Opioids

Question 1

Types of opioid receptors

Answer 1

mu (μ), kappa (κ), and delta (δ).

Question 2

Receptor involved in pain

Answer 2

Most opioids involved in pain management operate through mu receptors, often abbreviated MOR (Mu Opiate Receptor).

Question 3

How do opioids activate receptors

Answer 3

, morphine and other opioids function primarily as ligands of G protein coupled receptors.

Ligands for this large receptor family can function as full or partial agonists or as antagonists.

Question 4

Semisynthetic MOR agonists

Answer 4

Codeine/Tramadol

Hydrocodone

Oxycodone

Heroin

Question 5

What are codeine/tramadol

Answer 5

Codeine is a methyl ether derivative of morphine.

Codeine by itself is considered a weak opiate; as it has a relatively low affinity for MOR receptors.

Nevertheless, approximately 15% of administered codeine is O-demethylated to morphine in the liver by CYP2D6, which is responsible for the bulk of codeine’s analgesic effects.

Tramadol is similar to codeine in being classified as a weak opioid.In addition to being a weak MOR agonist, tramadol is also a serotonin and nonepinephrine reuptake inhibitor (SNRI), which gives it a unique mechanism of action and side effect profile (such as serotonin syndrome if given together with certain anti-depressants).

Most of tramadol’s analgesic action comes from its demethylation by CYP2D6. Can have mutations so metabolism is varied between people

Question 6

What is hydrocodone

Answer 6

Hydrocodone is stronger than codeine but thought to be less effective than morphine as an analgesic.

It also has antitussive activity.

Hydrocodone is very similar to oxycodone in both analgesic and side effects profiles.

There is limited evidence that hydrocodone may have slightly less abuse potential than oxycodone.

Vicodin: Hydrocodone packaged with acetaminophen.

Question 7

What is oxycodone

Answer 7

Oxycodone appears to have many of the analgesic effects of other opiates but also appears to have euphoric effects similar to heroin and therefore has significant potential for abuse and addiction.

Percocet: oxycodone packaged with acetaminophen

Question 8

What is heroin

Answer 8

Heroin is formed by the acetylation of both hydroxyl groups present in morphine. This makes the drug more hydrophobic than morphine and increases its ability to cross the blood brain barrier.

Heroin is therefore faster acting than morphine and also tends to be more intense and euphoric.

It also needs to be delivered by IV to maintain its desired properties.

Question 9

Semisynthetic MOR partial agonists/antagonists

Answer 9

Methadone

Buprenorphine

Naloxone

Naltrexone

Nalbuphine

Hydromorphone

Fentanyl

Carfentanil

Question 10

What is methadone

Answer 10

Methadone is a synthetic MOR agonist that is thought to have similar analgesic properties with morphine but less euphoria and less addictive potential.Methadone is also much longer lasting (24/26 hrs) in the system than morphine (4-6 hrs).

Because methadone lasts much longer in the system, adverse effects can last longer and be more difficult to treat.

Methadone is used orally in highly structured opioid use disorder treatment programs. Tolerance can occur

Question 11

What is buprenorphine

Answer 11

Buprenorphine is a partial agonist for MORs.Full occupancy of MOR receptors with a partial agonist like buprenorphine produces less of an effect than that seen with full agonists “ceiling effect”.

Buprenorphine therefore has a lower risk of abuse and dependence and is being used to treat individuals with opioid use disorders. Helps with withdrawal

Buprenorphine also functions as an antagonist for delta and kappa opiate receptors.

Buprenorphine is given orally.

Question 12

What is naloxone

Answer 12

Naloxone (NARCAN) is an MOR antagonist used to treat opioid overdose. Naloxone is not absorbed efficiently through the GI tract (due to greater than 90% being subject to first pass metabolism).

When given as an antidote for an opioid overdose it must therefore be given either intra-nasally or by IV.

Question 13

How does Buprenorphine/Naloxone Combination Therapy work

Answer 13

Buprenorphine is often used in combination with the MOR antagonist naloxone (packaged as zubslov, suboxone, bunavail).

When given orally as a combination drug the effects of buprenorphine dominate.

When injected, the combination drug’s effects are dominated by naloxone.

This combination therapy limits abuse, as the presence of naloxone can induce withdrawal symptoms when the combination drug is taken IV.

Question 14

What is Naltrexone

Answer 14

Naltrexone is an antagonist for all opioid receptors.

Naltrexone is taken orally.

Naltrexone is used as part of a complete treatment program to prevent patients that have recovered from an opioid abuse disorder from relapse.

Taking naltrexone while currently taking opioids can induce withdrawl symptoms.

Question 15

What is nalbuphine

Answer 15

Nalbuphine is an opiate analgesic of the agonist/antagonist class.

It is structurally related to naloxone.

It is an agonist for opioid κ receptors, where it is thought to exert most of its analgesic activity and an antagonist for μ receptors and so is thought to have less abuse potential.

