18 December 2012

A practical approach to clincal urine drug testing.


A near ‘holy grail’ status in the eyes of the community has partially eclipsed the useful place of urine drug testing when performed appropriately in the therapeutic milieu. Like DNA testing, the perception of urine toxicology has sometimes moved ahead of its technology.

There is a widely held belief that toxicology results can convict or exonerate, create or dissolve a family union as well as cause a worker to be employed or to be sacked. Doctors who are familiar with toxicology testing may help avert crisis points by using a balanced approach tempered by the usual medical safeguards. It is a conundrum that tests may be ordered by court officials, police, employers and even schools, yet such people are not generally qualified to interpret results and can therefore be prone to serious errors.

The first urine tests to prove clinically useful were probably in Vincent Dole’s classic study on methadone treatment in 1964 [ref 1]. Along with numerous other seemingly obsessive measures, Dole performed daily, witnessed urine tests on his in-patient subjects, proving beyond any criticism that the treatment resulted in favourable drug use outcomes. Paradoxically, at the time opiates could not be detected but instead they tested for quinine, an almost ubiquitous contaminant of street heroin in New York at the time (because its bitterness balanced the sugar used for ‘cutting’ the illicit heroin).


Whenever questions are raised about drug or alcohol use affecting a patient’s life, work or family a ‘spot urine’ test can be very useful. It can be done in the same way as a urine culture, and by the same lab under normal Medicare billing. The usual rules of informed consent should apply and patients should be reminded of the possible consequences, positive and negative in their own circumstances. If one is considering treatment or referral for a drug or alcohol issue a urine test is essential as a base-line. Like other blood tests or X rays, one sometimes orders them just because of some clinical doubt, again with consent. “I think that a urine drug screen might look good for the records … what do you think about that?” This question and any response can be a useful clinical exercise in itself. “What do you think a toxicology test would show right now?” “Well, actually Doc I was going to tell you …”.

Urine testing can be crucial in cases where child custody is involved. Likewise with driving, work safety or sports competition, a urine test or series of tests in the course of normal clinical practice can sometimes influence matters very significantly in the patient’s interests.

Patients who are taking quantities of opioid analgesics for chronic pain should have urine screening performed occasionally [ref 2]. This is a safeguard for both patient and doctor and is described as a part of ‘universal precautions’.


Attempts to make urine testing forensically rigorous include: (1) ID checking and witnessing the sample being produced; (2) ‘chain of custody’ procedures for transporting the sample to the laboratory; (3) parallel second sample for checking (either to the patient or a third party); (4) tests for adulteration. These procedures are only needed for ‘life and death’ or ‘safety critical’ situations. Doctors are familiar with such procedures in the case of blood transfusion cross-matching, for example, where mistakes could be life threatening. So for child custody cases, drug court convictions or employment dismissals such rigour is also required. However, as an aid to clinical medicine it is perfectly satisfactory to perform a ‘spot’ urine test at the surgery or clinic. A degree of supervision and a degree of ‘randomness’ can make the results more ‘dependable’ but neither is necessary on every occasion. Tests for adulteration are now routinely performed including creatinine levels to detect dilution. Low measured levels of a drug may become undetectable on a more dilute specimen. Some vitamins or other chemicals such as soap have been tried to inhibit certain assays.

Laboratory procedures vary widely and one should be familiar with what is offered locally. Most labs have a standard battery of immunoassays for common drugs of abuse such as opiates, cocaine, benzodiazepines and stimulants. Where necessary a confirmation may be performed, generally by ‘GCMS’ (gas chromatography mass spectrometry). In our service we have stopped testing for cannabis except in specific cases of cannabis dependency.


The common qualitative immunoassay for opiates is highly sensitive but not very specific. Hence we usually expect a confirmation for positives using more specific assays for codeine and morphine at least. Morphine can and is metabolised from codeine and yet it may also come from common analgesic combinations and even poppy seeds. Recent use of quantitative measures can help distinguish over-the-counter codeine from heroin/morphine. However, there are traps for the unwary since codeine ‘recovery’ from the usual glucuronide metabolite is highly variable. In addition, people may have taken codeine as well as morphine or heroin (di-acetyl morphine), complicating matters still further. Specific stimulants can usually be detected using modern testing, including amphetamine, metamphetamine (also known as methamphetamine) and MDMA (ecstasy).

By far the most useful result is a negative one. This indicates that the patient was highly unlikely to have used any drugs of abuse in the previous 4 to 6 days. This almost excludes drug dependence but does not exclude casual or binge drug use.


Some may find it surprising that people with no medical training are able to order pathology tests. The matter was raised again recently when an American college introduced mandatory urine testing for all students [ref 3]. While the request may be simple, the interpretation is rarely a simple matter, as shown by media exposés of anomalies, mistakes and sometimes even fraud. Furthermore, it remains to be proven whether there are more benefits or harms resulting in such groups. Should the medical profession become involved? Nobody is better qualified yet many of us may still feel uneasy about such interpretations. Yet interpretation is just a matter of fundamental pharmacology and chemical toxicology so that we should not need to second-guess the outcomes. Where there is any doubt, guilt should not be assumed. Yet in some situations the onus is put onto citizens to ‘prove’ that they are drug-free (as if a single test could prove that). As with the hangman of old, it should never be a doctor’s role to ‘convict’ a patient: if we cannot speak in their defence we should be silent in my view.

As with other pathology ‘group tests’ each lab will do a certain number of agreed tests with or without confirmation. There will be ‘cut-off’ levels quoted for each drug tested with a positive or negative result given. These may change over time and it is important to keep up to date with testing procedures to avoid errors, especially when comparing results from different labs.


A common scenario is a positive test for opiates and amphetamine-type stimulants in a person who claims to have taken no such drugs at all. On closer questioning over-the-counter cold and ‘flu medicines or even poppy seeds can and do cause positive tests. While selective confirmatory testing can sometimes distinguish these, doubts may remain about the origin of, say, morphine. Such doubts must never be allowed to disadvantage a worker, driver, parent or (especially) a school child.

The science of driver testing for alcohol has taken 20 years to get to its present state so it is not surprising that there are still anomalies and ignorance regarding testing for other drugs. In contrast to the close direct relation between alcohol levels and clinical intoxication, cannabis and diazepam, for example, are detectable many days after exposure and levels may bear little relation to ‘sobriety’. Hence a positive test for these drugs is of little relevance to driving or work performance and may just be a needless invasion of the person’s privacy.

Other special cases might be pethidine, buprenorphine and growth hormone. These are difficult to detect using normal techniques although they are of limited relevance in the normal clinical setting. Research for pharmaceutical compliance/adherence often depends upon urine testing although saliva and hair can also be used, the latter with its own ‘time capsule’ drug history.


We must not lose sight of the fact that this is just another pathology test, subject to all the same familiar faults, flaws and limitations. Thus if used selectively with appropriate interpretation, such testing can have a valuable place but should never be seen as a panacea.

Written by Andrew Byrne, Redfern GP specialising in dependency medicine.


1. Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. JAMA 1965 193:646-50

2. Heit HA, Gourlay DL. Urine drug testing in pain medicine. J Pain Symptom Management. 2004 27;3:260-7

3. http://www.nytimes.com/2011/10/11/us/at-linn-state-technical-a-fight-over-required-drug-tests.html?hpw New York Times 11/10/11

Reading list:

Clinical Drug Testing in Primary Care. Technical Assistance Publication Series TAP32. SAMHSA 2012  http://kap.samhsa.gov/products/manuals/pdfs/TAP32.pdf

Tenore PL. Advanced urine Toxicology testing. Journal of Addictive Diseases 2010 29:436-448

Chermack ST, Roll J, Reilly M, Davis L, Kilaru U, Grabowski J. Comparison of patient self-report and urinalysis results obtained under naturalistic methadone maintenance conditions. D&A Dependence 2000 59:43-49

Fellous J, Lowenstein W, Gourarier L, Bonan B, et al. Relevance of urinalysis monitoring of methadone maintenance patients: a clinical-biological agreement on 41 patients. Addiction Biology 2000 5:313-318

Cone EJ, Lange R, Darwin WD. In vivo adulteration: excess fluid ingestion causes false-negative marijuana and cocaine urine test results. J Anal Toxicol. 1998 22;6:460-73

Goldstein A, Brown BW. Urine testing in methadone maintenance treatment: applications and limitations. J Substance Abuse Treatment 2003 25;2:61-63

This article on urine testing in clinical practice was commissioned by Australian Prescriber (NPS) but rejected by their editorial team for unspecified reasons. The present article has some minor changes since the original submission. 

