26 July 2005

Benzodiazepine use in dependency patients

26th July 2005


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.

1 July 2005

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 ..

Buprenorphine, heroin drought, heroin prescription.

Foetal withdrawals with buprenorphine; uptake of buprenorphine in America; Australia's heroin 'drought' revisited; Barcelona death rates confirm protective effects from methadone;

Dear Colleagues,

From the plethora of publications on dependency recently I report on a number of items below so that readers may pick what might be relevant to their own practices, starting with a RCT of buprenorphine (pure) in pregnant women and results of foetal withdrawals.

Jones HE, Johnson RE, et al. 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 (Ref 1)

This shows favourable outcomes in 10 women and their babies on buprenorphine compared with 11 on methadone (randomised, double dummy trial). The proportion receiving medication for neonatal abstinence syndrome was lower in the buprenorphine and the doses used were lower (neither significantly due to the small numbers). Hospitalization period was significantly shorter in the buprenorphine treated subjects/offspring. This is yet another report showing the safety of buprenorphine in pregnancy. It is sensible that the combination drug was not used in these women. The best 'evidence' for the safety of buprenorphine in pregnancy comes probably from a lack of reports of serious foetal or maternal problems from France where the drug has been freely available from GPs for a decade.

Sullivan L, Chawarski M, O'Connor PG, Schottenfeld RS, Fiellin DA. The practice of office-based buprenorphine treatment of opioid dependence: is it associated with new patients entering into treatment? Drug and Alcohol Dependence (2005) 79;1:113-116 (Ref 2)

This piece attempts to categorize some characteristics of 96 buprenorphine prescribed addicts in America in comparison with 94 entering methadone maintenance at the same period. While not a piece of controlled research, it does indicate that methadone is more likely to attract previous methadone recipients while buprenorphine attracts a higher proportion who have never had methadone (or other maintenance) treatment.

Degenhardt L, Day C, Dietze P, Pointer S, Conroy E, Collins L. et al. Effects of a sustained heroin shortage in three Australian States. Addiction (2005) 100, 908-920 (Ref 3)

This is the latest and probably most comprehensive description of the so-called heroin 'drought' or shortage starting in early 2001 in Australia. There are detailed figures for crime, treatment entries, street prices, etc from three states. While NSW saw a temporary increase in crime, this was not seen in other states. The most dramatic effect was on overdoses which dropped by up to 75% from their high points around 1999. There appeared to be less injecting as shown by fewer syringes distributed. Treatment places were increased at the same time as the 'drought' began while Sydney's highest overdose area saw the opening of an injecting room which attracted thousands of injectors.

Most interesting are commentaries from 6 or 7 experts, each agreeing that a sustained drug shortage of this nature has never been reported before and that the cause was not an obvious alteration in drug policies (although some mention a 'tough on drug' strategy without documenting any substantial changes in customs, policing, treatment, etc).

Gossop points to police crackdowns in Canada and London resulting in enormous drug seizures and arrests, neither of which had any reported effect on illicit markets. None of the wise commentators speculates on China 'opening up' and causing opiates to be diverted from the relatively much smaller Australian market. The 'drought' began within weeks of the start of the so-called 'Chinese century' in January 2001. Ironically a commentator from the People's Republic writes in critical terms about 'harm reductionists' as though they were a pest to be eradicated. He is apparently proud that China 'has experienced a drug-free society for more than 30 years' without mentioning how this was achieved by the deprivation of civil liberties, travel, etc! And then he has the temerity to suggest that methadone and needle services should only be used as a last resort! Does he mean only when the HIV rates exceed 10% of the population? Or 20%? Hao then quotes a proverb using cats and mice to describe the drug war! His views, which some term 'zero tolerance', are so nauseating that they well plead the contrary case!

Brugal MT, Domingo-Salvany A et al. Evaluating the impact of methadone maintenance programmes on mortality due to overdose and AIDS in a cohort of heroin users in Spain. Addiction (2005) 100:981-989 (Ref 4)

This study followed over 5000 heroin users in a variety of treatment settings in Barcelona over a 6 year period, looking at mortality, HIV and other demographics. In 23,000 patient years of treatment there were just over 1000 deaths, one third from overdose, one third from HIV and another third from 'all other causes'. Only 11 overdose deaths occurred in patients currently receiving methadone treatment (50% were on MMT during the study period - mean dose 71mg daily). Being in methadone treatment conferred a 'protection' reducing the risk of death by a factor of 7. This also reduced the risk of contracting HIV.

Reported death rates dropped from 3.1/100 to 0.6/100 between 1992 and 1999 and the authors state: "the protective effects of methadone treatment was proved to have played a significant role." The overall decline is similar to that reported for France during the late '90s, where the drop in overdose deaths is attributed to massive increase in buprenorphine availability. Further, they estimate "that 86% of the overdoses and 38% of the AIDS deaths occurring among non-methadone users could have been avoided had they been in treatment."

This is not to say that all addicts should be on methadone for life. However, only a very experienced professional, after a complete assessment and probably knowing the patient for a time, should ever recommend a course of abstinence based treatments over supervised medical maintenance with psychosocial supports.

Despite containing possibly some of the most valuable lessons in the 40 years of methadone treatment, Addiction, true to type, gives this Spanish item no particular prominence. No editorial appears on the anniversary this month of this life-saving treatment. Methadone (along with related public health measures) has probably saved Australia from the HIV epidemic suffered in most other comparable countries. It also addresses addictions in a humanitarian manner for those unable or unwilling to go directly down the abstinence pathway. Even Australians who express disapproval of methadone treatment can still share in the multi-million dollar savings they have from its use in this country. Most New South Wales patients who were approved for methadone treatment are now off treatment (over 50,000 approved, ~17,000 currently).

Rehm J, Frick U, Hartwig C, Gutzwiller F, Gschwend P, Uchtenhagen A. Mortality in heroin-assisted treatment in Switzerland 1994-2000. Drug and Alcohol Dependence (2005) 79;2:137-144 (ref 5)

These authors report on the continuing success of the heroin prescription trial in Switzerland. Death rates have declined to rates comparable with other drug treatment subjects at around 1% per year, having been over 2.5% in the 1990s across the spectrum of drug users. This is all the more remarkable, they say, because only 'treatment refractory' subjects were admitted for heroin prescription, and these probably had a much higher expected mortality than the 2.5% estimated for opioid users generally in Switzerland in the 1990s.

Comments by Andrew Byrne ..


(1) Jones HE, Johnson RE, et al. 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

(2) Sullivan L, Chawarski M, O'Connor PG, Schottenfeld RS, Fiellin DA. The practice of office-based buprenorphine treatment of opioid dependence: is it associated with new patients entering into treatment? Drug and Alcohol Dependence 2005 79;1:113-116

(3) Degenhardt L, Day C, Dietze P, Pointer S, Conroy E, Collins L. et al. Effects of a sustained heroin shortage in three Australian States. Addiction 2005 100, 908-920

(4) Brugal MT, Domingo-Salvany A et al. Evaluating the impact of methadone maintenance programmes on mortality due to overdose and AIDS in a cohort of heroin users in Spain. Addiction 2005 100:981-989

(5) Rehm J, Frick U, Hartwig C, Gutzwiller F, Gschwend P, Uchtenhagen A. Mortality in heroin-assisted treatment in Switzerland 1994-2000. Drug and Alcohol Dependence 2005 79;2:137-144