IP7 Exam 2 - Pain

What is pain?

an unpleasant sensory and emotional experience associated with actual or potential tissue damage

Pain is common and commonly self-treated. (pain is whatever the patient says it is)

What is maladaptive pain?

Pain that is separated from the protective goal (pain that is not related to an injury or long after an injury should have healed)

What is neuropathic pain?

pain due to injured nerves/neurons

What is acute pain?

- typically nociceptive

- identifiable cause

- < 30 days

What is chronic pain?

- pain most days or every day

- > 30 days (or > 3 months per Dr. Miller)

What is high impact chronic pain?

pain that limits your life or work activities most or every day

Who is more likely to experience chronic pain?

- chronic pain affects 1 in 5 in the US (slightly more in women than in men)

- chronic pain accumulates with age (more chronic injuries, accumulated damage, more difficult to heal)

- race results unreliable (higher reported amounts in non-hispanic whites, but likely because these individuals are more likely to be diagnosed)

- more common in rural settings

How do we assess patient pain?

- no specific laboratory test (cannot tell if someone is in pain based on bloodwork)

- subjective pain assessment scales

- psychological eval for comorbid conditions (very important - chronic pain can cause depression, it is very important to treat both)

Characteristics of acute and chronic pain:

dependence and tolerance to medication

Acute pain: unusual

chronic pain: common (physical dependence is expected/known with opioids)

Characteristics of acute and chronic pain:

psychological component

acute pain: usually not present

chronic pain: often a major problem

Characteristics of acute and chronic pain: organic cause

acute pain: common

chronic pain: often unknown or resolved

Characteristics of acute and chronic pain: environmental/family issues

acute pain: small

chronic pain: significant

Characteristics of acute and chronic pain: insomnia

acute pain: unusual

chronic pain: common component

Characteristics of acute and chronic pain: treatment goal

acute pain: pain reduction

chronic pain: functionality

Characteristics of acute and chronic pain: depression

acute pain: uncommon

chronic pain: common

Characteristics of acute and chronic pain: signs (HTN, tachycardia, diaphoresis, mydriasis, pallor)

acute pain: common (but not diagnostic)

chronic pain: rare (no more symptomatic nervous system activation)

Is pain subjective or objective?

Pain is *always* subjective (patient self-report is the most reliable indicator of its existence and intensity, and is key in assessing chronic pain)

What approach is essential in assessing patient pain?

*patient-oriented* approach is essential

- pain is best diagnosed based on patient description and history

- validated scales (same patient over time) to inform treatment decisions

What pain scales can be used to assess patient pain?

- wong baker faces scale

- brief pain inventory (short for clinical trials, long for clinical use)

numeric rating scale (common for frequent use, 0-10, benchmark within 24 hours)

- pain-enjoyment-general activity scale (1-10 x3): pain on average over the last week, pain interference with enjoyment of life, pain interference with general activity

What red flag symptoms should healthcare professionals be aware of and be able to recognize?

- new onset numbness, weakness, vision changes, dizziness or syncope

- sudden severe onset of pain

- persistent pain > 3 days

- pain worsening despite treatment

- chest pain

- shortness of breath

- worsening pain with exertion

- bleeding disorder

- severe pain that diminishes ability to perform activity of daily living

- fever, nausea, vomiting, *unintentional weight loss*, or unexplained signs of systemic disorder

- suspected fracture

- pregnant

How do patients describe nociceptive somatic pain?

- sharp, dull, aching, worse with movement

- well-localized patients can often point directly to the location of pain

What is the mechanism of nociceptive somatic pain?

- response to harmful or potentially harmful stimuli. Signals to the brain through the process of transduction, conduction, transmission, perception, and modulation.

- involves the skin, *bone*, joint, or soft tissue (typically pain that is on the outside of you)

What are the common etiologies of nociceptive somatic pain?

- traumatic pain (cuts, scrapes, strains)

- arthritis pain

- musculoskeletal pain

- hemorrhoids

How do patients describe nociceptive visceral pain?

- diffuse, gnawing, cramping, squeezing, pressure

- difficult for patients to localize the pain

What is the mechanism and anatomy for nociceptive visceral pain?

- occurs in response to harmful or potentially harmful stimuli. Signals to the brain through the transduction, conduction, transmission, perception, and modulation.

