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: Byrne, Graham, Hallinan and Murinon


• Reply to Part I: from Hulse and Arnold-Reed


• Part II: Wodak and Graham


• Reply to Part II: from Hulse

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

References

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

Reference

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

References

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

Reference

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

Drugs in pregnancy

Tuesday 20th September, 2005

Presenters:
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).

References:

Fried, PA. Pregnancy & effects on offspring from birth through adolescence. In: Cannabis and cannabinoids: Pharmacology, Toxicology and Therapeutic Potential. Haworth Press, New York (2000). Eds Grotenhermenl F, Russo E.

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)]

Weinberg DS, Inturrisi CE, Reidenberg B, Moulin DE, Nip TJ, Wallenstein S, Houde RW, Foley KM. Sublingual absorption of selected opioid analgesics. Clin Pharmacol Ther (1988) 44(3):335-42

Finnegan LP. Women, pregnancy and methadone. Heroin Addiction and related clinical problems 2000: 2 (1): 1� 8

Fischer G, Jagsch R, Eder H, Gombas W, Etzersdorfer P, Schmidl-Mohl K, Schatten C, Weninger M, Aschauer HN. Comparison of methadone and slow-release morphine maintenance in pregnant addicts. Addiction (1999) 94(2) 231-239

Fischer G, Johnson RE et al. Treatment of opioid-dependent pregnant women with buprenorphine. Addiction (2000) 95; 2: 239-244

Hulse GK, O'Neill G. Methadone and the pregnant user: a matter for careful clinical consideration. ANZJ Obst & Gyn (2001) 41;3:329-332

Hulse GK, O'Neill G, Pereira C, Brewer C. Obstetric and neonatal outcomes associated with maternal naltrexone exposure. ANZJ Obst & Gyn (2001) 41;4:424-8

Hulse GK, O'Neill G. A possible role for implantable naltrexone in the management of the high-risk pregnant heroin user. Aust NZ Journal of Obstet Gyn. (2002) 42:93-94

Jones HE, Johnson RE, Jasinski DR, O�Grady KE, Chisholm CA, Choo RE, Crocetti M, Dudas R, Harrow C, Huestis MA, Jansson LM, Lantz M, Lester BM, Milio L. Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. Drug and Alcohol Dependence (2005) 79;1:1-10

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 ..

Is rapid detox followed by oral naltrexone effective?

JAMA 2005; 294:903-913

Collins ED, Kleber HD, Whittington RA, Heitler NE. Anesthesia-Assisted vs Buprenorphine- or Clonidine-Assisted Heroin Detoxification and Naltrexone Induction - A Randomized Trial.

Dear Colleagues, The current [August 2005] JAMA home page features this item with the caption: "Anesthesia-Assisted Heroin Detoxification: Collins and colleagues randomly assigned treatment-seeking heroin-dependent patients to anaesthesia-assisted rapid detoxification with naltrexone induction, buprenorphine-assisted rapid detoxification with naltrexone induction, or clonidine-assisted opioid detoxification with delayed naltrexone induction. They found that withdrawal severity, treatment completion and retention, and proportions of opioid-positive urine specimens during 12 weeks of outpatient treatment were comparable across the 3 methods of detoxification."

In fact, there are five items in this edition mentioning naltrexone, two being letters to the editor on a long acting injectable form for alcoholism. The current feature has a commentary by Patrick O'Connor on the role of detoxification. There is also is a glowing historical tribute to Vincent P. Dole and colleagues whose seminal methadone report was published in this same summer holiday edition of JAMA 40 years ago.

With veteran researcher Herbert Kleber, this group from Columbia describe a randomised comparison of naltrexone induction in heroin addicts using three methods: (1) rapid detox under 4-6 hour anaesthetic (2) buprenorphine bolus and (3) clonidine with traditional in-patient detoxification.

The study raises several important ethical questions while also giving perhaps the last word on rapid detoxification from opioids, a century after the first report [MacLeod, N. Cure of morphine, chloral, and cocaine habits by sodium bromide. BMJ (1899) 15/4/1899 p896]. The main results are unremarkable: viz (a) that almost 100% of anaesthetised patients successfully take their first dose of naltrexone, (b) that rapid detox is hazardous, (c), that the naltrexone "treatment" is of very limited benefit (75-90% of subjects dropped out by 12 weeks) and (d) that the particular method of detoxification has no significant impact on rates of medium-term abstinence.

