Escalation of Drug Use in Early-Onset Cannabis Users vs Co-twin Controls. Lynskey MT, Heath AC et al. JAMA 2003 289:427-433
Dear Colleagues,
Twin studies can be informative in causation theories. These authors state that in addition to having close or identical genetic make-up: ".. twin pairs, having been reared in the same household, would be expected to be highly concordant for environmental experiences." Thus most twins are exposed to alcohol, tobacco and other drugs at much the same age.
In their lead item in JAMA, Lynskey et al. find that for the exceptional minority of twin pairs (~300 out of 4000) in whom 'cannabis use before age 17' was discordant, that subsequent reported drug abuse/dependency was 2 to 5 times more prevalent in the early cannabis users. The authors find that this association lends weight to causation while admitting it is 'not possible to draw strong causal conclusions' of the 'gateway' theory. It is intriguing that they would address causation when this is a retrospective, cross-sectional study, a design which is not able to determine causation.
Since twins who used cannabis in the same year were eliminated, conclusions based on their similarities of upbringing must be guarded. These twins demonstrated at least one major difference in their environment and/or decision making on at least one occasion during adolescence. Whatever caused this may also explain the higher reported rates of other drug use, quite independent of any theoretical 'chemical priming' or 'gateway' effect.
These results are all derived single follow-up telephone interviews with an unknown party over matters relating to illegal drug use, child sex abuse and other personal issues up to 15 years earlier. Some may have chosen to (falsely) deny childhood cannabis use and then to also deny adult abuse or dependency. Others may have had faulty recollection for such distant events, making the findings less secure.
A certain minority of young people use hard drugs prior to using cannabis (around 1 - 2% from household surveys). Such subjects should be of considerable interest to those addressing the so-called 'gateway' theory. Lynskey et al. however, having found that up to 17 of their subjects used hard drugs before being exposed to cannabis, chose to exclude them from their study.
Another problem with this study is that the drug abuse/dependence findings are so high that they may indicate an atypical sample. For 'any illicit drug abuse/dependence' the prevalence was 33-48%; for 'alcohol dependence' it was 30-43% ['non cannabis by age 17' group first percentage followed by 'early users group' %]. Alcoholism is only thought to affect around 5% of adult males in the general population.
The authors state that their findings "..were consistent with early cannabis use having a causal role as a risk factor for other drug use and for any drug abuse or dependence." But further, they state: "While the findings of this study indicate that early cannabis use is associated with increased risks of progression to other illicit drug use and drug abuse/dependence, it is not possible to draw strong causal conclusions solely on the basis of the associations shown in this study." A 'causal' link between early cannabis use and later hard drug use remains unlikely on balance (National Academy of Science review) - and it is hard to imagine that a study of this nature could clarify the issue, no matter how well it was performed and analysed.
An associated editorial by Kandel teases some of the matters out while still seeming to assume that all cannabis use is problematic and needs to be discouraged by any effective means. Her own work from 19 years ago showed the strong association between alcohol/tobacco and illicit drug use.
Kandel indicates three factors necessary to prove the gateway hypothesis: (1) sequencing, (2) association and (3) causation. As she points out, the third is the hardest to prove.
In discussing the modern calls for prescribed cannabis, Kandel states that there is no empirical knowledge on whether medical cannabis will lead to problems. But cannabis products were widely prescribed in the first half of the 20th century without apparent problems arising (eg. tincture of cannabis). She says that it is a 'curious phenomenon' that morphine used for medical purposes 'does not lead to addiction'. Could it be equally 'curious' that medical cannabis does not do so either?
And unlike Lynskey et al., Kandel does not address the known non-chemical associations between cannabis and hard drug use. Having found from personal experience that drug education about cannabis was unreliable, young people may then reason that information about heroin and cocaine being dangerous is also unreliable. Similarly, having broken the law on cannabis, they may then have less compunction about breaking laws relating to other drugs. There is at least anecdotal evidence that some heroin addicts first used heroin when their dealer could not supply cannabis, amphetamine or other drugs of current choice. To his credit, Lynskey writes: ".. access to cannabis use may provide individuals with access to other drugs as they come into contact with drug dealers. ... [Dutch decriminalization of cannabis] may have been partially successful as rates of cocaine use among those who have used cannabis are lower in the Netherlands than in the United States." [One wonders what criteria the authors would need for 'complete' success of Dutch cannabis policy!]
Comments by Andrew Byrne ..
Citations:
Lynskey MT, Heath AC, Bucholz KK, Slutske WS, Madden PAF, Nelson EC, Statham DJ, Martin NG. Escalation of Drug Use in Early-Onset Cannabis Users vs Co-twin Controls. JAMA (2003) 289:427-433
Kandel DB. Does Marijuana Use Cause the Use of Other Drugs? JAMA (2003) 289; 4: Editorial
6 June 2003
5 June 2003
Flumazenil infusion for benzo addiction - still experimental but promising.
Intravenous flumazenil versus oxazepam tapering in the treatment ofbenzodiazepine withdrawal: a randomized, placebo-controlled study. Gerra G,Zaimovic A, Guisti F, Moi G, Brewer C. Addiction Biology 2002 7:385-395
This small randomized, placebo controlled study lends weight to the use ofintravenous flumazenil in the reversal of tolerance to benzodiazepines. Ina well designed study involving 50 patients addicted to benzodiazepines theauthors infused 2mg of flumazenil over 8 hours each day for 8 days in a daycare hospital setting. Twenty such patients were compared with another 20given oxazepam taper with saline placebo and another 10 given placebos ofboth.
Some of the effects of benzodiazepines were reversed almost immediately (eg.balance test performed each day on the subjects) while the modest dosesgiven for night-time sedation (15mg oxazepam) for 3 days were very effectivein inducing sleep, unlike the patients' previous experience which hadinvolved very much higher doses of flunitrazepam, bromazepam, etc. It appeared that the flumazenil reversed the tolerance to benzodiazepines evenfrom day one. There was no increase in anxiety symptoms and convulsions didnot eventuate, perhaps due to some intrinsic agonist activity of the drug.A previous study had shown re-emergence of panic symptoms in some patientswith a previous history but this involved the drug being infused over 5minutes and not 8 hours.
Most impressive, the patients all appeared to be fully detoxified whilerelapse occurred in only half the patients given the flumazenil whencompared with those on oxazepam taper. The relapse rates at days 15, 23 and30 were 25/55%, 30/60% and 40/70% in flumazenil vs. oxazepam taper groups.These results are impressive but need to be confirmed before being accepted.More research is certainly warranted in this difficult area as there iscurrently no single accepted management strategy for benzodiazepineaddiction.
The authors make much of receptors and GABA allosteric effects in theirdiscussion. However, this is a clinical paper and such speculation probablybelongs elsewhere. However interesting they may find it, the authors reallyhave no idea why the drug did what it did as far as I can read and themechanisms are only of distant relevance to the patients involved.
There is a very comprehensive list of references relating to the use offlumazenil for benzodiazepine addiction, from 1986 with animal studies andto controlled studies, observational work and opinion pieces since.
comments by Andrew Byrne ..
other reference:Mintzer MZ, Stoller KB, Griffiths RR. A controlled study offlumazanil-precipitated withdrawal in chronic low-dose benzodiazepine users.Psychopharmacology (Berlin) (1999) 147:146-50
This small randomized, placebo controlled study lends weight to the use ofintravenous flumazenil in the reversal of tolerance to benzodiazepines. Ina well designed study involving 50 patients addicted to benzodiazepines theauthors infused 2mg of flumazenil over 8 hours each day for 8 days in a daycare hospital setting. Twenty such patients were compared with another 20given oxazepam taper with saline placebo and another 10 given placebos ofboth.
Some of the effects of benzodiazepines were reversed almost immediately (eg.balance test performed each day on the subjects) while the modest dosesgiven for night-time sedation (15mg oxazepam) for 3 days were very effectivein inducing sleep, unlike the patients' previous experience which hadinvolved very much higher doses of flunitrazepam, bromazepam, etc. It appeared that the flumazenil reversed the tolerance to benzodiazepines evenfrom day one. There was no increase in anxiety symptoms and convulsions didnot eventuate, perhaps due to some intrinsic agonist activity of the drug.A previous study had shown re-emergence of panic symptoms in some patientswith a previous history but this involved the drug being infused over 5minutes and not 8 hours.
Most impressive, the patients all appeared to be fully detoxified whilerelapse occurred in only half the patients given the flumazenil whencompared with those on oxazepam taper. The relapse rates at days 15, 23 and30 were 25/55%, 30/60% and 40/70% in flumazenil vs. oxazepam taper groups.These results are impressive but need to be confirmed before being accepted.More research is certainly warranted in this difficult area as there iscurrently no single accepted management strategy for benzodiazepineaddiction.
The authors make much of receptors and GABA allosteric effects in theirdiscussion. However, this is a clinical paper and such speculation probablybelongs elsewhere. However interesting they may find it, the authors reallyhave no idea why the drug did what it did as far as I can read and themechanisms are only of distant relevance to the patients involved.
