Treating the Addicted Brain: Agonists, Antagonists and Modulators.
Speaker: Stephen Jurd, Psychiatrist, RNSH and RANZCP director of training.
Dear Colleagues,
Dr Jurd commenced by almost stating the obvious: the problem of addiction starts with the brain. The origin of the behaviour does not lie in reasoned thoughts, which are late in evolution, but in reward pathways, organised in the hind-brain. From this ancient part of the nervous system, the responses are transferred to the frontal lobes where conscious thoughts, decisions and deductions are made regarding diverse ways to satisfy the more primitive urges. While most reward pathways are related to survival and procreation, drug use mimics such responses chemically, causing satisfaction, pleasure and desire to repeat the experience. The concept of craving was discussed in depth - it is not easy to define and perhaps best to simply call it ‘the motivation to use the drug’.
Equally, a definition of clinical or behavioural ‘salience’ is difficult, yet it is crucial to understanding and defining addiction, first clearly done by the redoubtable Griffith Edwards. Dr Jurd suggested one way to define ‘salience’ is to look at the person’s ‘top-40’ items of interest which for non-addicted people would range across a variety of things from food to music to work, family and hobbies. For the compulsive drug user or alcoholic, gambler, etc this would be a very short list, largely related to their drug or behaviour of interest. This is the ‘narrowed repertoire’ of drug use behaviour.
We were told of a recent pivotal study by Anne Rose Childress working at Philadelphia with Charles O’Brien’s group. They found significant brain responses on real-time PET scanning from ‘split-second’ projections of drug-related images, despite them not being seen or recognised consciously in a group of 22 long term cocaine users. These were also closely correlated with drug, violence or sexually explicit images shown several days later in relevant cases (and not in controls). So, despite not realizing it at the time, these long-term cocaine users’ brains had registered the brief images unconsciously and committed them to memory. Thus for the first time we have evidence of addiction related cues and/or priming occurring ‘outside awareness’. There was also some corroboration of this remarkable finding from another study involving similar brain responses to cues for ‘‘unseen’’ monetary rewards (Pessiglione). The advertising industry may have known of these matters for years!
Decisions in adolescence are agreed to be most important in learning and memory, and some regard drug addiction as an ‘illness of youth’ [cf Stanton Peele ref below]. We were told that there are maximal numbers of synapses in the adolescent brain which then decrease with age. Synaptic structures are highly dynamic, and adult brains are able to make new cells. Both exercise and stroke can lead to increased neural production and brain cells move towards the injury site. All of this is contrary to traditional teaching about the CNS being unable to repair or replace damaged areas.
Addiction is not simply withdrawal, but craving, the inclination to use, the very nature of dependence and a whole clinical syndrome which persists, sometimes well after drug/alcohol use has ceased. DSM defines ‘early remission’ as up to 12 months. We were told that addiction is common, has social and medical impacts, as well as numerous psychiatric complications.
There must be a system of reward, hard-wired into the mammalian brain where intuitively certain people and/or events are memorable, striking and causing a ‘yearning’. And such a system would just be normal. Dopamine has been identified as the relevant neurotransmitter.
However one defines them, ‘cravings’ lead to the conscious motivation to seek and use the drug, with a euphoric recall, and with often pleasant associations. “This feels sooo … good”. This is the case for both stimulatory and sedating drugs. Dopamine from the nucleus accumbens is crucial for reinforcement and reward; attention, memory and learning. These mesolimbic pathways are not unique to opiates but are similar for nicotine, alcohol, benzodiazepines, stimulants, etc.
The next result is to trigger ‘yearning’ for the experience to be repeated. Drugs excite the reward pathway and this then leads to addiction. At a certain point the individual becomes aware of the dangers and the illogical nature of their behaviour, yet continues with it. Similarly, they may be able to rationalise with a counsellor, doctor or family member that it is harmful to continue (cortical), yet the behaviour persists (driven by limbic pathways).
We were shown a familiar brain diagram from The New England Journal of Medicine: Neural Reward Circuits Important in the Reinforcing Effects of Drugs of Abuse [Cami J, Farre M. 2003 349:975-986].
