existing and novel treatment for drug addiction

Question 1

what are the treatment types for drug addiction?

Answer 1

1. Cognitive Behavioural Therapy
2. Pharmacotherapy - Agonist/partial agonist (replacement/substitution), antagonist (blockade), aversive (negative reinforcement) and correction of underlying/associated disorders (such as depression).
   - Although these drugs have certainly helped a lot of people and we are in a better place from where we were 30 years ago, there is still major problems. They do not help everyone (resistance), side effects severe in some cases, tolerance, dependence, narrow therapeutic window and do not treat all symptoms. All this made developing drugs for treating mental disorders expensive and difficult.

Question 2

what are the phases of substance use that are targets for pharmacotherapy?

Answer 2

• Intoxication/overdose e.g. naloxone (opioid receptor antagonist).
• Withdrawal/detoxification e.g. methadone.
• Abstinence initiation/use reduction
• Relapse prevention
• Sequelae (psychosis/agitation

Question 3

what are the substances for which pharmacotherapy is available?

Answer 3

• Opioids
• Alcohol
• Benzodiazepines
• Tobacco (nicotine dependence)

Question 4

what are the substances for which pharmacotherapy is not available?

Answer 4

• Cocaine
• Methamphetamine
• Hallucinogens
• Cannabis
• Solvents/Inhalants

Question 5

what are some pharmacological treatment strategies for substance of abuse drugs?

Answer 5

• Agonist/partial agonist (replacement/substitution)
• antagonist (blockade)
• aversive (negative reinforcement)
• correction of underlying/associated disorders (such as depression, etc.)

Question 6

how can opioids be treated?

Answer 6

dependence treatment:
• Lofexidine (non-substitute method of detoxification) - Central ⍺2-agonist, suppresses some components of withdrawal syndrome by blocking the release of NA.
• Methadone (substitution method of detoxification - mu agonist) - Long-acting drug, no euphoria to morphine.
• Naltrexone (opioid antagonist) - prevents euphoria to opioids. Given daily to addicts to prevent lapses.
• Buprenorphine (substitution method of detoxification).

Question 7

describe how methadone can be used as an opioid dependence maintenance therapy

Answer 7

Methadone (must be administered through a registered narcotic treatment program).

• Long acting mu agonist
• Duration of action: 24-36 h – longer than heroin.
• Dose: important issue and philosophical issue for many programs.
• Will induce a euphoric effect but not as much as heroin.
• 30-40 mg (low dose) will block withdrawal, but not craving.
• illicit opiate use decreases with increasing methadone dose - 80-100 mg (high dose) is more effective at reducing opioid use than lower doses (e.g.: 40-50 mg/d)

Strain et al. 1999

Question 8

what are the benefits of methadone?

Answer 8

• Lifestyle stabilization
• Improved health and nutritional status
• Decrease in criminal behavior
• Employment
• Decrease in injection drug use/shared needles

CSAT,2005

Question 9

what do opioid receptor studies suggest?

Answer 9

So, these studies basically indicate that MOP and KOP systems exert opposite motivational control of positive reinforcement. While MOP activation induces the release of dopamine and produces reward, the KOP activation will decrease dopamine release have aversive, dysphoria, anti-reward effects.

Question 10

naltrexone (to maintain abstinence) is an antagonist treatment for opioid dependence therapy. Why antagonist naltrexone therapy?

Answer 10

• Block effects of a dose of opiate.
• Prevent impulsive use of drug.
• Relapse rates high (90%) following detoxification with no medication treatment.
• Dose (oral): 50 mg daily, 100 mg every 2 days, 150 mg every third day.
• Blocks agonist effects.
• Side effects: hepatotoxicity, monitor liver function tests every 3 months.
• Biggest issue is lack of compliance; but those who “test” naltrexone by taking a dose of opioid and experiencing no effect do better with the medication.
• Injectable naltrexone not currently approved for opioid dependence, but likely to also be effective.