- direct stimulation of afferent nerves due to tumor infiltration, distension of hollow viscus, infarct, or damage to soft tissue or viscera (i.e., cardiac, gastrointestinal tract, genitourinary tract, lung)

What are common etiologies for nociceptive visceral pain?

- menstrual cramps

- constipation

- gallstones

- kidney stones

- gastritis

- appendicitis

- cardiac conditions (i.e., ischemia)

What are the 5 steps of nociceptive pain?

1) transduction

2) conduction

3) transmission

4) perception

5) modulation

What happens during pain transduction?

- pressure, stretch, thermal (hot/cold), and/or chemical stimulation of nociceptors

- potentiated by inflammation (pressure stimulation) and low pH (chemical stimulation)

- potentiated by cytokine release (positive feedback loop)

What happens during pain conduction?

Action potential via afferent nerve fibers to spinal cord.

Mediated by voltage-gated sodium channels (NaVs) along the axon.

What happens during pain transmission?

- neurotransmitter release in the spinal cord (voltage-gated Calcium channels)

- afferents synapse in the dorsal horn, then go up to the brain

What is allodynia?

Pain due to a stimulus that does not normally provoke pain (non-harmful touch)

This can be due to nerve damage resulting in sprouting and inappropriate inputs (e.g., touch afferents) to secondary neurons in the dorsal horn.

What is hyperalgesia?

Excessive pain from small noxious stimulus.

Hypersensitivity to pain due to activated microglia in the spinal cord sensitizing afferents (like having a bruise in the spinal cord making something more painful than it should be)

What happens during pain perception?

- pain signal received alongside other sensory information

- relay in the thalamus (requires an additional neurotransmitter release, receipt by neurons headed to somatosensory cortex)

What happens during pain modulation?

Pain is attenuated by the descending pathway. This pathway inhibits/lessens the transmission of pain in the ascending pathway (makes it so you stop feeling pain after the injury is over)

What inhibits the pain modulation pathway?

tonically inhibited by gamma-aminobutyric acid (GABA)

GABA suppresses the pain modulating pathway = pro-pain

What enhances/supports the pain modulating pathway?

- endogenous opioids (e.g., enkephalins and beta-endorphins)

- norepinephrine

- serotonin

Pain is enhanced/facilitated by...

- glutamate

- substance P

- inflammation (chronic disease, obesity)

- positive feedback from inflammatory cells and microglia

Why is it important to treat acute pain?

Poorly treated pain strengthens pain pathways and increases risk for chronic pain.

Physiological pain systems are like muscles, as they are used they are strengthened. If you do not appropriately treat acute pain, you with strengthen the pain pathways and set yourself up for hyperalgesia (managing pain at the time of surgery/injury is important).

What is central pain?

No injury, but dysregulation leading to hypersensitivity (completely unexplained pain)

What can cause neuropathic pain?

Primary lesion or dysfunction of the nervous system.

- PNS: postherpetic neuralgia, diabetic neuropathy, chemotherapy-induced neuropathy

- CNS: damage or abnormal functioning of the CNS, ischemic stroke, multiple sclerosis

Is neuropathic pain adaptive or maladaptive?

maladaptive (it is disengaged from noxious stimuli or healing)

How do patients describe neuropathic pain?

- burning

- tingling

- shooting

- shock-like

May be episodic or continuous.

What is the pathophysiology for chronic pain (5 potential causes - know the bold 2)

Long-term changes - neuroplasticity

- *activated microglia in the CNS* (especially the spinal cord)

- increased nociceptive nerve fiber sensitivity

- hyperexcitability of central neurons

- *NMDA-glutamate receptor activation*

- central disinhibition (failure of the pain modulation pathway)

What are some examples of central pain?

- irritable bowel syndrome (IBS)

- temporomandibular joint disorder (TMJ)

- myofascial pain syndrome

- fibromyalgia

What is the first-line treatment for pain?

Non-pharmacological interventions are first line

(these are more likely to fix the root cause of the pain)

What is the MOA for salicylates (acetylsalycylic acid - Aspirin)?

non-competitive, irreversible COX 1 & 1 inhibitor (acetylation)

What are the potential ADRs/precautions for salicylates?

- bleeding

- Reye's syndrome

- avoid in hepatic/renal impairment

What are the NSAIDs?

