1
Q
What is the difference between substance use, harmful use and dependence?
A
Most people will use some sort of drug (i.e. caffeine). The issues become more troublesome when there is increasing regular use and start develop a necessity to the drug, or start self-medicating (i.e. take alcohol when they are sad). This can become a spiralling dependence, but this is a small number compared to those who use drugs experimentally. When people become dependent, it is very hard to become independent of the drug.
2
Q
What is the ICD-10 criteria for Dependence Syndrome?
A
- A strong desire or sense of compulsion to take the substance
- Difficulties in controlling substance taking behaviour in terms of its onset, termination or levels of use.
- A physiological withdrawal state when substance use has stopped or been reduced
- Evidence of tolerance: need to take more to get same effect
- Progressive neglect of alternative interests
- Persisting with substance use despite clear evidence of overtly harmful consequences.
The key thing is number 2: lack of control. If they don’t have control, they are very likely to be dependent. The relationship with their drug has changed. Who has the control, you or the drug? The drug is all or nothing - a key distinguishing factor; alcoholics can actually go days without drinking, but when they drink, they will drink excessively.
3
Q
What is the change for Dependence Syndrome Changes from DSM IV - DSM V, and why is it controvertial?
A
Abuse and dependence are now combined into a single disorder of graded clinical severity - substance use disorder (mild, moderate, and severe).
- Prof Lingford-Hughes does not agree with this as she believes the difference between abuse and dependence exists, and centres on control over the drug; where dependenders have no control over the drug.
- “Dependence” as a label for compulsive, out-of-control drug use has been problematic. Is confusing to physicians and has resulted in patients with normal tolerance and withdrawal being labelled as “addicts” and not getting adequate medication e.g. for pain.
4
Q
Describe the classical neurobiological model of of Substance Misuse
A
The key system we need to know about is the dopaminergic mesolimbic system. This allows for natural rewards such as food, sex to increase dopamine levels in a part of the brain called the ventral striatum (in human literature as NAcc is not seen in man) or nucleus accumbens (in animal literature). The neurones start in the midbrain at the ventral tegmental area. Other neurones from the VTA project to the frontal lobe (mesocortical pathway). Together they are called the mesocorticolimbic pathway.
Drugs of abuse, hijack this system, and increase the level of dopamine in the nucleus accumbens. All the drugs do it, you need to know the mechanisms of how they do. Only cocaine and amphetamine modulate the dopaminergic synapses, the rest affect dopamine indirectly.
- Cocaine blocks dopamine re-uptake
- Amphetamine also blocks dopamine re-uptake as well as enhances release of DA
- Alcohol, opiates, nicotine and cannabis increase the level of dopamine firing in the VTA
5
Q
How can you use imaging to infer striatal DA release?
A
The model of addiction centering on dopamine release into the NAcc (ventral striatum) is confirmed by PET and SPECT studies. Using [C-11]Raclopride (a D2 antagonist used to treat schizophrenia), you can measure the availability of D2 receptors, which is used to indirectly measure DA relase into the striatum.
6
Q
Discuss the evidence arround the theory that the euphoric effects of DA underpin the addiction to drugs.
A
FOR:
- In 1994, when it was demonstrated that intravenous infusion of central stimulant drug and SPECT or PET imaging (of dopamine receptor availability) could be used to indirectly measure DA release in the human striatum, they found that the magnitude of this increase was shown to predict the euphoria produced by the drug.
- HOWEVER, central stimuants specifically act on DA system, so this increase is expected. This finding shows an association rather than proof that change in striatal DA mediates the high.
AGAINST:
- While this may be true for stimulants, studies showed that for alcohol, cannabis and ketamine, these substances did not inevitably induce dopamine release in humans.
- No relationship between striatal dopamine release after cannabis, and any behavioural, subjective or physiological effects of cannabis. (Bossong et al 2009)
- In the case of alcohol, impulsivity and intoxication were linked top dopamine level, but not a drug high.
- Several studies have found that opiate administration was not associated with striatal dopamine release, despite producing a euphoric high. (Nutt, Lingford-Hughes et al 2015, Nature)
7
Q
What are the three ways/observations the dopamine system is linked to addiction?
A
- Dopamine and the drug high. Suggested that the euphoria mediated by dopamine release is responsible for the positive conditioning-led learning of addiction.
- Lower striatal dopamine receptor availability indicates the effects of abuse of the Dopamine system. Therefore, they take more drugs to achieve the same high.
- Reward - deficiency. There is a blunted striatal dopamine response after pharmacological challenge. Therefore, they take more drugs to achieve the same high.