There is a very comprehensive list of references relating to the use offlumazenil for benzodiazepine addiction, from 1986 with animal studies andto controlled studies, observational work and opinion pieces since.
comments by Andrew Byrne ..
other reference:Mintzer MZ, Stoller KB, Griffiths RR. A controlled study offlumazanil-precipitated withdrawal in chronic low-dose benzodiazepine users.Psychopharmacology (Berlin) (1999) 147:146-50
20 May 2003
Dental problems in addiction treatment subjects. Does methadone rot teeth? Can we prevent dental decay?
Tues 20 May 2003
Presenter:
Dr Peter Foltyn (Dentist, St Vincent's Hospital)
Main speaker Dr Peter Foltyn (Dentist, St Vincent's Hospital). Chaired by Dr Richard Hallinan who gave several amusing anecdotes from his father who is a retired dentist.
Dr Hallinan began by reminding us how much a smile is worth at a job interview as well as the draw backs of bad breath and poor nutrition which are so common in dependency cases. He invited the large audience (of over 40) to benefit from Dr Foltyn's 20 year experience in treating such patients in his practice at Darlinghurst, Sydney.
Dr Foltyn gave us all a timely reminder of the importance of good dental care and the pitfalls of a number of factors countering dental hygiene. He dealt with a number of important issues for patients with drug and alcohol problems including xerostomia (dry mouth). When the salivary mechanism is inhibited there is a break-down of the normal manner of diluting and removing debris resulting in a lower pH and an acidic environment for the teeth. This allows penetration of the enamel, especially at the gingival margins where it is thinnest and where is joins the dentine. Thus for patients who are taking antidepressants, anti-cholinergics and for some patients on methadone there is a need to counter dry mouth. The use of 'swish and rinse' at the time of medication (and at other times during the day and night) can be very effective in protecting the teeth. Chewing gum can stimulate salivation and sugar-free gums are now available.
Regular brushing after each meal, however, is still the mainstay of treatment/prevention. We were told that a medium brush with small, angled head is best and that much modern tooth paste is either unnecessary and in some cases may cause irritation to already delicate buccal surfaces. This, we were told, was largely due to the foaming agent used in virtually all proprietary brands available in supermarkets. Sodium laurel sulfate has been shown to increase irritation in some people but there are only two current brands available (largely at chemist shops) which omit the use of this chemical. The other agents common to most tooth pastes are an abrasive agent as well as a detergent. It may be that brushing with just water is as effective and less irritating to some people than when using some pastes. We were told that while some electric tooth brushes have certain advantages, they are not necessary for optimal dental care.
Another common cause of xerostomia in the hospital setting is head and neck radiotherapy. It can be so devastating for the teeth that occasionally extractions are recommended before radiation starts since healing is often so protracted afterwards. Also, infections can set in, including one type of osteomyelitis which is almost untreatable.
We were shown some shocking technicolour anatomy-atlas-type dental soft-porn to demonstrate these matters. Once getting over the initial shock of close-up dental views we then looked at projections of sequential Xrays of dentition in various states of dissolution (literally). Some were in AIDS cases, others nutritional deficiencies, radiation stomatitis and cancer cases, including Kaposi's sarcoma.
Plaque was discussed at length, as well as the various ways of dealing with it. It was pointed out that in some cases plaque can extend under the gingival margins, requiring tooled removal by the dental surgeon. Other exposed areas were dealt with and we were reminded about individual brushing, tooth by tooth on the three surfaces, lingual, buccal and interfacial. Gentle but purposive brushing to engage the gingival margin was stressed. Minor bleeding in inflamed areas is to be expected for a time but continued bleeding should always be examined by the dentist. Flossing to clean the inter-dental surfaces should also be done regularly. Three times yearly check-ups in patients at increased risk was also stressed.
Topical fluoride should be applied in such high-risk individuals and the dental fluoride 'tray' is the most effective way. It is like a mouth guard which should be smeared with fluoride paste/gel and inserted for ten minutes before retiring. Dr Foltyn said that dentists will apply the same thing for a fee, but to do it oneself regularly is more appropriate for most of our patients. It would appear that fluoride can be effective even in late stage dental wear and tear.
We were advised to tell our patients with poor dentition to avoid strong mouth washes with alcohol bases such as Listerine. A water based mouth wash with antiseptic is more appropriate and less likely to cause irritation. Chemists can advise on the types.
The methadone 'syrup' marketed in Australia still contains sorbitol which is a sugar. Although it is not actively absorbed and is safe for diabetics, as a sugar it is still a fuel for oral bacteria and alcohol with other constituents are not likely to help dental hygiene. The sugar-free 'solution' Biodone should probably be our 'first line' product and the 'syrup' mainly used for those sensitive patients who are unable to tolerate the pure medicine. But importantly, Dr Foltyn says that this must not give any false sense of dental security as xerostomia will occur to the same degree with both products.
The use of buprenorphine may also cause dental problems although one would hope to a lesser degree than oral methadone syrup. We need to watch carefully with this new medication and advise regular dental check-ups.
There are many other issues which had to be left to another session and there was lively discussion on this pressing issue. We need to examine better analgesia during and after dental surgery in dependency patients. Antibiotics in those with heart murmurs, prosthetic joints, etc need to be addressed. Putting more resources into high risk cases should be a public health priority as good teeth can improve self confidence, job prospects and even romance!
Dr Foltyn can be contacted for more information. He can send email copies of the excellent hand-out for dental recommendations in xerostomia (dry mouth) as well as the grizzly photographs. He requests that you place "Concord Seminar" in the title. pfoltyn@stvincents.com.au
References:
Sheridan J, Aggleton M, Carson T. Dental health and access to dental treatment: a comparison of drug users and non-drug users attending community pharmacies. British Dental Journal (2001) 191:453-457
Byrne AJ. Methadone and oral hygiene. Australian Dental Journal. 1996 41;1:61
comments and lecture summary by Andrew Byrne ..
5 May 2003
Can you compare cannabis with tobacco? BMJ editorial speculates.
'Comparing cannabis with tobacco'. Henry JA, Oldfield WLG, Kon OM. BMJ (2003) 326: 942-943
I would commend these authors on using the correct scientific term cannabis, unlike some colleagues who seem to prefer terms allegedly introduced by governments rather than scientists.
That said, this is one of the most un-scientific BMJ articles I have read. Despite their being opposites in most respects, Henry and co-authors try to compare cannabis and tobacco. While both are common psychoactive drugs, cannabis is a relaxant, tobacco a partial-stimulant. One is highly addicting, the other is not. One has been prescribed by physicians down the ages and continues to be recommended in certain clinical circumstances by doctors of good repute. Hence a 'comparison' is an intriguing concept unless clearly stated objectives are being examined (eg. dependency, mortality, side effects, beneficial effects, etc).
Cannabis has an extremely low mortality while tobacco's toll is legion. Nearly 20,000 Australians die from tobacco related disease each year with few if any cannabis reported deaths.
When examining any drug, one looks for costs and benefits but these authors have only looked for 'costs' and, for cannabis, then they can only point to 'associations'. Even if cannabis actually caused some cases of mental disease (and it does induce dependency in a small proportion of heavy users), the drug may also alleviate some conditions such as anxiety, insomnia, depression, anorexia or chronic pains.
These authors state that it might be seen as 'scaremongering' to speculate on the basis of cannabis being of equal toxicity as tobacco ... yet they go ahead and do just that: "the corresponding figure for deaths among 3.2 million cannabis smokers would be 30,000" [annually in the UK]. Can these authors be serious when no group of suspected cases is yet to be reported after the drug has been used for thousands of years in western society? If they are interested in speculation, why don't they look at alcohol consumption in cannabis smokers?
Quite apart from their tenuous position in trying to point to cardiovascular complications which may occur with smoking cannabis, they make numerous questionable and unreferenced statements in their paper including the howler about cannabis strength increasing over the years (by 10 to 20 times!). Even if this were true, it would mean less by-products for the same amount of drug and thus possibly safer smoking. Also, cannabis can be taken orally with no effect on the lungs at all, but these authors do not canvass that issue, nor other harm reduction steps. Without references, they also quote "Nederweed" ('the variety smoked in the Netherlands') which they claim has an *average* of 10-11% tetrahydrocannabinol. This is obviously unhelpful since Holland, like other countries, has a variety of cannabis and resins available on the market, including cannabis cookies.
These authors make much of the increase in cannabis use and the reductions in tobacco consumption in recent years. However, they are not open enough to discuss the legal status of the drugs. If these authors are honestly concerned about harms from cannabis then it is hard to understand why they would ignore the spectacular failing of current prohibitions in addressing these harms. The results of long term cannabis decriminalization (eg. South Australia, Holland) are equally ignored by these 'scaremongers' (to use their own term).
comments by Andrew Byrne ..
http://bmj.com/cgi/content/full/326/7396/942
I would commend these authors on using the correct scientific term cannabis, unlike some colleagues who seem to prefer terms allegedly introduced by governments rather than scientists.
