22 September 2005

Naltrexone implants: Claims and counter claims: None so blind

Addiction Biology 2005 10:201-204

Letters to the Editor

Naltrexone implants as treatment for heroin dependence:

Contents of this post

Part I of letter

There are a number of important methodological problems with this recent study of naltrexone implants (Hulse et al., 2004a). The selection of patients was opportunistic. No inclusion and exclusion patient selection criteria are provided. The authors do not state exactly how many specimens were obtained from each of the patients with either the 1.7g or the 3.4g implant, and the testing was not done according to any fixed protocol.
The most serious problem is the presentation of the data. Only blood concentrations �standardised� to 70kg body weight are reported, apparently to compare the two sizes of implant. It is, however, misleading to use plasma concentrations standardised to 70kg bodyweight in discussing the minimum effective concentration (2ng/ml). In the examination of kinetic data, relationships between plasma concentrations and body weight can be assessed, but actual plasma concentrations should have been reported, as has been done in the other reported studies on sustained release naltrexone preparations (Comer et al., 2002; Olsen et al., 2004). Concentrations �standardised� for bodyweight are not a useful clinical measure, and this study provides no helpful information into how to adjust the implantation protocols for bodyweight.
A high proportion of bodyweight-standardised blood concentrations reported in this study were below 2 ng/ml. Further, in a second study of sequential naltrexone implants (Hulse et al., 2004b), two out of five patients are reported as having plasma concentrations, standardised to 70kg body-weight, below 1ng ml for at least some of the time. Based upon the data presented in these studies it appears likely that blood concentrations were inadequate in several patients. Without actual concentration data, however, these studies allow no conclusions to be drawn about the proportion of subjects who had naltrexone �above therapeutic levels�.
These flaws, especially in the data analysis, make it very difficult to draw conclusions about the clinical performance of naltrexone implants in these studies.

Dr Andrew Byrne* MB BS FAChAM, Professor Garry Graham�, Dr Richard Hallinan* B, Dr Bridin Murnion BSc, MBChB

* Dependency physicians, 75 Redfern St, Redfern, New South Wales, Australia

# Department of Clinical Pharmacology and Toxicology, St Vincent�s Hospital, Sydney, Australia


Hulse GK, Arnold-Reed DE, O�Neil G, Chan C,T, Hansson R, O�Neil P. (2004a) Blood naltrexone and 6-�-naltrexol levels following naltrexone implant: comparing two naltrexone implants. Addiction Biology 9:59-65
Hulse GK, Arnold-Reed DE, O�NeiI G, Chan C-T, Hansson R. (2004b) Achieving long-term continuous blood naltrexone and 6-�-naltrexol coverage following sequential naltrexone implants. Addiction Biology 9:67 72
Comer SD, Collins ED, Kleber HD, Nuwayser ES, Kerrigan JH, Fischman MW. (2002) Depot naltrexone: long-lasting antagonism of the effects of heroin in humans. Psychopharmacology (Berl) 159:351 60
Olsen L, Christophersen AS, Frogopsahl G, Waal H, Morland J. (2004) Plasma concentrations during naltrexone implant treatment of opiate-dependent patients. BrJ Clin Pharmacol 58:219

Reply to Part I:

I write in response to Dr Byrne et al�s letter commenting on our recent publication (Hulse et al., 2004) in Addiction Biology. First, Dr Byrne comments on the vagueness of patient selection and study design. This is despite the methods section clearly stating that the study was a retrospective review of blood sample results from clinical records with subject selection, data inclusion criteria and number of samples collected per patient also delineated in the manuscript.
Secondly, with regard to Dr Byrne�s comments on the "serious" flaws regarding the validity of using body-weight standardised blood concentrations of naltrexone, we feel that this is open to interpretation. Our original manuscript submitted to Addiction Biology reported non-standard blood levels (as advocated by Dr Byrne). However, the standardisation was made in response to the journal reviewer�s comments on our paper. The rationale of the reviewer and journal was that as all subjects received a fixed quantity of naltrexone in their implant, if non standardised values were used then we would have to reconcile larger body mass (male) subjects with a lower circulating blood naltrexone concentration with smaller body mass (female) subjects with a higher blood naltrexone concentration when estimating longevity of implants. To overcome this we standardised blood concentrations to a body weight of 70kg. Exponential curves were fitted to the standardised values based on a least squares best fit method. These calculations take into account the variation in blood naltrexone levels between subjects.
Lastly, this paper is a research article and was not written to provide a clinical framework for the use of implants. It is therefore erroneous to attempt its use as such.