- propionic acid (ibuprofen, ketoprofen, naproxen)

- acetic acid (diclofenac)

- pyrrolizine carboxylic acid (ketorolac)

What is the MOA of the NSAIDs?

reversible COX inhibition

What are the ADRs/precautions with NSAIDs?

- GI irritation (take with food)

- avoid/use with caution in renal/hepatic impairment

- CV (thrombotic events)

What is the MOA for pyrazoles (Celecoxib)?

COX-2 inhibitor (selective)

What are the ADRs/precautions for pyrazoles (celecoxib)?

- avoid/use with caution in renal/hepatic impairment

- CV (thrombotic events)

What is the MOA for para-aminophenol (APAP - acetaminophen)?

- *analgesic, but not anti-inflammatory*

- antipyretic

- central PGE production/5-HT signaling?

What are the ADRs/precautions of APAP (acetaminophen)?

hepatotoxicity

What is a partial agonist?

Binds to and activates receptor with lower maximal effect.

Partial agonists can compete/interfere with a full agonist's effect (A partial agonist in the presence of a full agonist at the maximally effective dose will displace the agonist and diminish its effect - like buprenorphine)

What are the primary ADEs of ALL opioids?

- acute respiratory depression (this is what kills in an overdose)

- sedation

- nausea/vomiting

- constipation

- addiction, substance use disorders

How do opioids cause respiratory depression?

opioids block the carbon dioxide warning signals in the body.

Normally, when we don't breathe enough, we build up CO2 in the blood and the body notices that CO2 is high and increases the respiratory rate. With opioids, the receptors are blocked and the body won't increase the respiratory rate and we essentially suffocate.

True or false: dependence to opioids is rare and only happens in certain patient populations

False

Dependence to opioids is *expected* with chronic use. Opioids have a high potential for misuse due to dependence and euphoria.

What drug is used as the standard that all other opioids are compared to?

morphine

What are the 3 major actions of ALL opioid medications at GPCRs?

1) Blockage of calcium channels (so calcium cannot enter the cell, inhibits vesicular release and synaptic transmission)

2) opening of potassium channels (K+ leaks out of the cell, hyperpolarizing the membrane and inhibiting action potentials)

3) inhibiting adenylyl cyclase to decrease cAMP production (decrease PKA activation, decrease protein synthesis)

*the actions are always inhibitory*

What is the clinically relevant MOA of morphine?

mu opioid receptor activation

Effects: analgesia, sedation, euphoria, respiratory depression, constipation, altered hormone and neurotransmitter release

How do opioids act on the ascending pathway of pain conduction?

Activation of mu opioid receptors

- Gby binds & opens post-synaptic potassium (K) channels

- hyperpolarization

works post-synaptically making the next neuron harder to activate, makes spinal cord transmission event less likely

How do opioids act on the descending pathway of pain conduction?

- Gby binds & blocks voltage-gated calcium channels (VGCCs) in periaqueductal gray (pain & fear -> so you don't care as much about the pain)

- disinhibits descending pathway neurons (inhibiting the GABA-ergic neurons to "take the foot off the brake" and life the inhibition of the pain modulatory pathway)

*This is where the TCAs and SNRIs work too*

What MOA of opioids is associated with tolerance and dependence?

Gai/o subunit inhibits adenylyl cyclase (decreases cAMP synthesis, long term changes & neurons adapt). Works on both pre- and post- synaptic neurons.

*This action is short lived*, and with chronic use adenylyl cyclase is indifferent to this inhibition. There is a constitutive increase in AC activity and cAMP (makes it through alternative pathways). Then more drug is required to give an effect causing tolerance.

This is also what makes patients feel worse when the drug is taken away (causing dependence).

How do opioids act to give the feelin of euphoria?

Gby binds & blocks VGCCs in the ventral tegmental area (VTA)

- reduces vesicular release of GABA

- disinhibits dopaminergic neurons -> reward, euphoria

By inhibiting GABA-ergic interneurons, dopamine neurons are disinhibited and can stimulate the reward system in the brain. Over time, the body becomes accustomed to this feeling, and becomes dependent on the drug to feel normal (there is a dysphoric feeling when the drug is taken away).

What effects of morphine do patients experience tolerance with (will fade over time)?

High tolerance:

- analgesia

- euphoria

- sedation

- respiratory depression

- Nausea/vomiting

- antitussive

moderate:

- bradycardia

What opioid effects have minimal tolerance (little to no change with use)?