Written by Andrew Byrne, General Practitioner and Dependency Specialist.

A colleague in England has suggested that we should broach the area of hair testing as well so I am grateful to Dr Colin Brewer for the following observations:

It may be useful to consider the testing of other body fluids (eg. saliva) and also hair.

For people on amphetamine maintenance, it is possible to tell by analysis of the isomers on hair testing whether the patient is also using street amphetamine.

‘Doctor addicts’ are sometimes very cunning about using alternative or ‘custom’ opiates that don't show up in conventional screening, including pethidine, buprenorphine and fentanyl.

Hair testing has two big advantages. It can reveal occasional use, eg at weekends between regular testing or when patients have to be away for a while such as overseas workers, military folk or airline staff. Also, and uniquely, if there is doubt about a sample, the test can usually be retrospectively repeated on a second sample unless the subject has had a recent and very short haircut. Conversely, for a patient who normally has visible hair suddenly to become a skinhead when hair testing is mentioned is deeply suspicious, especially if they shave their armpits and private regions as well (although the eyelashes usually remain in such cases).

Due to the time frame involved, a mooted hair test can be helpful in the scenario of: 'well, actually doctor, I was going to tell you...'. Furthermore, the increased likelihood of detection can also act as a deterrent to illicit or irregular use when hair testing is being used at some frequency.

For alcohol, hair can now be used to detect occasional use by measuring ethyl glucuronide and similar compounds. This, too, has a strong deterrent effect against occasional use - as with other drugs - thus making such testing therapeutic as well as diagnostic.

In practical terms only one Australian centre can do this test commercially at present (in Adelaide) and it costs about $600 per test, regardless of the length of hair (1-3cm = 1-3 months approx). There is no Medicare rebate for this test so it is usually only useful for proving abstinence where important family court, road traffic or employment matters may hinge on such evidence.

[latter on hair testing written by regular BMJ columnist and London psychiatric consultant Dr Colin Brewer]

27 September 2012

New York Grand Rounds: ADHD and dependency; acupunture in addiction syndromes; ketamine in severe depression.

Wednesday, 2 May 2012 10.30am Grand Rounds.

I was privileged to hear three registrars at Bellevue Hospital in Manhattan discuss literature reviews on three interesting topics.

Dr Erin Zerbo spoke on ‘ADHD and Co-Morbid Substance Abuse’

Dr Crystal Tholany dealt with ‘Acupuncture in dependency practice’

Dr Joseph Kwon addressed ‘Ketamine for Treatment of Depression’

1. ADHD & Co: Dr Zerbo.

We learned that ADHD was extremely prevalent, affecting 6-9% of children with ½ to 2/3 of cases persisting into adulthood, making ~4.4% of US adult population (~8 million victims).

Since 10-30% of adults have substance use disorder (SUD) there is a very large overlap of these groups. This was shown starkly in The National Comorbidity Survey Replication (n=3000) where prevalence of ADHD in those with a SUD was 11% while in those without SUD it was only 4%. The same survey showed that SUD was present in 15% of those respondents with ADHD but only 5.5% of those not having the ADHD. Four other studies (each 100-300 subjects) showed a high prevalence (10-24%) of DSM diagnosed ADHD in those with alcohol, cocaine and opioid dependency.

This information puts ADHD clearly in the scope of dependency health workers although on the other hand almost 90% of ADHD subjects have no substance use disorder (SUD) at all. It was emphasised by Dr Zerbo that as well as having a more severe and more prolonged course, ADHD subjects with addiction are also less likely to fit in with existing treatments despite such treatments being known to be just as effective in this population group.

I was interested to learn that those with ADHD are likely to use the same spectrum of drugs as others with drug use disorders and no ADHD. However, the drug use is often from a younger age and is more severe with more co-morbid psychiatric and behavioural disturbances.

The criteria for diagnosis of ADHD included six symptoms of inattention, hyperactivity or impulsivity for more than 6 months, dating from before 7 years of age, in two or more settings involving clear impairment and in the absence of other psychiatric reasons for the symptoms. In adults one would expect: low frustration tolerance, chronic conflicts with peers and authorities, stubbornness and impulsivity (which are major obstacles for treatment).

To make the diagnosis in adults one would ideally (but not necessarily) have the substance use disorder stabilised for at least one month before making the diagnosis. Differential diagnoses include thyroid disease, sleep disorders, bipolar disorder, generalised anxiety, chronic drug or withdrawal related syndromes.

Treatment using stimulants, antidepressants, noradrenergic agents, etc can be very effective for ADHD symptoms but rarely does anything for the SUD directly. Hence opiate maintenance or other pharmacotherapy for SUD should be used just as insulin might be used if the patient were diabetic. Dr Zerbo has made the point that appropriate and early treatment of the ADHD will ensure lower drop-out rates from treatment, including opiate maintenance where this is necessary.

A case history given raises issues of polypharmacy as a complex in-patient from the Bellevue Hospital ward was discharged after stabilisation with the following medications: methadone 120mg daily, dextroamphetamine 60mg daily (slow release), gabapentin 300mg tds, hydroxyzine 25mg nocte (sedating antihistamine) and valproic acid 500mg bd. I was told by staff that such cases are not uncommon but reminded that Bellevue tends to attract some of the more difficult cases, being a tertiary referral centre.

A colleague from California tells me that it can be a regulatory nightmare getting permission to prescribe opiate maintenance along with stimulants even though there is obviously a group of patients who need both drugs. He said that only in the Veterans Administration setting was it possible to give comprehensive care in his experience.

Conclusions given by Dr Zerbo:

1. Patients with ADHD are at higher risk for SUD, and have a more severe and prolonged course if they develop SUD.

2. ADHD symptoms can be a significant barrier to effective SUD treatment.

3. Pharmacological treatments for ADHD are effective in patients with SUD; they have not been found to be addictive or to worsen the SUD (even while active).

4. ADHD is often under-prioritized, which can lead to greater morbidity for these patients and a longer time to remission.

My own conclusion is that we must be under-treating some of our dependency patients unless we have a proportion (at least 5% probably) taking prescribed stimulants. If we are not comfortable with that then we are not comfortable with evidence based medicine. I am not proud to say that we only have had three or four such cases in our practice in Sydney over the past decade. The regulatory hurdles are immense.

For more information on this subject: http://dependencyseminars.blogspot.com.au/2008/07/adult-adhd-substance-use-disorders-dr.php4

2. Dr Crystal Tholany spoke next about acupuncture in the treatment of dependency and withdrawal syndromes.

We were given a description of acupuncture and some proposed mechanisms for its apparent effectiveness in various medical settings. We were given the historical context for following thousands of years’ of use in China, its introduction into American medicine and especially in the treatment addiction and withdrawals and the several studies that have been published. There were connections through Japan, Hong Kong and the Bronx. All eyes were on whether it was better than placebo. Many modern settings use electronic as well or instead of mechanical stimulation to the fine needles inserted into the body.

It was found that acupuncture could lessen withdrawal symptoms dramatically. However, this was not evidence based and the effect wore off quickly once the acupuncture was ceased.

Trials show no change in symptoms after treatment stops but some changes remained in PET scans and pathology with several proposed mechanisms.

We were also told about ‘HANS Acupoint’ nerve stimulation which has some followers using sticky patches rather than needles at specific anatomical points found on charts. Studies showed much lower doses of methadone or buprenorphine were required to abolish withdrawal symptoms (published in Chinese Journals of addiction and pain): 1mg versus 13mg bup and 50mg methadone vs. 200mg ‘total of doses requested’ over a 14 day period.