8
Q
Discuss the evidence around the hypothesis that lower D2/3 availability is linked to dependence vulnerability
A
FOR:
- For cocaine and methamphetamine users, there is a reduction of DA receptor availability, which has been shown to be due to decreased D2/3 expression.
AGAINST:
- No differences in receptor availability between individuals who smoke, and healthy non-smokers irrespective of gender.
- No evidence of changes in striatal DA availability in cannabis addiction.
- Seminal papers by Volkow et al (1999,2002) show that the individuals with low striatal D2/D3, reported more pleasurable effects from stimulants!
9
Q
Discuss the evdience around the hypothesis that a blunted dopamine system is linked to a vulnerability to developing addiction.
A
FOR:
- Evidence of blunted striatal DA release after methylphenidate and opiates.
- Young people with high familial risk of addiction but not yet dependent, showed they had reduced amphetamine-induced DA release than matched controls.
- This may indicate that DA release predicts vulnerability to addiction rather than being the cause of addiction, and dopamine release if anything, has a role in resilience against becoming dependent.
AGAINST:
No blunting of DA release was found in cannabis dependence after amphetamine challenge.
10
Q
Describe the process of conditioning
A
In classical conditioning you are associating one stimulus with other stimulus that usually has a response. In the case of pavlov’s dog this is the ring of a bell (uncoditioned stimulus) is associated with food which produces an unconditioned response (salivation). After time, the bell and food become associated so that the bell becomes a conditioned stimulus to salivation (conditioned response).
11
Q
Describe the role of GABA in addiction
A
GABA inhibits the dopaminergic neurones of the VTA. The GABA-B receptor is the key system. Baclofen is a typical agonist. It is shown to improve abstinence rates in alcohol dependence. Other drugs that increase GABA levels have similar effect.
The basal release of dopamine is not harmful, only the phasic release. GABA acts as a break. Phasic firing of the dopamine neurones tells the brain this a good/interesting thing, implicated in conditioning.
12
Q
Describe the role of opiate receptors in addiction.
A
- Mu receptors inhibitory receptors on GABA-ergic neurones that project to the VTA dopaminergic neurones to act as a ‘GABA break’ to phasic dopaminergic firing. So Mu receptor activation blocks this GABA break, leading to increased DA in the NAcc –> pleasure.
- Kappa receptors ??location ??mechanism cause dysphoria. The kappa receptors are like a negative feedback trying to halt the pleasure.
During aquision of dependence behaviour: Alcohol stimulates the opiate receptors ?mu more than kappa? this increase in mu/dopminergic activity leads to an increase in kappa receptors. In dependence, your kappa system becomes dysregulated.
This high kappa tone persists after alcohol is stopped being consumed, leading to dysphoria/withdrawal. This effect drives relapse, and more alcohol is needed to counter the kappa tone. This kappa dysphoria may be what is driving the impulsivity that is seen when there is increased DA (due to kappa stimulation).
13
Q
Describe the role of cannabis in addiction/dependence
A
The GABA break is also regulated by the cannabinoid system. The CB1 receptor is on the GABA neurone, and is also inhibitory. Similar to the mu system. However, difficult to show that it changes dopamine levels.
The active susbtance in cannabis is delta9-tetrahydrocannibol, but also has other active substances such as cannabidiol (which may be antipsychotic). CB1 and CB2 receptors are G-protein coupled.
- CB1 is mainly found in brain, neuronal with a few on the microglia
- CB2 is mainly found in immune cells and the liver and spleen.
Our endogenous cannabinoids are anandamine and 2-AG
14
Q
What are the stages of the addiction cycle?
A
- Binge/intoxification. Here the stimulus-response habits are formed.
- Withdrawal/negative affect. This has a function of negative reinforcement.
- Preoccupation/craving. Involves representation of contingencies, outcomes, their percieved values and subjective states.
15
Q
What are the neurocircuitry involved of the stages of addiction?
A
- Binge/intoxification. Here the stimulus-response habits are formed.
- Role of the reinforcing effects of drugs that engage the reward neurotransmitters and associated mechanisms in the nucleus accumbens. Mainly by dopamine and opioid peptides.
- Withdrawal/negative affect. This has a function of negative reinforcement.
- The negative states of withdrawal may engage the activation of the amygdala, and subsequent release of corticotroping releasing factor (–> stress of cortisol).
- Preoccupation/craving. Involves representation of contingencies, outcomes, their percieved values and subjective states.
- This is mediated by the processing of conditioned reinforcement and the contextual information by the hippocampus and the executive control by the prefrontal cortex.
16
Q
What is contingency management?
A
Contingency management is using incentives/rewards to encourage the frequency of positive behaviour (in the case of addiction – abstinence). It is based on the theory of operant conditioning, whereby positive reinforcement of a behaviour will increase the probability that the operant (voluntary) behaviour will take place.
