Publication Date 30/04/2012         Volume. 4 No. 4   
Information to Pharmacists

Editorial

From the desk of the editor

Welcome to the May 2012 homepage edition of i2P-Information to Pharmacists. Rollo Manning has been having some time out having staples removed from the site of his open heart surgery.He is now at home recuperating in Darwin, having arrived home last Friday, beating a cold and hasty retreat from Canberra.We all wish him a speedy recovery and hopefully, he will be fit enough to contribute by next month.
This month, Pharmedia discusses the toll that is taken when someone complains about you to an authority without good cause. Well, the good news is that you can now take action to protect yourself if such a complaint is made, and that may even include action for defamation. Read about a recent case involving two doctors, with Mark Coleman drawing on personal experience to illustrate.

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News Flash

Newsflash Updates for May 2012

Newsflash Updates

Regular weekly updates that supplement the regular monthly homepage edition of i2P.
Access and click on the title links that are illustrated.

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Pipeline

Pipeline for May 2012

Pipeline Extras

A range of global and local news snippets and links that may be of interest to readers.
Pipeline Extras simply broadens the range of topics that can be concentrated in one delivery of i2P to your desktop.

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Feature Contribution

While doctors remain disempowered doctor shoppers needing help will die.

Dr Ian Colclough

Doctor shopping concerns everyone. It costs lives, erodes the fabric of our society and imposes unacceptable cost burdens on the Australian health system.
Online eScripts and Script Exchange interoperability are pivotal to solving doctor shopping and managing S8 and S4 drugs of addiction.

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Don’t Give Up

Gerald Quigley

As we wrestle with changes in healthcare, the patient more than ever wants a solution to his or her particular health challenge.
They want us to accept responsibility.
Perhaps as we wrestle with that puzzle, or that project, or that problem, the most likely reason we give up on it is the belief that “it can’t be done”.
That’s so different from “I can’t do it”.
Of course you can do it, and it can be done.
So why are we entrenched in the current pharmacy model?

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Seventeen Handy Tax Planning Tips for 2012

Chris Foster

Although the Government relies on the collection of taxes to balance its budget, it is critical as taxpayers to ensure that you do not pay any more tax that you have to.
Or, as the late Kerry Packer once told a Senate enquiry “Of course I am minimising my tax- and if anybody in this country doesn’t minimise their tax, they want their heads read, because as a government, I can tell you you’re not spending it that well that we should be donating extra!”

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Taking care of pharmacists’ health – what is it worth?

Kay Dunkley - BPharm, Grad Dip Hosp Pharm, Grad Dip Health Admin, MPS, MSHPA

How much are you willing to pay for services to support health and well-being?
The working environment for many pharmacists is not ideal.
In both hospital and community settings pharmacists often experience many of the following: long periods of standing, non-ergonomic computers, minimal opportunity to take a break including visiting the toilet or eating lunch, constant demands and the expectation of working quickly without making a mistake, dealing with distressed or difficult people, working extended and sometimes unsociable hours and being a victim of hold-ups and threats of violence.

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Good news for community pharmacy from the Minister of Agriculture

Neil Retallick

Joe Ludwig, the Minister of Agriculture, recently released Australian Food Statistics 2010-11.
It provides a message of hope for community pharmacies.
This singular agrarian message of opportunity is in stark contrast to the constant proselytising in most media how technology in the form of the internet is going to ring the death knell (or beep) for local pharmacies.

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Do it right, or not at all

Barry Urquhart

I applaud and endorse creative, positive and well executed business development and local area marketing initiatives.
A recent personal experience highlighted the adverse image and business consequences of poorly structured and executed campaigns.
An unsolicited letter and “info-sheet” were received by mail from the State General Manager of a national, high profile, public listed legal practice.
The salutation of the letter immediately suggested inadequacy. It stated:
 
“Dear Barry Urquhart”
 
Very few people are addressed with their full or given and surnames. “Barry” or “Mr Urquhart” are the norm.

Comments: 1

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I’ve been thinking about admitting wrong.

Mark Neuenschwander

Hmm. There’s more than one way you could take that, huh?
Like Someday when I get around to it (I’m not sure) I may admit that I was wrong about something. Actually, I’ve been thinking about the concept of admitting wrong.
So don’t get your hopes up. No juicy confessions this month except that I wish it were easier for me to admit when I have been wrong or made a mistake.

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Homeopathy – Silly, Safe or Satanic?