Question 11

Buprenorphine is an antagonist treatment for opioid dependence therapy. describe Buprenorphine

Answer 11

• Partial MOPr/KOP agonist/KOP antagonist (reduce euphoria).
• Lower risk of respiratory depression +ve.
• Lower retention rate –ve.
• Also, used with Naloxone (Suboxone). Lower risk of withdrawal symptoms/lower craving for opioids.
• Kappa receptor agonist= involved in dysphoria–> so if you block the kappa receptor= inhibit its aversive effect of opioid
• Therefore, this is blocking the rewarding system and the aversive system

Question 12

what does alcohol do?

Answer 12

• increase voltage-gated Ca2+ channels.
• decrease GABAA receptors.
• Potentiates GABA inhibition similar to Bz. At higher doses mood becomes more labile with euphoria and melancholy, aggression and submission – can lead to violence.
• Marked abstinence syndrome, changes in Ca2+ channels lead to excessive neurotransmitter release…
  • Tremor, nausea, sweating, fever, hallucinations
  • Seizures, confusion, agitation, aggression
• Alcohol dependence (alcoholism) is common (4-5% of population)
• Susceptibility to dependence, genetic factors - Linked to alcohol metabolism (alcohol dehydrogenase).

Question 13

how is alcohol dependence treated?

Answer 13

• Benzodiazepines (e.g. diazepam) effective against seizures. Tolerance to Bz are less than barbiturates. Dependence a problem – withdrawal syndrome seen upon stopping of drug – worse in short acting Bzs but addiction (severe psychological dependence) is not so much of a problem.
• Clonidine, ⍺2-adrenoceptor agonist (inhibits excessive transmitter release) - inhibit the exaggerated transmitter release that occurs during withdrawal.
• Propranolol, β-blocker (blocks excessive sympathetic activity).
• Acamprosate, weak NMDA antagonist (interferes with synaptic plasticity) – reduces craving.
• Disulfiram, causes accumulation of acetaldehyde making alcohol consumption unpleasant.
• Naltrexone, opioid antagonist reduces alcohol-induced reward and therefore reduces relapse.

Question 14

as alcohol is a psychodepressant, what are its withdrawal symptoms?

Answer 14

o	Deliria
o	Tremors 
o	sweating
o	Nausea
o	Sometimes hallucinations and seizures

This is due to excitability taking place in the brain–> therefore give benzodiazepines= suppress this hyperexcitability.
Shouldn’t be on Benzos for more than a week: drug of abuse and can become dependent on it. Also, interaction of benzo with alcohol together can cause respiratory depression.
Alcohol also acts on the GABA-A receptor to cause inhibition

Question 15

what are the 2 phases of alcohol dependence?

Answer 15

1. Acute Alcohol Withdrawal.
2. Relapse Prevention: Maintenance Medications To Prevent Relapse To Alcohol Use (FDA approved) …
   • Disulfiram
   • Naltrexone (oral and injectable)
   • Acamprosate
   Note: monitor any patient being treated for a SUD for emergence of depression/anxiety/ suicidality as this can occur during the course of treatment.

Question 16

describe what happens when BZD binds

Answer 16

BZD binding increases the probability (facilitate) of channel opening they increase the affinity of GABA.
BZD bind to a regulatory site that is distinct from the GABA binding site and therefore act allosterically.
BZD cause ­ in the frequency of channel opening but no change in conductance or mean open time.
Main subunits are ⍺,β, and γ with ⍺1β2γ2; ⍺2β3γ2 and ⍺3β3γ2 predominating in the brain. Sensitivity to BZD requires ⍺ and β subunits and γ2 subunit is required for full response to BZD.
Evidence from mutations of subunits in mice (i.e. transgenic mice models) show that ⍺1 mediates sedative, amnesic & anticonvulsant effects and ⍺2 mediates anxiolytic and muscle relaxant effects. Muscle relaxant effects may be useful in anxiety as in anxious patients increased muscle tone (headaches, tension etc.)

Question 17

Benzodiazepines are used for acute withdrawal. Describe these instances

Answer 17

Overdose:
– Prolonged sleep without CVS or respiratory depression.
– Can become life threatening (respiratory depression etc.) with other CNS depressants e.g. alcohol.
– Reversed with flumazenil (competitive antagonist).

