Hepatitis C diagnosis and management

1st February 2005

Update by Dr Greg Dore, St Vincent's Hospital, Darlinghurst.

This talk reminded us of the progress made in a disease which was not characterised until about 1980 and which we are still learning about today. Previously largely diagnosed as non-A, non-B hepatitis, it probably started in the 1960s in small numbers of parenterally acquired hepatitis, spreading quickly by the 1970s as injecting became popular in the drug using sub-culture.

Dr Dore showed various graphs indicating the dramatic increase in reported cases, pointing out the important distinction between such reports and true incidence or actual seroconversions. Many 'new' reports are diagnoses of patients whose infection was acquired many years previously. We learned that it is more instructive from a public health perspective to track reports from young people 15 - 22 years of age, where the figure more closely mirrors the true rate of seroconversion. This was rising through the 1990s but recent years have shown slowing and possibly a decline at last, in response to improved harm reduction policies. In reality, however, the actual pool of HCV positive patients continues to expand and is probably now over 200,000 in Australia, mostly from drug use. A small proportion acquired the infection from blood transfusions, haemophilia treatments, surgery, tattoos, body piercing, etc.

Six monthly testing in those at risk seems to be a common recommendation, but Dr Dore emphasised the individual needs. Conveniently, six months is also a reasonable interval for monitoring of disease progression in those who are HCV positive. We were then taken through the practicalities of testing. There are numerous possible approaches to screening/monitoring utilising the several available antibody tests, confirmations and HCV RNA pcr (polymerase chain reaction) which is a viral marker or highly sensitive test for presence of virus in the blood. For antibody tests, false positives occur at approximately 1 in 100 tests, presumably being at low titre in response to non HCV antigens. Thus in low risk groups they are frequent and in our high risk patient they can also occur from time to time. In assessing on-going hepatitis, Dr Dore finds little point in routine serum copper, ceruloplasmin or alpha-1 antitrypsin levels. These are all exceedingly rare and would likely be diagnosed at liver biopsy anyway. However he does advise testing for haemochromatosis using iron studies. He has found abdominal ultrasound examinations of limited use except for some cases of fatty liver.

The more widespread availability of HCV PCR as an indicator of actual virus in the blood has improved our approach to disease staging and to measure treatment responses. Under Medicare, GPs can only order this test if the transaminase levels are NORMAL on TWO occasions (serum can be kept frozen for later test requests). Thus we can reassure a certain proportion of cases (up to 40%) where the virus has become undetectable without specific treatment.

Drawing a parallel with HIV, Dr Dore explained the depressingly low rates of responses to original monotherapy (<20%) and subsequent sequential improvements with longer acting interferon (pegylated) combined with ribavirin in recent years (up to 80% response).

Criteria for biopsy and treatment were discussed in some detail. Persistently elevated liver function tests, >10 years disease duration, >35 years of aged were all relative indications for biopsy and treatment where appropriate. The genotype is also an important factor since types 2 and 3 are more likely to have a response (70-80%) than type 1 (~50%) after 6 month (for genotypes 2 or 3) and 12 months (genotype 1) of treatment. Type 1 appears to be less common in Australia than the USA.

There are worse prognostic features in patients who are overweight and who drink excessively as well as for those with co-existing HIV or hepatitis B. Indicators of more advanced liver disease (cirrhosis) include ALT/AST ratio greater than one, reduced platelet count and multiple spider n�vi. Continued injecting or drinking are not contraindications to treatment unless associated with a chaotic lifestyle, severe depression or untreated psychosis, where compliance is likely to be compromised. It is possible that the prospect of effective treatment with psychosocial supports might be used together as part of a therapeutic endeavour to improve outcomes (and save lives). Once hepatic decompensation occurs then biopsy and treatment are no longer appropriate.

A number of practical clinical issues were addressed, including the possibility of sexual transmission. This appears to be extremely rare, although some American data seem to have been skewed by their methods of collecting it. Dr Dore mentioned the very low risk with common, garden variety "vanilla" sex based on an Italian study of 800 'discordant' couples followed for over ten years. They found virtually no documentable disease transmission (the only few cases of seroconversions were of different genotypes!). However, we were told that there was probably a higher risk in both heterosexual and homosexual intercourse of a less orthodox nature, such as might expose small blood vessels. Hence for monogamous heterosexual couples, condoms are probably not needed but others would need individual assessment.

Next Dr Dore addressed the issue of vertical transmission which occurs in about 5% of cases. He advised a routine test at 18 months by which time maternal antibodies were no longer measurable. In cases of particular concern, PCR viral detection could be done as early as 6 weeks since this avoided the pitfalls of passively acquired antibodies in the absence of infection. For those offspring who unfortunately contracted the virus, yearly liver functions and possibly viral load should be considered until about mid-teenage when more detailed clinical assessment is probably worthwhile, despite the very low prevalence of significant disease activity. The ALT was a slightly better marker of disease activity in children than in adults.

Dr Dore has a pragmatic view of the possible non hepatic manifestations of HCV infection - depression, diabetes, fatigue, rashes, sicca syndrome, etc. Some of these may result from the disease, its treatment or intercurrent physical or mental conditions. We were told that fatigue, while sometimes possibly due to the infection, is more likely to relate to an emotional response to the condition.

Needle stick injuries were discussed from several aspects. A random needle injury had a negligible chance of passing on HCV but from a known subject in a recently used needle the chance of seroconverting is probably around 4%. For a needle used many hours previously by a drug user of unknown HCV status, the chances are therefore lower than this. Dr Dore said that he did not normally recommend courses of antivirals in such circumstances.

All in all this was an illuminating and enjoyable evening. There was lively audience participation.

comments by Andrew Byrne ..

Methadone review article raises more questions than it answers!

