities of morphine used for neonatal abstinence syndrome (NAS) and (2): ‘total hospital stay’. The prognostic significance of these outcomes is unknown to my best knowledge.
The numbers of enrolled subjects were not large enough to show anything but very major outcome effects as being statistically significant. Previous experience has consistently shown only modest differences between methadone and buprenorphine regarding neonatal outcomes. Hence this trial was under-powered on the numbers to find minor differences to statistical significance.
Aside from the unsurprising neonatal outcomes, there were some dramatic and remarkable maternal findings which are mentioned but not brought to the prominence they deserve in my view. These differences are so great that they may even invalidate the neonatal findings (for example if those with high tolerance or rapid metabolism were more likely to drop out).
To my mind the two most important findings of the study are as follows:
The methadone group (n=89) had 16 drop-outs (18%) while the buprenorphine group (n=86) had 28 drop-outs (33%) [p=0.02]. Even more dramatic, of the 16 methadone drop-outs, 2 were due to ‘dissatisfaction with the medication’ while the corresponding number for the buprenorphine candidates was 20, a massive difference. These findings are discussed in the text but should probably also be enshrined in the title of the article. There is no point in having favourable neonatal outcomes if a third of the mothers have left treatment before term.
Even with its failings, I believe that this study provides the most persuasive evidence to date showing the safety and effectiveness of methadone in pregnancy. Indeed, it clearly demonstrates that, in the absence of contraindications, methadone should be the first line drug for opiate dependence in pregnancy (as in the non-pregnant). Yet despite their finding that almost twice as many women dropped out in the buprenorphine group, these authors state, somewhat clumsily: “Although there were no significant differences in overall rates of NAS among infants exposed to buprenorphine and those exposed to methadone, the benefits of buprenorphine in reducing the severity of NAS among neonates with this complication suggest that it should be considered a first-line treatment option in pregnancy.”
Rather than an option, “first line” status implies an obligation in my book. Since buprenorphine is the only alternative medication licensed for opioid dependence then it is obviously an ‘option’, if a somewhat less effective one. This RCT confirms that during pregnancy, consistent with the existing body of research evidence, (pure) buprenorphine should be the second line drug and only used when methadone is found to be clinically inappropriate. I believe that it is unethical to prescribe Suboxone (buprenorphine/naloxone).
Comments by Andrew Byrne ..
http://methadone-research.blogspot.com/
15 December 2010
French study shows torsade rare to vanishing.
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;
Dear Colleagues,
These French authors have done our field a great service by replicating Anchersen’s national study from Norway which was so reassuring concerning the use of methadone in addiction treatment.
This study examined QT intervals in a small sample of methadone patients and then compared the results with national reports on adverse events involving methadone and/or cardiac issues including sudden death. These authors found a mean QT interval of 414 ± 29ms with no readings over 500ms, the level at which the risk of arrhythmia is believed to become significant. We are told that analysis of the 42 cases showed that longer QT intervals were associated with recent increases in methadone dose, tobacco smoking, the use of other medications and pre-existing cardiac disease. These findings are consistent with most other work published on this matter, with the notable exception of Wedam. The authors quote QT ‘dispersion’ which is the difference between the shortest and longest QT interval among the twelve leads readings on the standard cardiograph. Despite some initial promise, the significance of ‘dispersion’ has been questioned more recently and its relevance to methadone treatment is uncertain. Even normal values are not agreed upon by cardiologists.
The 550 reports to the official French ‘pharmcovigilence’ centre regarding methadone are of great interest and relevance to the current debate over supposed cardiac effects of methadone. In the ten years to 2007 only 5 reports (0.9%) involved QT problems, three of these with torsade de pointes including one death, a 19 year old who died after unsuccessful resuscitation. This case is not tabulated as having torsade but if he did, as implied in the text, he would represent the first confirmed death from torsade de pointes in the literature to my knowledge.
Over the ten years there were also 7 sudden deaths (1.3%) which the authors tabulate in detail. For some reason they postulate that some or all might be ascribed to arrhythmia. They state: “it is conceivable that serious toxicity might be mediated in part through cardiac effects rather than solely via respiratory depression.” Almost anything is ‘conceivable’ yet the real quesion is whether it is likely or even ‘credible’. In fact the data presented make it highly unlikely that torsade is involved to any significant degree, if at all. Were torsade the cause of just half of these deaths, and considering a reported mortality well under 10% (some say zero) then one would expect hundreds of non-fatal cases of torsade across France - yet only two were ever reported in the whole country over a ten year period. The expected under-reporting in such a voluntary scheme would apply to some extent to both mortality and torsade, even though the latter has become almost ‘notorious’ and was originally described in France and with a French name.
Further, these authors state of several deceased cases: ‘no overdose of methadone’. This is largely based on drug levels found at post-mortem. However, these are now known to be most unreliable alone in determining cause of death. Indeed, serious toxicity and death from narcotism have frequently been found with post-mortem blood methadone in the ‘therapeutic’ range while some patients in normal treatment have levels in or near the toxic range. Also, there are major changes in the levels of measurable methadone following death.
It seemed extraordinary that five of the deceased patients were being treated for psychosis so I wrote to the authors. I have now learned that certain antipsychotics are used commonly in France as alternatives to benzodiazepines, hence not all of these patients were schizophrenic. Each of these 5 patients who were prescribed anti-psychotics died in the first 5 days of methadone maintenance treatment for addiction and two were taking doses which were in excess of current guidelines. Nearly all were receiving four or more prescribed medications apart from the methadone. HIV drugs were involved in two cases. Hence these well-documented deaths also make it clear that polypharmacy is a major factor and the patients would have been self-evident as extremely high risk candidates for treatment.