Stimulants may also cause direct stimulation of dopamine production. On the other hand, sedatives inhibit the production of inhibitors of dopamine and so lead to increased dopamine concentrations. Thus in the reward pathway all drugs lead to increased dopamine at critical points in the hind-brain and so lead to increased learning, attention and focus on the drug use.
Aversive Agents
Disulfiram does not affect the dopamine pathway, but has its action through the frontal lobe using logic and reasoning. With this the person learns that “it is dumb to take alcohol with this”, and so even when cravings are strong the addict may choose not to consume alcohol, knowing the likely consequences.
Agonists/Replacements
Most of these provide a longer acting form of the drug which avoids the cycle of intoxication and withdrawal. For example methadone is a long half life drug, decreasing heroin use and improving quality of life. The person learns that they simply do not need to use additional opiates as there is little gain.
Nicotine is the same drug, with a safer delivery of drug via patches, gums and inhalers. Post-myocardial infarct patients do better on patches.
Dexamphetamine - there is no pharmacological basis to change to this from methamphetamine as the half-life of ‘dex’ is 10-12 hours compared to 9-15 hours for methamphetamine. A longer acting form may be more appropriate for addiction treatment.
Benzodiazepines – theoretically for alcohol but they are not satisfactory, both are disinhibitory agents, acting on GABA receptors.
Partial agonists
Buprenorphine (for opiate dependence).
Varenicline (a nicotine receptor blocker).
Antagonists
Naltrexone – a long acting opioid antagonist, works when taken but does not chemically modulate cravings for opioids (might do so psychologically according to Brewer). For alcohol with time it can modulate cravings but unlike disulfiram the person will not become ill if alcohol is consumed.
Rimonaband – cannabinoid antagonist - not yet available in Australia – used overseas for obesity(?).
Odansetron (Zofran) – serotonin-3 antagonist with promise for alcohol abuse in very low dose [see RCT Bankole Johnson link below].
Modulators
These take time to work, and act less on receptors but modulate other areas which then lead to change in receptors and/or their neurotransmitters.
Acamprosate modulates the balance of GABA. We were reminded that this drug is really only of benefit for those wishing to cease alcohol use completely whereas those on naltrexone are more likely to be able to manage controlled drinking better (although this is not approved under PBS prescribing criteria). In a similar way in depressives, SSRI drugs also take time to have their clinical effects, rather than a chemical effect on receptors which theoretically occurs straight away.
We were then brought back to the traditional in-patient treatment of alcoholism and drug addiction, something which is now rare as authorities have closed down many detox and rehab wards. The justification has often been that they were “not cost-effective”. Dr Jurd quoted the highly reputed “Project Match” which found double the rate of abstinence at one year in those who received an in-patient stay as part of their treatment when compared with those who only received out-patient services. Note that entrants were not randomised so the significance is limited to an non-causal association.
Two case histories were then presented and ‘work-shopped’ in some detail:
Case 1: A youth with excess alcohol use causing serious health, legal, and social problems.
Case 2: A middle-aged set-in-his-ways professional with smoking and alcohol excess with hypertension. He stopped nicotine after 12 months but unable to decrease his alcohol.
Summary written by Judith Meldrum and Andrew Byrne. Further details of the case histories and workshop discussion will be sent as a supplement later when time allows. See our summary of “The neurobiology of addictive behaviours” on web page: http://www.redfernclinic.com/c/2005/12/alcohol-pharmacotherapy-macquarie.php4 Web site: http://www.redfernclinic.com/concord/
References: Childress AR, Ehrman RN, Wang Z, Li Y, Sciortino N,,, O’Brien CP. (2008) Prelude to Passion: Limbic Activation by "Unseen" Drug and Sexual Cues. PLoS ONE 3(1): e1506
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001506#pone.0001506-Pessiglione1
Johnson BA, Roache JD et al. Ondansetron for Reduction of Drinking Among Biologically Predisposed Alcoholic Patients. A Randomized Controlled Trial. JAMA (2000) 284:963-97
Peele S. The Surprising Truth About Addiction. Psychology Today (2004) May-June: 43-46 http://www.peele.net/lib/surprising.html
Pessiglione M, Schmidt L, Draganski B, Kalisch R, Lau H, et al. (2007) How the brain translates money into force: a neuroimaging study of subliminal motivation. Science 316: 904–906 http://www.sciencemag.org/cgi/content/abstract/316/5826/904
6 July 2008
Concord Seminar summary: 'How not to be sued'. Speaker Prof Bob Batey.