That said, this is one of the most un-scientific BMJ articles I have read. Despite their being opposites in most respects, Henry and co-authors try to compare cannabis and tobacco. While both are common psychoactive drugs, cannabis is a relaxant, tobacco a partial-stimulant. One is highly addicting, the other is not. One has been prescribed by physicians down the ages and continues to be recommended in certain clinical circumstances by doctors of good repute. Hence a 'comparison' is an intriguing concept unless clearly stated objectives are being examined (eg. dependency, mortality, side effects, beneficial effects, etc).
Cannabis has an extremely low mortality while tobacco's toll is legion. Nearly 20,000 Australians die from tobacco related disease each year with few if any cannabis reported deaths.
When examining any drug, one looks for costs and benefits but these authors have only looked for 'costs' and, for cannabis, then they can only point to 'associations'. Even if cannabis actually caused some cases of mental disease (and it does induce dependency in a small proportion of heavy users), the drug may also alleviate some conditions such as anxiety, insomnia, depression, anorexia or chronic pains.
These authors state that it might be seen as 'scaremongering' to speculate on the basis of cannabis being of equal toxicity as tobacco ... yet they go ahead and do just that: "the corresponding figure for deaths among 3.2 million cannabis smokers would be 30,000" [annually in the UK]. Can these authors be serious when no group of suspected cases is yet to be reported after the drug has been used for thousands of years in western society? If they are interested in speculation, why don't they look at alcohol consumption in cannabis smokers?
Quite apart from their tenuous position in trying to point to cardiovascular complications which may occur with smoking cannabis, they make numerous questionable and unreferenced statements in their paper including the howler about cannabis strength increasing over the years (by 10 to 20 times!). Even if this were true, it would mean less by-products for the same amount of drug and thus possibly safer smoking. Also, cannabis can be taken orally with no effect on the lungs at all, but these authors do not canvass that issue, nor other harm reduction steps. Without references, they also quote "Nederweed" ('the variety smoked in the Netherlands') which they claim has an *average* of 10-11% tetrahydrocannabinol. This is obviously unhelpful since Holland, like other countries, has a variety of cannabis and resins available on the market, including cannabis cookies.
These authors make much of the increase in cannabis use and the reductions in tobacco consumption in recent years. However, they are not open enough to discuss the legal status of the drugs. If these authors are honestly concerned about harms from cannabis then it is hard to understand why they would ignore the spectacular failing of current prohibitions in addressing these harms. The results of long term cannabis decriminalization (eg. South Australia, Holland) are equally ignored by these 'scaremongers' (to use their own term).
comments by Andrew Byrne ..
http://bmj.com/cgi/content/full/326/7396/942
More psychosocial services improve outcomes. No surprise.
The Role of Wrap Around Services in Retention and Outcome in Substance Abuse Treatment: Finding From the Wrap Around Service Impact Study. Pringle JL, Edmondston LA et al. Addictive Disorders and Their Treatment (2002) 1;4:109-118
Dear Colleagues,
This lead article had the promise to describe one of the most useful studies since McLellan and Woody's work a decade ago on psychosocial supports in addiction treatment. Sadly, such is not the case as we are not even told what specific treatment these patients were receiving, so we cannot generalise to other settings. Also, there was no control group, making the conclusions of limited value.
The authors found unsurprisingly that improved retention and other outcomes in those who used extra support in ten main areas (legal services, nutrition, child care, education, domestic, housing, medical care, mental health services, transport, vocational services). Their almost 'motherhood' conclusion states that the findings "support policies that address clients' broader biopsychosocial needs while substance abuse treatment is provided". This is hardly surprising, but sadly it is the sort of argument used by some in the methadone "industry" and government to support limiting methadone treatment to formal clinics in the US. Yet 'medical' methadone using community dispensing is used successfully overseas as well as in numerous American trials.
Supervised methadone in opioid dependent citizens is the most common and best evaluated treatment. Yet inexplicably, I could not find mention of methadone in the entire 10 pages of this article which looked at outcomes at 3 and 12 months. While a range of treatments should be available to opioid dependent patients, methadone maintenance treatment (MMT) is often chosen treatment by heroin dependent subjects. The availability of MMT and its quality are known to be most important factors in (1) attracting patients, (2) retaining patients in treatment and (3) improving important outcome measures, including viral transmission and mortality from all causes. The outcome of excessive prescribing may be overdose death and inadequate doses may lead to early drop-outs, which can also lead to fatalities. Poor psychosocial services could also have untoward consequences in a proportion, although details have never been examined, but usually only their existance and utilization by trial subjects.
It is unfortunate and extraordinary that these researchers could closely examine one aspect of treatment while ignoring other crucial elements, especially those already known to directly affect outcomes. Methadone dose, administration and additional psychosocial supports have long been known to influence outcomes ... in some cases dramatically. I can see little scientific or clinical relevance for this odd item which seems to lack clinical input, except to almost completely ignore therapeutics which necessarily must occur hand in hand with psychosocial services in those who continue to attend for treatment. It is disappointing that there were apparently no physicians involved in this paper.
We know that even with rudimentary ancillary services, prescribed methadone with sufficient dose levels and supervision is highly efficacious, enabling most subjects to regain their independence rapidly (Yancovits 1991, etc). The remainder clearly need more help and these can be recognised in the clinical setting within weeks of starting treatment. While possibly beyond the scope of this study, those who need most help are, paradoxically, those who drop out of treatment early. While these researchers found that most subjects had a need for at least one wrap around service in the course of treatment, this probably applied to those giving the treatment as well (and those reading the article!).
comments by Andrew Byrne ..
Dear Colleagues,
This lead article had the promise to describe one of the most useful studies since McLellan and Woody's work a decade ago on psychosocial supports in addiction treatment. Sadly, such is not the case as we are not even told what specific treatment these patients were receiving, so we cannot generalise to other settings. Also, there was no control group, making the conclusions of limited value.
The authors found unsurprisingly that improved retention and other outcomes in those who used extra support in ten main areas (legal services, nutrition, child care, education, domestic, housing, medical care, mental health services, transport, vocational services). Their almost 'motherhood' conclusion states that the findings "support policies that address clients' broader biopsychosocial needs while substance abuse treatment is provided". This is hardly surprising, but sadly it is the sort of argument used by some in the methadone "industry" and government to support limiting methadone treatment to formal clinics in the US. Yet 'medical' methadone using community dispensing is used successfully overseas as well as in numerous American trials.
Supervised methadone in opioid dependent citizens is the most common and best evaluated treatment. Yet inexplicably, I could not find mention of methadone in the entire 10 pages of this article which looked at outcomes at 3 and 12 months. While a range of treatments should be available to opioid dependent patients, methadone maintenance treatment (MMT) is often chosen treatment by heroin dependent subjects. The availability of MMT and its quality are known to be most important factors in (1) attracting patients, (2) retaining patients in treatment and (3) improving important outcome measures, including viral transmission and mortality from all causes. The outcome of excessive prescribing may be overdose death and inadequate doses may lead to early drop-outs, which can also lead to fatalities. Poor psychosocial services could also have untoward consequences in a proportion, although details have never been examined, but usually only their existance and utilization by trial subjects.
It is unfortunate and extraordinary that these researchers could closely examine one aspect of treatment while ignoring other crucial elements, especially those already known to directly affect outcomes. Methadone dose, administration and additional psychosocial supports have long been known to influence outcomes ... in some cases dramatically. I can see little scientific or clinical relevance for this odd item which seems to lack clinical input, except to almost completely ignore therapeutics which necessarily must occur hand in hand with psychosocial services in those who continue to attend for treatment. It is disappointing that there were apparently no physicians involved in this paper.
We know that even with rudimentary ancillary services, prescribed methadone with sufficient dose levels and supervision is highly efficacious, enabling most subjects to regain their independence rapidly (Yancovits 1991, etc). The remainder clearly need more help and these can be recognised in the clinical setting within weeks of starting treatment. While possibly beyond the scope of this study, those who need most help are, paradoxically, those who drop out of treatment early. While these researchers found that most subjects had a need for at least one wrap around service in the course of treatment, this probably applied to those giving the treatment as well (and those reading the article!).
comments by Andrew Byrne ..
BMJ article. More deaths in ‘successful’ detox cases.