Importantly, unlike morphine and other potent mu agonists, nalbuphine produces less respiratory depression as the dose is increased due to its agonist- antagonist “ceiling” effect

Not a controlled substance

Question 16

What is hydromorphone

Answer 16

Hydromorphone is a semi-synthetic derivitive of morphine (trade name Dilaudid) .Hydromorphone is 2-8 times more potent than morphine itself with greater sedation but a shorter time of duration.

Hydromorphone is more lipid-soluble than morphine and crosses the blood-brain barrier more rapidly.

Hydromorphone is also a metabolite of hydrocodone as shown below.

Some have suggested that hydrocodone is a prodrug that needs to be converted to hydromorphone for effect.

This seems rather unlikely as conversion of hydrocodone to norhydrocodone (which has weak analgesic action) by CYP3A4 is the primary pathway for the metabolism of hydrocodone in most individuals.

Question 17

What is fentanyl

Answer 17

Fentanyl is derived from pithidine (Demerol) and is 50-100 times more potent than morphine as an analgesic and anesthetic (and 30-50 times more potent than heroin).

The higher potency relates to the hydrophobicity of fentanyl and its increased ability to cross the blood brain barrier.

Fentanyl (dashed line) would display a left shift relative to heroin (solid line).

Question 18

What is carfentanil

Answer 18

Carfentanil is an elephant tranquilizer that was never intended for human use.

It is substantially more potent than fentanyl.

Both carfentanil and fentanyl are synthetic opiates that are relatively easy to make from simple non-prescription ingredients.

Question 19

How are endogenous opiates produced

Answer 19

Endogenous opioids are peptides produced from larger proteins by proteolytic processing. These larger proteins pre-pro-opiomelanocortin, pre-pro-enkephalin, and pre-pro-endorphin give rise to endorphins, enkephalins, and dynorphins, respectively.

Each of the opioid peptides has a common amino-terminal sequence Tyr-Gly-Gly-Phe -(Met or Leu) and differ in C-terminal sequences whose sizes range from 5 to 31 residues.

These natural opioids are secreted by neurons in different regions of the body and differ in their affinity for the different opioid receptors.

Question 20

Common structure of opioid receptors

Answer 20

They are GPCRs

All members of this family of proteins have common structural features particularly at the level of secondary and tertiary structure (span the plasma membrane 7 times).

Trimeric G proteins are composed of α, β, and γ subunits and there are several members of each of these subunit families.

The α subunits of the trimeric G proteins bind the guanine nucleotides

In terms of primary structure, the opioid receptors are more similar to one other than to other members of the GPCR family.

There is a fourth receptor with sequence similarity to the three primary opioid receptors that is referred to as opioid-like receptor 1.

Question 21

What happens when a Gai protein is activated

Answer 21

when Gαi is activated by receptor binding an agonist Gαi binds to and inhibits adenylyl cyclase lowering cAMP levels.

βγ subunits bind to GIRKs, G protein regulated Inward Rectifier potassium(K) channels.

Question 22

The MORs interact with trimeric G proteins containing ____ subunits.

Answer 22

Gαi

Question 23

What does activation of GIRKs do to polarization?

Answer 23

Hyperpolarization of nerves that increases the action potential thresholds of nerves involved in pain sensation thereby decreasing pain sensation.

Question 24

Describe the nociception pain pathway

Answer 24

Primary afferent nociceptors convey noxious information to projection neurons within the dorsal horn of the spinal cord. A subset of these projection neurons transmits information to the somatosensory cortex via the thalamus, providing informtion about the location and intensity of the painful stimulus. Other projection neurons engage the cingulate and insular cortices via connections in the brainstem (parabrachial nucleus) and amygdala, contributing to the affective component of the pain experience. This ascending information also accesses neurons of the rostral ventral medulla and midbrain periaqueductal gray to engage descending feedback systems that regulate the output from the spinal cord.

Question 25

Role of opiates in pain pathway

Answer 25

When bound to agonists, opiate receptors found within many of these different neurons disrupt the transmission of nociceptive information. ## Footnote **agonist binding to opiate receptors activates Gαi, which in turn inhibits adenylyl cyclase and lowers cAMP levels**

Question 26

Role of βγ subunits in opioid receptors

Answer 26

The primary effects by which opiate receptor agonists temper nociceptive signaling is via the activation of βγ subunits of trimeric G proteins. Once activated, β**γ subunits stimulate inward rectifying potassium channels, causing hyperpolarization of nerves** involved in nociception increasing their thresholds for neuronal excitation and/or propagation of action potentials. **The activated βγ subunits also inhibit Ca2+ channels** controlling Ca2+-dependent neurotransmitter release at synaptic junctions.

Question 27

Opiate side effects

Answer 27

Resp. depression, constipation, pruritis, miosis, sedation, nausea, euphoria

Question 28

MOA of respiratory depression

Answer 28

The major life-threatening side effect of opioids is respiratory depression. This effect is mediated by **opiate receptors tempering neurons in respiratory control centers of the brain stem as well as mechano-receptors that transmit information from the periphery to control centers in the brain.** The effects of opioids on respiration are a frequent cause of mortality associated with opioid overdose. Respiratory depression, if not caught soon enough, can lead to hypoxia, acidosis, and death.

