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


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

Dr Richard Hallinan B Med FAChAM (RACP)

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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.
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: <>
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.

4. References

Ashton H. Protracted withdrawal syndromes from benzodiazepines. J Subst Abuse Treat. 1991;8(1-2):19-28. Available at <>
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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