Prof G K Hulse, Dr D E Arnold-Reed

School of Psychiatry and Clinical Neurosciences, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia


Hulse GK, Arnold-Reed DE, O�Neil G, Chan C,T, Hansson R, O�Neil P. (2004) Blood naltrexone and 6-�-naltrexol levels following naltrexone implant: comparing two naltrexone implants. Addiction Biology 9:59-65

Part II of letter

We have serious ethical concerns about a recent paper (Hulse et al., 2004) reporting naltrexone and 6-�-naltrexol levels following naltrexone implant.
In this paper, the authors have not followed the generally accepted sequence of studies in drug development. They have commenced a Phase II study before they (or others) have reported Phase I studies. Researchers in Phase I clinical trials test a new drug in a small group of people (generally 20�80) for the first time to evaluate the safety and likely safe dosage range and to identify side effects. In contrast, researchers in Phase II clinical trials give the study drug to a larger group of people (100�300) to see if it is effective and to further evaluate the safety of the drug.
Phase II studies of disulfiram implants were also conducted before Phase I studies had been undertaken (Johnson and Morland, 1991; Konoplitskaya et al., 1991). The Phase II trials were unsuccessful because extensive fibrosis sealed off the implants. Had Phase I studies been conducted first, this would have been detected and ineffective Phase II studies would have been thus avoided. Ideally, Phase I trials should always be prospective and this is a retrospective study.
There were other methodological problems including opportunistic selection of patients, no published inclusion and exclusion patient selection criteria and lack of clarity about the number of specimens obtained from each of the patients with either the 1.7g or the 3.4g implant.
The authors state that they have ethics committee permission to review patient records and to perform the study. However, they do not state explicitly that they have ethics committee approval for the novel naltrexone implant itself. The authors do not refer to any protocol to detect, record and consider adverse effects. The lack of such a protocol may well have led to an underestimation of adverse effects. Serious adverse events with implanted naltrexone have been reported (Hamilton et al., 2002). The authors do not provide or refer to any plan of action in the case of disease or trauma that would normally require standard opioid agonist therapy.
The treatment in this study has been approved by the Therapeutic Goods Administration (TGA), Australian Government Department of Health and Ageing, under the Special Access Scheme (SAS) (http: www.tga.gov.au does html sasinfo.htm). This scheme enables medical practitioners to supply unapproved medications to some very seriously ill patients under clearly specified conditions on a case-by-case basis. However for trial purposes, use of this therapy should properly be approved under the Clinical Trial Exemption Scheme (CTX) or the Clinical Trial Notification Scheme (CTN) under the Australian NHMRC guidelines (http: www.tga.gov.au does html clintrials.htm). In Australia, naltrexone-implants are required to be stamped with a notice in large print warning against use in human subjects. It is not clear if patients enrolled in this study have been informed about this notice.
The declaration of interest states that �one of the authors (G.O�N.) is a director of GoMedical, the medical device company which manufactures the implants�. Yet this declaration states that this author only �would be expected to receive pecuniary benefit (amount unspecified) from GoMedical in his role as surgeon performing the implants�. The declaration does not state whether or not any of the authors stand to gain from marketing the devices.
Studies of naltrexone implants should meet the same high and scientific standards as other studies evaluating novel medical treatments for the same condition. We believe that this paper does not meet the same standards now accepted for the evaluation of substitution treatment for heroin dependence.