It is possible that some side effects in the anaesthesia group (n=35) may reflect this team's lack of experience as well as their limited ability to elicit a clear history from their patients. All three subjects who developed major anaesthetic complications are said to have had "concealed" histories (of diabetic ketoacidosis, bipolar disorder, pneumonia and sleep apnoea) from the researchers. To ascribe each anaesthetic complication to deceitful subjects is rather unusual and there may be alternative views. Others have reported lower complication rates, yet there is no doubt that such treatment can be hazardous in this population, especially if they come directly from street heroin habits.

Prescription of naltrexone for opioid addiction as a 'treatment' has only little limited scientific support in unselected candidates in community treatment. Some believe that it may have benefits in carefully selected subjects (as stated by O'Brien in the same issue p888). So why did these authors go to so much trouble to 'induct' addicts into an ineffective treatment? I note that some providers now give very frank details about the expected success rates of their treatments. Yet others have claimed '100% success' rates and call their detoxification treatments 'painless'.

It is predictable that those taking pure buprenorphine were retained for slightly longer than those given clonidine, which may be little more than a placebo in this situation. And it is self-evident that the anaesthesia patients were more likely to take their first dose of naltrexone which is given while they are still unconscious.

In his accompanying editorial Patrick O'Connor tells us that over 3 million Americans have used heroin and ten times that number prescribed opioids. Even more worrying is that over 1% of school children in the US had used heroin in 2004. Thus we are dealing with an epidemic in anyone's terms.

As with McGregor and Ali's randomised study from Adelaide (D&A Rev) rapid detox shows no significant benefits over traditional detoxification in the medium term (3, 6 or 12 months). In view of the high risks and poor results, there should probably be no further studies of rapid detoxification in unselected subjects. It is still possible that longer acting forms of naltrexone may yet prove effective for those seeking abstinence. Formal research on the safety and effectiveness of such novel delivery methods is awaited.

comments by Andrew Byrne ..