17
Q
Describe the principles and practice of contingency management.
A
- Developing a strategy/therapeutic approach. The goal is to establish a clear contingent relationship between achieving the target behaviour and the reinforcement:
- Select a positive behaviour consistent with treatment goals which is under voluntary control and can be regularly and unambiguously measured. For heroin, this behaviour can be abstinence, which is measured through urinalysis.
- Develop a clear reinforcement schedule that promotes the chosen behaviour. The patient should have a choice in what reward they want. Provide simple, clear information explaining the procedures to patients.
- Measure whether the target behaviour is achieved. This should be done in an objective and consistent manner. Should also be done frequently.
- If the target behaviour is achieved, reward should be given immediately. Furthermore, the magnitude of the reward must be sufficiently large to compete with the other behaviour. There should be an element of escalation where each positive step is rewarded, but attainment of more significant treatment goals involves greater reward.
- Reinforcement must be withheld if the target behaviour is not achieved. However, you must remain with a positive and empathetic approach for all interactions, and neutral but not punitive for undesired results.
18
Q
Describe the theory of operant conditioning
A
BF Skinner argued that human behaviour was best understood by looking at the causes of an action and its consequences. Skinner’s theory of “Operant conditioning” identified different forms of reinforcement that increase or decrease the likelihood of a behaviour being repeated:
- Positive reinforcement - increasing the behaviour by providing a reward. E.g. giving a voucher if behaviour is attained.
- Negative reinforcement - increasing the behaviour by removing an averse stimulus when a behaviour occurs. E.g. less intense supervision if behaviour is attained.
- Positive punishment - decreasing the behaviour by administering an averse stimulus
- Negative punishment / extinction - decreasing the behaviour by not administering a reward.
19
Q
Discuss the moral and ethical issues raised by the use of financial (and other) incentives in contingency management of addiction
A
The use of financial incentives in healthcare is controversial because:
- Bribery: paying people to act against their wishes
- However, they are being offered rewards to achieve outcomes that are most desirable, not forced into acting against wishes
- Coercion: compels people to behave using pressure/duress
- But it is voluntary, with a prospect of gain, not loss
- Paternalistic: undermines individual autonomy
- But it could be said to facilitate autonomy when it makes it more likely that people act in line with their originally considered preferences (people who actually wanted to quit smoking)
- Unfair: people should not be paid to do what they should do
- But it is potentially a more effective way of changing behaviour and improving health
- Waste of money: poor use of the public purse, where there are many competing demands
- But there are potentially large health benefits from a modest increase in health expenditure. Also may be more effective than current strategies, plus saves a lot of money in the long-term
20
Q
Describe the evidence of efficacy of contigency management
A
- Retention: Contingency management is significantly more effective in retaining cocaine users in treatment than counselling alone.
- Methadone maintenance: Has the most substantial evidence base, proving large and consistent effects. Participants remain abstinent for up to 6 months, and is cost-effective.
- Higgens et al 1994, found higher abstinence in cocaine users when vouchers and lottery tickets where given. Involved urinalysis and counselling.
- Adherence to physical health interventions. Contingency management doubled (2x) the rate of HepB vaccination and TB testing, and tripled the rate of 6 month return.
21
Q
How does fMRI measure neuronal activity?
A
fMRI exploits changes in magnetic properties of the blood, e.g. as oxygen is removed. This can be detected using an MRI measure known as the blood oxygen level dependent (BOLD) signal. The BOLD signal is the ratio change in oxyhaemoglobin to deoxygaemoglobin in the venous blood. As neuronal activity in response to a particular thought process requires oxygen, the BOLD signal at that location during that process will increase.
- At the very low and very high levels of activity, it’s not a linear gradient (though it is linear in the middle)
The BOLD signal is, indirectly, a measure of neuronal activity. We can infer that these correlate to an increase in certain neurotransmitter systems due to the anatomical correlates of activity, but we cannot say unequivocally.
22
Q
What are the higher-order processes of interest in the study of addiction?
A
The higher-order processes of interest in the study of addiction are:
- Behavioural control
- Decision making
- Emotional reactivity
- Reward sensitivity
These are systems we believe are compromised in those who are likely to develop addiction disorders, as well as compromised because of neurochemical disturbances caused by drug intake. These neurochemical disturbances may disappear with abstinence, allowing patients to engage in better decision making and reward sensitivity. Importantly we may be able to develop drugs to treat these neurochemical disturbances.
23
Q
What is cognitive control?
A
Cognitive control refers to the process that allows behaviour to vary adaptively from moment to moment - e.g. response inhibition. Cognitive control can inhibit behaviours and impulses. The prefrontal context is predominantly responsible for this top-down control.