Loss of tolerance and overdose mortality after inpatient opiate detoxification: follow up study. Strang J, McCambridge J, Best D, Beswick T, Bearn J, Rees S, Gossop M. BMJ 2003 326:959-960
Dear Colleagues,
Concerned about the excessive overdose mortality in England in heroin users, Strang had the excellent idea of looking prospectively at detox candidates. This showed that out of 137 inpatient detox subjects 5 (3.6%) had died within a year. This is within the reported ranges for opioid dependent populations not in maintenance treatment (2 - 7%pa). Three deaths were overdoses and the other 2 may have been drug related (infection and renal failure in relapsed patients). However, and most importantly, these Maudsley researchers managed to contact and interview most of their survivors (103, 78% at a mean of 9 months). This confirmed strong associations with death vs. survival (1) living alone (80% vs 16%) and the possibly related matters of (2) spending longer in detox (25 vs. 15 days) and (3) completing 28 day detoxification (100% vs 67%). Consistent with other studies, all deaths were male and were more likely in intermittent users cf. regular heavy users. Sadly, of the 71% who were prescribed methadone the mean reported daily dose was approximately 29mg (sd ~23mg). Professor Strang's own recommendations are for a minimum of 60mg to be effective. These patients may have been offered inadequate and therefore ineffective methadone treatment. Such a situation may have seen patients who were not "ready" for detoxification applying for it.
Is it disappointing that despite follow-up questionnaires, we are not told what proportion of detox patients remained opioid-free at 9 months, although we are told that only 37 (27%) achieved complete abstinence and became what these researchers call 'lost tolerance' (LT) category. All 5 deaths came from this small group, thus yielding a mortality amongst 'successful' detox subjects ('completers') of 13.5% at one year (and 3 were dead within four months).
There have now been at least five good studies showing apparently increased mortality in heroin addicts who have detoxed from opioids including prison discharges (references below). Each adds to the now very worrying literature on overdose deaths.
There can be few who could be more deterred by legal sanctions against heroin use than recently released prisoners. Yet it is these very people who are at very high risk of both drug use and complications from that use, including risk of death (up to 14 fold in one study). It is believed that the reduced tolerance of people who have undergone any form of detoxification (including 'rapid detox') may render them at higher risk from overdose on illicit drugs of unknown strength.
We know that overdose cases are more likely to be occasional users, live alone, be male and, paradoxically, to have completed detoxification. These authors find the latter outcome 'counterintuitive' but also concede that reduced tolerance and unknown strength of street drugs could be a cause.
This study should not be taken to mean that detox should not be offered, but it demonstrates that it is not an evidence-based intervention and needs to be patient-instigated when other options have been unsatisfactory or inappropriate. Detoxification should never be compulsory since this is known to result in increased death rates as found in rigorous Swedish research.
Education about not injecting alone, using supervised facilities where available and using smaller quantities have the potential to avoid most overdoses.
comments by Andrew Byrne ..
this item: http://bmj.com/cgi/content/full/326/7396/959
Seaman SR, Brettle RP, Gore SM. Mortality from overdose among injecting drug users recently released from prison: database linkage study. BMJ 1998; 316:426-428
Miotto K, McCann MJ, Rawson RA, Frosch D, Ling W. Overdose, suicide attempts and death among a cohort of naltrexone-treated opioid addicts. Drug and Alcohol Dependence (1997) 45:131-134
Kakko J, Svanborg KD, Kreek MJ, Heilig M. 1-year retention and social function after buprenorphine-associated relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. (2003) Lancet 361:662-668
Grönbladh L, Öhlund LS, Gunne LM. Mortality in heroin addiction: impact of methadone treatment. Acta Psychiatr Scand 1990; 82: 223 - 227.
Loss of tolerance and overdose mortality after inpatient opiate detoxification: follow up study Strang J, McCambridge J, Best D, Beswick T, Bearn J, Rees S, Gossop M. BMJ (2003) 326: 959-960
Darke S, Hall W, Kaye S, Ross J, Duflou J. Hair morphine concentrations of fatal heroin overdose cases and living heroin users. Addiction (2002) 97:977-984
Dear Colleagues,
Concerned about the excessive overdose mortality in England in heroin users, Strang had the excellent idea of looking prospectively at detox candidates. This showed that out of 137 inpatient detox subjects 5 (3.6%) had died within a year. This is within the reported ranges for opioid dependent populations not in maintenance treatment (2 - 7%pa). Three deaths were overdoses and the other 2 may have been drug related (infection and renal failure in relapsed patients). However, and most importantly, these Maudsley researchers managed to contact and interview most of their survivors (103, 78% at a mean of 9 months). This confirmed strong associations with death vs. survival (1) living alone (80% vs 16%) and the possibly related matters of (2) spending longer in detox (25 vs. 15 days) and (3) completing 28 day detoxification (100% vs 67%). Consistent with other studies, all deaths were male and were more likely in intermittent users cf. regular heavy users. Sadly, of the 71% who were prescribed methadone the mean reported daily dose was approximately 29mg (sd ~23mg). Professor Strang's own recommendations are for a minimum of 60mg to be effective. These patients may have been offered inadequate and therefore ineffective methadone treatment. Such a situation may have seen patients who were not "ready" for detoxification applying for it.
Is it disappointing that despite follow-up questionnaires, we are not told what proportion of detox patients remained opioid-free at 9 months, although we are told that only 37 (27%) achieved complete abstinence and became what these researchers call 'lost tolerance' (LT) category. All 5 deaths came from this small group, thus yielding a mortality amongst 'successful' detox subjects ('completers') of 13.5% at one year (and 3 were dead within four months).
There have now been at least five good studies showing apparently increased mortality in heroin addicts who have detoxed from opioids including prison discharges (references below). Each adds to the now very worrying literature on overdose deaths.
There can be few who could be more deterred by legal sanctions against heroin use than recently released prisoners. Yet it is these very people who are at very high risk of both drug use and complications from that use, including risk of death (up to 14 fold in one study). It is believed that the reduced tolerance of people who have undergone any form of detoxification (including 'rapid detox') may render them at higher risk from overdose on illicit drugs of unknown strength.
We know that overdose cases are more likely to be occasional users, live alone, be male and, paradoxically, to have completed detoxification. These authors find the latter outcome 'counterintuitive' but also concede that reduced tolerance and unknown strength of street drugs could be a cause.
This study should not be taken to mean that detox should not be offered, but it demonstrates that it is not an evidence-based intervention and needs to be patient-instigated when other options have been unsatisfactory or inappropriate. Detoxification should never be compulsory since this is known to result in increased death rates as found in rigorous Swedish research.
Education about not injecting alone, using supervised facilities where available and using smaller quantities have the potential to avoid most overdoses.
comments by Andrew Byrne ..
this item: http://bmj.com/cgi/content/full/326/7396/959
Seaman SR, Brettle RP, Gore SM. Mortality from overdose among injecting drug users recently released from prison: database linkage study. BMJ 1998; 316:426-428
Miotto K, McCann MJ, Rawson RA, Frosch D, Ling W. Overdose, suicide attempts and death among a cohort of naltrexone-treated opioid addicts. Drug and Alcohol Dependence (1997) 45:131-134
Kakko J, Svanborg KD, Kreek MJ, Heilig M. 1-year retention and social function after buprenorphine-associated relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. (2003) Lancet 361:662-668
Grönbladh L, Öhlund LS, Gunne LM. Mortality in heroin addiction: impact of methadone treatment. Acta Psychiatr Scand 1990; 82: 223 - 227.
Loss of tolerance and overdose mortality after inpatient opiate detoxification: follow up study Strang J, McCambridge J, Best D, Beswick T, Bearn J, Rees S, Gossop M. BMJ (2003) 326: 959-960
Darke S, Hall W, Kaye S, Ross J, Duflou J. Hair morphine concentrations of fatal heroin overdose cases and living heroin users. Addiction (2002) 97:977-984
22 April 2003
American Association for the Treatment of Opioid Dependence (AATOD) National Conference
Integrating Evidence-Based Practices Within Opioid Treatment
Sun 13th to Wed 16th April 2003
I was privileged to attend the AATOD conference in the Renaissance Washington DC Hotel along with many of our field's eclipsing luminaries. Over 1000 health workers came from all over the US and overseas. Much was said in the formal lectures and workshops, but face-to-face meetings with long-time, long-distance colleagues, in some cases for the first time, was a unique pleasure.
On the Saturday there were pre-conference courses on buprenorphine prescribing in office based practice and another for 'methadone advocates' (NAMA). On the Sunday afternoon, two further parallel 'strands' took place, one for local policy folk, the other involving overseas researchers and clinicians. The latter described experiences in a variety of settings in Switzerland, Italy, Israel, Bulgaria, Ukraine, Slovakia and Slovenia. Two additional American collaborations included talks of neonatal abstinence syndrome (Dr Loretta Finnegan) and high dose methadone prescribing (Dr M. Shinderman). The Canadians and Europeans at the meeting added a much needed bredth of experience. This conference which was pervaded by reaction to the uniquely American antagonism to logical drug policies. This includes regulations preventing doctors from treating their dependent patients in accordance with long-standing concordant research, mostly performed in this country.