Loretta Marron OAM BSc

In May 2006 a group of eminent UK Professors, concerned about ways in which disproved treatments in their National Health Service (NHS) were “being encouraged for general use”, published a letter in the Times to say so. Six years on, despite calls from the British Medical Association for the funding to end, the NHS still spends around £4 million a year on homeopathy.
More recently, the Australian National Health and Medical Research Council (
NHMRC) came out with their own report against homeopathy. So why has nothing changed?

Comments: 4

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When choice outflanks prime

Harvey Mackay

Diplomacy is all about making the right choices.
When I persuaded my wife, Carol Ann, to say "I do" ages ago, we entered serious negotiations to nail down the ground rules for our marriage.
Then we hit on it.
In our family, I would make all the major decisions, and she would make all the minor decisions!
Many of my friends have asked me, "Harvey, how on earth could that ever work out?"
My answer: "Very simple . . . There have never been any major decisions."

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The Climate Change in Evidence-based medicine

Peter Sayers

Finally mainstream science and medical publications are waking up to the fact that evidence-based medicine has been hijacked by global Pharma companies and rewritten as part of a market plan, rather than a patient healthcare plan.
In the April edition of i2P it was reported that the British Medical Journal reported in its editorial that much of recent cancer research was fraudulent, and as a result, treatments based on this tainted evidence simply would not work (see Cancer Research Found to be Faulty )

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An Evidence-Based Conversation Between Ken Harvey, Gerald Quigley and Neil Johnston

Neil Johnston

Editor’s Note:
I recently received an email from Dr Ken Harvey the well-known academic from Latrobe University, who is trying to reform some aspects of the TGA, particularly in relation as to how drugs and complementary medicines are registered, and the quality of evidence used to support claims of efficacy.
It’s a subject that has gained traction since the beginning of the year, and there are a range of viewpoints that need to be sorted out so that coherent policies can be formulated that would be broadly supported by all health professionals (not just mainstream health professionals).
About the same time I received a communication from Gerald Quigley talking about the clinical and educational resources that exist within the Society of Hospital Pharmacists of Australia.
I reflected on both these communications and decided to publish them in a positive fashion, hopefully to create an ethical and clinical direction for community pharmacy.

Comments: 2

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Why clinical research should be freely exchanged

Staff Researcher

Dr Adam Dunn is a research fellow at UNSW’s Australian Institute of Health Innovation. Professor Enrico Coiera is the Director of the Institute’s Centre for Health Informatics.
Together, in the article below they are proposing a solution to the problems surrounding clinical evidence.
Something needs to happen to help resolve the current mess, particularly in respect of a full disclosure of evidence held by global drug manufacturers.
Currently, it could be said that thinking health practitioners have lost faith in the published evidence for any drug, no matter where it was published. Corruption has damaged any credibility the pharmaceutical industry once had, and diversionary tactics such as attacking non-mainstream medicine and their health professionals will not retrieve the situation.
What is needed is a totally new system and one where evidence can be fully and openly tested.

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An Evidence-Based Conversation Between Ken Harvey, Gerald Quigley and Neil Johnston- Part 2

Neil Johnston

Following the first conversation between Dr Ken Harvey, Gerald Quigley and Neil Johnston, which was recorded in last week’s update to i2P, Dr Ken Harvey stirred the pot a little by sending a letter to the editor with sufficient content to stimulate a second conversation.
What follows below is a copy of that letter with comments by the original participants.
Readers who have not read the first conversation should visit this link.

Ken has also placed additional comment on site at the foot of this original “conversation”
Anybody reading this material is invited to comment through the panels at the foot of the article (s). Gerald and I would particularly like to hear from pharmacists who may be feeling constricted within their own practice by being herded into a channel of activity that is uninspiring through lack of challenge and incomprehensible when you try to deal with “evidence” that is contradictory or developed from a fraudulent base.
What follows is Part Two of our tripartite “Evidence Based Conversation”.

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Friends of Science Fiction in Medicine

Neil Johnston

As pharmacists we believe we belong to a scientific discipline deeply involved in better patient outcomes.
We rely on “evidence” to base our own practice decisions on and we rely on reputable journals to deliver that evidence to us.
Deriving from scientific method it should be a very clear-cut process to test that evidence and build on it.
Yet increasingly, when evidence is tested for replication, it is found not possible to produce an identical result, suggesting that fraud or misrepresentation has occurred.

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A Lesson From SmartClinics

Peter Sayers

Most pharmacy owners would be aware that when you introduce a new professional service into the pharmacy environment that there is a period of time involved before the service begins to develop traction.
During that lead-time there is also a need to integrate the new service with as many of the existing services as possible.
The major service provided by pharmacy is dispensing. Another is “counter prescribing” often involving the sale of schedule 3 medications.
Other services are usually built around periodic promotions e.g. heart health and blood pressure monitoring; diabetes and blood sugar testing.

