1.2 OPIOID RECEPTOR AGONISTS, PARTIAL AGONISTS, & ANTAGONISTS

Keep an open mind

An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage

Pain

Whether or not there is actual tissue damage is you have that sensory and emotional experience that looks like tissue damage even though there is none, that counts as

pain.

T/F. A person's report of an experience of pain should be respected.

T

Why are we in the medical field?

To prolong life and, at the minimum, ease a person’s suffering

“Your pain is a lesson from God”

○ Some of the patients may find meaning in the pain. The bad thing is when you enforce it on someone without consent

Positive Model of Suffering

Ease suffering

Negative Model of Suffering

Nociception steps:

Transduction ⟶ Transmission ⟶ Modulation ⟶ Perception

Nociception Modulation

where most medications act on various neurotransmitter systems (Glu, Asp, Gly, GABA, neuropeptides, etc.)

are prominent receptors that involve pain

Opioid and Norepinephrine

When you recall what drug that increases Norepinephrine in the synaptic cleft can be used in managing pain, BLANK can be used for neuropathic pain

Duloxetine

can be used for migraine prophylaxis.

Amitriptyline

Pain Scale:

0-10

Mild

1-3

Moderate

4-6

Severe

7-10

Pain assessment should be complemented with

Functional Activity SCale

T/F The main goal of functional activity scale is chasing a “o“ score

F. unrealistic expectation of chasing a “0” score

the patient is able to undertake the activity without limitation due to pain

No limitation

the patient is able to undertake the activity, but experiences moderate to severe pain

Mild limitation

the patient is unable to complete the activity due to pain or pain treatment-related adverse effects

Significant limitation

Pain is not the only important measurement. For some pain syndromes, they might not bring the pain scale down to zero. The pain scales suggest that once pain starts, you can bring it back to zero. With that, you should consider other metrics like WHAT

functional activity

- Touch pain

Nociceptive

- When something destroys your nerve endings

Neuropathic

- An example would be when your depression is so bad, it manifests as a headache.

Psychosomatic

Duration of pain

<1 month

Acute

Duration of pain

1-3 months

Sub-acute

Duration of pain

>3 months

Chronic

The problem with chronic pain is

quality of life.

What is the point of living if your life is painful? The effects of chronic pain on your brain, there is too much excitatory activity in the brain, and your brain cells slowly die

Last Duration of pain

Breakthrough

Opioids and NSAIDs are not the only options for pain management. An example would be

two antidepressants (Gabapentine, Duloxetin, Amitriptyline) mentioned above and Ketamine.

○ Ketamine due to its NMDA receptor antagonist inducing analgesic effect.

T/F: For those without inflammation, give coritocsteroids

For conditions without inflammation, why would you give anti-inflammatories like corticosteroids? Always check the pathophysiology of the condition to give better recommendations.

Consequences of unchecked chronic pain: overuse of neurons

○ Excitotoxic cell death (cognitive dysfunction)

○ Disinhibition of “brakes” (more pain)

● Remember: not always NSAIDs vs opioid false dichotomy

● Opioid Agonists ○ Morphine S2 , codeine ○ Oxycodone S2 , hydrocodone ○ Oxymorphone, hydromorphone ○ Fentanyl S2 , Remifentanil S2 , Alfentanil, Sufentanil ○ Meperidine, Methadone

● “Opioids” ○ Tramadol ○ Tapentadol

● Mixed Agonists/Partial Agonists - Antagonists ○ Buprenorphine S2 ○ Nalbuphine S2 ○ Butorphanol

● Opioid Antagonists ○ Naloxone ○ Naltrexone ○ Nalmefene ○ Peripheral: Alvimopan, Methylnaltrexone, Naloxegol

● Others - Dextromethorphan, Levopropoxyphene, Capsaicin

C. OPIOIDS

Opioid Agonists

○ Morphine S2 , codeine ○ Oxycodone S2 , hydrocodone ○ Oxymorphone, hydromorphone ○ Fentanyl S2 , Remifentanil S2 , Alfentanil, Sufentanil ○ Meperidine, Methadone

● “Opioids”

○ Tramadol ○ Tapentadol

● Mixed Agonists/Partial Agonists - Antagonists

○ Buprenorphine S2 ○ Nalbuphine S2 ○ Butorphanol

● Opioid Antagonists

○ Naloxone ○ Naltrexone ○ Nalmefene ○ Peripheral: Alvimopan, Methylnaltrexone, Naloxegol

● Others

- Dextromethorphan, Levopropoxyphene, Capsaicin

naturally occurring opioids

Opiates

Morphine, Codeine

○ Thebaine, Papaverine

Opiates - naturally occurring opioids

○ Derived from Papaver somniferum

Papaverine

anything that binds to opioid receptors

Opioids

Can be an agonist, antagonist, or partial agonist as long as it binds to the opioid receptor

Opioids

● Central, peripheral opioid receptor binding

● Endogenous peptides and receptors

C. OPIOIDS

C. ENDOGENOUS PEPTIDES

● The body creates its own opioids.

