Addiction Pharmacotherapy

Question 1

What is the DSM 5’s definition of an opioid use disorder?

Answer 1

• a problematic pattern of opioid use leading to clinically significant impairment or distress, as manifested by at least 2 of the 11 criteria, occurring within a 12 month period

Question 2

What constitutes mild opioid use disorder? Moderate? Severe?

Answer 2

Mild: presence of 2-3 symptoms
Moderate: presence of 4-5 symptoms
Severe: presence of 6+ symptoms

Question 3

What are the criteria to constitute opioid use disorder?

Answer 3

1. opioids are often taken in larger amounts or over a longer period than was intended
2. there is a persistent desire or unsuccessful efforts to cut down or control opioid use
3. a great deal of time is spent in activities necessary to obtain the opioid, use the opioid or recover from its effects
4. craving, or a strong desire or urge to use opioids
5. recurrent use resulting in a failure to full major role obligations at work, school or home
6. Continued opioid use despite having persistent or recurrent social problems caused by effect of opioids
7. important actives are given up or reduced because of opioid use
8. recurrent opioid use in situations where it is physically dangerous
9. continued opioid use despite the knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance

Question 4

What is tolerance defined by?

Answer 4

• a need for markedly increased amounts of opioids to achieve intoxication or desired effect
• a markedly diminished effect with continued use of the same amount of an opioid

Question 5

What is withdrawal defined by?

Answer 5

• the characteristic opioid withdrawal syndrome
  -opioids are taken to relive or avoid withdrawal symptoms
  (not met for those taking opioids under medical supervision)

Question 6

What is the goal of hard reduction?

Answer 6

• attempts to decrease the harmful consequences of illicit drug use to the individual, family, community and society
• goals to reduce illicit opioid use, needle charing, criminal activity and mortality

Question 7

What is the pharmacological action of methadone?

Answer 7

• agonist of the mu-opioid receptor and is a weak NMDA antagonist

Question 8

What is the main use of methadone?

Answer 8

analgesia and withdrawal management in opioid dependent individuals
- no rush or euphoria in stabilized patients, blocks euphoria from heroin and other opioids

Question 9

What makes methadone so useful over the long term?

Answer 9

• has a long duration of action that allows for once daily dosing in methadone and maintenance therapy
• duration of analgesia is similar to morphine

Question 10

Why does methadone have such a good street value?

Answer 10

• used on the street to reduce the withdrawal symptoms of opioids -> have diarrhea, vomiting, bone aches and pains

Question 11

What is the absorption of methadone? How long until detected in the plasma? What is the peak plasma levels? Bioavailability?

Answer 11

• methadone is detected in the plasma within 30 minutes
• peak plasma levels are detected 2-4 hours after ingestion (we care about this because at the peak plasma level is the time that someone will stop breathing following a dose)
• po bioavailability is 90%

Question 12

What is the distribution of methadone? The half life? How many days does it take to reach a steady state with repeated dosing?

Answer 12

The drug is highly protein bound to both plasma proteins and tissue proteins

• the Vd is 4-5 L/kg
• the T1/2 is 22 hours (15-40 hours)
• 5-7 days to reach steady state with repeated dosing
• withdrawal typically is suppressed for 24- 36 hours with therapeutic doses

Question 13

What is methadone mainly metabolized by? What does this mean for the drug?

Answer 13

• primarily metabolized by cytochrome P450 3A4 to the inactive metabolite EDDP
• means that there will be a lot of observed drug interactions
• also weakly inhibits 2D6

Question 14

How does pH affect the amount of methadone excreted in the urine?

Answer 14

• amount of methadone excreted in the urine increases as pH decreases

Question 15

What are the most common side effects associated with methadone?

Answer 15

• constipation. dental, insomnia, neuroendocrine, sexual changes, sweating
• drowsiness, nausea, psychoactive effects, weight gain

Question 16

What are some of the major adverse effects associated with methadone?

Answer 16

QT interval prolongation with high doses

- ECG recommended for patients on high doses

Question 17

What are the drug interactions associated with methadone?

Answer 17

associated with the metabolism via CYP P450 3A4

• most often just have to monitor for signs of toxicity or withdrawal and adjust dose accordingly
• pharmacokinetic: induction/inhibitition
• pharmacodynamic: drugs with similar SE profiles

Question 18

What is the typical dosing regimen of methadone?