24
Q
What are the major players in the cognitive control networks?
A
Major players in cognitive control networks include:
- anterior cingulate cortex/pre-supplementary motor area (ACC/pSMA)
- dorsolateral prefrontal cortex (DLPFC)
- inferior frontal junction (IFJ)
- anterior insular cortex (AIC)
- dorsal pre-motor cortex (dPMC)
- posterior parietal cortex (PPC)
25
How is cognitive control implicated in addiction behaviour?
Cognitive control is implicated in the preoccuplation/anticipation (craving) stage of addiction. Excecutive control depends on the prefrontal cortex and includes the representation of contigencies, outcomes and their values (informed by conditioned reinforcement), as well as subjective states/contextual information (provided by the hippocampus).
Reduced neural processing related to cognitive control may render people more susceptible to drug use - i.e. relapse in addiction. Substance-abusers may attempt to control intrusive drug-related cognitions and/or inhibit the impulse to use drugs. Poorer cognitive control has been shown to predict poor treatment retention -e.g., poorer impulse control predicts treatment outcome.
26
Describe the studies in which cognitive control is imaged in patients with dependence issues
A study (Hester et al 2004) showed that cocaine addicts in very early abstinence where given a task to memorise a few letters (taxing the working memory). They where then shown flashes of letters, and had to respond to only those they had not seen. This is smart as it necessitates two parts of the brain, one involved in memory, and the other involved in control to override the reaction immediately initiated by the memory of seeing the letter.
* They found that there are specific areas of the brain involved in control that are **significantly** **reduced** in **cocaine** users compared to controls. Areas such as the **ACC**.
* Cocaine users found a **greater** **activation** of the **cerebellum** - not normally associated with this task. The authors suggested this could be another **suboptimal** **network** in cocaine addiction that is emerging.
* The areas involved in control also need dopamine, but because of their substance abuse, they deliver less dopamine to sustain those networks in the brain. They therefore perform worse in the test because they cant engage the network anymore, and instead attempt to use another suboptimal network in the cerebellum.
Some years later (Hester et al 2009) also showed there was impaired error awareness and anterior cingulate cortex hyperactivity in chronic cannabis users. This was done by doing a similar test where they see text like 'blue' written in the colour red. They should only respond when the colour matches the text, but they should also withhold from responding if they had just received a repeat.
27
Why is cognitive control degraded in drug abuse?
The areas involved in control also need dopamine, but because of their substance abuse, they deliver less dopamine to sustain those networks in the brain. They therefore perform worse in the test because they cant engage the network anymore, and instead attempt to use another suboptimal network in the cerebellum (Hester et al 2004).
28
How is stress response implicated in addiction behaviour?
Dysfunctional emotional and stress responses may be a pre-requisite for someone becoming dependent on substances of abuse. Dysfunctional responses may explain the significant contribution of stress-related mechanisms on craving (we find that stress significantly influences craving for the drug) and relapse susceptibility to substance use. Clinical observations in alcoholism, for example, document an association between self-reports of stressors and subsequent return to drinking.
29
How can fMRI be used for predicting relapse in addiction?
(Paulus et al - 2005) Subjects were instructed to predict where a stimulus appears on a computer screen - a simple decision making task. This was done during methamphetamine abstinence. The study showed that there where key signal differences in certain areas of the brain between those that would go on to relapse and those that would not relapse. This model is able to predict with a 95% that the person would stay clean.
Another study showed how fMRI response to alcohol predicted subsequent transition to heavy drinking in college students.
30
What are the limitations in using fMRI to understand the neurobiology of addictive processes?
* Artefacts (noise) not related to neural activity are everywhere.
* fMRI is not a magic bullet - simplistic claims based on localisation.
* We cannot unequivocally infer anything about specific neurochemistry in addiction
* The scanner is unfamiliar and uncomfortable - it doesn’t stimulate day-to-day life.
31
What is the DSM-V definition/symptoms of problem gambling?
Gambling disorder in DSM-5 is defined as a persistent and recurring problematic gambling behaviour leading to clinically significant impairment or distress, as indicated by the individual exhibiting 4 or more of the following in a 12-month period:
* Needs to gamble with increasing amounts of money in order to achieve the desired excitement
* Is restless or irritable when attempting to cut down or stop gambling
* Has made repeated unsuccessful efforts to control, cut back, or stop gambling
* Is often preoccupied with gambling (e.g., having persistent thoughts of reliving past gambling experiences, handicapping or planning the next venture, thinking of ways to get money with which to gamble).
* Often gambles when feeling distressed (e.g., helpless, guilty, anxious, depressed).
* After losing money gambling, they often return another day to get even (chasing ones losses).