● Endorphin (from POMC), Enkephalin (proenkephalin), Dynorphin (Prodynorphin)

○ Endorphin plays a role in your body’s own analgesia mechanisms

D. ENDOGENOUS RECEPTORS

● μ receptors (endorphin)

● δ receptors (enkephalin) – Limited analgesia, antidepressant, proconvulsant

● κ receptors (dynorphin) – Analgesia/proalgesia, dysphoria, depression, anticonvulsant

○ Mainly for pain inhibition

○ Agonist - Inhibits pain transmission neurons

μ receptors (endorphin)

■ Bind to receptor → Na+ channel blockade (presynaptic) and open K+ channels (postsynaptic)

■ Inhibits dorsal horn activity via nucleus reticularis paragigantocellularis (NRPG) and via stimulating 5-HT, NE release

■ Net result - Pain inhibition

μ receptors (endorphin)

Other variants/pathways

– itch

MOR1D

Other variants/pathways

– itch

MOA of capsaicin

– Limited analgesia, antidepressant, proconvulsant

These are theoretical effects because we don’t have many drugs that target this receptor

δ receptors (enkephalin)

Analgesia/proalgesia, dysphoria, depression, anticonvulsant

These are theoretical effects because we don’t have many drugs that target this receptor

κ receptors (dynorphin)

Opioid Receptor effects

Analgesia, Euphoria

Unfortunately, di naseseperate so potential for addicition

○ Sedation ○ Respiratory depression ○ Vomiting (CTZ)

There are μ receptors in the CTZ

Cough suppression (secretions may accumulate)*

■ While it can suppress cough, nowadays opioids are not recommended for cough suppression because the risks outweigh the small benefit

GI – constipation (RECEPTORS IN THE GUT)

Pruritis (itch) – pruritoceptive central circuits (esp spinal, epidural administration)

defined by presence of withdrawal syndrome:

Dependence

is the (physical) symptom you get when you stop. So, if you stop taking a drug and you get withdrawal effects, then you have a physiologic dependence on the drug.

Withdrawal

is the craving or dissociating behaviors to get the substance

Addiction

Usually, substances that are WHAT can cause WHAT but drugs that have WHAT are not alway WHAT. An example is antidepressants.

addicting, dependence, withdrawal symptoms, addicting

There is a part of the brain, WHAT, that alleviates opioids and mediates opioid withdrawal. The neurotransmitter that causes the withdrawal is WHAT

locus coeruleus, Norepinephrine

Increased pain:

Opioid-induced hyperalgesia

○ Increased sensitivity:

At baseline, it shouldn’t be painful but due to pain sensitivity, it is painful.

allodynia

○ Chronic, neurobiologic, with biopsychosocial etiologies ○ Craving, impaired control over drug use, compulsive use, continued use despite harm ○ Remember the biggest culprits

■■ After lawsuits, other companies stepped in ■ Why was the patient taking opioids in the first place? Because there was way too much economic marketing of oxycodone in the US. ■ Once the lawsuit had been filed oxycodone usage dropped. However, this gave opportunities for pharmaceutical companies. Other opioids took over. That is why there is an opioid crisis in the US

Opioid Addiction

○ There is administration of the drug, reduced efficacy, and increased drug dosing needed to maintain the same efficacy you have before.

Tolerance

– ““tolerance”” due to:

○ Worsening/other medical conditions

○ Drug interactions

○ OIH, adherence concerns, etc

○ Looks like there is reduced efficacy but they just need more pain management due to legitimate reasons.

Pseudotolerance

– behaviors related to anxiety over uncontrolled pain

○ Dose escalations, complaining, etc. ○ Behaviors disappear when pain control improved ○ Looks like they are drug-seeking but in reality they can’t control their pain. They are looking for opioids because they need it, they are not craving it.

Pseudoaddiction

T/F Coughs need morphine and opioids

○ Not all coughs are given opioids/morphine

■ Ex. Persistent coughs due to asthma, allergy, irritation, GERD, TB, or other underlying conditions

■ The most common differentials for coughs that persist are an allergic cough or cough from irritation due to acid reflux

T/F Diarrhea needs opiods/morphine

F ○ Should not be given opioids/morphine. Treatment options are ORS and Loperamide if urgently needed (e.g. nasa labas)

○ FOCUS, Most often use

Analgesia

○ Component of analgesia

Anesthesia

○ Thermoregulation (aggravated by anesthetics)

○ Increase myocardial O2 demand → ischemia

Postoperative shivering

Treatment

Niche use for post-operative shivering

Meperidine (single IV dose)

Pain

○ Severe Pain

○ Consider What

Pain Ladder and Dosage Form

There are different treatment options for pain and we don’t jump to using morphine immediately. It depends on the severity/quality of the pain.

Pain Ladder

Whether you will get the effects immediately or in an extended-release. We use patches for very specific pain/serious pain syndrome.

Dosage Form -

We use patches for

very specific pain/serious pain syndrome.

Why do we limit extended-release dosage forms

because the longer you expose the patient to opioids, the greater their risk of addiction and dependence.

