31 August 2004

No link between expansion of methadone treatment and methadone related deaths: Addiction journal study finds.

Addiction 2004 99: 846-854 (July)

Overdose deaths attributed to methadone and heroin in New York City, 1990-1998. Bryant WK, Galea S, Tracy M, Markham Piper T, Tardiff KJ, Vlahov D.

Dear Colleagues,

This comprehensive review of coroner's records yields important information on the relative harms of street heroin versus prescribed and street methadone in a large city during a period of continued increases in both 'markets'. This group from the New York Academy of Medicine quotes the origin of this study as suggestions that methadone was 'killing more people than heroin' (in the 1990s in England, where supervised dosing was exceptional). Some even advised that opioid maintenance treatment be reviewed or even withdrawn for this reason (Newcombe, 1996).

From 1990-98 the number of patients in NYC on methadone maintenance treatment (MMT) increased from 26,000 to 34,000 yet the number of deaths in which methadone was a contributor varied between 85 and 145 each year with no trend. Out of a total of 7451 overdose deaths reported during the 9 year study period, only 121 (1.6%) deaths were due to methadone alone. Another 900 (12%) were reported as due to methadone, in combination with cocaine (40%), heroin (30%), alcohol (41%). There was an overlap of 400 deaths in which both heroin and methadone contributed.

Heroin deaths increased from 300 to almost 700 per year in the first 4 years of the study period after which they levelled off and then dropped to around 500 annually in the last 3 years. These were more likely to be 'single drug' overdoses of which there were around 900, comprising 20% of all deaths attributed to heroin.

During most years of the study there were 3 to 6 times as many deaths from heroin as from methadone with an upward trend for heroin and no trend for methadone (p=0.16) from 1990 to 1998. Males accounted for 80% of the deaths with an even split of white, black and Hispanic at 33% each.

Considering the 5 boroughs of New York City, (Manhattan, Queens, Brooklyn, Bronx and Staten Island) this would appear to be up to 100 overdose deaths per million population annually overall. This compares with Australian figures of between 20 and 40 for the same period, up to 20 in the UK and as low as 2 in some European countries such as Holland and Switzerland. These figures seem to reflect the degree of 'zero tolerance' policy implementation, with lower mortality rates being seen with the introduction of harm reduction measures such as buprenorphine, methadone, injecting rooms, needle services and heroin prescription trials.

The authors report an 'intriguing' and unexplained finding that Staten Island had a much lower rate of overdose death (2.4% of the total). They recommend further study of how some areas, despite no shortage of drug users, report much lower fatality rates. They speculate on the possible effects of income levels and poverty by region.

The message from this study is that one can expand methadone treatment in an urban setting AND permit take-away doses (nearly all NYC MMT patients receive 'Sunday bottles') WITHOUT a corresponding increase in overdose deaths from methadone. Indeed, there is probably a corresponding reduction in the number of heroin overdoses, although this is harder to measure with the long time frames involved here.

Bryant WK, Galea S, Tracy M, Markham Piper T, Tardiff KJ, Vlahov D. Overdose deaths attributed to methadone and heroin in New York City, 1990-1998. Addiction (2004) 99: 846-854

comments by Andrew Byrne ..

10 August 2004

Cannabis interventions in dual diagnosis and opioid dependent patients

10th August, 2004


Dr Jan Copeland and Ms Etty Matalon, NDARC, UNSW.

Chair: Dr Ray Seidler
This seminar raised issues that we face every day in our practices regarding behavioural change associated with drug use. Although the worst consequences of cannabis pale in comparison with alcohol and other drugs, it is still a widely used drug which many perceive to be a major problem in their lives.