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Orthomolecular Medicine News Service, April 10, 2012 Top Vitamin D Papers of 2011

Staff Researcher

Dosage Recommendations and Clinical Applications

by William B. Grant, Ph.D.

(OMNS April 10, 2012) The biggest vitamin D story in 2011 was the report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine (IOM) [1]. This report was prepared during a two-year process by 14 nutrition experts, with funding from the U.S. Food and Drug Administration and the National Institutes of Health and Health Canada. The committee reviewed the evidence for beneficial and harmful effects of vitamin D, relying solely on randomized controlled trials (RCTs) of its liking for benefits, and prospective cohort studies for adverse effects. RCTs were considered to have the highest quality, with observational studies of moderate quality and ecological studies of very low quality. However, the case can be made that since solar UVB is the primary source of vitamin D for most people, observational and ecological studies are the most relevant and therefore are of high quality, and in fact, have provided most of the information on the health benefits of vitamin D. However, the committee appeared to have a bias of excluding RCTs on such outcomes as cancer and influenza incidence and effects during pregnancy that were not in line with its eventual recommendations.

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Encouraging news for heart patients

Staff Researcher

Inheriting gene variants that increase the risk of developing coronary heart disease does not necessarily mean an individual is going to have reduced life expectancy if he or she suffers a heart attack.
Two research papers revealing these findings by Dr Katrina Ellis and colleagues at the University of Otago, Christchurch have been highlighted in the leading international cardiology journal Circulation, along with 42 other papers from cardiac researchers around the world.

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Australian scientists discover key to halt nerve fibre damage in MS

Staff Researcher

Scientists from RMIT and Monash Universities announced today a discovery that shows blocking a specific protein may have the ability to act as ‘hand brake’ to the progression of the disease in people with Multiple Sclerosis (MS).
These findings are published today in the prestigious journal Brain from Oxford University Press. The study was led by Dr Steven Petratos from the Monash Immunology and Stem Cell Laboratories and RMIT University. The publication of this study is coincidentally at a time when Australians are asked to Kiss Goodbye to MS in many events leading up to World MS Day in May.

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Body clock genes unravelled

Staff Researcher

International travellers, shift workers and even people suffering from obesity-related conditions stand to benefit from a key discovery about the functioning of the body's internal clock.
Professor Chris Liddle
, from the Westmead Millennium Institute for Medical Research, the University of Sydney, worked with a team from the Salk Institute based in California, to demonstrate the importance of circadian receptors found in the brain and the liver. Their findings are published in Nature today.

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New way to protect eyes from strong light damage

Staff Researcher

Treating eyes with gentle infra-red light can help prevent the damage caused by subsequent exposure to bright light, new scientific research has found.
A breakthrough by researchers at Australia's Vision Centre offers new hope to people who suffer vision loss due to constant exposure to bright sunlight or artificial lights – such as construction workers, sportspeople, fishermen, farmers, welders, actors, entertainers and others.

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Researchers move closer to delaying dementia

Staff Researcher

Scientists at UQ's Queensland Brain Institute are one step closer to developing new therapies for treating dementia.
QBI's Dr Jana Vukovic said the work was aimed at understanding the molecular mechanism that may impair learning and memory in the ageing population.

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Tax time – a donation to PSS is a gift to your profession and a deduction for you

Kay Dunkley - BPharm, Grad Dip Hosp Pharm, Grad Dip Health Admin, MPS, MSHPA

As the end of the financial year approaches the Pharmacists’ Support Service (PSS) invites all Australian pharmacists to consider making a tax deductible donation to support the work of PSS.
PSS is an independent incorporated association and relies on the generosity of the profession to continue its work.
The service, which is based in Victoria, has expanded to Tasmania, South Australia and Northern Territory over recent years and now has the rest of Australia in its sights.
PSS is planning to establish a website for all Australian pharmacists and also develop resources and support networks in NSW, ACT, Queensland and Western Australia when sufficient funding becomes available.

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New drug shrinks brain tumours in melanoma patients

Staff Researcher

Australian researchers have reported promising results with a new drug that shrinks brain tumours in melanoma patients. Their findings are published in The Lancet medical journal today.
Medical researchers at the University of Sydney, Melanoma Institute Australia, Sydney's Westmead Hospital and Westmead Millennium Institute, say a new drug they have been testing to treat deadly melanoma in the body also shows, for the first time, an ability to shrink secondary tumours (metastases) in the brains of patients with advanced forms of the disease.

