existing and novel treatment for drug addiction Flashcards
what are the treatment types for drug addiction?
- Cognitive Behavioural Therapy
- 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.
what are the phases of substance use that are targets for pharmacotherapy?
- Intoxication/overdose e.g. naloxone (opioid receptor antagonist).
- Withdrawal/detoxification e.g. methadone.
- Abstinence initiation/use reduction
- Relapse prevention
- Sequelae (psychosis/agitation
what are the substances for which pharmacotherapy is available?
- Opioids
- Alcohol
- Benzodiazepines
- Tobacco (nicotine dependence)
what are the substances for which pharmacotherapy is not available?
- Cocaine
- Methamphetamine
- Hallucinogens
- Cannabis
- Solvents/Inhalants
what are some pharmacological treatment strategies for substance of abuse drugs?
- Agonist/partial agonist (replacement/substitution)
- antagonist (blockade)
- aversive (negative reinforcement)
- correction of underlying/associated disorders (such as depression, etc.)
how can opioids be treated?
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).
describe how methadone can be used as an opioid dependence maintenance therapy
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
what are the benefits of methadone?
- Lifestyle stabilization
- Improved health and nutritional status
- Decrease in criminal behavior
- Employment
- Decrease in injection drug use/shared needles
CSAT,2005
what do opioid receptor studies suggest?
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.
naltrexone (to maintain abstinence) is an antagonist treatment for opioid dependence therapy. Why antagonist naltrexone therapy?
- 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.
Buprenorphine is an antagonist treatment for opioid dependence therapy. describe Buprenorphine
- 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
what does alcohol do?
- 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).
how is alcohol dependence treated?
- 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.
as alcohol is a psychodepressant, what are its withdrawal symptoms?
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
what are the 2 phases of alcohol dependence?
- Acute Alcohol Withdrawal.
- 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.
describe what happens when BZD binds
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.)
Benzodiazepines are used for acute withdrawal. Describe these instances
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.
can Benzos be used for alcohol dependence?
- 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.
name and describe an alcohol relapse prevention medication
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)
what are the side effects and contraindications of disulfiram?
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.
what is the clinical dose for disulfiram?
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.
naltrexone can also be used for alcohol dependence. describe how it is used
•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.
Describe nicotine and its mechanism of action
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.
how can nicotine addiction be treated?
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.