The effectiveness of community maintenance with methadone or buprenorphine for treating opiate dependence. Simoens S, Matheson C, Bond C, Inkster K, Ludbrook A. British Journal of General Practice 2005 55:139-146

Dear Colleagues,

It is always gratifying to see dependency subjects covered in mainstream journals. This should raise awareness of effective opioid maintenance and other therapies for addictions amongst front line health workers. However, this 'Review Article' would be more likely to turn interested GPs, nurses or pharmacists away from being involved in addiction treatments.

The authors quote comparative research which consistently shows buprenorphine to be slightly but significantly inferior to methadone in most outcome measures. Yet their contradictory conclusion states: ". the evidence suggests that . buprenorphine may even be more effective than methadone, depending on dose".

While comparisons between methadone and buprenorphine are worth addressing, these authors seem to expect the literature to determine which is 'best'. Few would spend time arguing the general 'superiority' of one antibiotic over another. In doing so they miss the point that neither is used altogether appropriately in the UK (or most other countries). A review article might be expected to address better ways of matching patient to treatment, yet this is largely ignored here despite some useful recent research on the subject, including those with HIV, pregnancy, fast metabolism, etc.

They write further: "There was some evidence that primary care could be an effective setting [for opioid maintenance treatment] but such evidence was sparse". This academic peccadillo also applies to insulin, warfarin or most other pharmacotherapies. Although most research is performed in clinics, few would doubt its extension to community practice. It seems that these authors lack confidence in the Cochrane contributors on the subjects. The lingering doubts expressed by the authors might deny treatment to most of the patient population while we wait for yet more research!

One of the most important messages of this review paper, UK treatment standards, is almost buried towards the end. Exemplifying understatement (and some clumsy English) we are told: "With respect to community maintenance with methadone . higher doses of methadone are more effective. This is important because surveys of current prescribing practices of GPs in the UK suggest that methadone may still be underdosed." [In fact the mean dose in the UK is less than 40mg daily. While this is a good starting level it is only half the 'plateau' dose needed for optimum results.]

Thus the authors (all but one from Aberdeen) avoid properly addressing the scandal of methadone treatment in the UK which continues unaddressed to this day. Dependent citizens may thus drop out of inadequate treatment, relapse to heroin use, overdose or contract viral infections while the medical profession gets a bad name for gross mismanagement of opioid dependency. A similar state of affairs for diabetics, hypertensives or arthritis patients could make an election issue centring on the NHS.

After apparently searching the literature for negative items, our current authors also state: 'higher doses of methadone may increase craving for heroin and decrease subjective wellbeing'. This is based on one very small study which has never been replicated (Curran et al, Addiction 1999 94:665). The findings conflict with 2000 years of recorded experience where additional opioids are generally associated with reduced cravings and increased feelings of well being in the acute situation. The Addiction editor wrote to me that there may indeed have been a statistical error in this study but he declined to allow any correspondence on the matter, leaving its rather outlandish sentiments uncontested in the literature. One assumes that these 'Review Article' authors would have read the reference carefully before quoting its title. John Strang wrote recently that methadone may yet have a 'sting in the tail' without further explanation.

After 40 years of clinical experience methadone is no longer "on trial". The question is why people still express lingering yet unfounded doubts about its safety and effectiveness when used according to established practice guidelines. It appears that buprenorphine is in the same category giving patients and doctors choice at last.

comments by Andrew Byrne ..

Dutch heroin trials find better outcomes in those with prior abstinence based treatments

Matching of treatment-resistant heroin-dependent patients to medical prescription of heroin or oral methadone treatment: results from two randomized controlled trials. Blanken P, Hendriks VM, Koeter MWJ, van Ree JM, van den Brink W. Addiction 2005 100:89-95

Dear Colleagues,

This re-analysis of the Dutch heroin trials* shows that for most patient variables there was no difference in the proportion of 'responders'. The study randomised complex, 'resistant' opioid dependency cases to either standard oral methadone or medical heroin prescription, injected or nasal forms, depending on individual's usual route of administration. The factors examined included level of education, hospitalisations, psychiatric history, living arrangements, employment, cocaine use and previous abstinence based treatment. Although overall results were significantly better in the heroin groups, only one of these factors was associated with a difference in treatment outcomes when heroin was prescribed. The group reporting a history of abstinence based treatment had a defined 'response rate' in those randomised to 'medical' heroin of 61% versus 39% in the oral methadone group. This is highly significant both statistically (p=0.0003) and also from a dependency point of view. The finding appears to be corroborated since the response rate to standard methadone treatment was substantially lower in those who gave a history of having any abstinence based treatment (24 vs. 38%).

The authors speculate about this finding but no firm conclusion is reached. Workers in the field will be familiar with a group of 'failed' NA/AA subjects who often take methadone reluctantly at low doses and for short periods. Some can be our most frustrating patients, expressing guilt, depression and other negative feelings towards what they consider a poor option, despite the potential and evident benefits.

The study patients all had limited responses to traditional treatments available in Holland, including oral methadone. The mean age was 39; 80% were male and there was a high degree of psychiatric co-morbidity. Overall the 'response' rates in this trial*, were 25% for the oral methadone group and 45% for the others using the Addiction Severity Index (ASI) to 40% improvement levels.

It is depressing for outsiders (and possibly embarrassing for our British colleagues) that the UK has had thousands of patients prescribed injected heroin or methadone for decades, yet it is the Dutch who performed the first large randomised trial of this treatment. It is to the credit of the Addiction journal that it was prepared to publish this item despite its traditional avoidance of items of this nature. Maybe we will soon be reading a section on harm reduction!

In a report from Canadian Press dated 9th Feb 2005, a clinical trial has been approved by Health Canada in which 158 Vancouver addicts will be prescribed pharmaceutical-grade heroin for 12 to 15 months. A second site is being readied for the North American Opiate Medication Initiative (NAOMI) in Montreal, expected to open in April, and Toronto will be added shortly after that.