On Monday morning we were addressed by Association President Mark Parrino, Washington D.C. Mayor Williams, D.C. Health Director James Buford, DEA Diversion Administrator Laura Nagel and SAMSA Officer Charles Curie. Surveys showed that 7% of Americans interviewed had used an illicit drug in the previous month and it was estimated that 16,000,000 were regular drug users. Surprisingly, this was not used as evidence that current policies fail to protect US families against drug problems. We were, however, reminded that 'treatment works', despite common mythology to the contrary. The virtues and proven benefits of intensive psychosocial supports for maintenance patients were extolled. The speakers quoted from the few good studies which confirm scientifically what Hippocrates described over 2000 years ago (additional services improve medical outcomes).
Parrino and his knowledgeable presenters dwelt on the 'crucial' role of these psychosocial supports. Indeed, as with diabetes and other conditions, such services can significantly improve numerous treatment outcome measures. But we know that even with minimal services, dependent folk can attain positive results in many or even most cases. Nobody would suggest denying such services if they were available, but equally, to deny methadone or other medication in adequate supervised doses, because of a lack of counselors, funding, real estate, etc, would be unacceptable in other fields. The latest moves on buprenorphine prescribing may redress some of the calcification in US policies which continue to deny simple and effective treatments to most American addicts who cannot realistically advocate on their own behalves.
The morning workshops included 'ethnic considerations', smoking cessation, 'harm reduction' integration, office based prescribing and benzo abuse. It was disappointing to me that the conference organisers did not have more practising clinicians among the 14 plenary speakers, most of whom were administrators.
I attended a workshop on a needle exchange information initiative in New York City's Bronx, given by Dr Jennifer McNeely of the Albert Einstein Medical School. She pointed out just how difficult it was to get simple practical information to patients. She had to deal with various levels of administration just to be able to pass on the contact details of 3 Bronx pharmacies selling clean needles and syringes under the new Sate legislation. It would seem that a graffito on the washroom door with the phone contacts would have had the same effect. However, by going through the correct channels, McNeely has wisely ensured that in other states with similar waivers clinics will now be able to do the same thing, thus reducing viral transmission and ultimately saving lives. This in turn may reduce the hysteria in this country over issues such as needle availability. 'Harm reduction' and needle services were under the conference heading of "hot topics". This is intriguing since each is just so uncontroversial as to be official government policy in numerous other countries.
In the Q&A session, I mentioned some details of the Sydney medically supervised injecting center where 69,000 injecting episodes occurred over 2 years with no deaths or other significant problems. One clinic manager from Pennsylvania said that she cannot even get minor changes to her clinic approved and was very pessimistic about a syringe program opening in her state. And a legal injecting room seemed light years away.
Other workshops covered cardiac rhythms in opioid users, Federal Regulation, counselors eduction, 'recovery', addiction nursing, residential care and community transfers. Another was "Administrative Withdrawal: Ethics, Implementation, and Alternatives". Apparently in various places across the country currently there are hundreds or even thousands of patients experiencing this callous indignity for reasons I could not comprehend, considering the this country's abundance of resources.
Next we had an interesting session on the introduction of buprenorphine into practice in the US. Dr Laura McNicholas gave a brief overview of the pharmacology and therapeutics, then Dr David Feillin related a number of trials of the sub-lingual combination drug including naloxone. Most of these trials involved supervised administration of the drug as distinct from the current waiver arrangements to dispense up to a month's supply at a time without supervision. Also, most of the extensive buprenorphine literature has been performed with pure buprenorphine, yet the recommendation is for American physicians to use mainly the combination product with naloxone. The claims that this is safe and effective in both treatment and avoiding diversion are not based on much scientific evidence. This shows that the drug can be abused by novice or occasional users and further, that the naloxone is absorbed up to 10% and has some clinical effects such as pupil changes. In the Q&A session mention was made of a twelve month Swedish/American study which compared buprenorphine maintenance with detox. The detox group had near zero retention rates at 2 months and, worryingly, 20% of the subjects had died. One must question the ethics of giving a virtual placebo treatment to half of such trial cases without some formal safety net.
On the Tuesday morning there were 4 papers delivered at the first plenary session. Before introducing Marc Gourevitch of the Bronx in New York City, Andrea Barthwell alluded to a concept I have always avoided: "conquering addiction". The term "brain disease" was also used in the plenaries, reflecting official policy edicts from the 1990s. The problem is that if drug addiction is a brain disease, then about 90% of us have it! I feel on safer ground calling drug dependency a 'condition'. Then, like dandruff, pregnancy, obesity or baldness, it is the sufferers who can decide if and when it becomes a 'disease' (and there were numerous user representatives present at the meeting). Dr Gourevitch spoke modestly and authoritatively about co-existing disorders in dependent patients.
Dr Leonard Seeff was ill and at short notice Dr Larry Brown spoke well on the difficult subject of HIV in dependent patients. Dr George Woody then dealt with non drug related symptoms in dependent patients. He quoted DSM IV and even later definitions of the various presentations (mentioning that the DSM V was due out in 2010!). Symptoms from a number of pre-treatment surveys found high rates of anxiety, phobic disorders, ASPD, auditory hallucinations, etc. We were also told that just as drug users suffer from a wide variety of psychiatric disorders, equally, up to 50% of mental patients can present with co-existing substance abuse problems. When the primary condition is treated the other symptoms will resolve spontaneously in a proportion of cases. We were told that two weeks was a good interval in new methadone patients to reassess such problems which may need specific interventions such as antidepressants. It would appear that MMT can improve depression, anxiety and in some cases paranoid symptoms. It has long been believed that opioids have some anti-psychotic properties.
Regarding hepatitis and HIV infections, "prevention is better than cure" is an old maxim which was apparently NOT emphasised. Needle availability was an unpardonable omission in these plenaries. It is disappointing when respected scientific experts fail to say what needs to be said. Needle availability prevents viral disease transmission and does NOT encourage drug use. Several US states have introduced 'waivers' against the bans on pharmacies selling injecting equipment (see workshop above).
After the morning plenaries there were workshops on a variety of issues: dual diagnosis, homelessness, pregnant patients. In a well attended session, Dr Peter DeMaria spoke about 'Optimizing methadone doses'. He used a number of case histories to show that dose manipulation, splitting, increases, etc can turn around a 'failure' in treatment. One case history was a MMT patient who had used heroin continuously for 12 months in treatment while on 120mg daily. While it was helpful to examine the methadone level and a dose increase, it might also be questioned why the patient was treated for twelve months in this clearly unstable state, and all the attendant risks (but better late than never!).
DeMaria also took us back to the basic pharmacology of methadone to explain withdrawal symptoms with a helpful graph of methadone levels over 48 hours and thus two doses. He reminded us of the words of Sir William Osler: "Listen to the patient, he's telling you what's wrong with him". [I seem to recall that Osler continued: "... and if you listen hard enough he may also tell you the treatment"].
DeMaria stated that daily doses of 80 to 120mg are adequate for about three quarters of patients, but that others, some with aberrant metabolism need extra, split doses or alternative drug or non-drug treatments. Drug interactions were covered in detail, including phenytoin, fluvoxamine, antiretrovirals (three of them only), anti-fit meds etc. It was gratifying that the hall was packed with attentive clinicians from all over the US since one major consistent finding of surveys of clinics is inadequate dose levels across the board (this also occurs in Australia, Great Britain and elsewhere). Then we had mention of the stereoisomers of methadone and cytochrome metabolism ... rather too complex and speculative for us front-line workers perhaps, unlike the rest of this practical presentation.
Another session, by researcher and editorialist Stewart Leavitt, was entitled "Can Addiction Research be Trusted?" He helped us with just how to assess the clinical significance of particular studies from the anecdotal ('n=1') to RCT to the hallowed 'metanalysis'. But he warned that some such studies may be "gigo" (garbage in, garbage out) since overall conclusions are only as reliable as the data they are based on. Leavitt also gave us a timely lesson on the two common ways of interpreting studies over time (1) ITT or 'intention to treat' and (2) PP 'per protocol' (analysis of only those who finish the intervention). Both have pros and cons depending on the proportion of drop outs. He introduced the terms "PLUS-cebo" (for positive effects) and "NOCI-bo" (harm causing) for the more usual term for 'dummy' treatments which do often have apparent effects in trial subjects.
Leavitt then shattered the illusion of the "Farmington consensus" (which may not be a 'consensus' at all) that all research associated with 'inappropriate' sponsorship should be rejected for publication. This ban, largely aimed at tobacco and alcohol sponsorship, could also be levelled at drug companies, health authorities, policing interest, drug cartels, etc. Dr Leavitt pointed out that all research is biased by the nature of the authors, their background, ethnicity, funding, etc. Thus it is the reader who should look at what is disclosed regarding possibly conflicts of interest, who is writing/funding the research and then decide for themselves its 'rigour' and/or relevance for their practices. 'Publication bias' was also covered in which studies which have positive outcomes are more likely to be completed and published. Laura McNicholas MD from Philadelphia VA questioned some details from the floor concerning research samples - which were clarified. Extensive references and comprehensive handouts were given on a number of clinical and ethical matters of interest and the declaration that Leavitt's service is sponsored by a manufacturer of methadone and naltrexone.