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New global study: seagrasses can store as much carbon as forests

Staff Researcher

Researchers at The University of Western Australia have contributed to the first global analysis of carbon stored in seagrasses which shows they can hold as much carbon as the world's temperate and tropical forests.
The study 'Seagrass Ecosystems as a Globally Significant Carbon Stock,' published in the journal Nature Geoscience provides further evidence of the important role the world's declining seagrass meadows have to play in mitigating climate change.

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Research holds out hope for stroke patients

Staff Researcher

People with a curious condition that causes them to apply make-up on only one side of their face, or ignore food on half of their plate, are playing a new role in understanding stroke recovery.
Researchers from the Queensland Brain Institute (QBI) at The University of Queensland have found the condition, a subset of the stroke called ‘unilateral spatial neglect', tend to have the worst recovery outcomes in regaining lost functioning in their bodies, leading them to believe attention may have an important impact on recovering successfully.

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Know Your Rights - and Fight for your Life

Neil Johnston

Editor's Note: Sometimes we find ourselves in difficulty and the subject of an official complaint.
Often, the first knowledge of this complaint is when an inspector from some agency arrives on the doorstep and begins to interrogate you over the counter.
Sometimes (and I think deliberately) in earshot of staff, customers and patients.
Suddenly you find yourself fighting for your professional life.
We asked Mark Coleman what he would do if faced with a situation similar to what happened below:

Comments: 1

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X-Concord 2012 Seminar Summary - “Benzodiazepines and dependence”, with an emphasis on people on opioid pharmacotherapies

Dr Richard Hallinan B Med FAChAM (RACP)

articles by this author...

Dr Richard Hallinan B Med  FAChAM (RACP) is an addiction specialist with his interest in this field exceeding 20 years. He works for the South-Western Sydney Local Health Network. He has also collaborated with Dr Andrew Byrne at his surgery in Redfern, having joined in the year 2000. He has published several key papers on addiction and its associated problems, including hepatitis C, optimising methadone dose levels and has also performed studies on hormones, mood disorders and related matters in dependency patients. He currently convenes, in alliance with Prof. Paul Haber, the new series of Concord Dependency Seminars at Royal Prince Alfred Hospital in Sydney, now permanently transferred from Concord Hospital.

Over 70 people attended the first of the “X-Concord Seminars” for 2012 at RPAH on 29 February, to join discussions with an expert panel including Dr Nick Lintzeris, Dr Andrew Byrne, and pharmacist Denis Leahy.
Contents:
|
1. Presentation: Update of pharmacology and therapeutics (Richard Hallinan)
2. Case study (Jenny James), and
3. Panel and discussion (Nick Lintzeris, Andrew Byrne, Denis Leahy)
4. References

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1. Update of pharmacology and therapeutics.
Benzodiazepines increase binding of GABA, the major inhibitory neurotransmitter in the mammalian brain, to its GABAA subtype receptor, a “ligand-gated” chloride channel, increasing chloride flux into the nerve cell and hyperpolarising the cell membrane.
 
Benzodiazepines shift the GABA concentration-effect curve to the left, but they have no inherent effect without GABA (the actual “ligand”). This may be the reason for their relative safety, compared with barbiturates – they cause no fatal respiratory depression or cardiovascular collapse unless other substances are present.
 
In experimental animal models of anxiety, wandering, feeding, and drinking behaviours are deliberately suppressed by fear cues. Benzodiazepines release these suppressed behaviours and decrease “neophobia”, thus causing disinhibition without decreasing other non-suppressed activities or impairing motor function. Opioids and major tranquilisers do not do this. Barbiturates do, but only with motor impairment.
 
Aside from “anxiolysis”, benzodiazepines can cause sedation and hypnosis, with a sleep-like state resembling sleep on EEG – the person can be woken. They can provide the “illusion of anaesthesia”, with anterograde amnesia during surgical procedures but not relaxation sufficient for surgery OR loss of awareness.
 
There is some selectivity of benzodiazepines in inhibiting/suppressing seizure activity (clonazepam and nitrazepam are relatively selective) and for muscle relaxation (clonazepam are diazepam relatively selective).
 
However there is no consistent evidence of selective anxiolysis versus sedation in humans. The rate of onset and offset of action may be the most important factors in sedative versus hypnotic effect, and these vary widely among benzodiazepines.  
 
