Lecture 16: Opioids (Part 2)

Question 1

What are the characteristics of opioid receptors in the brain?

Answer 1

opioids bind to receptors expressed in many parts of the brain, including the cerebellum, nucleus accumbens, and hypothalamus

many of these regions are involved in pain perception, emotion, reward, and addiction

Question 2

What are the characteristics of opioid receptors in the brainstem?

Answer 2

opioid activity in the brainstem can affect breathing by quieting neurons that control respiration

respiratory depression is a dangerous side effect of opioid drugs, and is commonly cited as the cause of death in cases of opioid overdose

Question 3

What are the characteristics of opioid receptors in the spinal cord?

Answer 3

the transmission of pain signals in the spinal cord, especially in a region called the dorsal horn, is dampened by opioids binding to receptors on these cells

this is one intended target of opioid treatments and a mechanism of the drugs’ unrivaled analgesic properties

Question 4

What are the characteristics of opioid receptors in the peripheral neurons?

Answer 4

pain-sensing neurons send nociceptive messages from the periphery to the spinal cord

binding opioid receptors in these neurons is another way that opioid drugs curb pain sensations

Question 5

What are the characteristics of opioid receptors in the intestines?

Answer 5

opioid receptors are expressed in neurons regulating peristalsis

inhibition of these cells upon opioid binding leads to another side effect of opioid medications, constipation

Question 6

What is the effect of opioids on pain?

Answer 6

Mu and kappa opioid receptors are localized on primary and secondary afferents in the skin and spinal cord

agonist binding to opioid receptors inhibits pain transmission from skin to brain

opioid receptors are also localized in the brainstem (rostroventral medulla) where they increase diffuse noxious inhibitory control

the diffuse noxious inhibitory circuit is comprised of descending excitatory and inhibitory neurons in the medulla that inhibit neurons in the medulla that inhibit or activate pain synapses in the spinal cord

allows our brain to gate the amount of nociceptive information that reaches the brain

mu and delta opioid receptors are located on the ON cells in the medulla

activation of opioid receptors leads to inhibition of medulla ON cells

this produces a net reduction in nociceptive signals reaching the brain

Question 7

What is the relationship between opioids and reward?

Answer 7

dopamine is involves in motivated behavior

dopamine neurons are located primarily in the ventral tegmental area (VTA)

mu opioid receptors in the VTA are located on inhibitory GABAergic interneurons

so, opioids inhibit inhibition (called disinhibition) leading to dopamine release

Question 8

What is nociception?

Answer 8

relay of pain signal from periphery to the brain

Question 9

What is pain?

Answer 9

integration of that pain signal with cognitive and emotional context

(requires the brain, always subjective experience)

Question 10

How do opioid receptors inhibit pain?

Answer 10

decreasing nociception at the level of the nociceptor, in the spinal cord, and in the brain stem

decreasing the emotional and cognitive aspects of pain (make the pain bother you less)

drugs that target the sensory, as well as cognitive and emotional circuits, will always be better analgesics

Question 11

What are the characteristics of opioid agonists used for pain?

Answer 11

most opioid agonists used for pain are mu agonists

include drugs such as morphine, fentanyl, codeine, oxycodone

differences efficacy (full/partial agonist) and potency drive differences

Question 12

What are the characteristics of delta agonists?

Answer 12

delta agonists are being developed for chronic migraine

the development of delta agonists were initially limited because of severe side effects (seizures)

enthusiasm renewed with the discovery you can isolate the analgesic effects from seizures through biased agonism

TRV250 is a delta opioid receptor biased agonist, currently under development by Trevena

Question 13

What are the characteristics of kappa agonists?

Answer 13

kappa agonists that penetrate the brain have not been developed for pain because of dysphoria/hallucinogenic effects (i.e. Salvia)

peripherally restricted kappa agonists do not cross the blood brain barrier

these drugs bind kappa receptors in the skin and inhibit pain transmission, while avoiding central nervous adverse events

CR845, potent analgesic, anti-inflammatory, and anti-itch properties with little CNS effects, currently under development

Question 14

What is tolerance?

Answer 14

decreased response to the effects of the drug, necessitating ever larger doses to achieve the same effect

Question 15

What is opioid tolerance?

Answer 15

opioid tolerance develops to the analgesic, euphorigenic, sedative, and respiratory effects the drugs

an opioid tolerant individual can take enormous doses

Question 16

What is the mechanism of desensitization in opioid tolerance?