Pain management and dependency

North Sydney, Mon 22 Aug 2005

Dr Doug Gourlay

During the International Pain Conference, a meeting for 'locals' was convened by Professor Robert Batey of NSW Health at North Sydney on Monday 22 Aug 2005. We had an illuminating talk from one of the few specialists with expertise in BOTH pain management AND dependency, Dr Doug Gourlay of Mount Sinai Hospital, Toronto, Canada.
Our renowned speaker started with some definitions of addiction, physical dependency, tolerance, pseudo-addiction, with some prevalence figures in the general population.
We were given a logical approach to 'universal precautions' in opiate prescription patients. Infectious disease and dependency have some parallels: rather than isolating those already infected (eg. hepatitis, TB, leprosy) modern practice is to assume that all patients could harbour (or be victim to) infections just as all opioid recipients can sometimes demonstrate features of dependency. Thus we need to be alert and to respond with appropriate measures when needed.
Dr Gourlay reminded us of the difficulties in detecting high-risk patients on first consultation. While an accurate diagnosis is crucial to appropriate treatment, on-the-spot diagnoses are not always necessary or indeed possible in pain management and dependency. We have the benefit of seeing our patients' progress over time which allows a prospective diagnosis after accumulating more details of the patient's habits, history, examination and special tests. Predictors of progress in our field can be notoriously unreliable with some seemingly low risk patients displaying the most manipulative behaviour.
While most dependency diagnoses are made prospectively, one diagnosis we can only make retrospectively is 'pseudo-addiction'. In this, all the apparent features of addiction abate once the patient's pain has been addressed, whether physically, chemically and/or mentally. [If we postulate a 'psychic pain' and self-medication, this might be true of many dependency cases as well, since once they receive appropriate management any DSM criteria of addiction regress or even vanish.]
The items Dr Gourlay recommended we use in diagnosis included the CAGE features -Have you tried to Cut down? Do you get Annoyed by using too much medication? Do you suffer from Guilt? Have you taken medications early? 'Eye-opener' - as well as a number of other 'tell-tale' characteristics involving finances, work, drug seeking (eg. early requests for prescriptions), criminal behaviour and urine test results.
The 'tools' we have to use in dependency patients include (1) limiting quantities of medications ie. the frequency of pharmacy attendance (2) increasing doses of medications (3) utilising longer-acting forms of the appropriate medication (4) direct supervision of medication (5) supervised urine testing (6) treatment agreements � a drug diary. Dr Gourlay also reminded us not to stop opiates or benzodiazepines suddenly and that even high doses of one class of drugs will never suppress withdrawals from the other, although a transient improvement in symptoms might result. He gave a telling example of a new methadone patient denied benzodiazepines in early treatment despite a large habit. Most of our dependency patients have more than one drug habit.
Dr Gourlay has no hesitation in ordering urine tests on all his dependency patients. This includes pain management patients who have developed features of dependency - usually a small proportion, perhaps 10%. He reminded us that such testing needs to be done in a climate of trust and mutual respect. Results should never be used as a "gotcha!" manner nor used punitively. Like all pathology testing the results must only be used directly in the patient's interests. Direct observation, we were told, is not necessary in all cases but that some supervision, eg temperature testing or randomisation, is reasonable for compliance checking. We were given a compassionate and practical way to approach unexpected results. "Now I wonder if you can help me explain some unusual results we received on your recent urine specimen".
Another tool Dr Gourlay uses is a 'treatment agreement' ('never a contract') where the patient agrees to be frank about their drug use and that they will not use other sources of drugs, including prescribed medication, over-the-counter drugs or street drugs. Where they do, this should be discussed openly rather than be treated in a 'cat and mouse' manner in the therapeutic environment.
We were confronted with the statement that "no drug is addicting". Addiction requires an interaction between the drug, environment and individual. The vast majority of patients prescribed opioids never develop addiction. Dr Gourlay also said that opioids were often successful for patients with chronic non-cancer or neuropathic pain and always worth a 'trial' when other means had failed.
We were honoured to have the presence of Dr Joyce Lowinson and Dr Herman Joseph who were both associated with the early evaluation of methadone treatment at Rockefeller University in Manhattan from the 1970s.
After the main feature, we has a discussion of three complex case histories with comments from an expert panel comprising Bob Batey, James Bell, Peter Cox, John Currie, John Ditton, Paul Haber, Robert Graham and Adam Winstock. There was lively discussion over various difficulties in diagnosis and management in special circumstances, dependency, disabilities, children, alcohol, infectious disease, prejudice and other matters of mutual interest. The ethics and practicalities of urine testing was also covered.
Each case demonstrated some failings in early treatment despite warning signs being present. Each contained lessons in communications, diagnosis and a multidisciplinary, approach. There seemed some divergence of views from the panellists, but agreement with Dr Winstock that methadone is not a panacea and that psychological trauma also needs to be addressed.
For a poly-drug user on methadone for 18 years, it was surprising that with continued use of multiple opioids (pethidine and street heroin) she still was not prescribed sufficient methadone to suppress opioid use. She had also been drinking to excess and using benzodiazepines. Already taking 145mg, consideration of dose increases were not advised by all panellists. One even cautioned against consideration of blood level monitoring. It seems that some take the issue of high dose methadone in such cases to be potentially mischievous, even 'sending the wrong message' to the patient. Yet while no cure-all, we might expect that an appropriate methadone dose might reasonably be expected to suppress illicit opioid use after so long on treatment.
Dr Gourlay also stressed that in such cases, stabilising the substance dependency issues was essential before being able to deal with all the psychosocial issues that panel members had brought up ('setting boundaries'). Calling a 'case conference' is not much help if the patient cannot keep an appointment.
Dr Cox suggested admitting such complex patients to hospital as a strategy to sort matters out. Another panel member took the view that such efforts might just waste hospital resources and DG reminded us of the behavioural difficulties of such unstable cases in a general hospital setting, potentially creating resentment among staff.
Some implied a need to accept that certain situations are just not amenable to interventions. Yet in dependency practice, we often come across patients who used to be like these unhappy, unstable cases, and in whom various ministrations and time (especially the latter) have yielded stable, productive citizens in the long run.
Persistence on our part can reinforce the old saying that "when the student is ready, the teacher will appear" ... change is a process that occurs over time.

Summary of meeting by Andrew Byrne .. [final sentence and several other corrections with thanks to Dr Gourlay]

Two deaths; few other surprises; bup-combo vs clonidine for opioid detoxification.

Addiction (2005) 100: 1090-1100

A multi-center randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Ling W, Amass L, Shoptaw S, et al.