Subject: “Practising in Addiction Medicine: how not to be sued!”
Speaker: Professor Robert Batey.
Concord Seminar Tuesday 18th March 2008 7pm.
Held at Concord Hospital (Western Sydney, Australia), Conference Room No 1.
Professor Batey began by asking his audience to consider why this subject was being covered and also why he had been asked to speak on it. He pointed out that despite doctors being of a certain age and seniority, mistakes and miscalculations could still occur. A prevention strategy was essential using established safeguards. However, when these failed, such errors need to be dealt with appropriately and openly. This applies to doctors, nurses and all allied health professionals.
No amount of renown could avoid this issue. No connection with great physicians, great institutions or fine academic reputation could help when things go wrong. We were told that despite a love of the profession and hitherto keeping out of the way of lawyers, none of us should become complacent or over-confident that it would remain that way.
Connections with great physicians could help in one respect: by following their examples in what they taught about good medical practice.
The art and practice of medicine.
The value of spending time with patients.
The need to be ‘vulnerable’ rather than ‘all-knowing’.
The absolute necessity to know what you are doing while admitting any areas of uncertainty.
The reality that you might appear to be rude while still acting consistently and fairly.
Patients may accept mistakes if you demonstrate that your are sincere and competent.
We can all name some great physicians we have worked with but it would be hard to match Dr Batey’s list of mentors: Allan McGuiness, Charles Ruthven Blackburn, Sheila Sherlock, Mr Michael Stephens, Dr Dick Richards. Those who worked at Sydney’s Prince Alfred Hospital or Sydney University may know three of these.
Some behaviours which patients and colleagues may sometimes overlook include:
Aloofness.
Use of long phrases no one can understand.
Gruffness to the point of rudeness.
Late for rounds but never missing them.
However, this is contingent on the clinician displaying consistent excellence and reliability in the longer term, leading to the earning of respect.
In the field of Addiction Medicine there is another credential needed: A capacity to set boundaries. At this we were shown a slide of the Great Wall of China!
In order to demonstrate some ways NOT to practise we were shown some cases from 2007:
Mr TM
Presents with female partner
Both on methadone: 65mg and 50 mg respectively for >10 yrs
Receiving 4 take away doses.
Neither are employed at present but both had been working in local area 12 months ago.
No children at home
SO far so good but
They want to switch to oral Physeptone (methadone tablets) so they can just pick up scripts for 2 weeks supply.
They also admit to not sleeping well and to using benzodiazepines regularly.
No other major issues.
Main issue is a desire for increased “freedom”
Totally anti-buprenorphine as partner had tried to change and failed miserably
They talk constantly and when one stops to draw breath the other starts up
They have no insight into the issues
It is late in the day
You weaken and write their first script of physeptone tablets, enough for 5 days “to see how they go”.
No no no!
This is dangerous
It is unwarranted
It is indefensible
At this point……
Is there a way forward??
Mr JF:
40 yr old, unemployed hairdresser
Past heavy alcohol intake (120 gm/d as beer) Now nil
Lives alone, no contact with children
Had one admission for pancreatitis 8 yrs ago. Apparently this settled.
Now complains of abdominal pain on a daily basis
Taking:
Oxycontin 10 mg qid
Oxycontin 20 mg tds
Oxycontin 40 mg prn
Asks for proladone suppository twice a day to add to his pain relief program
You give him proladone
You have no idea what his pain is due to or indeed if he has pain at all.
He is dependent, he has a “dog’s breakfast” of a management plan.
BUT HE LOVES YOU for being so ‘caring’ !!!
The state pharmaceutical authorities may not be sympathetic - although after removal of the 2 month rule on opioid prescription in New South Wales in 2006 this may be ‘legal‘ even though it may be ‘poor medicine’.
Ms GG, aged 38.
Admitted to local hospital semi-conscious with signs of pneumonia.
Uncertain what is happening but assessment reveals:
Pneumonia of right lower lobe.
Obtunded with pin point pupils.
Injection marks L ante cubital fossa.
Poor nutrition.
Lives with husband and 3 children 10, 9 and 4.
She does not work, he is a motor mechanic.
No major past medical problems.