* Lies to conceal the extent of involvement with gambling
* Has jeopardised or lost a significant relationship, job, or educational or career opportunity because of gambling.
* Relies on others to provide money to relieve desperate financial situations caused by gambling.
The gambling behaviour is not better explained by a manic episode.
32
How can problem gambling be subcategorised?
Gambling can be specified as episodic or persistent:
* Episodic: Meeting diagnostic criteria at more than one time point, with symptoms subsiding between periods of gambling disorder for at least several months.
* Persistent: Experiencing continuous symptoms, to meet diagnostic criteria for multiple years.
Can also be specified by current severity:
* Mild: 4–5 criteria met.
* Moderate: 6–7 criteria met.
* Severe: 8–9 criteria met.
33
What is the prevalence of gambling, and problem gambling in the UK?
Gambling is a popular recreational activity in the UK:
* 63% of adults (16+) had gambled in the past year
* Men (66%) more than women (59%)
* Most common gambling was National Lottery (46%) and Scratchcards (23%)
* Excluding the National Lottery, 45% of adults have gambled in the past year.
Overall, 3.9% of adults were classified as at risk gamblers. Measured using Problem Gambling Severity Index. The numbers of British problem gamblers has risen by more than 50% between 2012 and 2015, from 280,000 to 430,000.
34
What are the risk-factors for problem gambling?
* Gender - men are more likely across all cultures
* Age - Young people are more likely to experience PG problems. In the UK, children are 4 times more likely to be PG than adults.
* Homelessness - x10 prevalence rates compared to normal London population. There are more PG becoming homeless than homeless becoming PG though.
* Impulsivity - strong predictor of problems at a young age
* Impaired functioning of brain regions related to decision making
* Gambling disorder runs in families. Problem gamblers are more likely to have a problem gambler parent. In treatment seeking samples: 10-44% have one or more parents with PG. Is this got to do with genetic or environment? A bit of both.
35
What are the psychological co-morbitidies associated with problem gambling?
* Substance use disorders 57.5%
* nicotine dependence 60.1%
* alcohol abuse/dependence 28.1%
* illicit drug abuse/dependence 17.2%
* Mood disorders 37.9%
* Major depressive disorder 23.1%
* Bipolar disorder 9.8%
* Anxiety disorders 37.4%
* Generalized anxiety disorder 11.1%
* Antisocial personality disorder 28.8%
36
Describe the psychological treatments for problem gambling
Generally cognitive behavioural therapy is given as there is evidence base for treatment. Usually 8 sessions are standard, in a group setting to 1-1.
* Of those who start CBT, 78.8% go on to complete treatment.
* Treatment completers have significantly fewer gambling days
CBT incorporates both behavioural and cognitive interventions with the aim of altering both behaviour and thinking moving away from unhelpful destructive patterns to more helpful ones. Focuses on the Here and Now. Sessions are psycho-educational.
* It targets Cognitive distortions and Cravings.
We can use balance sheets: Good about not gambling, Bad about gambling. Graphs to chart gambling activities. The treatment is based on rewards i.e. allow yourself to eat out once a week.
37
Describe the pharmacological treatments for problem gambling
Naltrexone is a promising mu kappa opioid receptor antagonist though not currently approved by the BNF. It modulates the mesolimbic dopamine circuitry therefore in theory diminishing the pleasure associated with gambling. Good date on efficacy in terms of relapse prevention. Dose 50mg as good as higher doses.
38
Classify drugs according to their effects (i.e. stimulant, depressants etc)
* Depressants
* Alcohol (not illegal though)
* Opioids
* Benzodiazepines
* GHB - GBL
* Ketamine
* Stimulants
* Cocaine - crack
* Amphetamine - methampthetamine
* MDMA - Ecstacy
* Psychedelics
* LSD - psylocybin
* Salvinorum
* Cannabis
39
Describe the classifcation of drugs according to the Misuse of Drugs Act (1971)
The original intention of the MDAct was to have a system of relative based harm against which penalties would be applied (penalty fits the crime). The act states that changes can be made to the classification if evidence becomes clearer with regards to their relative harms.
Classified into 'schedules', which carry different prison sentences for possession and supply. Those in bold are medicines:
* Class A: **Opioids**, **methylamphetamine**, cocaine, MDMA, LSD, Psilocybin, Crack cocaine
* Class B: **Amphetamines**, **Barbiturates**, **Ketamine**, Cannabis
* Class C: **Benzodiazepines**, **GHB**, **Buprenorphine** **Steroids**, **Growth** **Hormone**, Clenbuterol, Benzylpiperazine
40
What are the different sources of drug harms?
Drug harms come from:
* The physical harms of drug itself due to acute toxicity, and chronic effect.