It now appears possible, or even likely, that banning heroin in the 1950s 'sent the wrong message' to young people. It certainly denied medical patients the benefits of medical heroin in most countries. Far from eliminating heroin problems, the bans have been associated with rampant spread of illicit heroin use. It may be that the bans have contributed to the problems, in part by permitting easy access for minors as well as encouraging hasty and unsupervised use of drugs of uncertain purity. America is still unravelling the mayhem associated with prohibition of alcohol. It is to be hoped that we will be more scientific and methodical in undoing the many problems associated with heroin prohibition in western countries. Although many factors are still uncertain, these trials, injecting rooms, NA and other self help groups, legal diversion, decriminalization and education are all pieces in a larger puzzle of how to reduce drug use as well as reduce the harmful consequences of such use. Australia has scored many successes regarding tobacco and alcohol. Other drugs should follow and society will be the better and more prosperous for it.

Comments by Andrew Byrne ..

References

Blanken P, Hendriks VM, Koeter MWJ, van Ree JM, van den Brink W. Matching of treatment-resistant heroin-dependent patients to medical prescription of heroin or oral methadone treatment: results from two randomized controlled trials. Addiction (2005) 100: 89-95

*Original report: van den Brink W, Hendriks VM, Blanken P, Koeter MWJ, van Zwieten BJ, van Ree JM. Medical prescription of heroin to treatment resistant heroin addicts: two randomised controlled trials. BMJ 2003;327 310-0

Injecting rooms need support from experts, not alarmist doubts.

The case for piloting supervised injecting centres in the United Kingdom is strong. Wright NMJ, Tompkins CNE. BMJ 2004 328:100-102

Dear Colleagues,

With continuing high rates of drug related deaths in the UK, the BMJ is
right to again give prominence to the issue. The report by Wright and
Tompkins [ref 1] clearly demonstrates that there are new and promising
ways to address the current UK epidemic of overdose deaths from street
drugs, including medically supervised injecting facilities. Overseas
experience with injecting centres over 15 years has been uniformly
positive. Over one million injections occur each year in such centres
where deaths and serious complications almost unknown. Nearly all such
injections would otherwise take place in less savoury and thus less safe
environs. Such services also bring large number of addicts into contact
with health care workers, some for the fist time.

It is thus disappointing that in their following commentary [ref 2],
rather than unequivocally supporting such moves, Strang and Fortson
raise the canard of the differences between prescribed heroin for
dependency and injecting facilities (which they pejoratively call
'fixing rooms').

As a leading dependency expert, Strang knows the reassuring reports of
such centres in Europe, Australia and, most recently, Canada. The
concept has worked effectively elsewhere [ref 3], including apparently
unofficial experience in London. Strang and Fortson give no realistic
alternative strategy for the UK's high rates of overdose, HIV and
hepatitis C. They write that heroin prescription would only ever be a
'tertiary service', while injecting rooms a primary one.

These authors compare injecting centres to pubs, adding to the confusion
they are trying to address. Licensed premises, like Swiss heroin
prescription trials, supply the patrons' drug of choice in a safe
environment, while injecting centres only provide the supervised
environment for consumption of illicit drugs. Injecting centres are
perhaps more like patrolled beaches where people do risky, even
foolhardy things, while professional life-guards move into action if
needed in a non-judgemental manner.

Strang and co-author cannot know how insensitive their petty
reservations on injecting rooms must sound to grieving relatives when
every overdose death is potentially preventable. Rather than refuting
them, these authors raise old issues such as injecting rooms 'fostering
.. more .. drug use', drug dealing and operational protocols after over
a decade of positive experience. Their perfunctory dealing with 'harm
reduction' in the first sentence belies its being the foundation of good
medical and public health practice since the time of Hippocrates. It is
also official government health policy in some countries and has
prevented an HIV epidemic in Australia and Hong Kong.

Like heroin prescription, on current evidence we probably need a small
number of injecting rooms in drug 'hot-spots', as well as simultaneous
improved access to traditional drug treatments, detox services, harm
reduction measures and education.

Yours faithfully,

Andrew Byrne ..

References:

[1] Wright NMJ, Tompkins CNE. Supervised injecting centres. BMJ (2004)
328:100-102
http://bmj.bmjjournals.com/cgi/content/full/328/7431/100

[2] Strang J, Fortson R. Supervised fixing rooms, supervised injectable
maintenance clinics-understanding the difference. BMJ (2004) 328:102-103
http://bmj.bmjjournals.com/cgi/content/full/328/7431/102

[3] Burton, B. Supervised drug injecting room trial considered a
success. BMJ (2003) 327:122
http://bmj.com/cgi/content/full/327/7407/122-a


Extracts:
BMJ 2004 328:100-102 (10 January)

Wright NMJ, Tompkins CNE.

The case for piloting supervised injecting centres in the United Kingdom
is strong.

Medically supervised injecting centres are "legally sanctioned and
supervised facilities designed to reduce the health and public order
problems associated with illegal injection drug use." Their purpose is
to enable the consumption of pre-obtained drugs under hygienic, low risk
conditions. They differ from illegal "shooting galleries," where
users pay to inject on site. Worldwide, medically supervised injecting
centres (also referred to as health rooms, supervised injecting rooms,
drug consumption rooms, and safer injecting rooms or facilities) are
receiving renewed attention. In 2001, the first medically supervised
injecting centre in recent times was opened in Sydney, Australia.




BMJ 2004 328:102-103 (10 January)
Strang J, Fortson R.

Supervised fixing rooms, supervised injectable maintenance
Clinics - understanding the difference.

John Strang (psychiatrist), Rudi Fortson (barrister)

Harm reduction policies and practices (where anything goes, if it
actually reduces harm) have fundamentally altered our approach to the
drugs problem. Two innovations were recently considered by the Home
Affairs Select Committee-supervised injecting centres and supervised
injectable maintenance clinics-but with unhelpful confusion between the
two. They have different target populations, potential benefits, and
legal obstacles.




http://bmj.com/

Antipodean tabloid teacup tempest.

‘Addiction’: November 2004. A few seasonal observations.

# “Moo Joose” controversy.
# Addiction treatment compliance.
# Long-acting injectable ‘depot’ buprenorphine.
# Brief interventions on the web; twin study on alcoholism; ketamine brain damage; cannabis psychosis book review.