Answer 16

following agonist binding and G-protein signaling, beta-arrestin is recruited to shut-off signaling (desensitization)

receptor + agonist is pulled off the membrane and recycled in an endosome; is either degraded or recycled back to the membrane

repeated opioid use leads to less receptors on the membrane –> reduced agonist effect (tolerance)

Question 17

What is opioid physical dependence?

Answer 17

physical dependence develops following chronic opioid use and is revealed following abrupt discontinuance of drug as withdrawal

acute opioid withdrawal includes; rhinorrhea (runny nose), lacrimation (tearing eyes), chills, muscle aches, diarrhea, yawning, anxiety

withdrawal is high aversive and some symptoms can persist for months; may motivate the drug user to make robust efforts to avoid withdrawal

this can drive the transition to addiction, but dependence does not equal addiction

Question 18

What is addiction?

Answer 18

is a brain disease driven by dysfunction in reward, motivation, memory circuitry

Question 19

What is addiction characterized by?

Answer 19

inability to abstain consistently

impairment of behavioral control

drug craving

diminished recognition of significant problems with ones behaviors and interpersonal relationships

dysfunctional emotional response

Question 20

What are preventative treatments for opioid use disorder?

Answer 20

usually people will abuse prescription opioids by grinding oral tablets and snorting or injecting (faster onset, bigger high)

most preventative measures are about making this difficult

Question 21

What are physical barriers used as treatment for opioid use disorder?

Answer 21

prevent chewing/crushing of oral tablets for intravenous/intranasal drug use

Question 22

What are chemical barriers used as treatment for opioid use disorder?

Answer 22

can be added to resist extraction of the opioid by common solvents like water/alcohol

Question 23

How are agonist/antagonist combinations used as treatment for opioid use disorder?

Answer 23

an antagonist can be added to an agonist to interfere with euphoria associated with abuse

the antagonist is only released when oral tablet is tampered with (crushed, injected, etc.)

Question 24

How is agonist replacement therapy used as a treatment for opioid use disorder?

Answer 24

agonist replacement therapy is a comprehensive treatment approach including maintenance on an opioid agonist and cognitive behavioral therapy

agonist therapy blunts the symptoms of opioid withdrawal

replacement agonists have longer half-lives, so avoid the repeated high/crash cycle

Question 25

What are the advantages of agonist replacement therapy?

Answer 25

reduced drug cravings

better participation in addiction treatment (behavioral therapy) since withdrawal symptoms aren’t a distraction

improved social functioning

reduction in infectious disease/death associated with illicit drug use (particularly injection drug abuse)

Question 26

What is methadone?

Answer 26

methadone is a long-acting full agonist at the mu opioid receptor

it was the first replacement therapy approved for opioid use disorder

disadvantage is that it is full agonist, so overdose still possible

Question 27

What is buprenorphine?

Answer 27

buprenorphine is a partial agonist at the mu opioid receptor, an a antagonist at the kappa and delta opioid receptor

safer agonist profile

antagonist activity at kappa may improve mood

marketed as suboxone (buprenorphine + naloxone)

Question 28

What are supervised consumption sites?

Answer 28

provide a safe place to take drugs to reduce harm or poisonings (overdose)

clients bring own drug

are provided clean needles and medical supervision in case of overdose

any one can access (do not need referral) and can remain anonymous

Question 29

What is injectable opioid therapy (aka iOAT)?

Answer 29

clients must be referred to program by health care practitioner and must have failed all other addiction treatment

clients are prescribed specific doses of injectable opioids (usually hydromorphone) and are expected to self-specific doses at the iOAT clinic

clients are closely monitored for adverse reactions

Question 30

What are the advantages to opioid harm reduction?

Answer 30

reduce morbidity and mortality associated with opioid use

provide access to information and resources for additional treatment

Question 31

What are the disadvantages to opioid harm reduction?

Answer 31

moral argument for providing drugs to people with addiction

NIMBY related to location of SCS/iOAT clinics

Question 32

What is acute opioid intoxication treatment?

Answer 32

naloxone (Narcan)

non-selective competitive opioid receptor antagonist

available to the public (without a prescription) as intramuscular or nasal spray

works within minutes

lasts about 1/2 hour (multiple doses may be necessary)