While all benzodiazepines are lipid soluble and well absorbed orally, the rate of absorption varies from very fast (diazepam) to relatively slow (oxazepam), with others intermediate (eg lorazepam, clonazepam). Elimination half-lives vary from very short (alprazolam, oxazepam, temazepam of the order of 6-15 hours) to very long (clonazepam, diazepam, up to 100 hours).
 
Redistribution may also influence the duration of effect, with diazepam and temazepam having a fast “alpha phase” redistribution into a large volume of distribution, and lorazepam having a slower redistribution, into a small volume of distribution (see Rosenbaum 2009).
 
Thus, diazepam has marked rapid peak and ebb effects in acute dosing, but also large accumulation in chronic dosing.
 
There are important metabolic differences too, with some benzodiazepines (diazepam, alprazolam, clonazepam, nitrazepam) undergoing oxidative (cytochrome P450-mediated) metabolism, which is subject to drug interactions through enzyme inhibition or induction and also prone to be impaired in liver failure. Others are metabolised only by conjugation, where enzyme induction is not an issue and liver function less critical.
 
The use of benzodiazepines in anxiety disorders is both common, and much debated. In general the evidence of effectiveness is better for short term use. In the longer term, SSRIs may be more effective and the disadvantages of benzodiazepines including tolerance and dependence become evident (see Malcolm Lader’s recent review in Addiction).
 
There is good RCT evidence of the effectiveness of benzodiazepines in: panic disorder and panic attacks; in generalized anxiety disorder (but SSRIs may be more effective); as add-on therapy to SSRIs in OCD and panic disorders; and adjunctive therapy in acute mania/agitation; but NOT for posttraumatic stress disorder, where they may actually be detrimental.
 
Earlier enthusiasm for alprazolam in panic disorder has waned, with most guidelines suggesting SSRIs as first line, and a recent meta-analysis published in ANZ Journal of Psychiatry (Moylan et al 2012) showing no evidence for its superiority over other benzodiazepines.
 
Anecdotally at least, alprazolam has become one of the most “abused” medications in Australia and the USA, yet a recent French study of “doctor shopping” indicated diazepam as having a higher liability to “abuse”, after flunitrazepam, and ahead of alprazolam and clonazepam (Pradel et al 2010). Cole too (1988, cit in O’Brien 2005) found diazepam 20mg to have a higher street price and “use again” value – in Boston - than the equivalent dose of 2mg alprazolam.
 
The place of benzodiazepines is taken up in interesting commentary to Moylan et al (2012), with Starcevic pointing out the lack of direct comparative data for SSRIs versus benzodiazepines, and asking whether physiological dependence on benzodiazepines amounts to addiction any more than with SSRIs.
 
Tolerance develops to muscle relaxant and anticonvulsant effects of benzodiazepines, and it remains an open question whether tolerance develops to anxiolytic effects. However, on abrupt cessation after 6 months treatment, 1/3 of people will have moderate/severe withdrawal reaction and 2/3 will have mild withdrawal reaction, which can be prolonged.
 
Ashton’s classic 1990 study of people using chronic benzodiazepines showed several symptoms peaking during a 4 week diazepam withdrawal regimen (insomnia/nightmares in week 1, nausea/vomiting and restlessness/excitability in week 4; sensory hypersensitivity & perceptual distortion in week 5) and declining to baseline at 3 months. Other symptoms (anxiety, depression, tinnitus, headache, dizziness, paraesthesiae and motor symptoms) remained higher than baseline at 3 months.
 
Numerous studies have shown high levels of psychopathology and psychosocial distress in benzodiazepine using opioid dependent people, and benzodiazepines are a risk for fatal overdose in this group.  They are commonly used to bring on the effect of opioids more quickly or strongly.  Studying the effect of diazepam on methadone self-administration, Spiga et al (2001) found that diazepam pre-treatment significantly decreased the amount of methadone consumed and increased reports of “good, like, strong, and high”.  
 
Unwanted effects of benzodiazepines include memory problems (which may persist after cessation, especially in the elderly), emotional blunting, motor problems (slow reaction, incoordination, ataxia, falls especially in elderly people) disinhibition and sometimes paradoxical rage. People using large amounts of benzodiazepines may feel “10 feet tall, bullet proof, invisible”.  Nick Lintzeris and others have published evidence of cognitive impairment in MMT, but not BMT, patients given acute diazepam doses.  
 

2. Case Study: clonazepam and alprazolam

Dr Jenny James presented a complex case of benzodiazepine use in a person on MMT and antiretrovirals for HIV, with epilepsy since childhood (receiving clonazepam), and getting alprazolam for “panic disorder” (though the symptoms were more like PTSD). The difficult decision was finally taken to dispense daily, supervised clonazepam while tapering alprazolam. There were practical issues about how to ensure the clonazepam reached the clinic for dispensing, about the legality of “dispensing” medication twice, about privacy issues in dealing with others who might prescribe or supply benzodiazepines.
 
