Treating the Addicted Brain: Agonists, Antagonists and Modulators.

Concord Dependency Seminar Series. Tues 20th May 2008.

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:doi/10.1371/journal.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







Case 1: A youth with excess alcohol use causing health, legal, and social problems.

• Your 18 yo patient Mark faces serious charges related to two events of driving under the influence of alcohol since his 18th birthday - the second was high range BAL, the accident with near fatal consequences but only mild injury (a broken clavicle).
• He has a number (3 or 4) of prior arrests for alcohol-related offenses (drunk and disorderly) during 2007, however these were handled by the police with warnings, no fines and no convictions recorded.
• He was treated at St Vincents ED for severe lacerations to his chest and abdomen from diving while intoxicated into water at Darling Harbour earlier this year.
• Blood tests from hospital after his recent car accident are consistent with alcoholic hepatitis (AST 74, ALT 40, GGT 104).
• Mark gives a history of drinking alcohol regularly from age 15, and only occasionally before that. In his last year of school (Year 10, 2006) he drank nearly every weekend at parties, typically as much as 12 schooners of beer (180g or18 standard drinks).
• Although at that stage his drinking was not daily, he would often have 2-3 schooners of beer/day on the verandah after school, and would hide the bottles as his parents did not approve. Alcohol was freely available in the family home.
• He left school in year 10 and worked as a plumbers’ apprentice, but couldn’t cope and now does concreting
• His social life has been based on alcohol since age 15, all his friends drink.
• By age 17 he was drinking after work typically 2-5 schooners (30-75g), and going into town nearly every weekend, where he admits he would drink until he was "blind" - he would lose count of how much he drank, and found it increasingly difficult to get drunk.
• In 2008, with daily drinking part of the work culture, he was regularly getting heavily drunk.
• he used to play a lot of football, now he couldn't be bothered. Alcohol took priority - "I chose the grog over my girlfriends"
• since early 2007, he admits to feelings of loss of control, that he would like to be able to stop, feeling bad about needing beer to socialise (eg needing to take beers from the fridge with him when going out with mates).
• There is no history of injecting drug use, and he does not use cannabis or amphetamines.
• From primary school he was noted to be inattentive and hyperactive in class, and it was suggested he be assessed for possible treatment for attention deficit hyperactivity disorder (ADHD). His parents decided against such treatment.
• There is no history suggesting conduct disorder as a child and no evidence of antisocial behaviours as an adult, other than under the influence of alcohol.
• There is a strong family history of problematic alcohol use including three grandparents, one maternal uncle and Mark's own father, who has however now apparently returned to controlled drinking.
• Mark has been warned by solicitor that he has a high risk of a gaol sentence.
• What treatment is appropriate?

• Counselling?
• Groups?
• Acamprosate
• Naltrexone
• Disulfiram
• Dexamphetamine?
• SSRIs


Case 2: A set-in-his-ways 45 year old journalist with smoking and alcohol excess with hypertension. He stopped nicotine after 12 months but unable to decrease his alcohol.

• Your patient Robert is a 44 year old journalist who is worried alcohol and cigarettes are going to kill him.
• first alcohol was “shandy' as kid occasionally, then regular age 18, never alone at that stage, daily from age 21, still not alone, still sociable.
• Binging was frequent in his 20s, after he finished work at 2.30pm, he went across to the “journos” or to the pub and drank with till he dropped.
• Later his style was pub drinking alone for 2 yrs,
• He has been drinking alone at home for the last 8yrs.
• He was arrested for DUI after a MVA age 25, also charged once with drunken resist arrest.
• He has had no recent alcohol related work or legal problems. He never drinks and drives anymore.
• He is still –and contentedly - single and now works evening shifts till midnight, buys a six pack of beer and drinks it all from 12mn to 3am to get to sleep.
• If he bought a case of beer, he is sure he would lose control.
• He sometimes goes to footie on a Sat, tends still to stop at 6 beers. If he eats first, tends to stop.
• He almost never drinks anything other than beer nowadays
• He is quite happy with life, not interested in getting a social life, and really only concerned with his health, and not having a heart attack or stroke
• He holds down his job without difficulty
• Robert tried zolpidem for sleep when he tried alcohol abstinence for a week last year, short action was the main problem. He doesn’t think he has ever had alcohol withdrawal, but he hasn’t actually had a day off alcohol in many years except with zolpidem.
• Cannabis experimented only, nil current. Nil IDU
• Cigs 30-35 BH special filter; smoking since 17; 35 pack-years. Stopped smoking for 12/12 seven years ago, added 12 kg in weight. He tried NRT and failed.
• His father was a heavy drinker in his heyday, but less now; also HIS father. Mother is a non-drinker. Of 2 sisters, one is a “social drinker”, other is teetotaller.
• Robert has no other illnesses or symptoms on “systems review”.
• OE: BMI 30.5; BP 160/95, pulse 78 regular
• obese, smooth hepatomegaly, normal testicles and no g'mastia, koilonych, couple spider naevi only.
• Non-tender abdo and heart normal to palpation and auscultation.
• Height 169 cm, spirometry. 2.8/4.0 = 70%. (Pred VC 4.4 L, SD 0.5)
• Bloods tests are all satisfactory other than lowish testosterone (9.8 on a 3pm collection) and cholesterol borderline (was normal two years ago). LFTs normal
• Roberts is worried about his drinking and smoking, asks what he should do.
• He doesn’t think he could tackle cigarettes and alcohol at the same time
• He insists he really doesn’t want to stop drinking altogether, and hopes for “controlled drinking”.
• What are the priorities?
• Are medications appropriate for Robert?
• What should you write back to his GP?
• Robert’s blood pressure was stabilised on telmisartan and he set himself a goal of 3 schooners of beer/day and 2 alcohol free days per week. He agreed to try nictoine patches, two /day if needed.
• He canceled his follow up appointment.
• A year later he has returned, now 4 weeks off cigarettes using varenicline and seeks advice about his drinking which has not changed. He is still adamant that he wants to cut back rather than stop.
• He has major dental; work coming up in a fortnight.