On the eve of a century of publication, this issue demonstrates the best and worst features of Addiction. The content of individual issues sometimes reveals editorial shortcomings and apparent inconsistencies yet an examination of a whole year’s titles would leave little doubt as to this journal’s editorial policy directions. These are well known to regular readers. On the positive side, the issue maintains an elegantly balanced dual thematic ‘leitmotif’, this month being a combination of modern approaches to alcohol policy and compliance to pharmacotherapy treatment for alcohol and drug problems. Authors represented in November include such luminaries as Anderson, Berridge, Bigelow, Caswell, Curran, Hickman, Kleber, Klingermann, Petry, Rhodes, Saunders, Tsuang and West. It is to Griffith Edwards’ credit that few other scientific journals in the world could boast such a line-up of experts in the one monthly edition. Clearly Addiction has the confidence of those in the research field.

The ‘Moo Joose’ (alcoholic flavoured milk) story is an example of how an important and topical subject should NOT be dealt with. Where there is clearly a divergence of opinion the case should be made with commentaries from the protagonists and experts but here we have only one side of the matter as so often happens in Addiction. Mr Aldred and his Alcohol and Drug Foundation (Queensland) are roundly criticised in the item as having changed their view on this product as a result of influence from the alcohol industry. However, they were not asked by Addiction to provide a comment (personal communication, 14/12/04). Nor, it appears, was the alcohol industry or government.

While many of us may agree with aspects of Munro’s critical report, it is hardly useful to have our own misgivings repeated by experts who have little more information than we do ourselves. And sadly, it is nothing novel for the beverage industry to chalk up another victory regarding alcohol marketing, against the advice of public health experts. The invited commentaries are therefore not balanced, nor are all the facts yet to come in on the matter, as pointed out in one frank review by Virginia Berridge. To her credit, she points out that Munro’s item raises as many questions as it answers. Yet editor Edwards, perhaps in hasty indignation, allows this antipodean tabloid teacup tempest to dominate his ‘scientific’ journal (items 2 to 9). So much for his maxim of encouraging ‘robust debate between people of goodwill’.

‘Moo Joose’ may be novel, and the final outcome possibly instructive but there are also matters of major moment from closer to home needing to be covered. Edwards has still not addressed the scandalously low standard of dependency treatment given by many of his British colleagues to hapless addicts in England. Details of this have been documented in the small print of his own journal many times over the years. I understand from impeccable sources that the average methadone dose prescribed in the UK is around 37mg daily, and further, that the most commonly prescribed daily dose is 30mg! These facts may partially explain why maintenance treatments have such a poor reputation in the UK. The official UK guidelines state that 60mg is the usual effective minimum.

While on this subject, it is hard to understand how Professor Weiss from Harvard could possibly omit methadone compliance and retention in his item (No 10) entitled ‘Adherence to pharmacotherapy in patients with alcohol and opioid dependence’. [Addiction (2004) 99: 1382-92]. Could it be that Addiction does not want to ‘offend’ by mentioning methadone at all? (shades of ‘Don’t mention the war!’).

Perhaps the most interesting item was the evaluation of an injected depot formulation of buprenorphine against placebo comparison. In an experimental in-patient detoxification setting, Sigmon, Bigelow and colleagues found few differences in responses over 6 weeks between those given the active opioid and those given placebo (my more complete summary elsewhere).
Perhaps the wisest commentary is last, the second ‘letter to the editor’ (actually an invited commentary) being from Herbert Kleber who has been around a long time and seen much come and go. Despite accepting some potential benefits, he also expresses concerns about depot and implanted medications, detailing the disadvantages. These include costs, painful administration, infections and a lack of ability to adjust the dose. Some, such as depot injections, do not allow removal but commit the patient to weeks or months of treatment. It reminded me of a Sydney University professor who was given an injection of procaine penicillin, having omitted to mention his life-long allergy. He apparently spent the next fortnight going in and out of anaphylaxis, needing adrenalin and cortisone treatment. I note with concern that in Sigmon’s trial they did not give a test dose of buprenorphine so allergies, although unusual with pure opioids, would not be have been detected until after a depot injecting was given. Depot preparations usually include numerous other chemicals (to delay absorption, preservatives, stabilizers, etc).

An extraordinary item on time-frames in Swiss alcohol and drug clinics tries to tease differences between social times and clock times (Klingermann & Schibili).

Kypri, Saunders and colleagues take alcohol brief interventions to the web, reporting benefits on both drinking and personal problems which declined with time in university students with hazardous drinking.

Liu, Tsuang and colleagues provide yet another examination of the huge Vietnam war era twin register to determine genetic influences on the age of onset of alcohol dependence.

There is an item on the long-term effects of ketamine, a sometimes popular illicit psychodelic anaesthetic agent. The authors find that there are some transient and other more long-lived side effects from heavy ketamine use, warning that users and potential users should be aware of such effects on memory and subjective experience. As usual with such items, there is no comparison with subjects who drink alcohol to excess, nor the degree of harms or benefits resulting from the illicit status of the drug in most countries.

David M. Fergusson gives an erudite book review on ‘Marijuana and Madness’, quoting some authoritative reports favouring causation as well as one discounting it. Recent writings on the subject make it clear that cannabis still may actually cause some cases of schizophrenia, but at most it could only account for a very small proportion of the total number of cases (well under 10% and possibly as low as 2%. Thus only with a massive increase in cannabis use could changes in prevalence be detectable in mental health statistics. For a comprehensive review of the current evidence see the current Drug and Alcohol Review which contains several relevant items.

Finally come two informative items pertaining to our most destructive drug, tobacco. Aspects of nicotine replacement and bupropion are examined from a general medical practice angle as well as certain gender differences in treatment response.

This is the second last edition under the editorship of Griffith Edwards. On 1st January 2005 he becomes “Commissioning editor“ - whatever that may mean. We are assured by Robert West, the new editor, that there will be more of the same.

comments by Andrew Byrne FAChAM ..