There are also some unconvincing but interesting animal studies. In some intriguing para-placebo studies groups were randomised to receive either “sham” acupuncture of the real thing. This was the closest one might get to a RCT, showing that in addiction cases no differences were shown for symptoms yet some changes were noted on MRI scan findings. In fibromyalgia cases, however, there were some significant improvements in those receiving the true acupuncture under the blindfold.

So, like AA, therapeutic communities, ten-day detoxification and numerous other respected interventions, acupuncture remains a folk treatment and non-evidence based to date. After centuries of use it should not be dismissed but likewise it should not be recommended in place of known effective treatments regarding serious outcome measures including morbidity and mortality. Because this treatment has only been used quite recently in addiction it warrants further investigation, according to Dr Tholany. Naturally it must never be advised in preference to proven treatments like opiate maintenance but in those refusing such treatments and consenting to non-evidence based approaches it may a valid alternative.

3. Dr Joseph Kwon spoke about ketamine for treatment of depression.

Dr Kwon was the third of three senior registrars at Bellevue to deliver a brief paper at their Grand Rounds to which I was invited. Dr Kwon had performed a literature search and presented some history, pharmacology and made the case for this option to be investigated further and possibly used now under close supervision for treatment resistant cases of suicidal depression.

The reason this subject was broached was the recent focus on suicide prevention and the delayed onset of most current forms of treatment for depression. There was also a group of treatment resistant individuals who failed to respond to either antidepressants or ECT. These included both endogenous depression and those with histories of bipolar disorder.

Ketamine was discovered as a shorter acting form of phencyclidine in 1962, having dissociative anaesthetic properties as well as uses in local anaesthetics and analgesia. It was found to have sympathomimetic effects, causing a trance like state at high doses and had a low incidence of respiratory depression. The half life was 2 hours.

The drug’s effect is largely on inhibiting the glutamate system and a Wikipedia page indicates that it shares this property with nitrous oxide, alcohol, methadone, propoxyphene, tramadol, PCP, ibogaine and numerous other substances.

There are groups interested in this subject at Mt Sinai Hospital in New York as well as Bethesda Maryland and in the Netherlands (there was also a paper from New Zealand I noted). Numerous publications of small trials were cited to justify further work and even to use this treatment off-label in certain severe cases at the present time. There has been at least one RCT in an add-on trial with other observational studies being reported, largely very positive in their outcomes with low rates of side effects.

We were told by Dr Kwon that research had shown depression to be associated with increased glutamate in the occipital cortex and reduced levels in the anterior cingulate gyrus. Animal experiments with stressed mice showed better coping with shock when pre-treated with ketamine as also seen with other antidepressants (at least that was the inference).

We were informed that ketamine is fifth on a relatively long WHO list of ‘essential drugs’ for medical purposes.

A small number of invivo human trials were cited: infusions in emergency room situation were very effective apparently as promptly reversing many signs and symptoms of depression on validated scales. In cases of suicidality this type of intervention could clearly be life saving if used appropriately.

Small doses of ketamine (1mg/kg) were shown to improve postoperative depression (and also pain in depressed patients). Another three trials were mentioned involving single or repeated infusions, one with placebo control. No patient developed psychotic symptoms (schizophrenic patients were excluded).

Like morphine and other prescription drugs, it is also used as a mind altering drug recreationally. Taken at rave parties, for example, it seems to cause more dissociative symptoms than the much more popular MDMA. I was informed that it has become one of the most popular recreational drugs in Hong Kong in recent years.

I understand that some Australian centres use ketamine for acute analgesia in patients who are taking buprenorphine (presumably due to resistance to morphine from the antagonist properties of the maintenance drug). According to a colleague in London it could also be useful in those taking naltrexone. I note that ketamine is available in Australia as a parenteral anaesthetic/analgesic under the trade name Ketalar, available in vials for injection of 200mg per 2ml liquid. Product information states that doses must be titrated individually but that 150mg injected intravenously can cause ten minutes of surgical anaesthesia.

It is the writer’s view that ketamine could do with a ‘White Knight’ like Reckitt Benckiser which developed buprenorphine as a treatment for opioid dependence. As an old drug, ketamine is of little interest to drug companies in its present state. However, with some manipulation and focussed research a new patented version could be part of the way to both profits and improved treatment options. With the benefits promised by Dr Kwon’s presentation I would buy stocks in any company working in this direction.

As well as Dr Marc Galanter, head of department, and addiction psychiatrist Dr Phoebus Dhrymes, veteran dependency advocate Charles Winick was in the small audience at Bellevue for this morning session. As it happened, Winick gave a talk I attended at Columbia University the following week outlining some parallel issues with fundamental research on rehabilitation which, like acupuncture and AA, is not easily amenable to controlled trials although some have been attempted with positive outcomes. Yet another coincidence was that we were both due for appointments at the Drug Policy Alliance later that day - let’s share a cab! “Only in New York!” There were more stories on request of security in New York hospitals and other institutions these days … food in New York … ‘coffee’ in New York … and more.

Written by Andrew Byrne ..

Clinic web page: http://methadone-research.blogspot.com/

A month in New York: http://andrewbyrneinnewyork.blogspot.com/

New York in 1922 from grandfather: http://bpresent.com/harry/code/09n_new-york.php

Lord Howe Island story: http://www.redfernclinic.com/c/2007/10/lord-howe-island-naturalists_4153.php4

Our butterfly collection: http://schraderbutterflies.blogspot.com/

Shylock and anti-Semitism: http://cantorialcrossoverculture.blogspot.com/2011/04/shylock-shakespeare-and-jews-anti.html

28 August 2012

RPAH Grand Rounds were indeed GRAND!

Grand Rounds at Prince Alfred circa 1975. An institution within an institution.

Recently I chanced to meet two senior medical colleagues who had participated in the Grand Rounds at Royal Prince Alfred Hospital for the years that I was a student and resident there in the late 70s. These were Friday afternoon sessions in which two cases were presented plus one or two follow-up cases from the senior registrars involved. The two regular attenders were Dr John Hallinan, chief radiologist and Dr John Emder, a senior local GP and probably one of the last GPs ever to be allowed in the doors of the hospital in the great age of the specialist.

Medical Grand Rounds was a long standing venerable tradition at the hospital according to my father who had been a resident there around 1950. The Scot Skirving lecture theatre was a windowless Victorian conclave between A2 medical ward and the small veranda ward used for peritoneal dialysis. There was an element of anticipation each Friday afternoon as hurried last minute pathology results or research papers were incorporated into the presentations, some of which were so notable (or notorious) that some of the audience already met the patient(s) involved in our own ‘rounds’.

Some of the more exotic diagnoses included myasthenia gravis, osteogenesis imperfecta (the only time in my experience that an actual patient was wheeled into the hall), lacunar stroke, dissecting aneurysm, carotid sinus syndrome, hairy cell leukaemia, cerebral lymphoma, mononeuritis multiplex, small bowel leiomyosarcoma, splanchnic claudication, ‘HHH syndrome’ (later called AIDS), methicillin resistant staphylococcus infection, cardiac tamponade, mixed connective tissue disease, idiopathic thrombocytopaenic purpura, systemic lupus erythematosus and narcolepsy/cataplexy.

Dramatis personae: The main characters of this high academic drama included the following: Prof Ruthven Bickerton Blackburn (lord high physician and usual chair person), Prof Tony Basten (immunology), Prof Martin Tattersall (oncology: “I do not treat the relatives”), Prof Anne Woolcock (respiratory medicine … and in real life, wife to Prof Blackburn), John Greenaway (possibly the last physician in Macquarie Street), David Tiller (who could derive a social profile from a biochemical one), John Hassall (rheumatology).