* The route of use (infections, skin lesions and lung disease)
* The psychological harms of dependence to the drug and impairment of function
* The social impact on the user (loss of relationships etc)
* The physical harms to others by the user
* The social harms to others (crime, environmental damage, family adversities, economic cost, community)
41
What drugs are the deadliest?
Two ways of looking at this:
* In terms of number of deaths: **Tobacco and alcohol** are by far the dealiest, followed by opiates, cocaine, paracetamol, amphatamines, cannabis, ecstacy.
* Tobacco causes around 80,000 deaths a year, and alcohol around 28,000. Opiates account for 1,800. Paracetamol accounts for 200. For the first time last year, cocaine overtook paracetamol.
* Another way is **index of toxicity (deaths per million users)** where **opiates** are by far the most dangerous:
* Heroin/opiates = 20,000 (1 in 50 due to respiratory depression)
* Cocaine = 170
* Amphetamines = 70
* MDMA = 50
* Cannabis = 5
42
Describe the acute toxicity of drugs of misuse
* **Respiratory** **depression** especially in opioids such as heroin or methadone. Worse if other depressants such as alcohol or benzodiazepines are taken.
* **Hyperthermia** - caused by stimulants such as MDMA, worse if dancing.
* **Hypothermia** - ketamine or alcohol
* **Hyponatraemia** - especially MDMA if misunderstanding health guidance, and people drink lots of water.
* **Cardiac** symptoms and stroke - cocaine especially if taken with alcohol (cocaethylene), and amphetamines
* **Hepatitis** - MDMA
These drugs also cause brain syndromes:
* **Confusion**/**delirium** -depressants especially ketamine
* **Paranoia**/**delusional** states - stimulants and cannabis
* **Anxiety** attacks - stimulants, psychedelics and cannabis
There are about three deaths a week from **alcohol** **poisoning**.
43
What are the drug harms caused by the chronic effects of drugs?
Alcohol use disorders are responsible for the most frequent mental health disorders in males. **Alcohol is the main cause of disability in 15-24 year olds**. Alcohol is the **most common cause for death in men under 50.** Alcohol has a wide impact on human diseases.
Although there is a x20 increase in cannabis over the last 40 years, there is a decrease in schizophrenia incidence over the same time. It is argued that to prevent one man from developing schizophrenia, you would need to prevent 5000 young men from ever smoking cannabis.
Other chronic medical harms come include:
* **Cirrhosis** (chronic fibrotic cirrhosis)- from alcohol and khat chewers – but it’s unlikely due to khat itself, and could be instead due to pesticides sprayed on the khat
* **Bladder** **damage**
* **Sexually** **transmitted** **diseases** - disinhibited behaviour and sex workers
* **Neurological** **damage**
* Frontal syndromes – alcohol and cocaine/metamphetamines
* Peripheral neuropathy – alcohol, pressure and B1 def ?
* Wernicke’s encephalopathy – triad of ataxia, diplopia and confusion (medical emergency)
44
What are the drug harms caused by the route of administration?
Skin popping
Needle marks
Tooth loss / gum damage due to amphetamines
45
Describe the unscientific nature of the MD Act 1971
The ISCD (Independent Scientific Committee on Drugs) Drug Harms Model looks at drug harms to the user and to others. Using weighting and ranking criteria.
Looking at the correlation between the drug harm scores and schedule classifcation there is a correlation of 0.04 (so nothing)!!
Furthermore, many banned drugs have potential as treatments
* Cannabis – pain, sleep, spasticity, cancer, PTSD
* Ecstasy (MDMA) – parkinson’s, PTSD
* Psilocybin – depression, OCD, cluster headaches
* LSD – for terminal illnesses, addic#on (e.g. to alcohol)
* Mephedrone and naphyrone – for depression and addiction
But current regulations make them almost impossible to research
46
What are the different roles of pharmacotherapies in addiction?
Pharmacotherapies in addiction have their different roles:
* **Substitution** - give a drug to replace what they are taking
* **Withdrawal** - treat withdrawal to prevent complications - not just for physical discomfort.
* **Abstinence** - drugs to maintain abstinence, to prevent relapse
* To **prevent** **harms** - e.g. by brain damage or infections etc.
47
What pharmacotherapy is used for substitution in alcohol dependence?
Benzodiazepines (diazepam/valium) are rarely used as substitution drugs, and are controversial.
48
What is the mechanism of the effects of alcohol withdrawal?
Alcohol withdrawal is a result of receptor-level tolerance:
* Alcohol **acutely** **boosts** **GABAa** function, allowing more Cl- to enter the cell, and thus increasing the inhibitory function of the receptor. To compensate, after **chronic** drinking there is **decreased** **activity** of the receptor, where less Cl- enters the cell after GABA binding.