Dear Readers,

This 14 day trial showed buprenorphine-naloxone prescribed patients significantly more likely to stay in treatment and stop using street drugs than those taking clonidine. It also found much better completion rates for in-patients (77%; 22%; n = 77; 36) compared with out-patients (29%; 5%; n = 157; 74) prescribed the opioid versus clonidine. Considering the buprenorphine was given in therapeutic doses of 2mg daily up to the last day, these results are not surprising.

However, it is intriguing that there are so many inconsistencies in this report from such highly respected authors. Most useful randomised trials compare an intervention of known utility with a protocol of promising but uncertain benefit - using parallel protocols and clearly defined, positive end points regarding the subjects' health. There are usually equal numbers of participants but it appears this trial was halted early by a pre-determined protocol due to the poor outcomes of the clonidine group. Unusual for 'Addiction', this multi-centre trial does not appear to have a statement concerning the funding (although the buprenorphine combination tablets were supplied by the manufacturer). Nor could I see a statement on conflict of interest. In-patients and out-patients are included but selection criteria are not given, nor are they randomised. Also unusual for Addiction, there is more than half a page of acknowledgements containing 85 names and up to 20 institutions. Several aspects of the article remind me of the sort of item contained in sponsored journal 'supplements'. One wonders if the normal peer-review process occurred, so numerous are the inconsistencies, omissions and questions concerning a lack of specific clinical aims/focus in the piece.

As above, most of the findings are predictable from the literature. The study involved a comparison of two non-evidence based 'treatments', being clonidine for detoxification and buprenorphine combination for 'detoxification'. Both 'treatments' have been shown to be ineffective in trials with over 90% failure rates on conservative criteria at medium term follow-up (1 to 3 months). Thus this study, whatever its findings, is unlikely to add to the scientific literature or knowledge base. We know that prescribing buprenorphine in standard doses to heroin addicts attracts and retains subjects while also reducing heroin use. We also know that clonidine does not do any of the above to any measurable or consistent extent although its use still has supporters and there is some promise of its chemical cousin, lofexidine (Brit-Lofex) for withdrawal symptoms. As yet, we still do not know whether the buprenorphine combination (bup-combo) drug is as effective as pure buprenorphine. There are indications that it is less efficacious (Bell) although another paper (Strain) showed contrary-wise that the combination drug caused consistently higher blood levels of 10-40% and thus might be expected to yield a better response. Thus readers may ask why use a combination drug rather than the pure drug, especially when the combination drug is not approved for commencement of treatment. The combination drug's only claimed benefit is reduced attractiveness to the street market. Yet dose diversion would not seem to be an issue here, being largely supervised and only short-term.

Unsurprisingly, the authors find that a higher proportion of bup-combo opioid dependent patients remained in 14 days of prescribed "detox" than those given no opioids. Also, and most importantly, they found that in-patients fared much better than out-patients in all respects (apart from hapless pair who perished in the in-patient group).

The authors fail to clearly define 'opioid detoxification'. Some might find the prescribing of opioids during 'detoxification' incongruous. Opioid detoxification cannot really commence until the patient ceases all significant intake of opioids. Even on day 13, these patients were offered 2mg of buprenorphine, still ten times the standard analgesic dose of 0.2mg sublingual (the maximum dose given - on day 3 - was 16mg). A further period of 14 days follow-up for the bup group might have allowed a fairer comparison of the two approaches in this case.

Either way, the authors have not clearly defined what they mean by detoxification, nor have they explained their statement in the abstract that 'success' involved an 'opioid-free urine sample on the last day of clinic attendance'. Perhaps their pathologist was unable to detect buprenorphine. Later in the article they state this must be free of *illicit* opioids, without defining *illicit*. Buprenorphine, like methadone, morphine or codeine can be licit or illicit. Indeed, it was to address the issue of diversion that the combination drug was introduced into the USA. Yet we now know that it can be abused, and that there is little if any evidence of less diversion than for other prescribed opioids.

In several countries now, even heroin can be legally prescribed and it is possible that, prescribed in decreasing doses, it might have comparable or better results than buprenorphine reductions. The very next item in Addiction is, in fact, a favourable comparison of oral morphine with methadone from experienced researchers in Austria.