Dr Copeland began by giving an overview of the use of cannabis in the Australian community. The best figures come from household studies showing that about a third of Australians have ever used cannabis and about one in six young people aged 14-19 are daily smokers of the drug. Hospital admission details show that while rare in the over 50s, cannabis use problems were commonly reported on admission in the younger age groups. We were told that up to 31.7% of 'current users' met criteria for DSM IV cannabis use disorder and 21% for dependence on the drug. Even ignoring the DSM criteria, the extent of the problem is shown by the numbers seeking treatment in Australia which, Dr Copeland told us, have tripled in a decade.

Of a large sample of Australian heroin injectors, 40% had current cannabis dependence diagnosis, being almost as common as anxiety disorder (51%) and alcohol problems (49%). US findings were similar but one wonders if the patients were prescribed adequate doses of methadone where the mean daily dose should be over 70mg and possibly higher.

We were reminded that cannabis smoke was more potent than tobacco smoke in some respects, although much less in quantity is consumed by the average cannabis smoker. There is thus a potential for causing or exacerbating cancer, asthma, bronchitis, etcetera. UNSW surveys show that nearly all the cannabis used in Australia is smoked, even though oral absorption was possible, it was often delayed and unpredictable. New methods of delivery were being developed using sprays or 'super-heated' rather than burned material from the cannabis sativa plant. High potency forms of the drug such as hashish resin or oil contain high concentrations of the active ingredients, the main one being tetra-hydro cannabinol (THC). Paradoxically, they may therefore be less harmful in some respects, having fewer impurities. Various street myths about cannabis were discussed, especially regarding drug delivery, absorption, deep breaths, bongs (dry and wet varieties), etcetera.

Even in those who are not yet intent on quitting, Dr Copeland said that there was much useful advice to give people to reduce the harms from cannabis use. They should be advised not to use bongs, especially of the 'dry' variety. They should be taught that it is illogical to inhale deeply and keep the breath for as long as possible, as is often practised. They should probably avoid leaves, stems and seeds . and just use the high concentration 'heads' of the cannabis plant. This results in a higher concentration of THC and thus a lower amount of exposure to CO, tars, soot, etc for the given amount of intoxicant. Mixing cannabis with tobacco was probably unwise although the practice is almost universal, at least in Sydney. [I wonder if it is true that Melbourne practice is more commonly to smoke straight cannabis without added tobacco.]

Next Etty Malyon showed us a number of impressive, professional publications, some aimed at patients, others at health care workers to use in formal treatment programs. One was a self-help explanatory program aimed at assisting those who are ready to quit. Another contained a step by step program of implementing goals towards lasting change in those prepared for a more formal series of face to face interventions. The programs dealt with drug use cues, drug diary entries, choosing dates for change, writing up pros and cons of drug use, discussing all of the above, etc. Depression was raised on numerous occasions as needing to be seriously addressed in those trying to quit cannabis, meaning both drug and non-drug approaches need to be considered. These interventions would be ideal in general practice and some could be initiated in pharmacies, methadone clinics or needle outreach services.

These hand-outs are available at modest cost to practitioners. Contact Dr Jan Copeland at UNSW for details.

Like all drugs, cannabis may have good and bad effects. Hence, although it was not part of the evening's 'main feature', I include a recent newspaper report from Dr Copeland's own research centre (NDARC). They found that nearly two-thirds of people using cannabis for medical reasons had decreased or stopped taking other medications. Participants also reported that cannabis was useful in preventing side effects caused by conventional medicines. The most common medical conditions the cannabis users suffered were arthritis, chronic pain, depression, nausea, muscle spasms and weight loss. Up to 70 per cent of those using 'medical cannabis' would be willing to be involved in a trial of an alternative form of cannabis, such as a spray, according to their survey. Last year NSW Premier Bob Carr announced a trial of possible therapeutic benefits of cannabis. The NDARC survey was a recommendation of the working party on the medical use of cannabis.