Tolerance & Dependence:
- Tolerance – gradual escalation of dose needed to produce required effect. Tolerance results in a desensitization of GABA receptors and an increased sensitization of the excitatory neurotransmitter system, glutamate such as NMDA glutamate receptors. These changes occur as a result of the body trying to overcome the drug’s effects. Other changes that occur are the reduction of the number of GABA receptors (downregulation).
– Dependence – stopping treatment causes marked ­ in anxiety + tremor / dizziness, insomnia
– Withdrawal after chronic use similar to opiates (> with short acting BZD)/aggression, irritability, LC/NA involved, loss of appetite, hallucinations.

Question 18

can Benzos be used for alcohol dependence?

Answer 18

• BZD produce cross-tolerance with alcohol
• High risk of abuse of BZD
• High risk of relapse to alcohol use
• Combined use of alcohol and prescribed BZD can be very impairing and produce significant toxicity.
• If patient complains of anxiety:
  1. Consider use of serotonin reuptake inhibitors (this is first line treatment of anxiety disorders - not Benzos).
  2. Refer to psychotherapeutic interventions (e.g.: cognitive-behavioral therapy),
  3. Consider relapse to alcohol.

Question 19

name and describe an alcohol relapse prevention medication

Answer 19

Disulfiram (Antabuse - AVERSIVE):

• Blocks alcohol metabolism leading to increase in blood acetaldehyde levels; aims to motivate individual not to drink because they know they will become ill if they do.
• Antabuse reaction: flushing, weakness, nausea, tachycardia, hypotension

• Treatment of alcohol/disulfiram reaction is supportive (fluids, oxygen)

Question 20

what are the side effects and contraindications of disulfiram?

Answer 20

Side Effects:
• Common: metallic taste, sulfur-like odor
• Rare: hepatotoxicity, neuropathy, psychosis

Contraindications: cardiac disease, esophageal varices, pregnancy, impulsivity, psychotic disorders, severe cardiovascular, respiratory, or renal disease, severe hepatic dysfunction: transaminases > 3x upper level of nl.

Question 21

what is the clinical dose for disulfiram?

Answer 21

Clinical Dose: 250 mg daily (range: 125-500 mg/d).

Some question whether patients adhere to this drug, but studies have shown positive benefits in terms of alcohol use disorder outcomes if the patient adheres; it is also a good idea to have the patient attend substance abuse treatment where, at least in the beginning of treatment, disulfiram is administered by staff/family.

Question 22

naltrexone can also be used for alcohol dependence. describe how it is used

Answer 22

•Oral Naltrexone hydrochloride-DOSE: 50 mg per day
•Extended-Release Injectable Naltrexone (Vivitrol)… 1 injection per month
•Similar structure to naloxone (Narcan).
•Potent inhibitor of Mu opioid receptor binding…
May explain reduction of relapse because endogenous opioids involved in the reinforcing (pleasure) effects of alcohol.
May explain reduced craving for alcohol because endogenous opioids may be involved in craving alcohol.

Question 23

Describe nicotine and its mechanism of action

Answer 23

Highly addictive drug – responsible for more damage to health than all other drugs (including alcohol).
Rats will self-administer nicotine

Tolerance to some effects of nicotine – especially the nausea and vomiting. Nicotine acts on nAChR of the a4β2 subtype – these are highly expressed in the hippocampus and cortex (improving cognitive function) and ventral tegmental area (VTA) from where DAergic neuron project to the nucleus accumbens (reward pathways).

Vaccines – useful in animal models – stop self-administration.

Question 24

how can nicotine addiction be treated?

Answer 24

Nicotine replacement therapy (patch, gum nasal spray-still get high from nicotine but don’t inhale all the carcinogens, tars and CO which will kill you )…
• Relieves psychological and physiological withdrawal syndrome.
• Reduces cigarette consumption but not nicotine abstinence.
• Aims to decrease exposure to tobacco smoke, to reduce withdrawal intensity, including craving and to facilitate abstinence from tobacco smoking.
• All forms of NRT are slow delivery devices when compared to cigarettes
• Separation of nicotine delivery from context and rituals and slow onset makes dependence unlikely.
• No evidence that nicotine causes cancer.
• No evidence of increased cardiovascular risk with NRT.
• Medical contraindications - immediate myocardial infarction (< 2 weeks), serious arrhythmia, serious or worsening angina pectoris, accelerated hypertension.