The Tuesday evening dinner included 13 awards in honour of Vincent P. Dole and Marie Nyswander who together pioneered methadone treatment. While I have no objection to credit being recognised when it is due, Washington DC is hardly the place for accolades over drug treatment or policy in the centre of these continuing epidemics (addition, HIV, hepatitis C). Hence to avoid any ill feeling, I avoided this part of the proceedings and retired back to my lodgings early to gather my thoughts. It had been a marvellous three days meeting up with dozens of colleagues from all over the US as well as further afield.
I have great admiration for all these dedicated and hard working front-line professionals, some of whom operate in situations of poor funding, dangerous work environments and limited scope for professional advancement. Even simple advocacy can be hazardous in America. But one remains in hope of improvements, and that conferences like this might seed some such positive moves.
The above is not intended to be a comprehensive summary of the conference which also had 22 diverse poster displays and many other workshops, plenaries and 'round table' discussions I could not get to.
comments by Andrew Byrne ..
4 April 2003
Addiction summaries: methadone versus buprenorphine. Does clonidine work?
'Addiction' journal, April 2003.
# Randomized, controlled comparison of methadone vs. 'bup'.
# Methadone syrup injection in 1996/7 in Adelaide.
# Does methadone kill more people than heroin?
# Poor quality of agonist treatments in England/Wales.
# Does clonidine work for withdrawal symptoms?
# 'Reductions' of bup popular but 90% need repeat treatment.
Dear Colleagues,
This edition reveals an extraordinary wealth of clinically relevant research material ... but also shows an intriguing reversal of health priorities by the editors. Some truly 'landmark' research is 'buried', while the first two reports and their related editorials are on subjects of modest, local and/or historical moment. The injecting of methadone syrup in Adelaide from 1996/7 and opiate deaths in England 1993-98 are both subjects deserving of clarification. But as is so often the case with Addiction, the tenor seems to be to question whether methadone treatment is a valid intervention rather than how to use it more effectively. After 35 years of positive research, Addiction should abandon its persistently negative focus on methadone treatment. Agonist treatments are not perfect, but they are now used by most western health authorities as one helpful approach to opioid addiction.
As a lead research journal, Addiction's main focus should be how to maximise the benefits of this proven treatment, not to question its very existence. The first page of the April edition in entitled: "Methadone syrup injection in Australia: a sentinel finding?" The writers state that there is a lack of reports of methadone injecting outside of Australasia. They relate some alarming consequences of methadone injecting, each being potentially paralleled for street heroin injecting, yet neither the nature nor extent of the problem is backed up by references. In fact, one of their suggested solutions is to examine introducing a type of methadone which is suitable for injection. In fact, since this study was completed, a safer water solution of methadone has begun replacing the older 'syrup' mixture. It is disappointing that the Adelaide researchers only had 2 questions: had subjects 'ever injected' and 'was there any injecting in the previous 6 months?' Thus the story lacked quantitation. Hardly fodder for the lead research paper in the world's most venerable dependency journal!
'Addiction' might care to ask a guest writer to look at why agonist treatments are still so restricted and why so much is of such poor quality, especially in England, where Addiction is published. Established guidelines are almost completely ignored by doctors to the cost of their patients and the UK community. Professor Dole, who originated the use of agonist treatments in New York, states that injecting behaviour (and therefore its complications) can be almost completely eliminated in up to 95% of subjects by using adequate doses of methadone with appropriate supervision and sufficient support services. All treatment should be judged according to whether it is in accordance with established treatment guidelines (eg. Strang's UK guidelines). Maintenance treatments save the health care system more per dollar invested than most other interventions. They reduce crime, prevent HIV infection and probably also hepatitis C yet they are still maligned in a way which is not based on logic.
Amongst the plethora of clinical material, the April edition has two important items on subjects after my own heart. Mattick et al. have published their three-city study of double blind methadone versus buprenorphine maintenance (see my detailed review elsewhere). At 3 months they found only minor differences in retention, drug use and side effects between these two drugs. This trial is very important scientifically and of substantial clinical relevance. It probably should have been the first item in Addiction and certainly deserves an editorial, considering buprenorphine was released in the USA recently. This may seem a small criticism, but not so the fact that Hickman's study of opiate deaths in England gives text references as numbers, while the actual list is alphabetical, making the article incomprehensible to the reader. The author was kind enough to send me an earlier draft with his own numbered references. I am bemused by the lack of editorial control at Addiction which led to this error. One wonders that the proper peer review process did not prevent such an error. The management at Addiction owe Hickman and colleagues an apology for this humiliating error.
The content of Hickman's article relates to an issue into which I had a personal input back in 1997: that 'methadone kills more people than heroin'. It is a sad fact that the issue is still being debated rather than being acted upon. In fact the last time Addiction published my name unrelated to some gossip or ridicule from house writers, was on the issue raised by Newcombe. The item by Hickman shows that there are still many (possibly unnecessary) deaths from methadone in England and Wales, but not as many as caused by heroin, and the number is still increasing. Both Hickman and the editorialist touch on clinical practice in England, but neither seems able to state that there is strong anecdotal evidence pointing to abysmal compliance with clinical guidelines in England and Wales. The drug is usually prescribed by doctors with no training in addiction medicine, without supervision of the medication and at dose levels which are often inadequate to quell cravings for 24 hours. Such deficiencies are inconsistent with Strang's detailed official UK Dependency Treatment Guidelines (1999). There appears to be no coherent plan either by professional groups, the NHS nor the National Addiction Centre to address these failings, despite them probably leading to the deaths of many people annually. This edition would have been an ideal place to address the issue. I offered to write such a piece but editor Edwards, while conceding the need, has not followed up on the matter it would appear.
Another item, from the group at Johns Hopkins, gave trial subjects on 30mg daily doses of methadone injections of naloxone and medicated them with clonidine or lofexidine without placebo control. Approval was granted by The Johns Hopkins Bayview Medical Center Institutional Review Board and individual consent given. We are not told if this is a properly constituted ethics committee, but it is gratifying that subjects were offered either a 90 day reduction course of methadone and/or assistance with referral to a long term maintenance facility in Baltimore after their services in this somewhat brutal trial (for which they were paid volunteers). It is a moot point as to whether currently addicted individuals can consent to a single option, especially one which is not an appropriate treatment for addiction (fixed 30mg of methadone daily). Unsurprisingly, 6 subjects who agreed to participate dropped out at the prospect of naloxone injections. However, 8 of 14 who completed the twice weekly experimental in-patient protocol effectively showed that neither lofexidine nor clonidine did anything significant in reducing withdrawal symptoms. My patients have told me for years that clonidine does little for withdrawal symptoms. Now here at last is proof!
In yet another item from Baltimore 120 subjects were offered a three day course of buprenorphine using 'high' (4mg) or 'low' (2mg) dose. This can hardly rate as 'reduction treatment' since the drug takes at least 5 days just to stabilize. It is not stated which professional protocol this 'treatment' is taken from. One wonders at the wisdom of giving a "treatment" which has little if any scientifically proven benefit and then reporting near 90% failure rates in an international journal. There was apparently no safety net reported by these researchers who noted frequent relapses in their patients. At 1, 3 and 6 months there were progressively fewer patients were contacted (80%, 55%, 47%). The authors' first statistics do not take lost subjects into account and their 6 month abstinence figure of 62% (self report) and 25% (clear urine test) are then translated for clarity to 35 and 14 subjects out of the original 119 (29%, 12%). A proportion of those lost to follow up may have been dead but this is not addressed by the Gandhi and co-authors. Their conclusion that there was 'reduced frequency and intensity of drug use' following their "intervention" is based on respondents only and is thus of limited validity, like their 'treatment'. All patients deserve appropriate treatment and this means regular assessments and if agonist prescription is appropriate on one day, like insulin, lithium or Prozac, it is nearly always appropriate on the next. Discharge from treatment should never be arbitrary as it was for all of these patients.
comments by Andrew Byrne ..
# Randomized, controlled comparison of methadone vs. 'bup'.
# Methadone syrup injection in 1996/7 in Adelaide.
# Does methadone kill more people than heroin?
# Poor quality of agonist treatments in England/Wales.
# Does clonidine work for withdrawal symptoms?
# 'Reductions' of bup popular but 90% need repeat treatment.
Dear Colleagues,
This edition reveals an extraordinary wealth of clinically relevant research material ... but also shows an intriguing reversal of health priorities by the editors. Some truly 'landmark' research is 'buried', while the first two reports and their related editorials are on subjects of modest, local and/or historical moment. The injecting of methadone syrup in Adelaide from 1996/7 and opiate deaths in England 1993-98 are both subjects deserving of clarification. But as is so often the case with Addiction, the tenor seems to be to question whether methadone treatment is a valid intervention rather than how to use it more effectively. After 35 years of positive research, Addiction should abandon its persistently negative focus on methadone treatment. Agonist treatments are not perfect, but they are now used by most western health authorities as one helpful approach to opioid addiction.