In another item from London, Wolff, Winstock (yes, our own 'Adam', from Bankstown) and co-workers in an SSA conference abstract published in Addiction Biology, March issue, gave the results of self-report questionnaires given to 337 multiple sclerosis patients in three English hospitals (2 London, one county). With a 75% response rate, almost half had used cannabis at some point and about one in five used the drug monthly. Only four (4%) of the 110 who had ever used cannabis developed increased weakness while one (1%) reported hallucinations. Almost three quarters stated that they would try the drug if it were legal. It would appear to have benefits for certain patients and a low side-effect profile. Yet dependence develops in a proportion and the dangers of smoked products are ever-present, each limiting the usefulness of therapeutic cannabis at present.

It is intriguing that tincture of cannabis was very widely prescribed in Australia prior to the current prohibitions of the 1950s. I could find no reports of ill-effects or dependence.

comments by Andrew Byrne ..


Cannabis use in patients with multiple sclerosis. Wolff K, Chong MS, Wise K, Tanton C, Winstock A, Ennis M, Silber K. SSA Symposium Abstracts (in Addiction Biology March 2004 p103-104)

3 August 2004

Mortality risk among new onset injection drug users

Addiction (2004) 99:946-954

Vlahov D, Wang C, Galai N, Bareta J, Mehta SH, Strathdee SA, Nelson KE.

Dear Colleagues,

This important and elegant piece of research demonstrates several crucial features of drug use in a group of 256 'early' injecting drug users over a 12 year period. Subjects were recruited from a variety of sources, mostly word-of-mouth in Baltimore, USA, all with a history of less than 2 years since first injecting drugs. The study's end point was death yet several other important findings on the natural history of drug use are also revealed.

At recruitment 70% were male, 94% were African-American and mean age was 30. HIV rate was 22%. There were 90% currently injecting, 25% more than once daily. Just 25% had ever had drug addiction treatment, only 2% on methadone maintenance treatment (MMT). The authors state that 'needle sharing and shooting gallery use were not uncommon'.

With 69 known deaths among the 256 during the 12 year study period, the overall mortality rate was 3.3 per 100 patient years. Thus on average, over 3% of the sample died each year of the twelve. Yet the rate was not at all even, showing a peak at 6 to 8 years which was around 8 times the 'expected' US mortality. At 2, 4, 10 and 12 years from recruitment, the mortality figures were about 4 times that expected for the same sex/age controls. These figures in turn were about 2 to 4 times the actual Baltimore City mortality data which appear to be worse than elsewhere in the country.

These findings are surprising as there is neither an early nor a late peak of mortality as some had suspected, but a higher risk of death around 6 to 8 years from initial injecting with levelling out again after that. Even if the HIV cases are excluded, the peaks and other trends persist, but with less accentuation.

Follow-up rates at 5 and 10 years were ~75% and ~60%. The researchers found at the 5 (and 10) year follow up (respectively) that 54% (48%) were still injecting, 5.6% (5.7%) heroin alone; 15.7% (11.3%) cocaine alone; 79% (70%) alternating cocaine and heroin. Important to note is that fully half of the subjects had ceased injecting. About 9% were in treatment, 3% (6%) on MMT, 6% (3%) abstinence based. Self reported health rating of 'good' or better was reported by 82% at 5 years and 94% at 10 years. Needless to say, these figures exclude the large numbers who had dropped out or died.

It is a tragic reality of the American health care system that it took ten years for methadone treatment to become available for 6.3% of the sample (initially 2% and 3.1% at 5 years). Knowing that more than 75% of the 256 were heroin users, the uptake of methadone and abstinence based treatments seems very low and probably reflects the lack of treatment available in Baltimore as well as the low socio-economic status of many of the subjects in this study. The death rates of MMT patients is generally less than 1% per annum. If only the other good citizens of Baltimore had acted on the impressive economic good sense of funding methadone and other treatments for addictions, many of the deaths reported here would have been avoided (and household insurance premiums would probably have been lower).

comments by Andrew Byrne ..

2 August 2004

Slow release oral morphine versus methadone

Addiction (2004) 99: 940-945

A crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence. Mitchell TB, While JM, Somogyi AA, Bochner F.