Answer 18

• 10-30 mg to start
• high risk patients 10-20 mg to start
• remember it takes 5 days for plasma levels to reach a steady state
• increase by 5-10 mg every 3-5 days as tolerated. Avoid prescriptions that have dose increases without patients assessment
• > 60-80 mg increase by 10 mg every 1 to 2 weeks

Question 19

What are dose adjustments of methadone made based on?

Answer 19

• adjustments based on patients reported symptoms. how long they last for, what the symptoms are and when

Question 20

What is the usual therapeutic dose of methadone?

Answer 20

50-120 mg

Question 21

What are some common methadone withdrawal symptoms?

Answer 21

• agitation
• sweating
• nausea/vomiting
• chills
• goosebumps
• tachycardia
• rhinorrhea
• intense anxiety/dysphoria
• insomnia
• opioid cravings
• muscle aches
• diarrhea/abdominal cramping
• lacrimation
  (think of everything that has to do with horrible flu symptoms)

Question 22

What are the symptoms associated with methadone overdose?

Answer 22

• sedation
• lack of coordination
• respiratory depression
• emotional lability
• circulatory collapse/cardiac arrest
• sweating
• pinpoint pupils
• death

Question 23

In what situations is split dosing appropriate to do for patients?

Answer 23

for RAPID METABOLIZERS
- drowsy in the afternoon but withdrawal in the evening
- measurable methadone peak and trough
- peak: through ratio should be under 2
- if > 2 then may be a rapid metabolizer- should split the dose BID
PREGANCY
- metabolism changes in the 3rd trimester
- may require dose increase and split dosing
- methadone is standart of care for pregnant women dependent on opioids
- opioid withdrawal in pregnancy is associated with fetal complications and stillbirths
-must replace doses in the event of emesis

Question 24

What is the general treatment for those undergoing an overdose on methadone?

Answer 24

• treat with naloxone for a minimum of 24 hours with an additional 12 hours of monitoring
• can run an infusion or give small bolus doses hourly

Question 25

How does buprenorphine/naloxone work with addiction?

Answer 25

• buprenorphine: acts as a partial mu-opioid agonist that is absorbed sublingually
• naloxone: acts as a pure opioid antagonist (not absorbed sublingually - there for the SOLE purpose to prevent an effect if it is injected)

Question 26

Buprenorphine has good SL bioavailability but has low PO bioavailability due to very high _____

Answer 26

first pass metabolism

Question 27

Naloxone has poor ___ and ___ bioavailability

Answer 27

PO and SL

Question 28

Buprenorphine has a very high affinity for what opioid receptor? What action does this cause it to have?

Answer 28

• has a very high affinity for the mu-opioid receptor (will displace morphine, methadone and other full agonists)
• slow dissociation from the mu-opioid receptor
• low intrinsic activity at the mu-opioid receptors-ceiling effect
• antagonist at the kappa opioid receptor

Question 29

What is unique about buprenorphine in regards to its ability to precipitate withdrawal?

Answer 29

• will cause precipitated withdrawal in a person who has the taken a full opioid agonist and is physically dependent on opioids
• person must be experiencing withdrawal at the start of induction

Question 30

What is the adverse effect profile like in buprenorphine?

Answer 30

less adverse effects than other opioids (less sedation, less constipation)

Question 31

What is the onset of action of buprenorphine? When does peak effect occur?

Answer 31

• 30-60 minutes
• peak effect occurs 1-4 hours
• duration of action is dose dependent (4 hours to 3 days)

Question 32

What is buprenorphine metabolized by? Eliminated by?

Answer 32

metabolized by: CYP 450 3A4 and glucuronidation

eliminated in feces

Question 33

What are some of the most common interactions with buprenorphine?

Answer 33

• interacts with other 3A4 inducers/inhibitors
• other sedating drugs
• bezos combination produces additive respiratory depression - no plateau
• blocks analgesic effect of full opioid agonists- pain management can be difficult
• can cause QT prolongation

Question 34

Buprenorphine is considered ___ in overdose than methadone. May not prevent ____ symptoms in heavy opioid users and there is less withdrawal on discontinuation

Answer 34

safer

withdrawal