Question 25

Is NRT effective?

Answer 25

• All NRT forms increase quit rates at 6-12 months by 50-70% compared with placebo regardless of setting.
• No significant difference between the NRT forms
• In highly dependent smokers 4mg gum is more effective than 2mg gum
• No strong evidence of a benefit from higher doses of patch
• The intensity of additional advice and support does not increase the effectiveness of NRT

Question 26

Nicotine Replacement Therapy (NRT)
• No evidence that nicotine causes cancer
• No evidence of increased cardiovascular risk with NRT
• Medical contraindications:
– immediate myocardial infarction (< 2 weeks)
– serious arrhythmia
– serious or worsening angina pectoris
– accelerated hypertension

ADDICTION:
The gum and the patch deliver smaller amounts of nicotine amore slowly than absorbed from the cigarettes and therefore they are less addiction than tobacco. 10% report some dependence. Dependence potential is related to the speed of absorption of nicotine and so the patch is not addictive the nasal spray is moderately addictive.

Answer 26

MADDDD

Question 27

name 2 drugs that can be used to treat nicotine addiction

Answer 27

Bupropion

Varenicline (champix)

Question 28

Describe Bupropion

Answer 28

• Developed as antidepressant (blocks monoamine reuptake)
• Nicotinic antagonist.
• May ­ [DA] in nucleus accumbens
• Side Effects – Insomnia, dry mouth, tremors, rashes, weight loss, seizures (lowers seizure threshold), hypertension.
• Inhibitor of neuronal reuptake of noradrenaline and dopamine.
• Limits craving (substitution for some of the stimulant effects of nicotine).
• Marketed as an antidepressant and decreased desire to smoke observed in depressed patients.
• Doubles the success rate of quitting compared to placebo.
• Equally effective in patients who are not depressed – effectiveness is dose dependent.

Question 29

what issues do patients have with bupropion?

Answer 29

•	Adverse effects
–	Insomnia
–	Dry mouth
–	Tremors
–	Rashes
–	Weight loss
–	Seizures
–	Hypertension
•	Lowers seizure threshold
•	Important contraindications to use
–	Past seizures
–	Drugs that alter seizure threshold

Question 30

describe Varenicline (champix)

Answer 30

• Partial a4b2 nAChR agonist, full agonist for a7 nACHR
• More effective than NRT.
• High-affinity partial agonist at a4b2 AChR specifically designed for smoking cessation.
• Alleviates symptoms of craving and withdrawal, but produces much weaker effect than nicotine.
• Prevents inhaled nicotine from a cigarette activating the α4β2 receptor and blocks the pleasurable effect of smoking.
• Existing data indicate that varenicline is more effective than bupropion and some forms of NRT in achieving abstinence and is recommended for use as a first line therapy.

Question 31

how effective is varenicline?

Answer 31

• Existing data indicate that varenicline is more effective than bupropion and some forms of NRT in achieving abstinence and is recommended for use as a first line therapy1
• More efficacy and safety evaluation in the general population is needed, particularly in those with comorbid conditions2

Question 32

name some novel treatments for drug addiction

Answer 32

Dopamine receptor partial agonists

Modulators of gamma-aminobutyric acid (GABA) signalling

modulators of brain stress systems

Modulators of glutamate signalling

Question 33

what is the concept behind addiction vaccines?

Answer 33

Currently being studied with cocaine, meth and nicotine.

e.g. because of cocaine’s small size, it easily passes through to the brain. To create the vaccine, scientists attach cocaine to a large bacterial protein, which is then injected into the body.

The antibodies produced from this combined bacterial/cocaine molecule can later bind to new cocaine, preventing it from entering the brain

Question 34

Nicotine Vaccine
— Preliminary clinical trials (Phase II):
— The vaccine is safe
— Sufficiently high levels of antibodies needed to promote continuous abstinence (~doubles the placebo rates)
— Low levels are ineffective

Answer 34

What does the future lie?
• Multidisciplinary tools for improving the efficacy of public prevention measures against smoking
• E-cigarettes!!!

Question 35

therapeutics that block memory consolidation

Answer 35

mad