Victorian survey of methadone patients - not all good.

Ezard N, Lintzeris N, Odgers P, Koutroulis G, Muhleisen P, Stowe A, Lanagan A. An evaluation of community methadone services in Victoria, Australia: results of a client survey. Drug and Alcohol Review (1999) 18:417-423


Dear Colleagues,

This study reveals some interesting and important findings regarding the treatment of heroin dependency patients in Victoria, Australia where most patients attend pharmacies for their dosing with licensed GPs prescribing. It is a credit to the authorities that there has been such an expansion of treatment services to meet the increasing numbers of dependent citizens. It is especially important to document the functioning of methadone dispensing in community pharmacies since this is where most of the expansion of such treatment is occurring around the globe.

However, while changes will have occurred since 1995/6, the authors' positive conclusions still need to be tempered with some reservations about the limitations of current treatment delivery.

As in other states, there is a perception by Victorian dependency patients that pharmacy dosing sometimes lacks confidentiality (46% said it was 'too public') and that there is some discrimination in others being served first (42%). Dosing hours and location (only 66% satisfied) were also problems, especially when looking for work (53% said it 'interfered').

The authors state: "Results of the study were generally encouraging. The majority of clients surveyed stated they were satisfied with their relationship with their prescriber and their pharmacist, and with the methadone programme overall. Overall, our survey indicates that the Victorian community-based methadone service is in general an acceptable model of methadone service delivery for clients in the metropolitan area."

The survey of 195 patients would seem to indicate otherwise, revealing worrying deficiencies with treatment delivery as well as responses to that treatment. Only 72% were satisfied with their treatment and over a third stated that they would not have commenced treatment if they had know more about it, quoting 'hassles' amongst other problems.

Although the average duration of treatment was over 2 years, 40% of patients had received no take-away or dispensed doses at the time of the interview. Only 10% received 2 such doses weekly, and they were more likely to be female. The reason for this uniquely rigid regimen is not given.

The mean dose was 41mg (mode 30mg) with only 15% receiving 60mg or more. Almost half of the patients (44%) were still using heroin regularly by self-report.

These outcomes are consistent with the literature which yields a consensus that doses of methadone should normally be in the range 60mg to 120mg daily with only a small proportion of cases needing less or more than these levels. Hence up to 85% of Victorian patients may have been receiving inadequate doses in 1995/6.

Dr Vincent P. Dole wrote "With adequate dosage of methadone, taken daily, heroin use should be completely eliminated in 95% of all patients." He also recommended a minimum blood methadone level of 0.2mg/l to prevent cravings in such patients.

The lack of dispensed doses in this study is unparalleled in the world to my knowledge and is not based on sound scientific grounds. Like inadequate dosing, it is known to be associated with a significantly lower retention rates (Rhoades 1998). Dispensed doses for the Sabbath are given in many areas and reports have shown no differences from strict 7-day pick-ups (Gelkopf 1999).

comments by Andrew Byrne ..

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Dr Andrew Byrne,

General Practitioner, Drug and Alcohol,

75 Redfern Street,

Redfern,

New South Wales, 2016,

Australia

Tel (61 - 2) 9319 5524 Fax 9318 0631

Email ajbyrne@ozemail.com.au

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~



author of: "Methadone in the Treatment of

Narcotic Addiction" and "Addict in the Family"

How much do they spend on drugs? Are all users dealers?

Golub A, Johnson BD. How much do Manhattan-arrestees spend on drugs? Drug and Alcohol Dependence (2004) 76;3:235-246

Dear Colleagues,

This report analyses responses from over 2000 detailed questionnaires concerning specific sums paid for a variety of drugs in the 30 days prior to being arrested in Manhattan between 1998 and 2002.

The authors state in their results summary: "Among 2000-2002 arrestees, median drug expense in the past 30 days varied widely with frequency of use and drug-user type. Infrequent marijuana-only users spent as little as $5, daily marijuana-only users spent about $600. Arrestees who used both heroin and cocaine spent over $1000. Estimates with the 1998-1999 data were about half as large". "The amounts expended on drugs based upon the most recent episode(s) of drug consumption were almost twice as large as estimates derived from asking arrestees how much they had spent for drugs in the past 30 days."

While corresponding research is rare elsewhere, we do know that most heroin users applying for treatment in Sydney have been injecting (a minority smoke or sniff) almost daily and commonly between A$25 and A$100 (~US$600 - $2400 per month). Cocaine is much more expensive in Australia and is not seen in the form of crack at all. Injected cocaine is nearly always in binge-type use and is apparently uncommon outside of inner Sydney. Since retention in good quality treatment is high, and heroin/cocaine use is known to reduce dramatically while in treatment, the actuarial losses to the illicit market and reductions in law enforcement costs must be substantial, quite apart from humanitarian benefits and lessened viral disease transmission.

On related matters from New York, Davis, Johnson and other colleagues show that in upper, eastern Manhattan almost half of all drug users are also currently involved in some part of drug distribution. Those involved in dealing drugs were more likely to have HIV, higher incomes and to be in current drug treatment, but to have poorer education, housing and employment status than those not involved. While more women than men are involved, men are more likely to be involved in direct selling. [Citation: Davis WR, Johnson BD et al. Gender differences in the distribution of cocaine and heroin in Central Harlem. Drug Alc Dependence (2005) 77:115-127]

Comments by Andrew Byrne ..

Depression symptoms in new patients on methadone and buprenorphine. Randomised trial report.