Less often, and sometimes on special occasions, there would be guest appearances from Prof Jim McLeod (neurology and dean of faculty), Harry Kronenberg (haematology), John Allsop (neuro), John Turtle (endocrine), Richard Benn (bacto), Geoff Duggin (renal), Warwick Selby (gastro), John York (rheumatology), Dick Richards (cardio), Lou Bernstein (cardio staff), Rodney Shearman (gynae), John Sands (of the games fame), Frank Harding Burns (notionally drug and alcohol and an advocate for God and moderation), Geoff McDonald (another of the few Catholics), and perhaps a dozen others.

The senior registrars at the time were amongst the most gifted young doctors in the country, including Michael Field, Michael Halmagi, Roger Tuck, Ian Caterson, Bill Bye, Stephen Lee, Sheryl Van Nunen, Geraldine Room, Paul Russell, Ben Friedman and many others.

Classic statements:

“Myaesthenia gravis is called gravis because it IS ‘gravis’”.

“Sjogren’s syndrome does not require the existence of a rash”. Response from up-start registrar: “When I worked with Dr Sjogren in Stockholm he used to say otherwise”.

‘The only five medical causes of abdominal patient are myocardial infarction, diabetes, familial Mediterranean fever, porphyria and tabes dorsalis.’

After a long and tedious discussion about a patient with auto-immune cold agglutinins, cryoprecipitins and acute renal failure Dr Jonathan Leicester, who was not associated with the case, commented in his slow, measured way: “I wonder if the patient just had a chill on the kidney?” (huge laughter from the audience).

Dr John Greenaway (leaning over the wooden railing, frowning sternly): “Mr Chairman, I would take to task the treating team over all these investigations!”

Mr Bruce Leckie (thoracic surgeon invited concerning a chest lump, possibly parathyroid): “Look, Mr Chairman I have been sitting here for 30 minutes listening to all these differential diagnoses, fancy test results, nuclear scans and other learned speculation. In that time, I could have made a small incision in the patient’s side, exposed the lesion and in all probability, cured it. I’m afraid I have to go back to work!”

I have always enjoyed being a fly on the wall but after three years of passive attendance I was finally asked to present a case when working for the neurology team in C1 ward under HMOs McLeod and Allsop. It may have been posterior inferior cerebellar artery (PICA) syndrome and I did not do the case justice.

I had the misfortune to speak French better than John Allsop which put me on the back foot as he looked after the private patients from Noumea who would be brought from the airport by ambulance once weekly for triage. They would have all manner of interesting diseases, mostly strokes, but also myopathies, epilepsy, neuritis, tumours and other differential exotica. John’s speciality was demonstrating gait disturbances, sure to trigger the funny-bone of each new cohort of students as he looked like Quasimodo lurching large.

In attending RPAH Medical Grand Rounds I was immensely privileged to be witness to this magnificent piece of medical history the likes of which have probably not been seen before or since in this country. Who in their right mind would expect a high-powered group of people to muster at 5pm on a Friday these days unless it was for a keg of beer and a music box? In fact the latter occurred slight later on a Friday at the Gross Farm Hotel nearby in Missenden Road.

Written by Andrew Byrne MB BS FAChAM (RACP)
Dependency Physician
75 Redfern St
Redfern 2016
9319 5524

[with thanks to John Byrne, Richard Benn, Martin Tattersall, John Hallinan, John Hassall and John Emder.] 

  This item was 'politely declined' by MJA as being too Sydney-centric for their Christmas edition.  Such is life!

Rare non-fatal cardiac risk should not discourage the use of adequate supervised methadone doses which save lives.

Increased incidence of QT interval prolongation in a population receiving lower doses of methadone maintenance therapy. Roy A, McCarthy C, Kiernan G, McGorrian C, Keenan E, Mahon N, Sweeney B. Addiction 2012 107;6:1132-9

Dear Readers,

These Irish researchers examine QT intervals in relation to methadone dose, cocaine, opiates and benzodiazepine use in 180 stable maintenance patients (total clinic population 376). They find that 9-11% have ‘drug induced’ QT prolongation despite finding no relation to daily methadone dose (which was a healthy mean of 80mg, SD 27mg) and no control group. Nor was there any relation between QT interval and the presence of cocaine in toxicology tests.

The article’s title makes an implication about the relevance of high versus low dose methadone in relation to QT prolongation. Yet the very first report of nine dependency cases had six taking less than 130mg daily and four taking less than 100mg (ref 1 - but see below why this cannot be gleaned from the paper directly).

QT prolongation has been reported in a high proportion of potential methadone recipients, but who were not actually taking methadone at the time. In hospice patients being considered for methadone treatment Reddy found QT prolongation in 28%. Lipski and her colleagues in 1973 reported 19% of street heroin users had QT prolongation before starting methadone treatment.

It is clear that a population of patients taking a variety of medications and with certain underlying illnesses such as HIV and hepatitis C are at risk of having QT prolongation, quite apart from any methadone treatment. Alcohol is also believed to be a risk factor [ref 4]. With a lack of any reported cases of this arrhythmia in 37 years, one might reasonably infer that this issue was not a major clinical problem in methadone prescribed patients.

Yet in the past decade there have been just over 100 reported cases of torsade in methadone patients. So, as our patients have survived their addiction, viral infections (and especially treatment for those infections), a small proportion have reached an age at which they have become susceptible to a rare clinical entity which most large centres have now seen at least once. Torsade de pointes was so rare amongst methadone recipients in 2002 that it was thought to be a new entity [see ref 13 for an earlier report]. Yet torsade de pointes was delineated and re-branded in the 1960s by a French group (no relation to methadone which was not used in that country at the time) [ref 11]. In 1985 another French group also provided a systematic approach to torsade treatment such that for eight years they had a mortality of zero [ref 12].

One may ask why we do not see more torsade de pointes since QT prolongation has a high prevalence in out treatment population. In a RCT Wedam [ref 8] found ~10% of new methadone recipients in Baltimore had QTc > 500mg (but no torsade cases), yet contrary-wise nearly all of the reports of torsade are in longer-term patients [ref 5 and pers comm].

So QT prolongation, even at the level of greater than 500ms in this population of methadone recipients does not appear to confer a measurable risk of torsade de pointes tachycardia (and numerous torsade cases had normal ECG away from the arrhythmia episode).

While torsade is symptomatically a distressing and unpleasant condition, it is rarely if ever fatal and is “controllable 100% of the time” with modern treatment, according to US cardiologist Phibbs [ref 6].

Suggestions from some quarters that there may be large numbers of unrecognised deaths due to torsade are not credible for two reasons: (1) deaths of patients on methadone programs are reportedly very rare and (2) such deaths are usually rigorously investigated by coroners and positive findings are the rule with only very occasional ‘unknown causes’ which might include a fatal arrhythmia [Anchesen; Perrin-Terrin, refs 9 and 10].

It is regrettable that in his seminal article on the subject Krantz did not delineate pain from addiction subjects [1]. This appears to have caused a decade of confusion about the supposed effect of extremely high doses of methadone (see Annals Editorial comments relating to “very-high-dose methadone”). When the cases were separated for the reader in a follow-up paper [7], it became clear that torsade may occur in those taking average doses as well as with the supra-therapeutic doses cited by Krantz’s group (up to 1000mg daily in the pain cases). Yet only two of nine addiction cases were taking such doses when developing torsade de pointes. Six of the nine were prescribed between 65mg and 125mg (mean 96mg), which are dose levels found commonly in methadone maintenance treatment reports. There were no deaths among these nine MMT patients. Indeed there are no documented torsade deaths in MMT as far as I can find in the entire literature (one suspected death in France has been reported).

Krantz’s finding of nine cases of torsade in a small catchment over a relatively short period remains to be explained as it has never been duplicated anywhere else in the world to my best knowledge. Most reports have been of one or two cases. One wonders if there were other factors at play such as a viral induced cluster, the high altitude in Denver or some other factor unique to Krantz’s area.