Adverse events: The section on side effects starts out with a long, confusing, 'de Quincey-esque' sentence of 62 words. In the following 57 lines comes a tedious and confusing 'lecture' to the reader on the technical difference between 'serious adverse events' and 'adverse events'. Only at line 37, and after the reassuring statement 'Few serious adverse events occurred in either protocol' do we first learn of two deaths in this 14 day, 344-subject study. This implies a very high average mortality and requires some detailed explanation. All we are told is that one death (in the bup-combo group) was due to 'respiratory failure' (could this be 'code' for drug overdose?) and one was from the clonidine treated group ('bacterial endocarditis' - usually a slow or sub-acute disease in drug addicts). We are told (without coronial references) that 'neither death was attributed to study medication'. However, we are also told that patients in both groups took an average of three other medications during the trial, including 'OTC' acetaminophen (paracetamol), ibuprofen, loperamide and diphenhydramine as well as prescribed oxazepam, lorazepam, phenobarbital, hydroxyzine, methocarbamol, trimethobenzamide, Donnatal (containing phenobarb), zolpidem, trazadone and doxepin.

I have never heard of a patient dying whilst undergoing supervised detoxification from opioids, so these mortality reports need to be taken very seriously, especially when the patients were in a NIDA approved treatment protocol in registered and (presumably) accredited medical facilities. I can only speculate (as the authors do not) that this was a trial which attracted the most severely ill American addicts and/or may not have provided the best means to rehabilitation for their condition. Neither trial protocol is an 'evidence based' or proven modality for heroin addiction, even though both may be reasonable choices for subjects as long as they also have the option of more effective avenues such as traditional methadone maintenance. In many American (and Australian) cities there are still long waiting lists and/or methadone is beyond the financial reach of many addicts.

The authors state "In the out-patient group, 18 serious events occurred, with 14 in the bup-nx group and four in the clonidine group." Equal numbers of serious events occurred in the in-patient groups, including two with suicidal behaviour and one with persistent vomiting in those receiving bup-nx. I am mystified how an in-patient can have a 'motor accident' whilst under treatment, yet, along with 'spine surgery' we are offered this as an 'adverse event' without further explanation. It is also hard to understand how a patient who was assessed as suitable for detoxification could have died so quickly of sub-acute bacterial endocarditis. Detoxification is highly unwise in those with active septicaemia. One patient dropped out due to 'sensitivity to a study medication' (unspecified). This 'unfortunate' omission becomes a 'serious' one if buprenorphine were implicated.

The most important finding of this trial is probably that in-patient detoxification was so much more efficacious than community treatment (despite there being no randomisation). The differences were dramatic and they point up the inappropriate decisions made by successive administrations to close down drug and alcohol detoxification wards in New South Wales and elsewhere. Much of this was based on claims by so-called experts of their services not being 'cost-effective' or 'evidence based'. This trial shows that by using counselling and the Californian "Matrix" protocols and a 'placebo' such as clonidine, excellent in-patient detox results can be obtained in selected patients.

Comments by Andrew Byrne ..

Conflict of interest: Dr Byrne earns a proportion of his income dispensing methadone and buprenorphine to registered dependency patients.

Please note that Professor Charles O'Brien has written an excellent editorial in this 'Addiction' pointing out many of the above problems. Were he or I a reviewer, this month's edition might have been thinner.

Ling W, Amass L, Shoptaw S, et al. A multi-center randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Addiction (2005) 100: 1090-1100

Encourage hepatitis B vaccination in those at risk

Aust N Z J Public Health (2005) 29;4:305-7

Rogers N, Lubman DI. An accelerated hepatitis B vaccination schedule for young drug users.

Dear Colleagues, This study offered a free 3-week hepatitis B vaccination schedule to drug users under 23 years of age who were attending an outreach service. Out of a total patient population of around 500, 90 young people were recruited to the trial, of whom 71% completed all three injections. A further 11% had 2 injections. This enviable rate is much higher than other reports quoted.

This trial shows that drug users are often willing to be involved in preventive health measures when these are offered. Since drug users are at high risk for viral diseases, we should be encouraging all involved to ensure that they have maximum protection. The Sydney injecting room might be another place where a strategy like this could yield enormous benefits.

comments by Andrew Byrne ..