Both she and he are on methadone program.
She is on 80 mg/d and he 90 mg/d.
Both get 6 takeaway doses per week.
No safe storage sites at home
No urine drug screens performed in past year.
Pharmacist concerned regarding stability.
Why does she get 6 T/A’s….. “Well, my husband gets them”.
She responds to Narcan injection subcutaneously.
Admits to injecting her doses.
Assessed for HCV and HBV and has both.
1 Child has evidence of exposure to HBV.
Vaccination program not completed.
Is this all OK?? Should there be a full review of their dependency treatment?
Mr BJ had Crohn’s disease for 15 yrs.
Several recurrences when Inflammatory Bowel Disease (IBD) treatment reduced.
Surgery x 3, fistula complicating this.
Intermittent analgesia when in hospital.
Tried heroin from friend “for pain relief”.
Now on methadone program 50mg/d.
Presents wanting pain relief from IBD.
He convinces you of his pain.
He asks for morphine injections prn.
You are convinced of his need for pain relief.
You write script for morphine ampoules and arrange for him to come in for doses when needed.
He is found dead with signs of O/D. Not a good situation.
Ms HT is a 78 year old widow
Dependent on benzodiazepines you commenced years ago for insomnia.
You become convinced benzos are bad for people and discuss trying to withdraw them which she refuses.
Admitted to hospital for an acute surgical problem
She experiences a significant withdrawal as no-one took a medication history. She decides that she was not adequately informed about the risks and sets a litigation process in motion.
Who should have done more?
The next topic was “WHAT AM I DRIVING AT” which reminded us that it is OUR RESPONSIBILITY to ensure that patients are safe to drive, operate machinery and look after children while taking medication. All patients should be warned that new medication and changes in doses of existing drugs, including alcohol, may affect ability to perform adequately.
Professor Batey’s final advice to us was:
Spend time taking a good history and performing a full physical examination.
Communicate appropriately with your patients.
Document findings and management plans in the notes.
Evaluate progress rationally and regularly.
Do not become enmeshed with patient stories rather than reality.
Set boundaries clearly and compassionately.
Seek peer support.
Adhere to good clinical practice guidelines.
Seek second opinions in unusual circumstances where guidelines may not apply.
Speaker: Professor Robert Batey.
Concord Seminar Tuesday 18th March 2008 7pm.
Held at Concord Hospital (Western Sydney, Australia), Conference Room No 1.
Professor Batey began by asking his audience to consider why this subject was being covered and also why he had been asked to speak on it. He pointed out that despite doctors being of a certain age and seniority, mistakes and miscalculations could still occur. A prevention strategy was essential using established safeguards. However, when these failed, such errors need to be dealt with appropriately and openly. This applies to doctors, nurses and all allied health professionals.
No amount of renown could avoid this issue. No connection with great physicians, great institutions or fine academic reputation could help when things go wrong. We were told that despite a love of the profession and hitherto keeping out of the way of lawyers, none of us should become complacent or over-confident that it would remain that way.
Connections with great physicians could help in one respect: by following their examples in what they taught about good medical practice.
The art and practice of medicine.
The value of spending time with patients.
The need to be ‘vulnerable’ rather than ‘all-knowing’.
The absolute necessity to know what you are doing while admitting any areas of uncertainty.
The reality that you might appear to be rude while still acting consistently and fairly.
Patients may accept mistakes if you demonstrate that your are sincere and competent.
We can all name some great physicians we have worked with but it would be hard to match Dr Batey’s list of mentors: Allan McGuiness, Charles Ruthven Blackburn, Sheila Sherlock, Mr Michael Stephens, Dr Dick Richards. Those who worked at Sydney’s Prince Alfred Hospital or Sydney University may know three of these.
Some behaviours which patients and colleagues may sometimes overlook include:
Aloofness.
Use of long phrases no one can understand.
Gruffness to the point of rudeness.
Late for rounds but never missing them.
However, this is contingent on the clinician displaying consistent excellence and reliability in the longer term, leading to the earning of respect.
In the field of Addiction Medicine there is another credential needed: A capacity to set boundaries. At this we were shown a slide of the Great Wall of China!
In order to demonstrate some ways NOT to practise we were shown some cases from 2007:
Mr TM
Presents with female partner
Both on methadone: 65mg and 50 mg respectively for >10 yrs
Receiving 4 take away doses.