Question 29

MOA of opioids causing constipation

Answer 29

Opiate-induced constipation is caused by the fact that MORs are also expressed on cells of the enteric nervous system of the digestive tract. The same mechanisms through which opiates temper transmission on nociceptic stimuli also operate on the neurons of the enteric nervous system controlling gut motility. **Without these nerve impulses controlling the contraction and relaxation through myenteric motor neurons, the propulsive motility patterns participating in the peristaltic reflex are reduced causing constipation.**

Question 30

Strategy for avoiding opiate constipation

Answer 30

The goal is to create **opiate antagonists that do not cross the blood brain barrier** such that when they are given systemically they interfere with effects on peripheral nerves without influencing anti-nociceptive effects of opioids in the CNS.

Question 31

Drugs for opioid-induced constipation

Answer 31

**Naloxegol** is one such drug approved to treat opioid-induced constipation. Naloxegol is created by linking the MOR antagonist naloxone to polyethylene glycol, thus preventing naloxegol from crossing the blood brain barrier and interacting with MORs on neurons of the CNS. Another drug approved for opioid-induced constipation is methylnaltrexone. **Methylnaltrexone** is an antagonist for peripheral μ-opioid receptors. Methylnaltrexone is a quaternary amine that does not cross the blood-brain barrier.

Question 32

What opiate has been used for diarrhea and MOA

Answer 32

**Loperamide (Imodium)** ## Footnote Loperamide, like morphine, is an **agonist for MOR**, but unlike morphine, loperamide is actively **pumped out of the CNS by the P glycoprotein pump and so does not accumulate in the CNS.** Through its suppressive effects on nerve impulses controlling GI motility, loperamide is able to treat certain forms of diarrhea.

Question 33

MOA of pruritis

Answer 33

**Both MORs and serotonin 5-hydroxytryptamine subtype 3 receptors are present in the spinal trigeminal nucleus referred to as the itch center** and the effects of opiates on signals mediated through 5-HT3 receptors are thought to contribute to the pruritic side effects observed with opiates. 5-HT3 antagonists have shown mixed results in treating pruritus associated with opiate administration.

Question 34

Miosis MOA

Answer 34

Excessive constriction of pupils of the eye by opiates is mediated by high concentrations of **MORs in the Edinger-Westphal nucleus** that controls the muscle involved in pupil constriction ## Footnote **Constricted pupils can be used as a sign of opioid use or overdose.** **Restless patients withe enlarged pupils can be a sign of opioid withdrawl.**

Question 35

MOA of euphoria and addiction

Answer 35

Inhibitory effects on GABA inhibitory neurons controlling pleasure centers, stimulates dopamine release in nucleus accumbens

Question 36

MOA of opioid tolerance

Answer 36

**Repeated administration of agonists to a GPCR leads to receptor phosphorylation** by G protein coupled receptor kinases and subsequent **binding of arrestin proteins that interfere with the interaction of receptor with its cognate G protein.** **The interaction of receptors with arrestins can lead to receptor internalization and subsequent degradation.** As receptors become desensitized more agonist may be required to obtain desired effects and clinical tolerance develops. Not all receptors responding to a particular agonist are desensitized in the same manner and so there may be differences in timing or magnitude of tolerance that occurs for the different responses to opiates.

Question 37

What is opioid cross tolerance

Answer 37

Opioid cross-tolerance can occur via **multiple agonists targeting a single receptor subject** to the desensitization mechanisms ## Footnote When switching opioids it is useful to take into account that the **cross-tolerence between opioids may be incomplete, so caution must be taken to avoid an overdose when switching between agents.**

Question 38

Drug interactions of opioids

Answer 38

Opiates may interact with other drugs through pharmacokinetic mechanisms. Opiates may be rendered more or less effective by other drugs that either inhibit or induce opiate metabolism through cytochrome p450 or other drug metabolizing enzymes For example**, alternative substrates and inhibitors for CYP3A4 (fluconazole, clarithromycin, cimetidine)** can **increase opiate actions** including side effects like respiratory depression. On the other extreme, drugs like r**ifampin known to induce many CYP isozymes including CYP3A4 can reduce the effectiveness of opiates metabolized by CYP3A4.**

Question 39

Opioids metabolism

Answer 39

Question 40

Opioids pharmacodynamics

Answer 40

Opioids have major interactions with alcohol and benzodiazapenes Part of the synergy between opiates and benzodiazepines may be pharmacokinetic, as diazepam has been shown to inhibit hepatic p450s involved in opiate metabolism. The major factor underlying the co-abuse of opiates and benzodiazepines however is thought to be pharmacodynamic and the **ability of benzodiazepines to enhance the rewarding and re-enforcing effects of opiates.** The complications of co-abuse of opiates with **benzodiazepines or alcohol include enhanced risk of lethal overdose by respiratory depression.** The respiratory depressant effects of benzodiazepines and alcohol on their own are thought to be mild but in conjunction with opiates, can be deadly.