lecture 31: emerging treatments for drug dependence: clinical evaluation

Question 1

What are substance use definitions?

Answer 1

• substance/drug use = sanctioned by society
• substance/drug misuse = unsanctioned; involves risk without apparent harm
• substance use disorder (ICD; DSM V) = drug use resulting in [harm] problems
• substance dependence = daily physical need for the drug = homeostasis (neuroadaptation)
• substance addiction = as above + harm/s
• tolerance = more drug to get same effect
• withdrawal = illness after stopping dependent use (neuroadaptation reversal)
• intoxication = impairment associated with high dosage

Question 2

What is the epidemiology of substance use disorders?

Answer 2

• lifetime prevalence substance use disorders ~15-20%; dependence ~6-8% population
• tobacco (nicotine dependence) ~16%
• increasing prevalence/epidemic opioid use disorders (dependence) and opioid related deaths (analgesics)
• alcohol use disorders:
  
  • lifetime risk disorder !20%
  • 25% seek medical help
  • 15-20% GP patients
  • dependence ~4% M and 2% F (~80% males, 60% females drink)
• endemic cannabis, ATS (methamphetamine), “synthetics”, prescription psychotropics
• overwhelming majority SUDs and addiction establish before third decade of life

Question 3

What is the neurobiology of addiction?

Answer 3

• all drugs of abuse target the brain’s pleasure centre
• brain reward (dopamine) pathways
  
  • these brain circuits are important for natural rewards such as food, music and art
• typically, dopamine increases in response to natural rewards such as food
• when cocaine is taken, dopamine increases are exaggerated, and communication is altered

Question 4

What is seen in brain scans of a meth abuser at different time points of abstinence?

Answer 4

• is this a brain disease
• or an acquired condition
• or are these people just weak?
• changes in the brain’s signalling
• this shows the density of dopamine receptors
• reasonable recovery after 24 months

Question 5

What is environmental neuroadaptation?

Answer 5

• micrographs of nucleus accumbens neurons in animals exposed to nonaddictive drugs display dendritic branches with normal numbers of signal-receiving projections called spines (left and centre)
• but those who become addicted to cocain sprout additional spines on the branches, which consequently look bushier (right)
• presumably, such remodelling makes neurons more sensitive to signals from the VTA and elsewhere and thus contibutes to drug sensitivity
• recent findings suggest that delta FosB plays a part in spine growth

Question 6

What is the relationship between genes and addiction?

Answer 6

• Goodwin D: Alcoholism and Genetics
• Schickit M: sons of alcoholics
• Van den Bree: Genetic and environmental influences on drug use and abuse/dependence in male and female twins
• McClellan A: drug dependence, a chronic medical illness
• Gerra G: OPRK1 polymorphism
• Bevilacque L: genes and addictions
• Schuckit M: alcohol use disorders
• i.e. a lot of research

Question 7

What is the bio-psycho-social model of drug dependence / addiction?

Answer 7

• genotype + environment (Psych-soc) = phenotype
• drugs as reinforcers of behaviour (prim/sec)
• addiction NOT caused by single agent/event
• addiction process analogous with other chronic diseases e.g. heart disease and diabetes
• treatment focus: reduce mortality and morbidity

Question 8

On what does target organ damage depend?

Answer 8

• genes and environment

Question 9

How do genes influence vulnerability?

Answer 9

• genetic variation in COMT influences the harmful effects of abused drugs
• met/met (low, equal cannabis/no cannabis use)
• met/val (low, more cannabis use than no)
• val/val (high cannabis use, low no use)
• val/val more likely to suffer the harmful effects of abused drugs e.g. psychosis

Question 10

What is the relationship between genes and treatment response?

Answer 10

• genetics can help predict the outcome of treatment for alcohol dependence

Question 11

What kind of disease is drug addiction?

Answer 11

• drug addiction is a chronic disease

Question 12

What is a comparison of relapse rates between drug addiction and other chronic illnesses?

Answer 12

• drug addiction: 40-60%
• type I diabetesL 30-50%
• hypertension: 50-70%
• asthma: 50-70%

Question 13

How GP “confidence” to treat illegal drug use or alcoholism compare to other chronic diseases?

Answer 13

• hypertension: 82.8
• diabetes: 82.3
• depression: 44.1
• prescription drug abuse: 30.2
• alcoholism: 19.9
• illegal drug use: 16.9

Question 14

What is the treatment for nicotine addiction?

Answer 14

• most smokers are “addicted”
• QUIT strategy; CBT (relapse prevention); others including acupuncture, hypnosis, groups etc
• nicotine replacement therapy (NRT): gum, lozenge, puffer, transdermal patch
• relapse prevention pharmacotherapy (“anti-craving”) e.g. Varenicline, Bupropion, Cytisine
• immunotherapy: vaccine in phase 3 trials

Question 15

What are the effects of methoxsalen on nicotine concentration and smoking desire?

Answer 15

• desire to smoke decreases with increasing concentration of methoxsalen (30 and 30mg, 35 at 10mg)
• increasing concentration of blood nicotine with increasing methoxsalen dosage

Question 16

What is the endogenous cannabinoid system?