As a lead research journal, Addiction's main focus should be how to maximise the benefits of this proven treatment, not to question its very existence. The first page of the April edition in entitled: "Methadone syrup injection in Australia: a sentinel finding?" The writers state that there is a lack of reports of methadone injecting outside of Australasia. They relate some alarming consequences of methadone injecting, each being potentially paralleled for street heroin injecting, yet neither the nature nor extent of the problem is backed up by references. In fact, one of their suggested solutions is to examine introducing a type of methadone which is suitable for injection. In fact, since this study was completed, a safer water solution of methadone has begun replacing the older 'syrup' mixture. It is disappointing that the Adelaide researchers only had 2 questions: had subjects 'ever injected' and 'was there any injecting in the previous 6 months?' Thus the story lacked quantitation. Hardly fodder for the lead research paper in the world's most venerable dependency journal!
'Addiction' might care to ask a guest writer to look at why agonist treatments are still so restricted and why so much is of such poor quality, especially in England, where Addiction is published. Established guidelines are almost completely ignored by doctors to the cost of their patients and the UK community. Professor Dole, who originated the use of agonist treatments in New York, states that injecting behaviour (and therefore its complications) can be almost completely eliminated in up to 95% of subjects by using adequate doses of methadone with appropriate supervision and sufficient support services. All treatment should be judged according to whether it is in accordance with established treatment guidelines (eg. Strang's UK guidelines). Maintenance treatments save the health care system more per dollar invested than most other interventions. They reduce crime, prevent HIV infection and probably also hepatitis C yet they are still maligned in a way which is not based on logic.
Amongst the plethora of clinical material, the April edition has two important items on subjects after my own heart. Mattick et al. have published their three-city study of double blind methadone versus buprenorphine maintenance (see my detailed review elsewhere). At 3 months they found only minor differences in retention, drug use and side effects between these two drugs. This trial is very important scientifically and of substantial clinical relevance. It probably should have been the first item in Addiction and certainly deserves an editorial, considering buprenorphine was released in the USA recently. This may seem a small criticism, but not so the fact that Hickman's study of opiate deaths in England gives text references as numbers, while the actual list is alphabetical, making the article incomprehensible to the reader. The author was kind enough to send me an earlier draft with his own numbered references. I am bemused by the lack of editorial control at Addiction which led to this error. One wonders that the proper peer review process did not prevent such an error. The management at Addiction owe Hickman and colleagues an apology for this humiliating error.
The content of Hickman's article relates to an issue into which I had a personal input back in 1997: that 'methadone kills more people than heroin'. It is a sad fact that the issue is still being debated rather than being acted upon. In fact the last time Addiction published my name unrelated to some gossip or ridicule from house writers, was on the issue raised by Newcombe. The item by Hickman shows that there are still many (possibly unnecessary) deaths from methadone in England and Wales, but not as many as caused by heroin, and the number is still increasing. Both Hickman and the editorialist touch on clinical practice in England, but neither seems able to state that there is strong anecdotal evidence pointing to abysmal compliance with clinical guidelines in England and Wales. The drug is usually prescribed by doctors with no training in addiction medicine, without supervision of the medication and at dose levels which are often inadequate to quell cravings for 24 hours. Such deficiencies are inconsistent with Strang's detailed official UK Dependency Treatment Guidelines (1999). There appears to be no coherent plan either by professional groups, the NHS nor the National Addiction Centre to address these failings, despite them probably leading to the deaths of many people annually. This edition would have been an ideal place to address the issue. I offered to write such a piece but editor Edwards, while conceding the need, has not followed up on the matter it would appear.
Another item, from the group at Johns Hopkins, gave trial subjects on 30mg daily doses of methadone injections of naloxone and medicated them with clonidine or lofexidine without placebo control. Approval was granted by The Johns Hopkins Bayview Medical Center Institutional Review Board and individual consent given. We are not told if this is a properly constituted ethics committee, but it is gratifying that subjects were offered either a 90 day reduction course of methadone and/or assistance with referral to a long term maintenance facility in Baltimore after their services in this somewhat brutal trial (for which they were paid volunteers). It is a moot point as to whether currently addicted individuals can consent to a single option, especially one which is not an appropriate treatment for addiction (fixed 30mg of methadone daily). Unsurprisingly, 6 subjects who agreed to participate dropped out at the prospect of naloxone injections. However, 8 of 14 who completed the twice weekly experimental in-patient protocol effectively showed that neither lofexidine nor clonidine did anything significant in reducing withdrawal symptoms. My patients have told me for years that clonidine does little for withdrawal symptoms. Now here at last is proof!
In yet another item from Baltimore 120 subjects were offered a three day course of buprenorphine using 'high' (4mg) or 'low' (2mg) dose. This can hardly rate as 'reduction treatment' since the drug takes at least 5 days just to stabilize. It is not stated which professional protocol this 'treatment' is taken from. One wonders at the wisdom of giving a "treatment" which has little if any scientifically proven benefit and then reporting near 90% failure rates in an international journal. There was apparently no safety net reported by these researchers who noted frequent relapses in their patients. At 1, 3 and 6 months there were progressively fewer patients were contacted (80%, 55%, 47%). The authors' first statistics do not take lost subjects into account and their 6 month abstinence figure of 62% (self report) and 25% (clear urine test) are then translated for clarity to 35 and 14 subjects out of the original 119 (29%, 12%). A proportion of those lost to follow up may have been dead but this is not addressed by the Gandhi and co-authors. Their conclusion that there was 'reduced frequency and intensity of drug use' following their "intervention" is based on respondents only and is thus of limited validity, like their 'treatment'. All patients deserve appropriate treatment and this means regular assessments and if agonist prescription is appropriate on one day, like insulin, lithium or Prozac, it is nearly always appropriate on the next. Discharge from treatment should never be arbitrary as it was for all of these patients.
comments by Andrew Byrne ..
How does buprenorphine compare with methadone? A rigorous multi-centre study from Australia.
Buprenorphine versus methadone maintenance therapy: a randomized double-blind trial with 405 opioid-dependent patients. Mattick RP, Ali R, White JM, O'Brien S, Wolk S, Danz C. Addiction 2003 98:441-452
Dear Colleagues,
This vital multicentre trial comparing 3 months maintenance treatment gives us invaluable information on the use of buprenorphine for heroin addicts. Unlike some other fixed dose studies, the patients in both groups here were treated in a clinical, 'naturalistic' manner with flexible doses supervised with true 'blinding' of medications (each started with active/dummy). Inductions and dosing practices were in broad accordance with established guidelines, such as those from the UK (Strang, 1999) and the various Australian clinical guidelines. In the second month of treatment daily doses of up to 150mg of methadone and 32mg of buprenorphine were used (means 57mg and 11mg respectively). Dose increases were in response to patient reports of cravings, illicit drug use and doses just 'not holding' them.
If the overall numbers randomized to each treatment are considered (205 and 200), the retention rates at 13 weeks can be calculated at 58.5% for methadone and 48% for buprenorphine. My amateur statistical estimation sees this as reaching significance. However, in their own calculations, these authors exclude the patients who did not receive an initial dose (significantly, 3 for methadone and 8 for buprenorphine, a drug with more clinical limitations on starting) making their retention rates 59.4% and 50.0% (p=0.06). While this may seem picky, the authors also spend some effort looking at this significance. Regarding (1) the mean length of stay, 59 vs. 67 days and (2) evidently by applying a survival analysis across the 13 weeks there was a significant difference between the groups (but not at 6 weeks). The authors speculate about a possible 'type I error' since there were some parallel questions with possible 'overlapping' factors.
The overall findings are that this study again confirms that in the normal clinical context buprenorphine is almost as good as methadone at retaining opioid-dependent patients in treatment. It also showed equal benefits regarding reduced illicit heroin use and equal side effect profile for those remaining in treatment. This profile is much more extensive that my own experience: up to two dozen significant side effects suffered by patients in both groups (eg. nausea 16-17%; vomiting 8%; 'flu symptoms 7-10%; headache 11-13%). In my own practice I have seen virtually no side effects with buprenorphine and only sweating, constipation and some sexual dysfunction as prominent problems in some methadone patients. I understand that these researchers spared no effort in regularly canvassing for reports of side effects, some of which just might have been from withdrawals or other causes, hence a possibility of over-reporting compared to other research.
The question seemingly posed originally by these researchers, "is buprenorphine better than methadone" is no longer a useful question to my mind. We now known from years of research that buprenorphine works well as an outpatient treatment for opioid addiction, in many ways comparable with methadone prescription. Now we need to implement the treatment in a logical fashion for those who may benefit from it. The drug is much more expensive than methadone. It has limited long term safety data, although that which exists is reassuring. Buprenorphine is not proven safe in pregnancy although there too, early studies indicate no problem in many pregnancies studied while the drug was continued.