Dr. Alex Wodak, Dr Robert Graham

Alcohol and Drug Service, St. Vincent�s Hospital, Darlinghurst, NSW, 2010, Australia


Hulse GK, Arnold-Reed DE, O�Neil G, Chan C-T, Hansson R, O�Neil P. (2004) Blood naltrexone and 6-�-naltrexol levels following naltrexone implant: comparing two naltrexone implants. Addiction Biology 9:59-65
Konoplitskaya KL. Pkhakadze GA. Narazayko LF. (1991) Biocompatibility of a prolonged-action anti-alcohol preparation. Biomaterials 12:701 704
Johnsen J. Morland J. (1991) Disulfiram implant: a double-blind placebo controlled follow-up on treatment outcome. Alcoholism: Clinical & Experimental Research 15:532 536
Hamilton RJ, Olmedo RE, Shah S, Hung OL, Howland MA, Perrone J, Nelson LS, Lewin NL, Hoffman RS. (2002) Complications of Ultrarapid Opioid Detoxification with Subcutaneous Naltrexone Pellets. Academic Emergency Medicine 9:63 68

Reply to Part II:

Doctors Wodak and Graham are correct in their assertion that the development and registration of pharmaceutical drugs commonly involves the successive testing of the drugs in phase I prior to phase II and subsequently phase III trials. There is however, within many countries, the ability for physicians under clearly specified conditions on a case-by-case basis to prescribe or use non-approved pharmaceuticals for some seriously ill patients. Legislation that allows this commonly holds that prescribing of non-registered pharmaceuticals can occur where there is a high risk of mortality associated with the morbidity under treatment. Perhaps the most recognised instances of this supplement use is oncology, where use of cancer treatment drugs, which have been successfully used overseas, but not registered in the practitioner�s country, might be used by the practitioner to treat a cancer. Clearly where this takes place, it is important to evaluate outcomes associated with these treatments.
As noted by Drs Wodak and Graham, this legislation in Australia is known as the Special Access System (SAS) and administered by the Commonwealth Therapeutic Goods Administration (TGA). Given increased risk of mortality amongst heroin users, this SAS has been used by a number of Australian community and hospital based physicians in at least 4 of the 6 Australian States to administer sustained release naltrexone preparations. These preparations have included a number of those developed in the US with a likely clinical pharmacokinetic life of 6-8 weeks and the locally Australian produced GoMedical implant. For the last 5 years the TGA in Australia has continued to allow naltrexone implants to be administered under SAS. It is estimated that in the past few years, in excess of 3,000 heroin dependent persons have been treated by this method in the States of Victoria, New South Wales, Queensland and Western Australia.
Clearly, as with the cancer scenario, it would be foolhardy and I suggest irresponsible not to superimpose some type of monitoring and evaluation on these patients. The result of analysing naltrexone blood samples from a cohort of SAS treated patients was in fact the basis for the two papers published in Addiction Biology. As such, this was not a phase II drug development study. This is made clear in the paper, in that Drs Wodak and Graham should seek to suggest otherwise is misleading. Lack of methodological clarity raised by the two doctors is also misleading, given that this again this is clearly delineated in the paper. Clearly an international journal such as Addiction Biology has in place checks and balances to ensure that this type of information is made available to the readers and they and the paper�s separate and independent assessors found it adequate.
Drs Wodak and Graham refer to the lack of protocol to detect, record and consider adverse events. This is the type of protocol that would be required where a randomised clinical trial was in place, yet these were SAS not clinical trial treated patients. In the context of SAS patients, monitoring of adverse outcomes is the responsibility of the treating physician, and I would hasten to note that the TGA has mechanisms for collecting this adverse information from SAS treated patients. In making their case the doctors refer to "serious adverse events associated with implant naltrexone." (Hamilton et al., 2002). Of course those who are familiar with this literature will recognise that this article refers to morbidity and mortality in the US resulting from the use of implants to precipitate rapid opiate detoxification and not sustained release naltrexone for the purposes of naltrexone maintenance. This typifies Drs Wodak and Graham�s letter with subtle non-truths to create illusion to support a fictitious case; words " twisted by knaves to make a trap for fools". There is no place for this type of misrepresentation and Drs Wodak and Graham stand reprimanded for this deceptive behaviour. This includes both the misrepresentation of the aforementioned article and the attempt to present SAS patient data collection as a clinical trial.
Questions are also raised about the statement of declaration and pecuniary interests of the authors in marketing the implant. I would hasten to note that the wording of this disclaimer was superimposed by the Journal and perhaps any issues of concern should be raised with them. However, for the record, we state categorically that neither I nor any member of my research team has, or will receive pecuniary interest in marketing of this implant product. We are a University clinical research facility and our sole objective is the unbiased reporting and evaluation on clinical activities. For Drs Wodak and Graham to suggest otherwise is both disturbing and a personal affront.
Of course, the reader could be forgiven for believing that all this information will be new to Drs Wodak and Graham, but alas, I understand they are already conversant with all the facts. That these two doctors suggest that evaluation of SAS patients treated with naltrexone implants should not take place is to me not only abhorrent, but lacking in vision. In fact the opportunity to monitor and access valuable information from SAS treated patients with implant naltrexone in Australia has been recognised by the Commonwealth Department of Health and Human Services, who in consultation with the TGA (a subsection of this Branch) identified additional funding and identified areas of information to be garnished from these SAS patients. This includes histological information on tissue reactivity around the site of implant, ultrasound to assess biodegradability and I might add additional pharmacokinetic blood collected similarly to that published in Addiction Biology. Similarly, the National Health and Research Medical Council (NH&MRC) has recently funded for hospital morbidity, mortality and mental health data to be collated from a large cohort of these SAS treated patients. Ultimately, this information, coupled with more data collected from randomised double blind clinical trials will be used to assess the viability of the Australian implant for transTasman registration. I also understand from the Australian Commonwealth Department of Health that as part of this assessment, the National Drug and Alcohol Centre in Sydney, of which Dr Wodak is an adjunct senior lecturer, has been or will be funded to garnish morbidity and mortality data from similarly treated SAS patients. This would put Dr Wodak�s facility in exactly the same position as my research team, yet Dr Wodak makes no reference to this.
It would appear that Drs Wodak and Graham are not only at odds with myself, but also the Commonwealth Department of Health, the Therapeutic Goods Administration and the NH & MRC in their objection of data being sought from SAS treated patients. For clinical researchers to not garnish valuable information from patients treated by new methods under the SAS legislation would be a tragedy, yet for some, this simple concept seems incomprehensible. "There are none so blind as those who will not see."