* On the flip-side, alcohol **acutely** **antagonises** **NMDA** function, decreasing Ca2+ influx and decreasing excitation. **Chronic** alcohol use leads to **NMDA** **up**-**regulation** (associated with impaired memory) to compensate.
Therefore the sudden withdrawal of alcohol after chronic use would lead to a **hyper**-**excitable** state caused by decreased GABAa and increased NMDA function --\> **increased** **Ca2**+ **influx**. This is harmful as it can cause **seizures**, which are especially harmful in younger patients.
49
What are the effects of alcohol withdrawal?
The sudden withdrawal of alcohol after chronic use would lead to a hyper-excitable state caused by decreased GABAa and increased NMDA function --\> increased Ca2+ influx. This is harmful as it can cause **seizures**, which are especially harmful in younger patients. The purpose of preventing withdrawal is to prevent the brain damage which can occur as a result of these. Often parts of people's brains are '**fried**' and they cannot drive for a year. Can often be **fatal** leading to death.
* The **more detoxes** one undergoes, the **more glutamate** **excitation** becomes out of control. This is also associated with increased likelihood to relapse.
* Furthermore, the **more detoxes** a patient undergoes, the **more cognitive impairment** they experience.
50
What pharmacotherapy is used to treat alcohol withdrawal?
To counter the excessive central glutamate excitation, treatment regimens include:
* **Benzodiazepines** - they are effective in reducing signs and symptoms of withdrawal, and are recommended as the treatment of choice. No particular benzodiazepine is recommended over others, so take kinetic considerations into account (e.g. **lorazepam** or **oxazepam** in liver failure).
* **Carbamazepine** (a glutamatergic anticonvulsant) has also been shown to be efficacious and can be chosen as an alternative to benzodiazepines. Effective and used widely in other parts of the world.
51
What pharmacotherapy is used to aid in alcohol abstinence?
To overcome the blunted dopamine reward system, we give a dopamine agonist **disulfiram**.
Disulfiram **inhibits** **aldehyde** **dehydrogenase** preventing acetaldehyde (metabolite of alcohol) conversion to acetate. The **build**-**up** **of** **acetate** causes **unpleasant** **symptoms** of nausea, flushing, headache, vomiting, palpitations, hypotension. These unpleasant symptoms means it is often contra-indicated. But many patients who are ex-alcoholics say this was important to instil a fear in drinking. Disulfiram also **prevents dopamine conversion to noradrenaline** in the brain by blocking dopamine ß hydroxylase (DBH).
To those who tend to be 'samplers' we give **naltrexone**.
52
How are harms prevented in alcohol dependence?
There is a signfiicant role of nutrition and vitamin supplementation in alcohol dependence. Most people will be deficient in vitamins. A key one is thiamine (Vitamin B1), which plays a key role in metabolism in the brain. Thiamine deficiency adds to the already “toxic” situation of withdrawal (increase in glutamate) where brain cells are at risk of becoming excitable (seizures) or dying. A lack of thiamine can lead to lactic acidosis, then inflammation, then Wernicke's encephalopathy or Korsakoff's syndrome.
53
What syndromes are caused by thiamine deficiency?
Wernicke's encephalopathy is an acute event caused by thiamine deficiency, which leads to a sequence of metabolic events resulting in energy compromise and ultimately neuronal death in certain neuronal populations with high energy requirements.
* Classic triad of **Ataxia**, **Confusion** and **Eye** **signs** such as ophthalmalgia or nystagmus.
* Reversible
Korsokoff's syndrome is chronic, and non-reversible causing memory loss and confabulations.
54
What is the role of baclofen in the treatment of alcohol dependence?
Baclofen is a GABA agonist (anxiolytic) used to increase the GABA-break. It has been shown to **improve** **abstinence** **rates** in alcohol dependence (not heroin or cocaine). Some people report **reduction** **in** **anxiety** and **craving**. One double blind RCT in Italy looked at the effectiveness and safety of baclofen:
* Found it was well tolerated, no difference in dropout rates
* Main side effect was sedation (in this case, need to reduce dose)
* Less likely to lapse and relapse
However, another study in the USA showed no superiority of baclofen vs control.
* They found that it was anxiolytic but not useful for treating alcohol dependence.
Why was there a difference?
* The USA study had more intensive psychosocial support than the Italian study
* Completely different groups of patients. The Italian study had unwell cirrhotic patients, all of whom wanted treatment. Whereas the USA only had 23% of patients who wanted treatment.