Answer 16

• CB1 (CNS) and CB2 (Immune) identified but more are likely to exist
• CB1 agonist: (THC/CBD) products: sativex, dronabinol, for anorexia, wasting (AIDS) and nausea associated cancer (special access scheme)
• CB1 antagonist: rimonabant appetite suppressant; antiaddiction; ?antipsychotic
• cannabis: THC, cannabidiol/CBD, etc
• THC addiction: treatments similar for tobacco smoking, psychosis and liver risks
• legal THC for malignant pain, MS, epilepsy, glaucoma etc california; ?CBD
• decriminalised THC: SA for personal use (Dutch)
• legal highs: synthetic cannabis, kronic etc

Question 17

What is world alcohol consumption?

Answer 17

• we are equatable with russua and america

Question 18

What is the lifetime risk of death from an alcohol related disease by number of standard drinks per day, per 100 people with that drinking pattern?

Answer 18

• 2 standard drinks recommended
• not daily to avoid habituating
• reasonably strong correllation with escalation of habits

Question 19

What is a standard drink?

Answer 19

• for healthy adults, moderate drinking = 2 standard drinks (20gm) regularly/or less (not daily)
• unlikely harmful
• up to 4 (40gm) infrequently unlikely harmful
• higher dose/frequency exposures carry increasing risk
• pregnant women and children should abstain
• 1-2 standard drinks occasionally not likely harmful to patients with “most” medical conditions; precautions for elderly/ill, illicit drug users, high risk activities…

Question 20

What is alcohol withdrawal syndrome?

Answer 20

• chronic drinking → downregulate GABA and upregulate glutamate (NMDA) = neuroadaptation
• reversal of neuroadaptation = hyperadrenergic state and excess glutaminergic activity (neurotoxic)
• complications:
  
  • hyperadrenergic state = hypertension, tachycardia etc
  • withdrawal seizures, delirium, hallucinosis etc
• medical management:
  
  • thiamine
  • fluids
  • electrolytes
  • benzodiazepines e.g. Diazepam/Oxazepam, AWScales..

Question 21

How is alcohol (ethanol) dependence/addiction treated?

Answer 21

• identify and manage co-morbidity (e.g. ABI)
• rehabilitation (CBT/RP programmes; AA, RR.. etc)
• relapse prevention/RP pharmacotherapy
  
  • e.g. naltrexone, acamprosate, disulfiram (Antabuse) prorgramme,
  • ?baclofen, vigabatrin, topiramate, valproate (under investigation: kappa antagonists)
  • reward drinkers have best response to naltrexone - incredibly dampens the enthusiasm/reward signalling, don’t drink to the same extent
  • acamprosate is minimally effective but works in some
  • dilsulfiram (antabuse) - if you take this tablet every night, makes you averse to alcohol, most people don’t want to take, one of the most evidence based treatments, but very low compliance so only 3-4% of alcoholics take it

Question 22

What are aspects to consider in heroin addiction?

Answer 22

• heroin = diacetylmorphine
• smoke, “chase”, inject
• BBV (Hep B/C; HIV); sepsis (SBE); NB: OD Risk! (~2% annual mortality)
• OST: methadone; buprenorphine; naltrexone formulations
• harm minimisation: syringe exchange, support networks, injecting rooms, naloxone, drug courts: diversion programmes, ? heroin trial
• less than 1% of the community inject
• use to be available across the country
• it is the injecting that is really bad

Question 23

What is seen with chronic groin injecting?

Answer 23

Question 24

What is seen with chronic leg/skin injecting?

Answer 24

Question 25

What is seen with temazepam IV and digital infarction?

Answer 25

Question 26

What is the opioid supply in australia?

Answer 26

• oxycontin going up
• morphine going up

Question 27

What is seen with iatrogenic addiction (pethidine)?

Answer 27

• multiple operations for abcesses for a drug that doctors were prescribing

Question 28

How are opioid (illicit and pharmaceutical) dependence/addictions treated?

Answer 28

• rehabilitation programmes (CBT/RP; NA etc)
• relapse prevention pharmacotherapy: ORT
  
  • agonist (maintenance) therapy e.g. (Subutex) and methadone syrup; buprenorphine, buprenorphone-naloxone (suboxone)
  • antagonist therapy: e.g. naltrexone tablets with “program” or via implant; depot injection (soon)

Question 29

What is opioid replacement therapy (ORT) by replacement medications in victoria from 2000 to 2011?

Answer 29

Question 30

What is ORT with suboxone and subutex?

Answer 30

• suboxone contains both buprenorphine and naloxone (subutex = buprenorphine alone)
• buprenorphine is a partial agonist and therefore has less toxicity risks:
  
  • less overdose risk (less child poisoning)
  • less potential interaction risk
  • less sedating than methadone
• previously an opioid analgesic, buprenorphine is now commonly used to treat opioid addiction
• naloxone blocks the effects of opioids (short-acting)

Question 31

How are stimulant (e.g. amphetamines, cocaine) dependence/addictions treated?

Answer 31

• rehabilitation programmes (CBT/RP; NA etc)
• relapse prevention pharmacotherapy includes:
  
  • SSRI (Fluoxetine = SERT-inhibitor) for MDMA (ecstasy, etc)
  • disulfiram (?dopamine B-hydroxylase +/- paired association with ethanol)
  • topiramate: dexamphetamine substitution?
• immunotherapy for cocaine and methamphetamine in phase 3 trials

Question 32

summary

Answer 32

• use disorders are mostly self-limiting conditions - brief interventions
• drug dependence/addiction is for most a chronic relapsing and remitting comorbid disease - prolonged interventions = CDM approach
• drug dependence/addiction has a biopsychosocial aetiology and therefore requires a multidisciplinary approach to management