This study makes it hard to understand the findings of Krantz who found more cases in his own small district than in the whole of France in a decade. Suffice it to say that the findings are even more reassuring than the national figures from Norway published by Anchersen and colleagues.
Comments by Andrew Byrne ..
Related article (includes one of the same authors): Molokhia M, Pathak A, Lapeyre-Mestre M, et al. Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France. Br. J. Clin. Pharmacol. 2008 66:386–395
In this exhaustive paper using a rational methodology an estimate is made of the incidence of drug induced long QT syndrome (LQTS) at 11 per million per year. The literature shows that over 50% are due to class III antiarrhythmics (presumably in those with existing cardiac rhythm disturbances), closely followed by anti-infective drugs and antihistamines (with presumably some antipsychotics). The drug methadone is not even mentioned in the entire paper so we presume that in 2008 it was not even on the radar for these experienced and thorough researchers. This casts yet further doubt of the contention of Dr Mori Krantz that cardiac problems constitute a public health priority in methadone treatment in America.
Dear Colleagues,
These French authors have done our field a great service by replicating Anchersen’s national study from Norway which was so reassuring concerning the use of methadone in addiction treatment.
This study examined QT intervals in a small sample of methadone patients and then compared the results with national reports on adverse events involving methadone and/or cardiac issues including sudden death. These authors found a mean QT interval of 414 ± 29ms with no readings over 500ms, the level at which the risk of arrhythmia is believed to become significant. We are told that analysis of the 42 cases showed that longer QT intervals were associated with recent increases in methadone dose, tobacco smoking, the use of other medications and pre-existing cardiac disease. These findings are consistent with most other work published on this matter, with the notable exception of Wedam. The authors quote QT ‘dispersion’ which is the difference between the shortest and longest QT interval among the twelve leads readings on the standard cardiograph. Despite some initial promise, the significance of ‘dispersion’ has been questioned more recently and its relevance to methadone treatment is uncertain. Even normal values are not agreed upon by cardiologists.
The 550 reports to the official French ‘pharmcovigilence’ centre regarding methadone are of great interest and relevance to the current debate over supposed cardiac effects of methadone. In the ten years to 2007 only 5 reports (0.9%) involved QT problems, three of these with torsade de pointes including one death, a 19 year old who died after unsuccessful resuscitation. This case is not tabulated as having torsade but if he did, as implied in the text, he would represent the first confirmed death from torsade de pointes in the literature to my knowledge.
Over the ten years there were also 7 sudden deaths (1.3%) which the authors tabulate in detail. For some reason they postulate that some or all might be ascribed to arrhythmia. They state: “it is conceivable that serious toxicity might be mediated in part through cardiac effects rather than solely via respiratory depression.” Almost anything is ‘conceivable’ yet the real quesion is whether it is likely or even ‘credible’. In fact the data presented make it highly unlikely that torsade is involved to any significant degree, if at all. Were torsade the cause of just half of these deaths, and considering a reported mortality well under 10% (some say zero) then one would expect hundreds of non-fatal cases of torsade across France - yet only two were ever reported in the whole country over a ten year period. The expected under-reporting in such a voluntary scheme would apply to some extent to both mortality and torsade, even though the latter has become almost ‘notorious’ and was originally described in France and with a French name.
Further, these authors state of several deceased cases: ‘no overdose of methadone’. This is largely based on drug levels found at post-mortem. However, these are now known to be most unreliable alone in determining cause of death. Indeed, serious toxicity and death from narcotism have frequently been found with post-mortem blood methadone in the ‘therapeutic’ range while some patients in normal treatment have levels in or near the toxic range. Also, there are major changes in the levels of measurable methadone following death.
It seemed extraordinary that five of the deceased patients were being treated for psychosis so I wrote to the authors. I have now learned that certain antipsychotics are used commonly in France as alternatives to benzodiazepines, hence not all of these patients were schizophrenic. Each of these 5 patients who were prescribed anti-psychotics died in the first 5 days of methadone maintenance treatment for addiction and two were taking doses which were in excess of current guidelines. Nearly all were receiving four or more prescribed medications apart from the methadone. HIV drugs were involved in two cases. Hence these well-documented deaths also make it clear that polypharmacy is a major factor and the patients would have been self-evident as extremely high risk candidates for treatment.
This study makes it hard to understand the findings of Krantz who found more cases in his own small district than in the whole of France in a decade. Suffice it to say that the findings are even more reassuring than the national figures from Norway published by Anchersen and colleagues.
Comments by Andrew Byrne ..
Related article (includes one of the same authors): Molokhia M, Pathak A, Lapeyre-Mestre M, et al. Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France. Br. J. Clin. Pharmacol. 2008 66:386–395
In this exhaustive paper using a rational methodology an estimate is made of the incidence of drug induced long QT syndrome (LQTS) at 11 per million per year. The literature shows that over 50% are due to class III antiarrhythmics (presumably in those with existing cardiac rhythm disturbances), closely followed by anti-infective drugs and antihistamines (with presumably some antipsychotics). The drug methadone is not even mentioned in the entire paper so we presume that in 2008 it was not even on the radar for these experienced and thorough researchers. This casts yet further doubt of the contention of Dr Mori Krantz that cardiac problems constitute a public health priority in methadone treatment in America.
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