Debate still continues about the role of baclofen. **Baclofen** may be better for severely dependent alcoholics, **those** **aiming** **for** **abstinence**. Prof Lingford-Hughes personally found baclofen effective in **patients** **with** **an** **anxiety** **element** to their dependence.
55
What is the role of Naltrexone in alcohol dependence?
Naltrexone is **started after detoxification**. Used to **reduce** **risk** **of** **relapse** in '**samplers**'. Safe to drink as well.
Naltrexone is a **mu-receptor antagonist** - so it **takes the pleasure away from drinking**. Remember how mu receptors on GABAergic neurones inhibit the GABA-break, and therefore increasing DA in the VTA.
NICE recommends oral naltrexone for 6 months, stop if drinking alcohol for 4-6 weeks.
56
What is the role of Nalmafene in alcohol dependence?
**Started** **whilst** **drinking** **to** **reduce** **drinking.**
Nalmefene is a **mu** **opiate** **antagonist** BUT a **kappa** **partial** **agonist**. Remember how mu is involved in acquisition, but kappa is involved in relapse/reinstatement. Nalmefene decreases the pleasurable effects of alcohol by antagonising mu receptors, and also causes dysphoria by stimulating the kappa receptors. This **leads** **to** **reduced** **drinking**.
NICE recommends nalmefene for the use in treating alcohol dependence and when patients start drinking?
57
Outline the drugs used to treat alcohol dependence, and when they should be used.
Start whilst drinking to reduce drinking - **nalmefene**
During detox give **Benzodiazepines** such as **lorazepam** or **oxazepam** or give **carbamezapine**. (To reduce excitotoxicity).
Starting post-detox:
* To support abstinence - acamprosate, **disulfiram**
* Reduce risk of relapse in 'samplers' - **naltrexone**
* Support relapse in those with prominent anxiety - **baclofen**
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Should alcohol abstinence be the only goal?
* Half of patients don’t want to abstain, but simply reduce their drinking.
* However, after treatment many patients who reduce their drinking want to abstain.
59
What pharmacotherapy is used for substitution in opioid addiction?
**Methadone** is the key substitute. It is primarily a mu agonist. Whereas with heroine they may inject 3-6 times a day, and have various highs and withdrawals, methadone attempts to provide this cover throughout this day through one injection.
The issue with methadone is that it is a full agonist, and so can **potentially have a lethal dose to cause respiratory depression.** There is therefore a shift from using methadone to a partial agonist - **buprenorphine**, which occupies all receptors, but is only a **partial** **agonist**, and so is much more unlikely to cause respiratory depression (unless taken with other drugs).
Buprenorphine has a **long half-life** and so can provide **longer** **cover**. Although the plasma level may go up and down, because the effects are limited by the pharmacokinetics of the drug, the **effects** **stay pretty** **stable** throughout a day or two. It gives them a half-opiate effect to help them deal with emotions. They also experience less dysphoria.
Buprenorphine of these drugs stop 'on top' heroin. Even if you take a full agonist, it cant get access to the receptors which are occupied by buprenorphine.
60
How much methadone or buprenorphine do we give as a substitute in opiate dependence?
We don't have any data to guide our prescription of methadone. We do have imaging studies looking at how buprenorphine occupies the mu-opioid receptor.
* Opiate addict show increased mu opioid receptor levels
* Opiate addict after 2mg shows that many mu receptors are occupied
* Opiate addict after 16mg shows that all mu opioid receptors are occupied, same with 32mg, so there is no point in giving a larger dose than 16mg
This is very useful in the clinic to know that taking more drug will not necessarily help. It is harder to show similar receptor blockade with methadone. As there is no reduction in the availability of opioid receptors in the presence of methadone. We don’t know wether to give 50mg, 75, 100, etc.
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What pharmacotherapy is used to treat opiate withdrawal?
You don't need to give opioids to treat opioid withdrawal. You need to reduce and taper the opioid use. Some people take several years to do this.
When you look at alcoholic withdrawal, you get symptoms related to the noradrenergic storm from the locus coeruleus.
62
What pharmacotherapy is used to help abstinence in opiate dependence?
Given naltrexone but poor compliance.
63
What pharmacotherapies are used to treat nicotine addiction?
Nicotine is a stimulant, so these would be different, but the strategy is the same:
* Substitution - give a drug to replace what they are taking
* Nicotine replacement, nicotinic partial agonist (varenicline)
* Withdrawal - treat withdrawal to prevent complications
* Nicotine replacement, nicotinic partial agonist (varenicline)
* Abstinence – to prevent relapse
* Nicotinic partial agonist (varenicline), dopaminergic/noradrenergic (bupropion)
* To prevent harms eg brain damage, infections etc
* In addition to psychosocial smoking cessation therapies.
Neuro BSc Module 3
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