It is often instructive to go back to the original sources and while most cite Lipski et al., few seem to have actually read the paper which is elegantly written. Even some major authors on the subject apparently believed that Lipski and colleagues were examining the effect of methadone on the QT interval. They were in fact examining why so many heroin users in New York died of apparent overdose but with relatively low levels of morphine at post-mortem examination, proposing arrhythmia in some such cases (from heroin or other street drugs). As they had no way of testing QT effects from heroin, ECG changes were examined in new entrants to treatment at their methadone program (which closed down recently, to the shame of the otherwise venerable Mt Sinai Medical Center in northern Manhattan).

In short, these early researchers performed 12-lead cardiographs on 75 patients new to methadone treatment. About half had not yet started treatment and had used heroin in the previous 24 hours. The rest were already taking methadone and a range of other drugs as shown by urine testing. The first group had prolonged QT intervals in 19% of subjects while the new patients who had started treatment had a rate of 34%. The latter were reportedly using combinations of heroin, cocaine, methadone and other drugs. So their theory was not confirmed yet their findings indicated a possibility that methadone extended the QT interval despite this being asymptomatic in all cases. Further, there were no reports of arrhythmias in MMT patients for the next 29 years.

This leaves us asking why one would spend time and money highlighting, emphasising and investigating the torsade issue while ignoring the vastly more important issue of standards of treatment. Drop-outs, deaths, overdose, viral infection, unemployment, etc, are all well documented consequences of deficient doses, inadequate supervision and a lack of psychosocial supports which are still sadly common. Each of these factors was clearly delineated in Dole’s first report in 1965 - and which modern prescribers ignore to their patients’ eternal cost.

Notes by Andrew Byrne .. Clinic web page: http://methadone-research.blogspot.com/


1. Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, D. Robertson AD, Mehler PS. Torsade de Pointes Associated with Very-High-Dose Methadone. Ann Intern Med. 2002 137:501-504

2. Reddy S, Fisch M, Bruera E. Oral methadone for cancer pain: no indication of Q-T interval prolongation or torsades de pointes. Journal of Pain and Symptom Management 2004 28;4:301-303

3. Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. American Heart J 1973 86:663-8

4. Hyslop B. Prolongation of the QT interval on methadone: how important is methadone dose? New Zealand Medical Student Journal 2007 6 Aug

5. Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006 101:1333-1338

6. Phibbs B. Advanced ECG: boards and beyond. 2006 Elsevier

7. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy. 2003;23:802-805

8. Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

9. Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical relevance of QTc interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction 2009 104;6:993-999

10. Perrin-Terrin A, Pathak A, Lapeyre-Mestre M. QT interval prolongation: prevalence, risk factors and pharmacovigilance data among methadone-treated patients in France. Fundam Clin Pharmacol. 2010 Sep 6

11. Dessertenne PF. La tachycardie ventriculaire a deux foyers opposes variables. Arch Mal Coeur 1966 59:263-72

12. Salle P, Rey JL, Bernasconi P, et al. Torsades de pointe. Apropos of 60 cases. Ann Cardiol Angeiol (Paris). Jun 1985;34(6):381-8

13. Bittar P, Piguet V, Kondo-Oestreicher J et al. Methadone induced long QTc and "torsade de pointe". Swiss Medical Forum 2002 S4;P244:36S

Roy A, McCarthy C, Kiernan G, McGorrian C, Keenan E, Mahon N, Sweeney B. Increased incidence of QT interval prolongation in a population receiving lower doses of methadone maintenance therapy. Addiction. 2012 107;6:1132-9

14 August 2012

Pilot RCT points to reduced retention, increase abstinence from illicits and alcohol with more supervision.

A pilot randomised controlled trial of brief versus twice weekly versus standard supervised consumption in patients on opiate maintenance treatment. Holland R, Matheson C, Anthony G, Roberts K, Priyardarshi S, Macrae A, Whitelaw E, Appavoo S, Bond C. D&A Rev 2012 6:483-91

Dear Colleagues,

My old professor held that it was nice to learn of controlled research supporting one’s long-held clinical beliefs. This pilot study by a Scottish group fit’s the bill in my book.

There were 60 stable methadone maintenance patients randomised to daily supervised doses (existing treatment), twice weekly supervised doses and daily unsupervised (dispensed) dosing in community pharmacies with surveys and urine tests over a three month study period. The unsupervised patients were still required to collect their medication bottles at the pharmacy daily (this seems to be a uniquely British practice).

The authors state: “This small study was not statistically powered to estimate the effectiveness of different forms of supervision. Nevertheless, our findings are of interest as results suggest that increasing levels of supervision decreased retention (a negative finding), while reducing illicit heroin and alcohol use (a positive finding). This was not statistically significant (with the exception of the alcohol result) and should be treated with caution.” [alcohol problems were reduced from 47 to 33%, a significant reduction, only in the supervised group - other groups showed the same or worse figures].

In their introduction the authors state: “..there is no evidence base for deciding the optimal period of supervision”. In fact there is some controlled research for observed dosing (ref 1) but in opiate treatment the common practice has been of early supervision and the use of take-away doses later in treatment (as also followed by this service in Scotland). This regimen is used in a large proportion of research reports, virtually all with successful outcomes compared with controls - and with few adverse reports. This is the research basis for all opioid maintenance treatments used around the world today. It also parallels what we do with unstable mental patients or diabetics who are commencing treatment. They are usually given supervised treatment for days, weeks or sometimes months rather than bottles of pills, syringes or other therapies to take home for self administration. This is just sound therapeutics utilising available resources.

Controlled research over days, weeks and a few short months has also been done on dose supervision for patients with malaria, HIV, tuberculosis, HCV and renal tract infections with demonstrated benefits, sometimes dramatic ones. The uncharted territory is in long-term treatment since most formal research is of limited duration. Hence the crucial importance of this type of study in longer-term patients. With the authors’ positive and negative findings above, they appear to be supporting the need for initial supervision with early introduction of take-away doses in appropriate cases.

A substantial black market price for any drug and/or a shortage of the treatment availability (such as HIV meds in the third world or America) can yield a strong incentive to sell or divert medication. New patients and those in difficulties may benefit from on-going observation of their dosing (called ‘DOT’ in some work: Directly Observed Therapy) regardless of what they are being treated for.

In the UK uniquely, addicted patients who are new to treatment are often given doses to consume at home despite no controlled research base for this. Indeed, in some countries this would be considered unethical and dangerous, like the criticism of ‘giving alcohol to alcoholics’ (also debateable - see below Toronto experience ref 3).

New York Mayor Giuliani and Senator John McCain have joined a small number of high profile people with serious attempts to restrict the US methadone program, (which is largely *supervised*). Methadone treatment was called “disgusting and immoral” and “an Orwellian drug swap.” It would be even easier to criticise the UK program which is largely unsupervised. While there are calls for methadone maintenance to be curtailed (Ref 2) there are still UK experts trying to defend the use of unsupervised methadone treatments despite its unproven nature. Such moves to restrict opiate programs have naturally caused disquiet amongst this most vulnerable and stigmatised group.

Supervision using adequate methadone doses and graduated take-home provisions for suitable patients - an approach which is evidence-based and time honoured. And in the UK, even those on official government funded treatment, many receive treatment which is sub-optimal and ineffective (Ref 4). As well as ensuring compliance and protecting the patient/family, dose supervision also protects this treatment from needless controversy. In an exhaustive email exchange with one of the most respected addiction writers in England recently the only concession on this matter I received was: “Andrew, on one thing at least we agree - that supervision may be needed to allay public and political concern. Another is of course that done well it eliminates diversion. And these two facts are of course related.”

I say no more.

Comments by Andrew Byrne ..