Dear Colleagues,

This study took 18 consenting methadone maintenance (MMT) patients and transferred their treatment to once daily, supervised slow-release oral morphine. They then reported up to 8 weeks progress and return to methadone. Fifteen managed the transfer without difficulty, three returning to MMT prematurely. Reports of symptoms, side effects and preferences over up to six weeks in the 15 were positive, about three quarters preferring the morphine tablets, only one in five preferring the original methadone. While this is not scientific proof of a superior treatment, it is certainly an indication that morphine can be an acceptable alternative for most MMT patients, with certain reported benefits in a proportion of them.

The initial conversion ratio used was 3.5:1 but every single patient required increased doses for withdrawal symptoms, up to an average of 4.6:1. thus, for example, a patient on 100mg of methadone might need up to 460mg of morphine. At least two of the 11 cases (18%) returned to MMT on higher doses (45 to 50 and 120 to 130). One of these, interestingly, was already on the maximum dose according to the range quoted (25-120mg daily), but evidently needed still more on medical review when returning to methadone.

The mean methadone dose in this Adelaide trial at 78mg daily is higher than previous reports. However, it is likely that the optimal mean dose is yet to be reached, although increases are happening slowly elsewhere (D'Aunno et al). Until the mean dose of methadone is nearer 100mg (like Dole's very first report) it is probable in my view that a proportion of patients will suffer, simply by being prescribed inadequate doses. The lowest doses overall may be in England and Victoria (Aust) where one finds poor quality maintenance treatment along with either too much supervision (Victoria) or too little, as in the UK. New South Wales also has many treatment deficiencies, most glaring being a lack of treatment services in high risk areas such as the Hunter Valley, South-western and inner Sydney. There are also unreasonable restrictions and a lack of flexibility in some aspects of management, especially with buprenorphine.

I understand that in NSW, morphine has been approved for over 100 patients who have been previously registered as dependency cases. The approvals are mostly for slow release oral morphine for 'pain management', often after motor accidents, infections or skin grafts following overdoses. Supervision of doses is not always compulsory. It is not usually possible to completely separate an individual requirement for opiates for (1) dependency or (2) analgesia purposes . and it may not matter, except for some legal aspects.

This study from Adelaide adds further evidence that a wider variety of opioids can be safe and effective in dependency situations and the old view of 'methadone for dependency and morphine for pain' is dated and arbitrary. Thus we now need to find out if we can improve on 'trial and error' to determine optimal management for our patients using methadone, buprenorphine or alternative oral or even parenteral opioids in pharmacotherapy for dependence.

Congratulations to Addiction for showcasing this seminal study as the lead article for the month. Note this study followed a rigorous report by the same authors on morphine's pharmacokinetics (see below). The first such report I can find is from Dr Sherman in Melbourne, followed by Whitton et al in Sydney (both 1996).

Refs: Mitchell TB, White JM, Somogyi AA, Bochner F. Comparative pharmacodynamics and pharmacokinetics of methadone and slow-release oral morphine for maintenance treatment of opioid dependence. Drug Alc Depend (2003) 72;1:85-94]

Whitton G, Sunjic S, Webster I, Wickes W. Use of morphine mixture to stabilize opiate dependence. 1996 Drug Alc Review 15: 427

Sherman JP. Managing heroin addiction with a long-acting morphine product (Kapanol). Med J Aust 1996:165;239

Comments by Andrew Byrne ..

1 August 2004

Adolescent drug use study; curious conclusions; curious editorial practices at 'Addiction'. Author replies.