Dean AJ, Bell J, Christie MJ, Mattick RP. Depressive symptoms during buprenorphine vs. methadone maintenance: findings from a randomised, controlled trial in opioid dependence. Eur Psychiatry. 2004 Dec;19(8):510-3

Dear Colleagues,

This well conducted double blind, randomised study examined psychiatric symptoms used the Beck Depression Inventory (BDI) in a subgroup of consenting patients seeking maintenance treatment for opioid dependence. There were 54 subjects who were each tested at entry and at 3 months into treatment. While we are not told the proportion who had depression, the mean BDI dropped from 22 (�10) to 12 (�10) in methadone patients and 25 (�11) to 13 (�9) in those on buprenorphine. By my calculations, the methadone patients saw a mean reduction of 48% in their severity while for buprenorphine, it dropped by 46%. We are told that the difference between the groups was not significant and that larger studies would be needed to determine if there is actually any difference. In my view, any residual difference would be modest, and other factors would probably prevail in clinical decisions about which drug to prescribe. While a BDI reading of 22 would only indicate a moderate depression individually, these are mean figures with standard deviation of 10 so there must have been a number of severely depressed subjects in each group.

The mean doses (for third month) were 48mg (� 20) for methadone and 9mg (� 4) for buprenorphine. Both would probably be considered lower than optimal although they are higher than in a number of other quoted reports.

Thus the conclusion should be that both methadone and buprenorphine treatments are associated with dramatic reductions in overall depression symptoms in the first three months of maintenance treatment. Some still warrant specific antidepressant treatment and indeed, one in ten had been prescribed such drugs during the study period. This is likely to improve retention and reduce illicit drug and/or alcohol use.

The authors state: "The reasons for improvement include both pharmacological and psychosocial stabilisation and may also reflect poorer retention rates for depressed subjects". This latter seems inconsistent with their finding that 'Baseline BDI scores ... were not predictive of treatment retention'.

It is always gratifying to have ones long-held clinical impressions confirmed by controlled scientific research. While the comparative findings may be novel, the observations about depression are not. Several relevant references are over 20 years old. We should all be reassured to learn that both methadone and buprenorphine treatments are probably equally effective in addressing symptoms of depression. This finding supports the general therapeutic practice (in countries where both drugs are available in normal practice) that methadone is the more common first line drug and buprenorphine is used very successfully for those who are unable or unwilling to take methadone. As with naltrexone (and probably any other drug), doctors who preferentially use buprenorphine will often find limited results with a proportion of patients, notably those with high tolerance, who may later transfer successfully to methadone or other treatments.

comments by Andrew Byrne ..

How to get the most from methadone treatment - better treatment practices can help patients and staff.

Abstract: This article presents strategies to improve the results of methadone treatment which currently are very variable. Dose levels and take-away provisions can have profound effects on the effectiveness of methadone treatment. Here we have some practical approaches to the patient who is not doing well in treatment.

Patients need sufficient doses and adequate psychosocial support.

A large and consistent body of research evidence gives us clear indications how to optimise the use of methadone in treating heroin addiction. Doses need to be sufficient in order to retain patients in treatment, reduce needle sharing and keep illicit drug use to a minimum. In addition, the regimen of dosing, supervision, urine testing and psychosocial supports need to be appropriate and acceptable to the patient population.

Some may be surprised at the statement that "95% of opioid dependent patients can achieve abstinence from injected drugs while in treatment". This is a quote from Dr Vincent P. Dole who originated methadone maintenance treatment. He said that to maximise outcomes in this way, methadone needs to be given in sufficient doses, in the right clinical circumstances and with adequate psychosocial supports [ref 1].

Clinical recommendations in several countries recommend doses in the range 60mg to 120mg daily for the majority of patients [ref 2] However, for a variety of reasons, many patients are still taking lower doses with correspondingly unsatisfactory results [ref 3.].

The initial methadone study in 1964 employed doses up to 180mg daily with a mean of 103mg (range 10-180mg) [ref 4.].

Cross tolerance between heroin and methadone.

Since there is cross tolerance with other opioids, patients who continue to use heroin regularly should be candidates for additional methadone. If heroin use has been sporadic and small in quantity, patients may well be advised to persist with the current dose. However, when heroin use has become regular such as several times weekly, a dose increase should be considered, usually of 5 to 10mg daily. This assumes that there is not excessive sedation from the dose and if there is any doubt an examination 3 hours after a supervised dose is often instructive and reassuring for both clinician and patients.

Inadequate doses of methadone can also be associated with increased cocaine use [ref 5]. Patients on inadequate methadone doses may also find it more difficult to stop drinking or to detoxify from benzodiazepines. Most importantly, they drop out of treatment and return to illicit drug use.

The patient's dose should be sufficient to abolish cravings for 24 hours. Sometimes the patient may not describe cravings, but will have other symptoms indicative of an inadequate dose. These can include a general malaise or frank depression. Patients will have one or two responses to such a situation, either suffer in silence or resort to illicit opioid use. Either way the patient is likely to be less than fully functional.

Patients needing more than 120mg may be rapid metabolisers and/or they may have had higher than average tolerance. Only a small proportion, perhaps a fifth of the total, need high dose (>120mg daily) and some only for short periods. Metabolism is a function of the patient's cytochrome enzyme characteristics and has little to do with how much drug they used or to their 'degree of addiction', etc. There is also a substantial minority, perhaps another 20%, who fare perfectly well on doses of less than 60mg daily.

There have been isolated reports of doses up to 300mg daily but these should only be used in specialist centres in clinical research settings. This may be due to altered opioid tolerance and/or metabolism and can be due to drug interactions or pregnancy. (see blood levels, below).
There may be a resistance to high doses from both patients and staff. This may be due to a natural conservatism or misunderstanding of the treatment. On occasions, genuine side effects can limit the usefulness of methadone. Some patients will tolerate such side effects, while others will reduce their dose or drop out. Doctors are used to this 'balancing act' with side effects caused by many other drugs. The patient is the final judge and will decide based on benefits versus adverse effects. Where outcomes are unsatisfactory despite dose adjustment then alternatives should be looked at such as adding an antidepressant or even changing the patient to buprenorphine.

Apart from some sedation in the first days of treatment, there are few side effects reported with methadone. Sweating and constipation are the only common side effects and these are rarely dose limiting. Impotence and menstrual irregularities are common with heroin and usual improve on methadone. The improvements following appropriate dose adjustments are usually very gratifying. Any side effect can be addressed by graduated dose reductions.