Prof G K Hulse

School of Psychiatry and Clinical Neurosciences, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia


Hamilton RJ, Olmedo RE, Shah S, Hung OL, Howland MA, Perrone J, Nelson LS, Lewin NL, Hoffman RS. (2002) Complications of Ultrarapid Opioid detoxification with Subcutaneous Naltrexone Pellets. Academic Emergency Medicine 9:63 68

20 September 2005

Drugs in pregnancy

Tuesday 20th September, 2005

Associate Professor Paul Haber and Christine Stephens, Nurse Manager Drug Health, RPAH.

This seminar gave us an overview of the Drugs in Pregnancy Service (DIPS*) at RPA Hospital, covering issues around drug use in pregnancy, followed by some case histories to illustrate approaches to various management dilemmas. Christine Stephens outlined the general approach DIPS used over time, stressing the change to a family unit focus that happened after their 1994 review. 'DIPS' aims to build relationships between the patient, her family and the various service providers before the baby is born, and they to try to be as inclusive as possible in their approach to team management. Early intervention is of prime importance. They also aim to build up supports for the family that are needed in the baby's first two years of life, and stress the value of having health care providers involved who are committed for the long-term. Liaison is done with GPs, Redfern Aboriginal Medical Service, family support units, DOCS, Benevolent Society, Early Childhood Centres and other relevant groups from as early in the pregnancy as possible. As well as this focus on the multi-disciplinary approach to pregnancy and post natal care, 'DIPS' tries to foster inter-agency collaboration between such groups, being very aware of the difficulties inherent in inter-agency communication. Comprehensive discharge plans with clear assignment of responsibilities and GP attendance at case conferences are examples of two methods used to achieve this.