Addiction (2004) 99:897-906

The adolescent behavioural repertoire as a context for drug exposure: behavioural autarcesis at play. Chen C-Y, Dormitzer CM, Butierrez U, Vittetoe K, Gonzales GB, Anthony JC. Addiction (2004) 99:897-906
[NOTE: comments from senior author below]

Dear Colleagues,

This extensive 6-country, 12,000-subject survey of adolescent behaviours derived from the authors' hypothesis of the existence of some innate individual behavioural protection, termed 'autarcesis' by them. It is self-evident that some children are more inclined than others to use drugs or alcohol and, for that matter, to become involved in other risk taking behaviours. It is of crucial interest to parents to know if this is amenable to change. From previous research, we know that about half of the influence leading to drug dependence is environmental and the other half genetic. However, to my knowledge, there is no documented means either to predict which specific individuals are at a greater risk of initiating drug use, nor any definite means to alter the risk. That notwithstanding, there could be nothing more attractive to parents than to know of such factors, if they exist, to improve their children's chances of avoiding drugs.

The study was a massive exercise involving a cross sectional survey including details of drug 'exposure' ('were you offered?') and drug use as well as numerous other activities such as praying, church attendance, sports and dating, etc. The average age of 12,000 subjects was 16 (r 12-19). Being school based questionnaires, the study excluded those underprivileged children not attending school.

Unsurprisingly, those who spent time praying and going to church were less like to be exposed to and to use drugs. This interesting finding is not of much scientific merit with no indication of causation. Drug exposure/use may protect young people from attending church - or vice versa. For a more scientifically rigorous evaluation initial drug exposure and its capital consequence see the study by Vlahov and associates in New York in the same journal [Mortality risk among new onset injection drug users. Vlahov D, Wang C, Galai N, Bareta J, Mehta SH, Strathdee SA, Nelson KE. Addiction (2004) 99:946-954 - summary on request.].

The evidence provided by the authors does not prove their interesting theory on my reading, yet they seem confident that it does. I would proffer that a motor car may display 'autarcesis', just as these authors propose in these children. It has protection against rain, heat, wind and collision. Yet such protection is not a single, definable quality, but rather a combination of all the elements required to make a solid conveyance: steel, tyres, duco, glass, electrical and braking systems for example. Nevertheless, safety of the young from external mischief is such a major issue that this debate must be useful. There can be few issues as pressing as drug uptake and use among the young in our societies.

Addiction editor Griffith Edwards has evidently permitted this study to be viewed by at least two chosen experts prior to publication since two "letters to the editor" give individual comments on the study in the very same edition of Addiction. I am concerned that Edwards did not wait for the normal process of scientific discourse, neither did he caption these letters as invited commentary which they appear to be. Further, in this case Edwards chooses to print two highly critical comments ahead of the usual time for genuine correspondence from the scientific community (or 'people of goodwill' as Edwards puts it). To be productive, such commentary should be even-handed, giving differing points of view. Even the titles given to these letters are critical ... and some might even say derogatory ["Is 'autarcesis' the emperor's new clothes? A comment on Chen et al. (2004)"; "Protection from etymologic infection"]. A detailed reply from the authors appeared a month later as a normal letter-in-reply. When I raise these issues, I am reminded of editorial finality, bordering on truculence (copy on request). 'Letters' authors I have contacted state that they were asked to comment on a pre-publication items, which they duly did. Edwards might be lucent enough to let us know exactly how many such requests were made and what criteria were used for publication.

Having over 12,000 adolescent subjects in 6 countries with NIDA backing, this study is rather 'weighty' in several respects. Yet there seems to be a 'disconnect' between its data and its conclusions regarding a nebulous yet attractive concept of autarcesis or 'drug-proofing'. These wide-ranging data still deserve closer scrutiny in my view, and the authors should be commended on such a novel study of adolescent drug experiences.

comments by Andrew Byrne ..

The senior author Professor Jim Anthony was asked by me to comment on the above. He wrote the following and suggested it be appended herewith:

"Autarcesis is not an object or a property. It is the name of a process or force that has manifestations we can observe. One distant analogy is gravity. Gravity, like autarcesis, is not an object nor is it a property. It is a process or force.