Hence, like the second antibiotic introduced after penicillin, buprenorphine should be used initially for those unable or unwilling to take methadone. It may be that it will become a first line drug at some stage but in my book it is currently an excellent alternative in cases where there are problems with methadone. My own practice has 15% of our maintenance patients taking buprenorphine. The state of NSW has 1,600 out of 16,000 on the newer drug 2 years after its introduction under the same general conditions as for methadone maintenance (but fewer take-home provisions).
Comments by Andrew Byrne ..
Dear Colleagues,
This vital multicentre trial comparing 3 months maintenance treatment gives us invaluable information on the use of buprenorphine for heroin addicts. Unlike some other fixed dose studies, the patients in both groups here were treated in a clinical, 'naturalistic' manner with flexible doses supervised with true 'blinding' of medications (each started with active/dummy). Inductions and dosing practices were in broad accordance with established guidelines, such as those from the UK (Strang, 1999) and the various Australian clinical guidelines. In the second month of treatment daily doses of up to 150mg of methadone and 32mg of buprenorphine were used (means 57mg and 11mg respectively). Dose increases were in response to patient reports of cravings, illicit drug use and doses just 'not holding' them.
If the overall numbers randomized to each treatment are considered (205 and 200), the retention rates at 13 weeks can be calculated at 58.5% for methadone and 48% for buprenorphine. My amateur statistical estimation sees this as reaching significance. However, in their own calculations, these authors exclude the patients who did not receive an initial dose (significantly, 3 for methadone and 8 for buprenorphine, a drug with more clinical limitations on starting) making their retention rates 59.4% and 50.0% (p=0.06). While this may seem picky, the authors also spend some effort looking at this significance. Regarding (1) the mean length of stay, 59 vs. 67 days and (2) evidently by applying a survival analysis across the 13 weeks there was a significant difference between the groups (but not at 6 weeks). The authors speculate about a possible 'type I error' since there were some parallel questions with possible 'overlapping' factors.
The overall findings are that this study again confirms that in the normal clinical context buprenorphine is almost as good as methadone at retaining opioid-dependent patients in treatment. It also showed equal benefits regarding reduced illicit heroin use and equal side effect profile for those remaining in treatment. This profile is much more extensive that my own experience: up to two dozen significant side effects suffered by patients in both groups (eg. nausea 16-17%; vomiting 8%; 'flu symptoms 7-10%; headache 11-13%). In my own practice I have seen virtually no side effects with buprenorphine and only sweating, constipation and some sexual dysfunction as prominent problems in some methadone patients. I understand that these researchers spared no effort in regularly canvassing for reports of side effects, some of which just might have been from withdrawals or other causes, hence a possibility of over-reporting compared to other research.
The question seemingly posed originally by these researchers, "is buprenorphine better than methadone" is no longer a useful question to my mind. We now known from years of research that buprenorphine works well as an outpatient treatment for opioid addiction, in many ways comparable with methadone prescription. Now we need to implement the treatment in a logical fashion for those who may benefit from it. The drug is much more expensive than methadone. It has limited long term safety data, although that which exists is reassuring. Buprenorphine is not proven safe in pregnancy although there too, early studies indicate no problem in many pregnancies studied while the drug was continued.
Hence, like the second antibiotic introduced after penicillin, buprenorphine should be used initially for those unable or unwilling to take methadone. It may be that it will become a first line drug at some stage but in my book it is currently an excellent alternative in cases where there are problems with methadone. My own practice has 15% of our maintenance patients taking buprenorphine. The state of NSW has 1,600 out of 16,000 on the newer drug 2 years after its introduction under the same general conditions as for methadone maintenance (but fewer take-home provisions).
Comments by Andrew Byrne ..
Lancet article - strong science but serious ethical issues.
1-year retention and social function after buprenorphine-associated relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. Kakko J, Svanborg KD, Kreek MJ, Heilig M. (2003) Lancet 361:662-668
Dear Colleagues,
The Swedes have produced some of the most quoted data showing the life saving properties of methadone maintenance, partly because this treatment is so severely restricted in Sweden. Thus trial candidates who are randomized not to receive prescription treatment, or who are discharged from treatment, rarely receive agonist maintenance therapy which might be available in the normal course of medical practice in other ‘normal’ countries.
From work performed in the 1980s, Grönbladh and colleagues showed a very high mortality in those rejected from methadone treatment - almost 8% per year. In an even more rigorous and controlled study using sublingual buprenorphine, Kakko et al. have found what the accompanying Lancet editorial calls: "massive 20% mortality at one year in the placebo group versus 0% in the buprenorphine group [which] is immensely concerning". Indeed, a trial using placebo in heroin addiction treatment would be considered unethical in Australia.
This trial provides strong support for buprenorphine maintenance since at a fixed dose of 16mg daily it had a 12 month retention rate of 75% and no deaths, compared with placebo: 0% retention at 2 months and four out of twenty being dead from overdose by 12 months. All 'placebo' (actually '6 day reduction') cases had access to intensive levels of psychosocial supports, some of which were reported to have induced paradoxical cravings. I understand that one of the 5 buprenorphine drop-outs has also since died.
The mortality rate is even more worrying considering that these candidates were chosen from over 400 applicants based on less severe dependency and less poly drug/alcohol use. Thus none of the chosen candidates was suitable for the stringent Swedish criteria for methadone prescription (4 years hospital-documented multiple daily heroin use). All but one were injectors.
All of the placebo patients showed positive urine tests for opiates before dropping out of treatment. Thus none was an early abstinence success - despite this being the consented aim of the trial. About 75% of urine tests of the buprenorphine patients were negative for illicit substances tested for. Thus despite continued if less frequent drug use was still associated with good retention and reduced health problems measured in a variety of ways by these researchers.
Swedish drug policy is based on the belief that all drug addicts can and should stop using certain proscribed drugs immediately (abstinence orientated, or 'zero tolerance'). While this has been long abandoned in most other countries, Sweden continues despite their own research showing excess deaths, continued drug use and high rates of viral disease transmission when such policies are pursued. One fails to understand how in such a modern democracy such ill-founded policies are used.
Yet the world's two most persuasive studies are from their own country showing that if heroin addicts are left untreated (or "treated" in the compulsory manner used in Sweden) then the result is a high mortality of young Swedes from a totally preventable and treatable cause, drug overdose.
For related editorial commentary: Law FD, Nutt DJ. Maintenance buprenorphine for opioid users. Editorial. Lancet (2003) 361:634-5
comments by Andrew Byrne ..
Dear Colleagues,
The Swedes have produced some of the most quoted data showing the life saving properties of methadone maintenance, partly because this treatment is so severely restricted in Sweden. Thus trial candidates who are randomized not to receive prescription treatment, or who are discharged from treatment, rarely receive agonist maintenance therapy which might be available in the normal course of medical practice in other ‘normal’ countries.
From work performed in the 1980s, Grönbladh and colleagues showed a very high mortality in those rejected from methadone treatment - almost 8% per year. In an even more rigorous and controlled study using sublingual buprenorphine, Kakko et al. have found what the accompanying Lancet editorial calls: "massive 20% mortality at one year in the placebo group versus 0% in the buprenorphine group [which] is immensely concerning". Indeed, a trial using placebo in heroin addiction treatment would be considered unethical in Australia.
This trial provides strong support for buprenorphine maintenance since at a fixed dose of 16mg daily it had a 12 month retention rate of 75% and no deaths, compared with placebo: 0% retention at 2 months and four out of twenty being dead from overdose by 12 months. All 'placebo' (actually '6 day reduction') cases had access to intensive levels of psychosocial supports, some of which were reported to have induced paradoxical cravings. I understand that one of the 5 buprenorphine drop-outs has also since died.
The mortality rate is even more worrying considering that these candidates were chosen from over 400 applicants based on less severe dependency and less poly drug/alcohol use. Thus none of the chosen candidates was suitable for the stringent Swedish criteria for methadone prescription (4 years hospital-documented multiple daily heroin use). All but one were injectors.
All of the placebo patients showed positive urine tests for opiates before dropping out of treatment. Thus none was an early abstinence success - despite this being the consented aim of the trial. About 75% of urine tests of the buprenorphine patients were negative for illicit substances tested for. Thus despite continued if less frequent drug use was still associated with good retention and reduced health problems measured in a variety of ways by these researchers.
Swedish drug policy is based on the belief that all drug addicts can and should stop using certain proscribed drugs immediately (abstinence orientated, or 'zero tolerance'). While this has been long abandoned in most other countries, Sweden continues despite their own research showing excess deaths, continued drug use and high rates of viral disease transmission when such policies are pursued. One fails to understand how in such a modern democracy such ill-founded policies are used.
Yet the world's two most persuasive studies are from their own country showing that if heroin addicts are left untreated (or "treated" in the compulsory manner used in Sweden) then the result is a high mortality of young Swedes from a totally preventable and treatable cause, drug overdose.
For related editorial commentary: Law FD, Nutt DJ. Maintenance buprenorphine for opioid users. Editorial. Lancet (2003) 361:634-5
comments by Andrew Byrne ..
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