DIPS do a comprehensive assessment of the family unit, and explore the psycho-social circumstances of extended family members and whether any family members also have drug dependency problems. As well as making sure appropriate supports are in place, DIPS will also ensure a family is not over-serviced, as this can be a hindrance to a family developing independent coping skills. DIPS are pro-active with regards to child protection case planning, always being upfront and willing to assist families in making the necessary changes. They aim to identify potential risks, eg finding out about safe storage of take-away methadone. They provide a lot of education about what to expect post discharge. As an example Christine outlined the importance of explaining to parents the changes that take place in babies who have been on morphine and are relatively settled, and become less settled when the morphine is ceased. In this scenario it is important to teach parents settling techniques before they are discharged and give them information about the spectrum of normal newborn behaviour.

DIPS aim to get women to attend a minimum of 5 antenatal visits as research has shown this to be the minimum number of visits needed to positively influence outcomes. They provide alcohol and other drug assessments and treatments including provision of inpatient withdrawal programmes and provide beds for women with intractable pregnancy-related vomiting. They do a lot of their ante-natal care on a one-on-one basis as their patient population tend not to go to parenting classes. They address nutritional and dental issues, social, lifestyle and pregnancy related issues, ever with a family-centred approach. 38% of their patients are of Aboriginal and Torres Strait Islander background, are often on a temporary Centrelink benefit and most are not alone, with partners, friends and relatives usually around. There are 20% of referrals which come from "out of area", most coming from the ante-natal clinic, GPs and other clients.

Presentations of women with untreated drug dependency into labour ward are now only 4.2%, a vast improvement, we were told, from the early 90s. DIPS staff have learnt that it is important not to just have one mode of operation but to be flexible and cut down barriers to access as much as possible.

The principle drugs of concern used by patients at this service are heroin, benzodiazepines, cocaine and alcohol. It was noted that alcohol is often less likely to be acknowledged by the patient to be a problem. Paul Haber told us that there is no evidence that light and infrequent drinking causes foetal harm, and outlined the NHMRC guidelines that suggest women consider not drinking at all whilst pregnant or otherwise limit intake to 1 or 2 drinks once or twice a week. Heavy drinking in pregnancy is clearly linked with the development of the foetal alcohol syndrome, where alcohol kills the cells that should form the midline structures in the brain and the face. It was acknowledged that many women with alcohol dependency are never seen at all by drug and alcohol services.

The effects of some other drugs in pregnancy were outlined. Because cannabis is usually used with tobacco it is not easy to look at its effects in isolation. Tobacco is known to increase the chance of low birth weight babies and decrease the length and head circumference of newborns (also can cause microcephaly). A Canadian study (Fried, 2000) was quoted in which heavy use in the mother was associated with adverse long-term effects on the offspring. These involved subtle changes in some finer points of global functioning but not intelligence. Tobacco use, on the other hand, was shown to be associated with lower IQ in a dose dependent manner in the same review of outcomes, some going for up to mid-teenage years.

Use of hydroponic cannabis (assuming it is stronger) was said to be more harmful to the foetus than 'bush' THC. Some believe the opposite to be the case as higher THC concentrations, if associated with less raw cannabis use, may limit exposure to other more dangerous burnt products in the smoking process (personal communication G. Chesher, retired associate professor of pharmacology, Sydney University).

The increased risk of SIDS among babies born to mothers who smoke is thought to be related to tobacco use rather than cannabis. Some women now 'cook' with cannabis to avoid using it with nicotine (eg. 'cannabis/hash cookies'). There was discussion about contradictory information that cannabis can cause nausea as well as treat it at different times. Because of the lack of evidence surrounding foetal safety and cannabis use in the mother, as with most other drugs, we should advise women not to use cannabis during pregnancy.