Citation: Holland R, Matheson C, Anthony G, Roberts K, Priyardarshi S, Macrae A, Whitelaw E, Appavoo S, Bond C. A pilot randomised controlled trial of brief versus twice weekly versus standard supervised consumption in patients on opiate maintenance treatment. D&A Rev 2012 6:483-91

Ref 1. Rhoades HM, Creson D, Elk R, Schmitz J, Grabowski J. Retention, HIV Risk, and Illicit Drug Use uring Treatment: Methadone Dose and Visit Frequency. 1998 Am J Public Health 88:34-39

Ref 2. Methadone to be dumped in Scotland as treatment for heroin addiction. http://www.news-medical.net/news/2008/05/27/38661.aspx

Ref 3. Podymow T, Turnbull J, Coyle D, Yetisir E, Wells G. Shelter-based managed alcohol administration to chronically homeless people addicted to alcohol. CMAJ 2006 174;1:45-49

Ref 4. The prescribing of methadone and other opioids to addicts: national survey of GPs in England and Wales. Strang J, Sheridan J, Hunt C, Kerr B, Gerada C, Pringle M. Brit J General Practice (2005) 55 (June 2005); 515: 444-451

Disclosure: Dr Byrne owns a clinic which, like addiction clinics in most countries supervises methadone, buprenorphine, diazepam, antabuse and other medications for a fee.

9 May 2012

Postcard from New York. Tuesday, 8 May 2012.

Dear Colleagues,

I have been in New York City for three weeks and will try to summarize some of my activities relating to dependency issues (opera blog below for those interested).  I will give more detailed accounts of some of these meetings in the future but wanted readers to know what issues were being looked at currently in the dependency field at the four or more centers of learning here in New York. 

It has been a terrible time for public funding of research in our field and some of the most well endowed and well known organisations have been threatened with closure over a lack of continuing funding from NIDA under current austerity measures as well as increasingly strict guidelines and requirements for such funding.  I noted a lack of enthusiasm across the board in the development and research areas but continued optimism in those involved in the clinical side of dependency medicine and what Americans often refer to as ‘recovery’, a word seldom used by Australian patients and clinicians in my experience.  It may be partly due to the lack of public funds that drug company sponsorship is also eagerly sought, despite it ensuring that research is almost always slanted towards the use of big-profit drugs and avoidance of ‘bread and butter’ medications (see many references for this and work of Marcia Angell, previous NEJM editor). 

My trip began with a 3 hour seminar/dinner at Columbia University in which Dr Deborah Hasin told us that the essential change to DSM-V is that the new classification will lose the distinction between abuse and dependency so that there will only be one diagnosis based on 11 criteria.  Substance Use Disorder (SUD) will be ‘moderate’ if 2 or 3 are present and severe SUD if there are 4 or more.  Patients with just one of the criteria will have no DSM diagnosis and will not be considered to have SUD.  The old criterion of involvement in frequent legal issues has been removed while 'cravings' has been added this time.  The time frame for such reports needs to be within 12 months apart in general.  The concept of 'dependence' now only refers to the physiological states of tolerance and withdrawal.  I cannot help thinking that the new definition will have no benefits and may cause confusion in the 'dependency' field for years to come.  It is slated for introduction in May 2013. 

Grand rounds at Bellevue Hospital were chaired by Dr Marc Galanter: three addiction medicine registrars discussed literature reviews on three topics: ADHD in SUD (and vice versa); Acupuncture in dependency treatments; Ketamine in the treatment of severe depression.  These were each comprehensive and equally fascinating - more anon. 

Fort Hamilton, Brooklyn, is where the Guantanamo Bay trials were televised for New York journalists, family members and others.  I was asked to give Grand Rounds on methadone maintenance treatments in Australia there and was paired with one of their experienced doctors, Lucas Dreamer who spoke about buprenorphine.  It was intriguing that most American doctors who routinely prescribe buprenorphine in their practices (on in this case the Veterans Administration) have never prescribed methadone for addiction cases (and vice versa for many doctors in methadone clinics).  There was a lively discussion about maintenance, detox, psychosocial service, induction and transfer from one agonist to the other. 

I also gave a talk at Beth Israel Medical Center only a stone’s throw from the institution where methadone was first used in addiction treatment.  The department ‘Leaders’ seemed pleased to hear about treatment down-under.  There were discussions about hepatitis C, diazepam ‘maintenance’, needle provision and injecting centres. 

I had a brief discussion with a colleague from NDRI who is investigating drug courts in America.  These vary in the way they operate in different states with methadone and buprenorphine available as a treatment option in only a minority of cases (30-40%).  Reasons for a lack of maintenance treatments included court bans, financial factors, lack of prescriber and sometimes that the person was already detoxified by the time of reaching the court. 

The Drug Policy Alliance gave me their usual 'open arms' welcome at their new offices in 33rd Street.  Boss Ethan Nadelmann and his capable staff are working on a series of initiatives from ‘medical marijuana’ (cannabis to Australians), chronic pain medications, buprenorphine and much, much more. 

Today would have been the 99th birthday of Dr Vincent P. Dole who died in 2006.  Dr Dole, who was a great friend, colleague and mentor to me and lots of others, changed the lives of many people during his long career.  In fact he pioneered blood ion measurement (sodium/potassium, etc) and cholesterol aggregation research years before they became commonplace, prior to his ground-breaking work on drug addiction treatments at Rockefeller University in 1964. 

I was interviewed by a senior anthropologist who is doing an in-depth study on the history and implementation of buprenorphine treatment.  Her group is only too aware of the commercial factors involved in each aspect, some very positive and in the interests of dependency patients while other moves by the manufacturer or distributor may have in fact denied substantial numbers of dependent patients receiving any opioid maintenance treatment at all, both in America and elsewhere.  It is by no means unique for drug companies to endeavour to 'evergreen' their profitable products using numerous well known means.  However, in this case it may be unique that a drug developed over 30 years ago remains in the high-profit bracket. 

Dr Tom Haines brought me up to date with the situation in Portugal as well as the history of how their government brought in decriminalisation of all personal drug use 12 years ago … stemming amazingly from the persistent use of derogatory humour by a popular radio personality and whose views were then supported by the Law Faculty at Lisbon University and both political parties numerous early public forums on the subject.  While it has not eliminated drug use, the Portuguese ‘experiment’ has been a success in every other way according to reports which have been published in reputable places.  In a way, the implementation of interdiction of drugs from the 1950s was in fact a world-wide, uncontrolled experiment, only to compare with the American experiment with alcohol in the 1920s.  We never learn from history!

My last evening in the city is back to where I started with a panel discussion including Dr Jerome Carroll, Herman Joseph, Charles Winick and George De Leon on the past, present and future of dependency interventions starting from the 1950s.  This is the final meeting for Dr Carroll who has run these meetings for over ten years. 

I hope these brief notes are of interest to readers. 

Andrew Byrne .. (back to Australia next weekend). 

Clinic web page: http://methadone-research.blogspot.com/  

Opera blog: http://andrewsopera.blogspot.com/

DSM - V drops 'dependency' forever!

Drugs and Society meeting at Columbia University. 7.30pm Tuesday 17th April 2012.

I have just had the privilege of attending a presentation of the newly proposed DSM-V criteria for substance use disorders (SUD) which is due for implementation in May 2013. The talk was to have been given by Charles 'Chuck' O'Brien who was apparently entwined in 'grants' and was replaced by Deborah Hasin who is also on the committee devising the new DSM standards.

Dr Hasin is an epidemiologist who has done work with adolescent drug use, HIV, alcohol, household surveys, natural history, etc. She was at home at Columbia University where the meeting was held at their Faculty House in Amsterdam Avenue near 110th Street in Manhattan (West Harlem). Deborah is one of about fifteen members of the DSM-V committee looking as substance use disorders, chaired by Dr O'Brien from U Penn. There is also international representation from Australia (John Saunders), Holland (Wim van der Brink) and elsewhere. We were told some details of the process being followed with consensus and unanimity being attempted rather than confrontation and disagreement. In fact, we were told that there was agreement on most of the issues, often after extensive reviews of the research and discussion.

The DSM-IV was implemented in 1994, replacing the DSM-III and “IIIR”. There was also a 'text review' to DSM IV in 2000. Dr Hasin told us that this very meeting was one of many in the review process and she assured us that our views would be reported back to her committee members.

Dr Hasin gave us a splendid talk about the process being undertaken by the DSM review committee and the brief they were given to redefine the diagnostic categories for drug use disorders.