Benzodiazepine use in dependency patients

26th July 2005

Presenters:

Richard Hallinan and Andrew Byrne, Redfern Dependency Practice

Richard Hallinan and Andrew Byrne, who are both committed to best practice in dependency medicine, presented this useful seminar on benzodiazepine use. The session began with an overview of the pharmacology of benzodiazepines, and some relevant comparisons were made with alcohol, opiates and major tranquillisers. Differences between the various benzodiazepines particularly in relation to half-lives were outlined, and indications, side effects, tolerance and withdrawal were all discussed. A handout was available detailing all of these points.

Special mention was made of benzodiazepine (BZD) use by patients on methadone maintenance treatment (MMT) and it was noted that this group of people often have particularly high levels of psychopathology and psychosocial distress, including higher rates of unemployment, incarceration, HCV, and HIV/HCV risk-taking behaviour. BDZ users on MMT also tend to be on higher methadone doses and to have higher blood levels, although methadone concentrations adjusted for dose are actually lower in this group. The reason for this is unclear as there is no evidence that diazepam increases the clearance of methadone. One hypothesis is that there is a tendency for rapid methadone metabolisers to seek BZDs, in which case split methadone dosing might be useful. It may also be that these people are self-medicating, or "just can't get enough of a 'good' thing".

An approach to BZD abuse in MMT patients was outlined. It was suggested we make sure that psychopathology (eg anxiety and depression) is adequately treated, alcohol problems are addressed and information obtained from the Doctor Shoppers Hotline in appropriate cases. Consideration should be given to moving from short to long acting forms of which diazepam is the most common. Also, supervised dispensing should be considered where 'control' or impulsivity are problems. It is also essential to optimise the methadone dose, being flexible about dosing times or, occasionally, split-dosing (which needs prior approval from the PSB).

Reasons for BZD use were outlined, and are important to understand when looking at treatment options. People take BZD for many reasons, including alleviation of anxiety and insomnia, self-medication of depression, self-medication of withdrawal from opiates and BZDs, to come down off stimulants, and to get an increased "buzz". So-called "Poly-drug users" swap from one drug like speed or heroin to another such as BZD, and may simply do this because BZDs are the cheapest or most available drug at the time. It was noted that BZDs in Australia are subsidised on the PBS, whereas they are very expensive and hard to obtain in the U.S. so it is no surprise that their use amongst the marginalized in the USA is far less.

Aims of treatment of BZD dependence were clarified within the overall context of harm reduction goals. This includes abstinence and it was pointed out that harm reduction has sometimes erroneously been seen to include legalizing drugs, which while worthy of discussion, is quite a separate issue. Our first dictum should be "Do No Harm" and we shouldn't forget that an important part of this is just saying "no" when appropriate.

When assessing a patient for treatment we need to understand their personal history of abstinence, by asking questions such as "when were you last abstinent?", "how many times have you achieved abstinence?", "how did you become abstinent?", and "what did it feel like when you were abstinent?". We need to understand that previous abstinence may not necessarily have been a happy and stable time for every patient.

It was pointed out that the statistics regarding measurement of harm relating to BZD use are limited, but nonetheless worrying. Doctors must weigh the harms and benefits of BZDs both in the community and in individuals (as we do with all other prescribing). PBS prescribing figures reached a peak in 1988 and have fallen since then. It is well accepted that some people function well on a small dose of diazepam, so this drug may have a useful place in legitimate treatment plans. It is gratifying that in Australia, appropriate regulation has seen the end of temazepam capsules, along with Mandrax (methaqualone and diphenhydramine), meprobamate (Miltown), bromides, barbiturates and high dose flunitrazepam, which have all vanished from scene.

Harm from BZD dependency was discussed, and includes an array of physical, social and behavioural disturbances. Special mention was made of the damage to nerves and blood supply when subjected to pressure for prolonged periods of time. This scenario can occur with overdose and increased use which leads to long periods of reduced consciousness in fixed positions. Nerve palsies, skin necrosis and the compartment syndrome can occur. Thrombosis and infections from injecting, criminal activity including prescription fraud, convulsions from withdrawals, and deepening of depression are all possible consequences of BZD use. Rates of domestic violence are probably parallel with alcohol abuse.