Cocaine use in pregnancy was also discussed and in this case there is no doubt of the deleterious effects to both mother and foetus. It is associated with maternal hypertension and increased chances of miscarriage, stillbirth and placental abruption. Babies are often born small for their gestational age and neonates experience a significant withdrawal syndrome. It is now recommended that all neonates born to mothers who have used cocaine have a scan done to detect cerebral infarcts, as there is a significantly increased risk of this occurring. Cocaine is harmful throughout all stages of pregnancy and many perinatal deaths are associated with maternal cocaine use.

There was a brief discussion of ecstasy use in pregnancy and Prof. Haber told us that the risks to the foetus were comparable to amphetamines. It was stated that about one third of "ecstasy" tablets have no psychoactive component, one third have a variable quantity of MDMA and one third contain other psychoactive drugs. This should be born in mind when monitoring the pregnancy of women who give a history of ecstasy use, although the strength may be more reliable in some circles.

Four interesting case histories were discussed to help guide us in our management of common scenarios. The first case involved a woman on methadone maintenance with intractable vomiting. Firstly it was recommended that she be advised not to have a methadone dose on an empty stomach and not to run or exercise straight after a dose. Both prochlorperazine (Stemetil) and metoclopramide (Maxalon) tablets or injection can be used, the former being also available in suppository form. The role of ondansetron (Zofran) is increasing, with obstetricians using it as a second line agent, especially as buccal �wafer�. It is not suitable for long-term use and is quite costly with a potential for side effects in pregnancy.

A change between formulations may help some women (Biodone sugar-free versus the syrup). In women on high dose methadone (and some others who are sensitive) split dosing (half morning and night) may be helpful. Take-away methadone may be increased for the period of vomiting so women can sip their doses at home.

A second case history also looked at the problem of pregnancy related vomiting, this time associated with weight loss. It was pointed out that many women lose weight in the first trimester of pregnancy and that this in itself is not a concern. What is important is to assess the fundal height to check that the nutritional status of the mother has not affected the well being of the foetus. The woman may need detailed information about nutrition and diet. Most antenatal clinics now only do a baseline weight of the mother at first presentation, as it is the fundal height that reflects intrauterine growth, and frequent maternal weighing may cause unnecessary worry.

The third case history brought up the issue of buprenorphine use in pregnancy. Whilst it is a �category C� drug, it was pointed out that so is methadone. There is limited local research into the effects of buprenorphine in pregnancy and on neonates. However, worldwide there are now greater than 250 published cases of buprenorphine use in pregnancy and most have reported safe outcomes. Currently pregnant women are advised to transfer over to methadone maintenance treatment, and this should ideally occur as an in-patient. There was much audience debate about this issue, but it was generally agreed that it is wise to get a second opinion if considering prescribing buprenorphine to a pregnant woman. If a woman is unable to take methadone, then the outcome following buprenorphine treatment is likely to be much better than having no prescribed treatment. Christine touched on the similarities and differences between babies experiencing neonatal abstinence syndrome according to whether their mother was on methadone or buprenorphine. The duration of total treatment time with morphine is much the same for babies coming from either situation, though indications are that for buprenorphine there are fewer needing morphine and for shorter periods. It was also emphasised that not all babies of mothers on MMT or buprenorphine require morphine, and that the chances of a baby developing NAS are not strongly dose-related.

The final case history promoted a discussion about child protection issues. In this particular case, a mother on MMT was found to have morphine metabolites in her urine at 3 weeks post-partum. Her baby was healthy and had not required any morphine post delivery. The importance of setting up frequent reviews with this patient was emphasised. A urinary drug screen result in isolation is not so much a reason to notify DOCS, but is certainly an indication to see the patient more often and explore what is happening in her life. Relevant issues to explore include whether the procurement of drugs is impacting on the family's finances, and whether drug use interferes with the mother's ability to attend to the needs of her newborn. We should ask about who else cares for the baby, and who else comes to the house. Do any drug dealers visit the house, or does the mother take her baby with her to procure drugs? Is she in a stable relationship or does she have several partners? We were reminded of the fact that two-thirds of deaths of babies occur in households where there are significant problems with drug and alcohol use, so we must always satisfy ourselves with regard to the safety of children.