The committee had discussed changing 'abuse' to 'misuse' but opted to remove any 'loaded' terminology, remaining completely scientific with 'substance use disorder' (SUD). Likewise, 'pathological' gambling was rejected since any diagnosis in the manual was obviously 'pathological' so it became a redundancy and will be called something like ‘gambling disorder’.

The essential change, now virtually concluded, is that the new classification will lose the distinction between abuse and dependency so that there will only be one diagnosis based on 11 criteria. The diagnosis will be moderate SUD if 2 or 3 are present and severe SUD if there are 4 or more. The old criterion of involvement in frequent legal issues has been removed while 'cravings' has been added this time. The time frame for such reports needs to be within 12 months apart from cravings which can last for many years after drug use has ceased, causing an immediate anomaly.

The concept of 'dependence' now only refers to the physiological states of tolerance and withdrawal, something which I predict will cause confusion in the 'dependency' literature for years to come. I worry that the entire process may end up like accreditation, forming an unproductive bureaucracy, language and series of steps to nowhere.

Shopping, sex, eating and internet/gaming disorders have been put into the too hard basket while gambling itself has been taken on board with the same criteria but with minor differences as above.

The criteria for inclusion for 'Substance use disorder' ('SUD') are (simplified):

1. Repeated use with negative consequences

2. Repeated use in hazardous situations

3. Repeated use despite interpersonal issues

4. Tolerance

5. Withdrawals

6. Repeated use for longer or in larger quantities than intended

7. Unsuccessful desire and/or attempts to cut down drug use

8. Long periods taken to obtain drugs or recover from the effects

9. Repeated use causes neglect of other important activities

10. Repeated use despite known continuing adverse consequences on health

11. Cravings

1 criterion = no DSM diagnosis

2-3 criteria positive = Moderate diagnosis of SUD

4 or more criteria positive = Severe diagnosis SUD

Under the existing DSM-IV the first three (plus repeated legal problems) were used to define substance "abuse" (one or more) while 'dependency' required three or more of the remaining criteria (excluding cravings which were not included until DSM-V).

In the ‘case’ to justify the changes Dr Hasin quoted numerous published papers which examined the ‘discrimination’ of individual criteria against an overall diagnostic measure. Various rather complex graphs were shown, each with a flattened ‘S’ curve purportedly showing the effect of up to 15 chosen criteria upon the "latent trait" for problem severity measured in some non-linear manner. Each tracing was coded with its criterion below and each formed a flattened 'S' curve starting from a flat take-off on the X axis, ending similarly on a possible maximum parallel above. I noted that Dr Hasin herself was co-author of some of these papers. She has done extensive public health research in Israel where we were told that American surveys had been translated into Russian and Hebrew (but apparently not Arabic).

We were told that the close approximation of these curves showed the degree of contribution concordance each had with the overall occurrence of problematic drug use in the various (population) samples (none were clinic or patient samples). While the overall impression was that each of the criteria had a similar contribution, the value of the process in population studies was questioned by some delegates so we were then shown some curves of clinic / dependency populations (oops, should not use the term ‘dependency’ any more!).

Dr Hasin's point seemed to be that the inclusion of 'legal issues' added little to the statistical 'mix' for diagnosis. Yet several people in the room pointed out that it was legal issues alone which originally brought some of their most needy patients into treatment. Furthermore, with 10 or more criteria, removing any one would likewise have had little effect on the diagnosis. In practice, the great majority of our patients by the time they get to treatment have not 2 or 3 of these criteria but most of them.

I was a little surprised that there was no patient representative on the committee. Perhaps I should not have been surprised that a majority of delegates contribution to a psychiatry manual were not MD’s or psychiatrists. This is not to question the superb qualifications and need for non-medical input … in fact one member even had two PhD degrees in her credentials (I had thought it was a ‘typo’!).

The new DSM-V definitions remind me of accreditation in a way. The supposed improvements will be of very limited value to my view. The definitions have hazy time-lines with most being 'in the past 12 months have you had …'. As an exception, ‘cravings’, a new criterion, can last for decades after any drugs have been consumed! There is a somewhat closer parallel with smoking, drinking and other medical diagnoses ... but to what end I am not sure. There is absolutely nothing about the quantities of drug used, we were told due to the illicit nature of most of the drugs (now no longer the case with so much prescription drug abuse). However this does not stop every clinician in the field taking such a history, albeit with the inherent difficulties. Hence under the new system $10 per day smoked heroin use on two days per week could be the same under DSM-V as $500 per day if the consequences and reported symptoms were the same. 'Remission' is another problem issue they have decided to avoid altogether. "A lack of symptoms" one delegate said of remission. But for how long? And what of ‘recovery’? Don't ask!

Gambling is ‘in’ the new DSM classification, partly, we were told, because about 20% of substance users have gambling problems and a substantial proportion of gamblers have alcohol/drug troubles too.

But shopperholics and sex addicts and internet habitues don't use enough substances to be included apparently, at least in the SUD section ‘and related disorders’ department. We were told that eating problems and sexual problems had lobby groups of their own and thus were left well alone by this committee. Internet/gaming victims likewise.

Denise Kandel had some most interesting stuff to tell about her mouse experiments ... I am getting the references ... also about adolescent drug use definitions.

Gross and Edwards’ definition of alcoholism in 1960s and is still the basis for all of these modern definitions.

Dr Hasin was thanked for her input and she promised to get feedback working in both directions. True to her word an email mooting a survey appeared only a week after the meeting calling for volunteers to become involved in the process.

Written by Andrew Byrne ..

19 March 2012

Concord Seminar on benzodiazepine dependence.

X-Concord Seminar on benzodiazepine dependence: 29 Feb 2012 plus tribute to honour Dr Alex Wodak whose retirement coincided with this seminar.

A panel discussion was given at Royal Prince Alfred Hospital chaired by Dr Richard Hallinan, Staff Specialist in Addiction Medicine. Present were numerous experienced clinicians, some by invitation, others out of habit. Pharmacist Denis Leahy, Nick Lintzeris, director of Langton Centre and a doctor from Redfern. There were over 70 people in the packed audience.

Dr Hallinan gave a short presentation on the ion channel GABA receptor and the difference in its interaction with barbiturates and benzodiazepines and why the latter are so much safer in overdose. We were shown the basic molecular structure involving the fusion of a benzene ring (“benzo”) with a heterocyclic, two-nitrogen (“di-azo”) molecule and various attachments to form the individual characteristics of the different forms of benzodiazepines.

We were then told of the variations in absorption rates, half-lives, metabolic pathways, active and inactive metabolites, blood levels, fat and water solubility and volumes of distribution (initial and steady state) of the common benzodiazepines. These included chlordiazepoxide, diazepam, oxazepam, temazepam, nitrazepam, flunitrazepam, alprazolam, medazolam, clobazam and clonazepam. We learned a little of the history of these drugs which largely replaced the barbiturates in the 1960s. Their effects on convulsive thresholds, anxiety, sedation, muscle relaxation, amnesia, panic disorders and PTSD were canvassed, including mention of a recent comprehensive review by Malcolm Lader, the widely published English benzodiazepine ‘guru’ in the Addiction journal.

Dr Jenny James who is a GP at a western Sydney Aboriginal Medical Service was then asked to present a case. This was an enormously complex case which Dr James and her GP colleagues had looked after for several years, amongst their busy and varied general practice. She pointed out that there are no dedicated staff for counselling, family therapy, case management or other ancillary services which are either carried out by the doctors as a drop-in service or not done at all. There were issues of dual chronic viral infection, doctor shopping, mental illness and intercurrent drug use while on methadone treatment. There followed a question and answer session with response from panel members, including a pharmacist and two drug specialists. It was clear from the history that the difference between general practice and specialist practice is that history and progress can be gleaned over months by the former while the latter cannot afford to get it wrong and thus needs to be more comprehensive and multi-disciplinary … where this is possible considering the ‘urgency’ of our patient group and the lack of resources in the face of large numbers seeking treatment.