Pharmacist Denis Leahy argued strongly that doctors and pharmacists have a duty of care to communicate with colleagues where there is risk of harm. He has no hesitation in calling a prescribing doctor, or annotating a prescription “not dispensed’ to alert other pharmacists. He estimated that at least 5% of early or outsize prescriptions were actually forged. Another audience member was advised by his medical defense union that duty of care was not sufficient defense against the Privacy Act (implying that the defense union would not defend an action). Another suggested “shopping around” for medicolegal advice on issues like this, because it often depends on who you speak to.
 
Nick Linzteris commented that it was important to come back to the basics in managing this sort of problem and above all to shift the focus away from discussion of the benzodiazepines. Excessive preoccupation with securing the supply of the medications is characteristic of dependence. One approach is to deal with psychosocial problems including housing, finances, domestic violence, identifying and treating comorbid psychiatric disorders including anxiety and depression, consider opioid dose increases or split dosing for methadone, get information from Doctor Shoppers Hotline, consider change to long acting benzodiazepines and supervised dispensing.
 
In relation to alprazolam and panic disorder, Dr Julian Keats commented “this is treating a short and self-limiting state with a medication that is too slowly absorbed to work effectively for it…it also reduces their capacity to learn to cope in other ways…”
 
In relation to purported seizure disorders as grounds for using benzodiazepines, Dr Jill Roberts said standard practice in the NSW gaols was to seek actual documentation of the disorder: in the absence of such documentation, the person is managed for benzodiazepine withdrawal using a validated withdrawal scale, and virtually never have problems of seizures in this situation.
 
Dr Andrew Byrne succinctly commented: it was a miracle that they had managed to treat this person at all, and keep them alive! Read the rest of Andrew Byrne’s summary and comments on the discussion arising, on the place of benzodiazepine maintenance in and outside opioid pharmacotherapy settings here:
http://methadone-research.blogspot.com.au/2012/03/concord-seminar-on-benzodiazepine.html <http://methadone-research.blogspot.com.au/2012/03/concord-seminar-on-benzodiazepine.html>
 
 
3. Panel and discussion.

In the second half, discussion moved to some questions, mostly submitted in advance:

·     “Why is alprazolam listed on the Australian Pharmaceutical Benefits Scheme for panic disorder?”

An audience member wryly suggested: “Successful marketing”. It should be noted that the PBS approved indication is “Panic disorder where other treatments have failed or are inappropriate”. Asked whether there was any indication for the use of alprazolam, two psychiatrists in the room responded with one voice: “One word, two letters – NO”. Alprazolam is strongly positively reinforcing and rapid offset of effect leads to withdrawal symptoms and risk of negative reinforcement.
 
 
·     “Why do we use diazepam rather than clonazepam for managing benzodiazepine withdrawal or maintenance regimens?”

The question arose because clonazepam, like diazepam, is very long acting but, unlike diazepam, does not have the acute peak effect through fast absorption and short alpha phase half-life which could be positively and negatively reinforcing. Also there is a published study of clonazepam “detoxification” versus clonazepam maintenance treatment in MMT (Weizman et al 2003).  At 2 months, only 27% of the “detox” group  were benzodiazepine-free, while 79% of the clonazepam maintenance group refrained from using additional benzodiazepines over the maintenance dose.
 
Aside from the fact that diazepam is cheap, has unrestricted listing on the PBS (clonazepam is restricted to use in seizure prophylaxis), and doctors in Australia are simply more familiar with it, Nick Lintzeris pointed out that when managing alcohol and benzodiazepine withdrawal states, you want an agent that acts quickly and can be titrated rapidly.
 
Dr Peter McCaul, medical director of the “Corella” inpatient withdrawal facility at Fairfield, commented that a standard inpatient stay is insufficient for reductions off  substantial daily doses of benzodiazepines: he aims in these cases to reducs the daily dose to the order of 30mg during the inpatient stay, then reducing by 5mg/week, and from 10mg, by 2mg/week, on an outpatient basis.
 
 
·     “Why don't we hear about abuse of lorazepam ("Ativan")?”

The same reasons of lack of PBS listing might account for why lorazepam is less used in Australia than in the UK. Several of the important studies of benzodiazepines in alcohol withdrawal management have been of lorazepam. Our guest psychiatrists pointed out that lorazepam is commonly used in psychiatric units in Australia for sedation and managing agitation, as it has fairly smooth constant pharmacokinetic profile without accumulation of effect (see above).
 