Neither are employed at present but both had been working in local area 12 months ago.
No children at home
SO far so good but
They want to switch to oral Physeptone (methadone tablets) so they can just pick up scripts for 2 weeks supply.
They also admit to not sleeping well and to using benzodiazepines regularly.
No other major issues.
Main issue is a desire for increased “freedom”
Totally anti-buprenorphine as partner had tried to change and failed miserably
They talk constantly and when one stops to draw breath the other starts up
They have no insight into the issues
It is late in the day
You weaken and write their first script of physeptone tablets, enough for 5 days “to see how they go”.
No no no!
This is dangerous
It is unwarranted
It is indefensible
At this point……
Is there a way forward??
Mr JF:
40 yr old, unemployed hairdresser
Past heavy alcohol intake (120 gm/d as beer) Now nil
Lives alone, no contact with children
Had one admission for pancreatitis 8 yrs ago. Apparently this settled.
Now complains of abdominal pain on a daily basis
Taking:
Oxycontin 10 mg qid
Oxycontin 20 mg tds
Oxycontin 40 mg prn
Asks for proladone suppository twice a day to add to his pain relief program
You give him proladone
You have no idea what his pain is due to or indeed if he has pain at all.
He is dependent, he has a “dog’s breakfast” of a management plan.
BUT HE LOVES YOU for being so ‘caring’ !!!
The state pharmaceutical authorities may not be sympathetic - although after removal of the 2 month rule on opioid prescription in New South Wales in 2006 this may be ‘legal‘ even though it may be ‘poor medicine’.
Ms GG, aged 38.
Admitted to local hospital semi-conscious with signs of pneumonia.
Uncertain what is happening but assessment reveals:
Pneumonia of right lower lobe.
Obtunded with pin point pupils.
Injection marks L ante cubital fossa.
Poor nutrition.
Lives with husband and 3 children 10, 9 and 4.
She does not work, he is a motor mechanic.
No major past medical problems.
Both she and he are on methadone program.
She is on 80 mg/d and he 90 mg/d.
Both get 6 takeaway doses per week.
No safe storage sites at home
No urine drug screens performed in past year.
Pharmacist concerned regarding stability.
Why does she get 6 T/A’s….. “Well, my husband gets them”.
She responds to Narcan injection subcutaneously.
Admits to injecting her doses.
Assessed for HCV and HBV and has both.
1 Child has evidence of exposure to HBV.
Vaccination program not completed.
Is this all OK?? Should there be a full review of their dependency treatment?
Mr BJ had Crohn’s disease for 15 yrs.
Several recurrences when Inflammatory Bowel Disease (IBD) treatment reduced.
Surgery x 3, fistula complicating this.
Intermittent analgesia when in hospital.
Tried heroin from friend “for pain relief”.
Now on methadone program 50mg/d.
Presents wanting pain relief from IBD.
He convinces you of his pain.
He asks for morphine injections prn.
You are convinced of his need for pain relief.
You write script for morphine ampoules and arrange for him to come in for doses when needed.
He is found dead with signs of O/D. Not a good situation.
Ms HT is a 78 year old widow
Dependent on benzodiazepines you commenced years ago for insomnia.
You become convinced benzos are bad for people and discuss trying to withdraw them which she refuses.
Admitted to hospital for an acute surgical problem
She experiences a significant withdrawal as no-one took a medication history. She decides that she was not adequately informed about the risks and sets a litigation process in motion.
Who should have done more?
The next topic was “WHAT AM I DRIVING AT” which reminded us that it is OUR RESPONSIBILITY to ensure that patients are safe to drive, operate machinery and look after children while taking medication. All patients should be warned that new medication and changes in doses of existing drugs, including alcohol, may affect ability to perform adequately.
Professor Batey’s final advice to us was:
Spend time taking a good history and performing a full physical examination.
Communicate appropriately with your patients.
Document findings and management plans in the notes.
Evaluate progress rationally and regularly.
Do not become enmeshed with patient stories rather than reality.
Set boundaries clearly and compassionately.
Seek peer support.
Adhere to good clinical practice guidelines.
Seek second opinions in unusual circumstances where guidelines may not apply.
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