The main question of the evening was whether the treating doctors should be prescribing benzodiazepines for patients like this one and if so, with what degree of supervision, quantities and restrictions (alcohol was the big contraindication). It was contended that alprazolam (Xanax) was not an appropriate drug for any definable psychiatric condition and some present felt that like Rohypnol and Normison (capsules) before it, it should be banned from the Australian market. Personally I have not prescribed Xanax (alprazolam) for over a decade and I would be delighted if it were off the market or at least limited to 0.5mg tablets.

The concept of ‘staged supply’ in community pharmacy was mentioned by Dennis Leahy from Stanmore Station Pharmacy. The last federal budget included a small subsidy from the PBS for employing this strategy for those with impulsive and compulsive drug consumption … which means most of our patients, at some of the time.

Dr Jill Roberts said that about 90% of prison inmates on OTP have current benzodiazepine histories on admission, requiring careful diagnosis and management. The Justice Health service has a routine detoxification regimen, using a withdrawal scale. A common starting dose is 20mg diazepam twice daily, especially in those with a history of seizures. This high figure of 90% would seem to be consistent with the extraordinary finding from Malcolm Lader that ‘in the UK about half of all BZD prescriptions were given to patients who are currently in an opioid treatment program’.

Experience has shown that some patients fare well taking substantial quantities of benzodiazepines while others seem to lurch between episodes of varying intoxication which often involve aberrant behaviour, legal diversions and occasionally injuries or even worse.

It was interesting to note from the delegates at this meeting just how much the field has changed. In the past there were significant numbers of doctors who claimed that prescribing sedatives to opiate maintenance patients was never appropriate. At this meeting, however, nobody expressed this sentiment. In fact virtually everyone had been involved with certain dependent patients being prescribed a limited supply of (usually) diazepam for certain periods of time, under supervision, despite the logistic difficulties. In also seemed agreed that there was a certain minority group in whom complete withdrawal was not realistic, just as occurs with opiates, alcohol, tobacco, etc.

So can one use methadone maintenance as a paradigm? Is there a diagnosis of dependence? Have there been reasonable efforts to withdraw? Are there episodes of serious sequelae from the benzodiazepine use? Is there dual or poly drug abuse? Psychiatric diagnosis? Has the patient been compliant with their opiate treatment? Is alcohol a factor? Some of our colleagues are currently asking these very questions regarding stimulants, however for sedatives the response is simpler as diazepam, for instance, is not an S8 (restricted) drug in most states.

What would be the minimum criteria for prescribing diazepam to a dependent patient? Having a good history, physical examination, urine test, experienced dispensary would all be essential in my view. An absence of current alcohol use would also be another safeguard. Given all of these factors, we still need a working diagnosis, goals and review process. Does the patient have anxiety or depression? Some may contend that the diagnosis does not matter too much, just like the reason for which a person allegedly uses heroin. ‘If they are dependent, they are dependent’. And the treatment, or at least the principles, should be the same.

So in our own service we use diazepam 5mg - 25mg according to history, initially daily or second daily from the dispensary along with the methadone (or buprenorphine in the few such cases who are taking the ‘weaker’ maintenance drug). Some patients state that they prefer to take some of their dose in the evening and we try to accommodate this where possible. If they state they are sedated on 5 to 10mg Valium we question the diagnosis of dependence and ask to examine the patient 3 hours after such a dose. Others seem to be able to take much higher doses and show no signs of intoxication (on gross testing).

Our goals and follow-up review are the same as for any other behavioural treatment: housing, social, financial, drug-use and general medical parameters are reviewed before further ‘dispensed’ doses are permitted up to a week’s supply at a time (one day supervised) which seems to suit a large proportion of long-term dependent patients. Even without active prompting, doses have generally reduced and a small number have withdrawn, some long-term. A proportion can be expected to relapse to sedative use, just as happens with every other chemical addiction. Better luck next time!

The use of diazepam and other tranquillisers for ‘maintenance’ therapy may be off-label in some cases yet in many there will be a diagnosis of panic disorder, anxiety or insomnia (where benzodiazepines have been shown to be effective) or PTSD, convulsions or depression where such drugs do not have an established evidence base.

Dr Nick Lintzeris gave a heart-felt sentiment of sadness but gratitude regarding the retirement that very day of Dr Alex Wodak to whom so much is due for making the D&A field what it is today in Australia. His influence on policy and practice here and overseas has been unsurpassed, even by Griffith Edwards in the UK … and we all remain in his debt.

Commentary by Andrew Byrne ..
Clinic web page: http://methadone-research.blogspot.com/

Ref: Lader M. Benzodiazepines revisited - will we ever learn? Addiction 2011 106:2086-2109

Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution-a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction 2010 105;11:1870–1874

Byrne A. Benzodiazepines: the end of a dream. Aust Fam Physician 1994 Aug; 23(8):1584-1585

16 January 2012

Tranquillizer use rife amongst OTP subjects world-wide, most legally prescribed.

Prolonged use of benzodiazepines is associated with childhood trauma in opioid-maintained patients. Vogel M, Dürsteler-MacFarland KM, Walter M, Strasser J, Fehr S, Prieto L, Wiesbeck GA. Drug & Alcohol Dependence 2011 119:93-98

Dear Colleagues,

While these authors have emphasised an association between childhood trauma and benzodiazepine (BZD) use, their study tells us much more about opioid dependent patients in treatment in Switzerland and beyond. Their bibliography is also exemplary and it clearly demonstrates that the current approach, zero tolerance in the main, is simply not working. As the authors state: “if abstinence from BZD is conveyed as primary treatment aim, as has generally been the norm in the past, this finding illustrates the limits of current therapeutic management and therapeutic options”.

We are told that ‘point’ and ‘lifetime’ BZD use reportedly occurs in 18-55% and 35-94% of OTP patients from numerous reports including from Australia. The current surveys were taken in two large opioid maintenance programs in Basel, Switzerland. These provided a variety of medications, including prescribed heroin, both oral and injected, methadone, morphine, buprenorphine and codeine.

Of 315 patients approached, 193 (61%) responded to a survey including childhood trauma (a validated instrument ‘CTQ’ was used), drug use and other clinical and demographic characteristics. Reports of drug use were confirmed with urinalysis showing a high degree of concordance. Psychiatric diagnoses were obtained from the detailed medical files which were updated regularly.

The rate of reported benzodiazepine use in the current sample was 61%, 47% being ‘prolonged’ (>2 months duration) while lifetime use was 85%. Thus almost half of the cohort had prolonged use at some time in the previous five years.

There was at least one childhood trauma sub-score of moderate to severe level in 67% of the subjects who completed the survey. As well as BZD use, the degree of trauma was significantly related to methadone dose (or equivalent for other opioids).

After multivariate analysis the authors found that there was an association between prolonged benzodiazepine use and (1) excessive childhood trauma, (2) hepatitis C, (3) psychiatric family history and (4) methadone dose in milligrams. The odds ratios were 1.5, 4.0, 2.3 and 1.01

Rather than using the loaded (British) term ‘misuse’, these authors wisely stick to ‘use’. They also categorise sedative use into (1) ‘hedonistic’ or ‘recreational’ use, (2) self-medication to counteract or amplify the effects of primary drugs of abuse (eg. to ‘come down’ from stimulants), (3) prescription use for anxiety, insomnia, PTSD, panic disorders, etc, and (4) ‘off-label’ prescription as benzodiazepine ‘maintenance’. The great majority of patients obtained their BZD from legal prescription (84% of those with ‘prolonged use’).

The authors point out that none of these associations can prove causality. This will always be difficult to determine when so many overlapping issues occur in OTP patients such as childhood abuse, PTSD and self medication. However, the authors seem persuaded that ‘zero tolerance’ is no longer tenable as a policy, just as it did not work for opioids (or alcohol in a different era). They support the measured prescription of benzodiazepines in research trials as advanced by Liebrenz in Addiction.

In our own practice we provide diazepam under close supervision and in limited quantities to those who are unwilling or unable to cease the use of benzodiazepines, and who agree to alcohol abstinence, in the context of OTP.

Summary written by Andrew Byrne ..

Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution-a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction 2010 105;11:1870–1874