Treatment approaches to BZD use rely on an accurate diagnosis, which should depend on a detailed history with relevant physical examination. Urinary drug screening can be useful, along with information from pharmacists and reports from HIC services. Some unusual features of benzodiazepine users were noted, including possession of a Medicare card with a high terminal digit (8 or 9), fiddling with the position of furniture within the consulting room, talking to the GP with great familiarity and requesting the drug by specific name. The assessment of BZD use should parallel that which is done for opiate users, including the level of dependence and addressing resultant medical and social harms. Co-existent mental health issues should be treated and methadone treatment at optimal dosage. As with all other drug use, there is a spectrum of patterns of use, including non-dependent occasional use, irregular binge use, dual dependency (eg with opiates) and "pure" BZD dependency. It may be useful for the patient to keep a drug diary, as memory may fail in this patient group.

If considering regular prescribing of BZD with a view to abstinence, there are some useful "check-list" questions we can all ask ourselves. They include: "What alternative strategies has the patient tried?", "have I seen their drug diary?", "what is their motivation for abstinence?", "have I seen a UDS result?", "have I sought information from the HIC hotline?", "are they on optimum doses of methadone or pain treatment?", "is treatment for mental health conditions adequate?"

Prescribed BZD must be tailored for the individual, but it was emphasized that slow reductions in doses may take months in established dependency. It is unrealistic to expect a patient with long-term BZD dependency to be able to maintain abstinence following a 2-4 week reduction regime. Diazepam is the preferred BZD to use for reduction regimes owing to its long action and familiarity. Several case histories were discussed to help illustrate management plans.

Australian Health Insurance Commission (HIC) services were also discussed. There are two separate services: firstly, "Prescription Shopping Information Service". Doctors must first register if they wish to access any information. Doctors are given a PIN number, and can find out information on numbers of BZD PBS prescriptions and numbers of doctors seen, above a certain threshold. No information is kept on private prescriptions. Toll-free phone is 1800 631181. The second HIC service is a "voluntary agreement" print-out of PBS items available after the patient signs the consent form. Forms available from 1800 420074. These services may be useful not only because of the information they provide, but because patients know their doctors can access certain information about their BZD use.

The meeting ended after some complex but somehow familiar case histories with lively discussion about the various possible approaches.

Dr Jenny James. Daruk AMS.

Hep C in dependency patients: prevalence and outcomes

Hepatitis C virus prevalence and outcomes among injecting drug users on opioid replacement therapy. Hallinan R, Byrne A, Amin J, Dore GJ. J Gastro Hepatology 2005 20;7:1082-1086

Dear Colleagues,

This item from our own surgery shows that of 178 injectors on methadone/buprenorphine maintenance treatment, 75% tested positive for hepatitis C (HCV) antibodies. Of 130 untreated HCV cases, 53% had normal ALT enzyme levels and half of these were HCV-RNA negative, indicating probable viral clearance.

Older patients on methadone/buprenorphine were significantly more likely to have normal ALT levels and to be HCV-RNA negative. This might be explained by low levels of injecting and hepatitis C re-infection in this group.

Younger patients were less likely to have hepatitis B (HBV) immunity through vaccination or exposure, pointing to the need to target this at-risk group effectively for catch-up vaccination.

Of 58 active hepatitis cases meeting pre-liver biopsy criteria for subsidised HCV treatment, 34 had relative contraindications to antiviral treatment, including drug and alcohol/psychiatric reasons. There were 11 whose only contraindication was continuing to inject. Recent studies show that patients with active injecting drug use can still be successfully treated with HCV antivirals.

At the time of this clinical audit only 6 patients had ever been referred for specialist HCV assessment, however since the end of the study the rate of referral has increased considerably and several patients have completed or commenced HCV treatment, some in the primary care interferon prescribers project of the Australasian Society for HIV Medicine (ASHM).

This study emphasises a unique public health opportunity. The emerging epidemic of hepatitis C is occurring predominantly in the drug using population, thus detection and referral should be possible at methadone clinics, GPs, pharmacies, needle services and injecting rooms frequented by this population. Hence, despite the enormous looming problem of active hepatitis, liver failure and cancer, it is possible that early detection and treatment could avert many of the consequences and save health funds in the long term.

We believe that it is incumbent on all those who treat drug addicts to ensure that their patients have HIV and HCV testing at least annually, and recommend HBV vaccination where appropriate. This is as fundamental as doctors doing cervical cancer smears at certain intervals in appropriate women in the course of normal community practice.

Comments by Andrew Byrne ..