 
·     “We've had patients coming to me asking for Gabapentin or Lyrica (pregabilin) to get them off benzodiazepines? Is there any evidence for this?”

Nick Lintzeris pointed out the difficulties of getting the right sort of evidence to support this indication. There are certainly suggestive studies for benefit of these drugs, but studies of people with anxiety disorders and mild “iatrogenic” benzodiazepine dependence no not translate easily to the sorts of patients we see with more severe and polysubstance dependence. We need to study the right populations, work out the right outcome measures and have long term follow up to give clear answers.
 
 
·     “Why does "Xanax" use seem to be associated with so many criminal offences?”

One response was that the newer “high potency” benzodiazepines might actually be less sedative in relation to their anxiolytic effect, such that people become disinhibited without falling asleep (which might be better for everyone concerned).
 

We didn’t have time to deal with several other submitted questions. Here are some responses from Richard Hallinan, assisted by Paul Haber.
 

*    
“We had a patient on MMT under a neurologist who was prescribed “Frisium” (clobazam) as daily dose but also PRN: he was told by the neurologist it was OK to occasionally take it if he ‘felt a fit coming on.’.... What is the basis for this?”


This is a therapeutic dilemma. Seizures may be preceded by an aura and rapid treatment of an aura has the potential to prevent an evolving seizure. However, the drug being used is prone to unsanctioned use, particularly in a patient with known drug dependence problems. Any addiction specialist would be wary of a person asking for a prescription on this basis. “PRN” use of any benzodiazepine invites problems, and seizure disorders are a common pretext for seeking benzodiazepines. Clobazam is generally only used as an adjunctive agent, so another warning sign might be a patient who is apparently not taking any other agent.
 
However, clobazam is rather a niche drug. It is available as adjunctive therapy for epilepsy in many countries (though not approved for this indication in Australia, nor in the USA except for Lennox-Gastaut syndrome).
 
Clobazam and its active metabolite have long elimination half-lives, which makes sense for seizure prophylaxis. There is no particular pharmacological reason to suppose greater efficacy for clobazam than clonazepam in seizure disorders. However, some evidence suggests that sedative effects of clobazam are less severe than those of other benzodiazepines. Some neurologists do prefer it, especially in children who may have behavioural problems with other antiepileptic agents. PRN use, ie if someone ‘felt a fit coming on’, could have a rational basis, as this medication can be used both to interrupt prolonged seizures, and to interrupt a cluster of seizures.
 
(Thanks also to neurologist Dr Armin Mohammed for advice in response to this question)
 

*  
“If an MMT patient is entirely stable except for benzos in their urine tests, saying they only take them once a week, are they considered fit for takeaway doses?”
 
Urine tests for benzodiazepines are of limited usefulness in diagnosing problematic or dependent use, because they stay positive for so long, well after the drug is pharmacologically eliminated. Even a series of positive tests may still signify no more than occasional use. A negative test (if it is a true sample) is very useful, suggesting a substantial period of abstinence from benzodiazepines.
 
A goodly third of people in OST at least sometimes use benzodiazepines, and if they were all prohibited from takeaway doses, the system might be brought to its knees.
 
More important are clinical indications of intoxication, or its absence, from report by dispensing staff, including pharmacists. If a person consistently presents with no evidence of intoxication, provision of takeaways is supported.
 

*   
“Why did "Rohypnol" go out of fashion?”

Flunitrazepam was much favoured in the 1980s by heroin users who used it to bring on and amplify the effect of heroin, and was associated with high rate of overdoses. Its fall in popularity in Australia may be part due to the response of listing the drug as a Schedule 8 medication, and reducing the maximum tablet size from 2mg to 1mg, thus reducing availability, probably by increasing physician awareness of the potential problems. As a schedule 8 drug, it is illegal to supply it to known substance-dependent patients.
 
In NSW, a written authority of the NSW Ministry of Health is required to prescribe or supply flunitrazepam for more than two months even to a person who is NOT drug dependent. This is more restrictive than for morphine or oxycodone.
 
After a similar change in regulations regarding flunitrazepam in Germany in 2011, “…Rohypnol tablets disappeared almost overnight from the black market.”
 
The drug’s manufacturer Roche has ceased supply in Australia (it is available as a “generic” produced by Alphapharm.  As noted above, flunitrazepam has remained a highly preferred drug in France.
 