"An autarceologic process is one that helps shield the organism from exposure to a toxic agent or that helps the organism resist the toxic exposure once effective contact has occurred, but autarcesis is a non-specific process. That is, any shielding or resistance strengthening is generic and is not specific to any particular toxic agent as an induced antibody response might be specific to an antigen.

"There are other forces or processes that help shield or protect against a toxic agent, but they have the character of 'specific' shielding or 'specific' resistance strengthening (see 'antibody').

"Our thesis is that aspects of thhe adolescent behavioral repertoire serve an autarceologic function, helping in a non-specific way to shield the youth from drug-taking or to induce in a non-specific way a strengthening of resistance against offers or opportunities to try drugs.

"This feature of the adolescent behavioral repertoire is not 'innate' by any means, and we think of it as a very malleable repertoire (particularly once drug use 'comes on board').

"In many ways, the autarcesis concept is superior to 'risk factor' and 'protective factor' concepts because it conveys a mechanism, albeit of a non-specific character."

Jim Anthony, Epidemiology, Michigan State University

Methadone and buprenorphine related deaths rare in Paris study

Addiction 2004 99: 978-988

A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths. Pirnay S, Borron SW, Giudicelli CP, Tourneau J, Baud FJ, Ricordel I.

Dear Colleagues,

This adds to the modest amount of published research on the major French 'experiment' with buprenorphine, starting in 1996. To add another variable, two years after the release of unrestricted buprenorphine prescription, methadone treatment also became available, albeit in a more structured manner.

This is a detailed report of 60 consecutive overdose deaths in Paris over a 5 year period from 1997 in which buprenorphine (34), methadone (35) or both (9) were found in the post-mortem toxicology. An exhaustive investigation of each case classified the relative contribution (if any) of the two drugs towards the death. Unfortunately as a retrospective study, the authors were not able to determine the subjects' treatment status.

Despite buprenorphine being prescribed at a rate about 8 times that of methadone in France, the numbers of deaths most likely attributable to each drug were about the same (12 versus 14). In these deaths, as in other reports, an average of about 4 other drugs (excluding nicotine) was found, and in one case there were 13 additional drugs! Alcohol, benzodiazepines and other opioids were the most common, sometimes in very high concentrations. Heroin (morphine) was also found in toxic levels in 5 buprenorphine cases and 6 methadone subjects. Other cases either had clear alternative causes of death (eg. homicide, suicide, burns, carbon monoxide, etc) or else the cause of death could not be determined (12 cases).

In 1995 there were ~500 opioid overdose deaths in France. This annual rate had reportedly dropped to 100 by 1999. During this period, Australian overdose deaths increased relentlessly. Due to its restricted status, methadone in France is generally reserved for the more difficult cases. The authors state: "From the beginning, methadone appears to have had the image in France of 'a drug of last resort' for the most desperate cases". Hence the higher per-patient death rates are probably a combination of the drug's higher toxicity as well as it being used in higher risk circumstances clinically in France.

When compared, the figure of 60 deaths in a five year period is reassuringly low. This is in stark contrast to 900 methadone overdose deaths reported in New York City over a 9 year period (Bryant and colleagues in last month's Addiction). The difference is so great that it would appear France is doing something right while America is doing something wrong. Treatment access is doubtless a factor, and one can only speculate about the contribution of so-called US zero tolerance or 'harm maximization' policies as being related to the marked differences in outcomes in what is essentially the same social phenomenon in two very large, sometimes very tough cities on opposite sides of the Atlantic. New York's Rockefeller laws, with long mandatory jail terms for relatively minor drug offences, seem not to have had the desired effect, yet it seems they are politically very hard to reverse. It is good to know that the US has finally introduced buprenorphine treatment but sad to learn that, like methadone, most of the people who need it either cannot afford it or it is simply find that it is not available in their neighbourhood.

Comments by Andrew Byrne ..

Pirnay S, Borron SW, Giudicelli CP, Tourneau J, Baud FJ, Ricordel I. A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths. Addiction (2004) 99: 978-988