Written by Jenny James, Daruk AMS (edited by Andrew Byrne).

*Note that the hospital DIPS has now been renamed the Perinatal and Family Drug Health Service (PFDHS).


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Fried PA, Smith AM. A literature review of the consequences of prenatal marihuana exposure: An emerging theme of a deficiency in aspects of executive function. Neurotoxicology and Teratology (2001) 23;1:1-11 [The Ottawa Prenatal Prospective Study (OPPS)]

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13 September 2005

Addiction summaries: LAAM, morphine, personality disorders.

Addiction August 2005 edition.

Dear Colleagues,

Despite the disappointing results of naltrexone in opioid treatments, Addiction's August edition includes three other items on retention rates and reduced heroin use in maintenance therapies in various situations (LAAM, long-acting oral morphine and in subjects with borderline personality disorders taking methadone treatment).

The group from Vienna headed by Dr Fischer reports a rigorous 14-week double blind, cross-over study of long acting morphine versus methadone. They find comparable results for retention and illicit drug use, with particular benefits to general health in the oral morphine group. The doses may explain some of the differences: morphine (mean 680mg daily, max 800mg) and methadone (mean 85mg daily, max 100mg).

A veteran team from California has belatedly demonstrated not only that LAAM (l-alpha methadyl acetate) is free from detected cardiac complications, but it has certain benefits over methadone for some subjects. It is disappointing that this drug has now been withdrawn by its manufacturers, probably for spurious reasons. The reported cardiac events are extremely rare, and they have never been shown to be due to LAAM. Indeed, it is still possible that LAAM actually reduces the likelihood of coronary abnormalities, especially if stimulants and/or alcohol are implicated.

Those with antisocial personality traits (45% of a large, mixed addict cohort were classified as 'borderline type') were found to have responded just as well to treatments, yet still displayed higher rates risk and harm across a range of domains. Nothing surprising here, but nice to see common observations documented scientifically in a well conducted longitudinal study ('ATOS').

Nancy Petry from Farmington, Connecticut presents another study comparing pathological gamblers with and without antisocial personalities, also finding worse parameters, younger subjects and, interestingly, a link with illicit drug use.

Citations: Eder H, Jagsch R, Kraigher D, Primorac A, Ebner N, Fischer G. Comparative study of the effectiveness of slow-release morphine and methadone for opioid maintenance therapy. Addiction (2005) 100:1101-09

Longshore D, Annon J, Anglin MD, Rawson RA. Levo-alpha-acetylmethadol (LAAM) versus methadone treatment retention and opiate use. Addiction (2005) 100:1131-39

Darke S, Ross J, Williamson A, Teesson M. The impact of borderline personality disorder on 12-month outcomes for the treatment of heroin dependence. Addiction (2005) 100:1121-30

Pietrzak RH, Petry NM. Antisocial personality disorder is associated with increased severity of gambling, medical, drug and psychiatric problems among treatment-seeking pathological gamblers. Addiction (2005) 100:1183-1193

Comments by Andrew Byrne ..

Benefits of LAAM demonstrated after its withdrawal from market!

The effects of racemic D,L-methadone and L-methadone in substituted patients - a randomized controlled study. Verthein U, Ullmann R et al. Drug and Alcohol Dependence 2005 80;2:267-271

Dear Colleagues,

This interesting and definitive study from Hamburg informs us that pure 'levomethadone' and racemic (mixed levo-dextro 50:50) methadone are clinically equivalent in the expected ratio of 1:2 with no significant difference in withdrawal symptoms or other clinical aspects of maintenance treatment. The pure enantiomer is more expensive and thus should probably be phased out in Germany, the only country where it had widespread use.

Despite no real evidence, some have speculated that certain methadone side effects might be due by the inactive L or 'dextro' component. This careful, cross-over, randomised trial with 75 subjects has only found mild, transient differences in sudden experimental substitutions of medication. These did not reach significance and confirm what was done by Judson in 1976.

Comments from Andrew Byrne ..