 
*  
“What is better for shift workers/jet lag: temazepam or "Stilnox"?”

Temazepam 20mg, nitrazepam 5mg, and zolpidem 10mg did not differ from placebo on next morning driving tests, while most other benzodiazepines and zopiclone did. See Verster et al 2004 for a review.

 
 *
And from Dr Geoff Robinson, Wellington NZ:  “I wondered if there was any discussion on benzo maintenance and driving, about which there is much furore in NZ clinics and varying opinion on driving safety.”

Both psychiatric disorders and psychiatric drug treatments produce changes of psychomotor performance which can disturb and/or interfere with the ability to drive safely.
 
Not only benzodiazepines, but antidepressants (especially tricylics), neuroleptics and antihistamines can affect driving competence. As do the effects of sleep deprivation, and other untreated problems including anxiety disorders, depression and substance dependence.  Opioids appear to be safe after relatively short periods of stabilization.
 
There is little direct evidence (though some epidemiological evidence) on driver safety with chronic dosing of benzodiazepines (most studies are after one or two doses only). For assessing tolerance over time the problems of getting appropriate research data are enormous. Data on combinations of psychoactive agents, such as chronic opioid/benzodiazepine dosing, are almost entirely lacking.
 
(Coffee is good, by the way: see Mets et al 2012)
 
Psychometric tests of driving ability are poor predictors of results in on- the-road driving tests. (Verster and Roth, 2012). One might ask: if psychometric tests fail as a test of driver ability, how can a clinician, even an addiction specialist, be expected to decide?
 
Given that medications and combinations of medications may adversely affect driving, a public health perspective considers whether the driving related harms of people leaving treatment (for example through threatened notification to authorities), might be greater than the risks of continuing treatment. Medico-legal liability is another issue. Doctors have to find a balance between these. Official guidelines help.  
 
Adam Winstock gave a very practical talk on this at Concord some years ago. http://dependencyseminars.blogspot.com.au/2006/01/adam-winstock-and-richard-hallinan-on.html

 
4. References

Ashton H. Protracted withdrawal syndromes from benzodiazepines. J Subst Abuse Treat. 1991;8(1-2):19-28. Available at http://www.benzo.org.uk/ashpws.htm <http://www.benzo.org.uk/ashpws.htm>
 
Lader M. Benzodiazepines revisited--will we ever learn? Addiction. 2011 Dec;106(12):2086-109.
 
Mets MA, Baas D, van Boven I, Olivier B, Verster JC. Effects of coffee on driving performance during prolonged simulated highway driving. Psychopharmacology (Berl). 2012 Feb 8. [Epub ahead of print]
 
Moylan S, Giorlando F, Nordfjærn T, Berk M. The role of alprazolam for the treatment of panic disorder in Australia. Aust N Z J Psychiatry. 2012 Mar;46(3):212-24. (free full text on Medline)
 
O'Brien CP. Benzodiazepine use, abuse, and dependence. J Clin Psychiatry. 2005;66 Suppl 2:28-33.
 
Pradel V, Delga C, Rouby F, Micallef J, Lapeyre-Mestre M. Assessment of abuse potential of benzodiazepines from a prescription database using 'doctor shopping' as an indicator. CNS Drugs. 2010 Jul;24(7):611-20.
 
Jerrold F. Rosenbaum. Handbook of psychiatric drug therapy. 6th Ed. 2009.
 
Spiga R, Huang DB, Meisch RA, Grabowski J. Human methadone self-administration: effects of diazepam pretreatment. Exp Clin Psychopharmacol. 2001 Feb;9(1):40-6.
 
Starcevic, V. Reconsidering benzodiazepines in the treatment of panic disorder. Aust N Z J Psychiatry 2012 46: 271. (free full text on Medline)
 
Verster JC, Veldhuijzen DS, Volkerts ER. Residual effects of sleep medication on driving ability. Sleep Med Rev. 2004 Aug;8(4):309-25.
 
Verster JC, Roth T. Predicting psychopharmacological drug effects on actual driving performance (SDLP) from psychometric tests measuring driving-related skills. Psychopharmacology (Berl). 2012 Mar;220(2):293-301. Epub 2011 Sep 16.
 
Weizman T, Gelkopf M, Melamed Y, Adelson M, Bleich A. Treatment of benzodiazepine dependence in methadone maintenance treatment patients: a comparison of two therapeutic modalities and the role of psychiatric  comorbidity. Aust N Z J Psychiatry. 2003 Aug;37(4):458-63. (free full text on Medline)
 
 
 
(Seminar summary by Richard Hallinan)

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