Strategies to encourage appropriate dosing.

It is often helpful for the prescriber to engage an unstable patient more intensively. While there is continued use of illicit opioids and/or stimulants there should probably be regular weekly consultations with the treating doctor. Such visits need be no more than 20 minutes in most cases. It is helpful to discuss a range of related issues such as general health, dose levels, side effects, supplementary drug or alcohol use, 'track' marks, vein care, finances, employment and family matters. Not all of these matters need to be broached at each visit.
It may then be helpful to focus on the person's major particular presenting problem or nominated goal. For example: 'I've just got to save some money for rent'; 'I really need to get away from the needle'; 'My liver pain is getting worse and worse'; 'I should take less time off work or else I might lose my job'; 'I need to spend more time with the family'. Any one of these would be a useful starting point as there is often intercurrent drug use contributing to the problem and making the goal less achievable. A notation should always be made in the medical records for future reference.

After these practical problems have been identified, it is then useful to assess the patient's responses to treatment, including current dose level and past history of MMT. It may be helpful to place the patient's treatment into perspective by pointing out the wide range of methadone doses used, even up to 300mg or more. Such "high-pointing" may have a reassuring effect in itself by taking the emphasis away from 'minor' dose adjustments.

It is then useful to discuss the benefits and drawbacks of a higher dose in the individual case. Side effects are usually minor when compared with the consequences of continued illicit drug use.
The patient may have been on higher doses previously with good results. Experience has shown that the majority of patients who have a relapse tend to have to return to their own maximum "plateau" dose before regaining control.

Some patients will volunteer that they have taken large doses of 'street' methadone and can report the results. "Have you ever taken extra methadone?" "What happened when you did?" "How much did you take?" "Did you get 'stoned'?" "Did you use other drugs or alcohol afterwards?" This is all taken in the strictest medical confidence, and it is worthwhile saying so, even to the point of not writing actual details in the regular medical records if the patient prefers.
Fear of eventual reductions.

There is often a resistance to higher doses because of a fear of 'coming down again' and 'how hard it will be'. We need to reassure patients that reductions from 100mg to 50mg are the easy part and can often be done within a month or two. However, the major effort is needed for the lower steps of reductions such as from 50 to 25, or 25 to zero, according to most patients. Such drops usually take months and sometimes even years.

Fear of methadone in pregnancy.

Some women state that pregnancy is a good reason for not increasing doses. But in a setting of continued heroin use it is more important than ever. It is much safer to take a little more methadone and eliminate extraneous street drug or alcohol use wherever possible. While abstinence is doubtless preferable, there is also a high risk of foetal complication from relapse during the stressful episodes which inevitably occur, even in normal pregnancies.

Fear of incarceration.

Another common piece of 'home logic' from the patient may be: "I might be arrested and then I will hang out in the cells". Patients who give false names for minor infringements or 'warrants' cannot very well request methadone in their own name. We can reassure such anxious patients on two accounts. Those fearing arrest should also be reminded that when taking adequate doses of methadone they are far less likely to be apprehended. And if arrested, a stable patient on higher doses is more likely to be able to provide a good record of attendance and progress, thus making bail or acquittal more likely.

But patients who are taken into custodial care should receive every endeavour by their doctor to have their medication continued by some means or other. All prisons have medical services with access to appropriate medications. Methadone and even buprenorphine are becoming more routine in jails around the world. It works as well and may be even more important than in the community due to the higher risks in prison.

Fear of termination of treatment.

We should also reassure patients that their treatment will not be terminated arbitrarily. It is no longer acceptable to cease treatment abruptly, especially as a 'punishment' for continued illicit drug use. If there are serious behavioural problems, patients may sometimes be transferred to another service, but they should always have some realistic medicated option, even though it may not be as convenient.

Intolerance of methadone additives.

Another barrier to correct dosing may be the various constituents of prescribed methadone. Sorbitol, alcohol, preservatives, flavouring, colouring and other ingredients appear to affect some people adversely. Sugar-free solution is now available in Australia and its release has revealed a substantial proportion of patients are much better off without the additives in the older preparation. Considering the poor dental health of many methadone patients it may be that the pure solution should be use first-line.

In summary, unstable and unhappy patients should carefully consider the matter of dose for a reasonable period before deciding on an increase. The dose can always be reduced again if desired. It is very important that the patient does not feel forced into higher doses without consent. It is the patient who must bear the consequences of higher or lower doses. And there is often excess sweating and constipation. Research shows added benefits when patients have a direct input into their dose level. This happens with other forms of therapeutics such as analgesic, antidepressant, antipsychotic and anxiolytic treatment.

Blood 'trough' levels for guidance and reassurance.

Another strategy in some cases is to order a 'trough' blood methadone level, 24 hours after a supervised dose. This is advisable for patients taking doses above 120mg daily, at least once, to demonstrate their rapid metabolism. It is a safeguard for both patient and doctor. In those who are still using other drugs, the level is very often in the low range, indicating the scope for substantial dose increases. This information always helps patients and their doctors to know that they are not having the drug 'build up' in the body, nor that it is 'getting into the bones' or cause other residual side effects. It is very rare to find levels in the 'toxic' range (>1.0mg/l) but a small number may have very high tolerance and require such levels under specialist treatment. It is clear that those in the range 0.2 to 0.6mg/l do better than those with levels below that range. Most patients are quite happy and stable in the lower end of that range. Dose increases should only be implemented with patient consent and for clinical reasons such as illicit drug use, cravings, insomnia, depression, etc, and only when these symptoms do not resolve with simple measures and the passage of some time.

Ref 1. Dole VP. In Ball J, Ross A: The Effectiveness of Methadone Maintenance Treatment. Springer-Verlag, New York 1986. Foreword p viii.

Ref 2. Drug Misuse and Dependence - Guidelines on Clinical Management. 1999 The Stationary Office. Working Group Chair: Strang J.