■ Specific pain ● Cancer pain, sickle cell disease, end-of-life care

Dose cannot be safely titrated in acute pain

Extended Release (ER)/patches

● Increased risk of persistent opioid use and respiratory depression with longer use ● If possible, choose WHAT

Immediate Release (IR)

■ preferred in acute pain management ● (i.e. post-operative pain) ■ breakthrough pain ■ If possible, the shortest duration and IR dosage form

Immediate Release (IR)

■ Many of them are metabolized by CYP

■ Codeine –(CYP)→ Morphine → …

■ Oxycodone –(CYP)→ oxymorphone → O3G

■ Methadone (2B6) • Esterases – heroin

CYP (variable)

Excretion – mainly renal

○ For patients with renal impairment, steer clear of some opioids that are renally excreted. ○ Since there is renal impairment, opioids will not be excreted which may result in toxicity caused by high concentrations. ■ May worsen if the opioid is nephrotoxic

● Cancer pain, sickle cell disease, end-of-life care

Extended Release (ER)/patches

○ Persistent moderate-to-severe acute pain – esp. traumatic injuries, post-op

■ No better than NSAIDs for musculoskeletal injuries

Except for patients with WHAT

Ischemic pain in STEMI, BUT: ● Delayed gastric emptying: delayed absorption of Ticagrelor (P2Y12 inhibitor) for STEMI ● ON-TIME 3: similar results

Hold back blood. There is an insufficient amount of blood supply. Less oxygen in the organs leads to pain and eventually organ death

MORPHINE

Except for patients with ongoing bleeding or a high risk of bleeding

T/F Do not reject giving someone morphine just because we are being conservative.

T

Analgesia dependent on CYP2D6

J. CODEINE

These products are linked to other known harms (i.e., breathing problems), and there is limited evidence to support the effectiveness of these products in children and adolescents. There are other products available in Canada to help relieve the symptoms of cough and cold in children.

Therefore, Health Canada, as a precautionary measure, is advising Canadians against the use of these products among children and adolescents under 18 years of age.

J. CODEINE

Can be converted to morphine

■ Binds to the μ receptor but is less active than Morphine

■ Ratio not always known

■ Dependent on CYP2D6 expression of individual

J. CODEINE

CODEINE vs morphine. which is active

Morphine

GAMBLE!!! si codeine

● Because you can never know how much Codeine will stay as is and how much of it will be converted to Morphine.

■ Not worth the risk. It is more advisable to use morphine instead of gambling with codeine.

itself is already active. Its metabolite has activity. The variability won’t be as dramatic

Oxycodone

Oxycodone

■ Moderate to severe acute pain – esp. traumatic injuries, post-op

IR

Oxycodone

Chronic cancer/sickle cell disease/end of life care pain

ER

Misuse-deterrent formulation: agonist-antagonist

○ Comes with Naloxone (opioid receptor antagonist)

○ If taken orally: only oxycodone will take effect as naloxone has poor BA

○ If taken parenteral: Naloxone will act as an antagonist to oxycodone and will have no effect.

■ Theory: people will stop using it

People who used an injected drug crushed the opioid up and injected it directly. Oxycodone comes with naloxone and because of that, you won’t get the opioid effect. The thing with naloxone is that it is not well-absorbed orally, if intravenously it is well-absorbed.

IV SI NALOXONE

ORALLY WALA NA SI NALAXONE

Misuse-deterrent formulation: agonist-antagonist

Actual: people shift to other drugs

● Based on the evidence, when they introduce it, instead of reducing overall opioid use and addiction they resort to other drugs.

● You got them to be addicted to the drug, and tried attempting to correct that through releasing the new formulation, they are still addicted.

○ Opioid Agonist Therapy (OAT) for Opioid Use Disorder

○ Moderate to severe pain; may be more effective in neuropathic, cancer pain

L. METHADONE

● Stigmatized among clinicians when it comes to pharmacologic options. ○ “You are giving a pill for addiction but at the same time the pill is kind of addicting”

‘● When you look at the evidence of pharmacotherapy in treating opioid use disorder, Methadone is a good agent to use due to good outcomes.

● Consider other clinical outcomes other than stopping the use/addiction of opioids.

L. METHADONE

More Life-saving in descending order:

● Methadone - Buprenorphine - Antagonist

Fentanyl misconception

But as a drug, taken in appropriate amounts, you're not going to intentionally expose someone to that much fentanyl. Realistically, misconceptions such as simply touching or inhaling fentanyl would kill you ignores basic concepts of pharmacokinetics

metabolized very rapidly (blood and nonspecific tissue esterases) → short t1/2 (useful in anesthesia)

Remifentanil

May be preferable in renal disease (no active metabolites)

Fentanyl

In the U.S., fentanyl overdoses are often caused by

improper handling.

During the "block-and-divide" process, where fentanyl is split into smaller doses, leftover powder can contaminate surfaces like tables. This contamination can spread to other parts of the illegal drug supply, increasing the risk of accidental exposure.