Ref 3. D'Aunno T, Folz-Murphy N, Lin X. Changes in Methadone Treatment Practices: Results from a Panel Study, 1988 - 1995. American Journal of Drug and Alcohol Abuse 1999 25;4:681-700

Ref 4. Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. J Amer Med Assoc 1965;193:646-50 '193(8) 80-84'

Ref 5. Hartel DM, Schoenbaum EE, Selwyn PA, Kline J, Davenny K, Klein RS, Friedland GH. Heroin use during Methadone Maintenance Treatment: The Importance of Methadone Dose and Cocaine Use. Am J Public Health. 1995;85:83-88.

written by Dr Andrew Byrne and Dr Richard Hallinan

Sincere thanks are due to Dr Stefan Goldfeder who suggested the exercise originally and gave useful comments on the manuscripts at several points during its gestation.

APSAD Conference, Fremantle, Western Australia - Day 3

Wednesday 17th November 2004

Day Three

Dear Colleagues,

The third full day of this conference found some delegates somewhat jaded after the conference dinner the night before. A relief then at 9am to find that every chair in the plenary hall attended by a box labelled "Hangover recovery kit"! With my aversion to advertising of almost all kinds I had to pass it up.

Straight to business, however, with a brilliant talk by Thomas Stopka from California describing numerous studies on "secondary needle exchange". For Australians this is a rather odd concept, although it does happen to some extent, even in Australia. In places where there is major difficulty obtaining clean needles and syringes, there are retail intermediaries, entrepreneurs or unofficial purveyors of clean "works". Some may be diabetics with legal access to injecting equipment. Others are non-drug users (incorrectly termed 'alcoholics' by injectors interviewed in the US). But the majority as described by Dr Stopka are unemployed drug users who make a small income out of a restricted market [another overlooked benefit of prohibition!].

An example was a group of people living close by, converting a two-hours-per-day needle program into a 24 hour program, albeit with limited stock each day - and at a premium price. An inducement used in some areas is the provision of additional clean needles for each old one returned. Thus, as in the case of aluminium cans, people can be found 'cleaning' back lanes and stairways, ridding them of discarded 'works', in order to profit (even though the equipment provided has a commercial value of only a few cents).

It is a sign of the drastic toll which continues to be exacted by the American public due to its own laws that serious discussions regarding extraordinary research such as this exists. Only in recent months were Californian pharmacies permitted (under certain restricted circumstances) to sell syringes to drug users. I understand that up to 8000 people annually contract HIV from contaminated syringes in California. It is to be hoped that this figure can be reduced towards zero as new policies are gradually incorporated into the scene.

Next we heard from Paul Gruenwald on the important subject of alcohol policy - from global to local approaches. It was a wide ranging and very logical description of what can be done, what has been done (and undone) and what SHOULD be done for the future. There seems little controversy on the basics. While prohibition does not work (introduced as 'another Californian', Dr Gruenwald should know), age limits, differential taxation, venue licence conditions, law enforcement, labelling, drink driving strategies and education all have a place in reducing consumption and therefore, resulting harms. We were told that a 10% increase in price causes a 7.5% decrease in consumption and this in known to include the most heavy drinkers. Age limit changes also have potential benefits but these can hardly continue into middle age! Venue regulation enforcement, server responsibility and other details can also reduce consumption and harms.

After morning tea we heard from Kate Conigrave on alcohol screening in pre-operative cases in a large teaching hospital. She pointed out that previous work from Scandinavia published in the BMJ shows that it is possible to reduce post-operative complications dramatically by simply diagnosing and acting upon alcohol excess in the weeks before surgery (they used disulfiram 'Antabuse' as well as other measures). She pointed out how difficult it was from their own attempts at Sydney's Prince Alfred Hospital to co-opt anaesthetists, surgeons, secretaries, etc, due to all the other presumably necessary 'fuss' entailed in getting to surgery. In their own pilot study, only dedicated research assistants working in pre-admission clinics could reach sufficient numbers of patients, yet their efforts even then were often fruitless because operations were scheduled for the next day or two, long before any useful alcohol intervention such as disulfiram (Antabuse), counselling et cetera could be instituted.

There were parallel sessions on stimulant use, party drugs, policy, harm reduction and aboriginal issues. For the remaining stoics, the afternoon sessions comprised some innovative areas for APSAD. These included a study of rat mortality using buprenorphine and benzodiazepines which had been mentioned by Nick Lintzeris at last year's meeting but here was presented in person by Suzanne Nielsen. She had measured the breathing rates of variously drugged rodents, no mean feat in my book, and pointed out that buprenorphine is no benign drug when used in combination with other drugs, especially alcohol or benzodiazepines.

Robert Ali gave an enlightened presentation on why official doctors' groups should be involved in policy activism. He pointed out that many common causes of death were related to obesity, drugs, behaviours, life-style choices, diet, etc. Many of these were amenable to changes with simple measures. Likewise, regarding alcohol, tobacco and illicit drugs we should be able to give expert advice on what is best for our patients and for society generally [and this might balance in some small way what is best for breweries, tobacco industry, their shareholders and the 'sleaze' factor in lobbying]. All attending were given a copy of the booklet "Illicit Drugs Policy" published by the RACP, RANZCP and GROW (Self Help).

This conference has been a high point of the year for those of us up to our necks in dependency work. The convenors Simon Lenton, Steve Allsop and other Perth colleagues are to be congratulated for getting together a group of interested and interesting folk from all around the country (and the world) in a congenial venue. We were fortunate to have some of the most important players in research and clinical matters in our field present at the conference. Walter Ling (bup, ntx and other fields), John Grabowski (who first 'proved' that take-away doses improve outcomes), S. S. Lee who is running harm minimisation in Hong Kong and workshops for China; Robert Ali (multitude of inputs from clinical science to policy and administration); Nick Crofts (Asian Harm Reduction Network and many other contributions); Alex Wodak who almost single-handed 'invented' needle programs almost 20 years ago (to name just a few of the 'notables').

We look forward to the next APSAD conference in Melbourne, 2005.

comments by Andrew Byrne ..