(the 3 C's)

- miosis (pupillary *c*onstriction)

- *c*onstipation

- *c*onvulsions

Opioids should be used with caution with this drug class due to increased CNS depression

sedative-hypnotics

Opioids should be used with caution with this drug class due to increased sedation and cardiovascular effects

antipsychotics

Opioids should be used with caution with this drug class due to extreme hyperthermia and potential for coma

MAO inhibitors

(this is due to the risk of serotonin syndrome)

Opioids should be used with caution with this drug class because they can precipitate withdrawal

opioid antagonists

Why do we avoid opioid use in pregnancy?

risk for fetal dependence

How is the efficacy of opioids determined?

efficacy is categorized based on how it treats pain, it is NOT based on potency

What cyp enzymes are important for opioid metabolism?

CYP2D6 is necessary for activation of codeine and tramadol. (also hydrocodone, but a lesser concern)

Morphine is inactivated by CYP3A4

What are the CPIC guideline recommendation for codeine use in ultrarapid metabolizers of CYP2D6?

Avoid codeine use in ultrarapid metabolizers of CYP2D6 because of potential for serious toxicity. If opioid use is warranted consider a non-tramadol option.

What are the CPIC guideline recommendation for codeine use in poor metabolizers of CYP2D6?

Avoid codeine use because of possibility of diminished analgesia. If opioid use is warranted, consider a non-tramadol option.

What are the CPIC guideline recommendation for tramadol use in ultrarapid metabolizers of CYP2D6?

Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.

What are the CPIC guideline recommendation for tramadol use in poor metabolizers of CYP2D6?

Avoid tramadol use because of possibility of diminished analgesia. If opioid use is warranted, consider a non-codeine option.

Which opioid can cause tachycardia?

Meperidine

- structurally similar to atropine (mAchR antagonism)

- toxic metabolite (normeperidine) with serotonergic effects (risk of serotonin syndrome)

- tachycardia

(*this is the exception, all other opioids cause bradycardia*)

Which opioids are the highest potency?

Fentanyl and fentanyl-like agonists

(includes sufentanil, remifentanil, alfentanil)

Which opioids are considered "centrally acting"? Why?

Tramadol and Tapentadol

In addition to working on the mu opioid receptor, these agents also have action on *inhibiting 5-HT and NE reuptake* (SNRIs) which are important in increasing levels of serotonin and norepinephrine and activating the descending/modulating pathway. Because of this, they are preferred options for neuropathic pain.

How does tapentadol potency and metabolism compare to tramadol?

- more potent

- majority metabolism by glucuronidation (does not depend on CYP450 enzymes for metabolism)

- indicated for diabetic peripheral neuropathy

What is methadone commonly used for?

substance use disorder

(Used in medication for addiction therapy/MOUD).

Has a much longer half-life, so more steady drug levels and less withdrawals/euphoria.

What CYP enzymes are important for methadone metabolism?

- CYP2C19

- CYP2B6

- CYP3A4

These all form active metabolites.

What is the MOA of loperamide? How does this contribute to its use?

MOA: peripherally-restricted opioid agonist

Only acts in the PNS (so it does not cross the BBB, no pain relief, no euphoria). Uses the constipation ADR of opioids to our advantage, acting in the periphery as an anti-diarrheal (strong constipating effect, available OTC).

What is the MOA of butorphanol? Why is its use limited?

MOA is mixed

- KOR agonist

- MOR partial agonist/can have antagonist effects

Use is limited by dysphoria (because of kappa receptor activation, more so than buprenorphine). This agent can precipitate withdrawal.

What is the route of administration for butorphanol?

nasal spray

What is the MOA for buprenorphine? How does this contribute to its use?

MOA:

- MOR partial agonist

- KOR agonist

Because it is a partial agonist, can displace agonists and limit analgesic activity (ceiling effect). This agent can precipitate withdrawal and is used in addiction recovery (diminished effect without full withdrawal symptoms)

What are the principles of opioid antagonists?

- no effect when administered alone to opioid-naive individuals (this means they are relatively safe to give if unsure of the patients opioid status)

- immediately reverse effects of an agonist (can be used as antidotes)

- precipitate withdrawal in dependent individuals (may be desirable in respiratory depression situations, but less desirable to patients who are not in crisis)

What are the opioid antagonists?

- naloxone (parenteral, nasal)

- naltrexone (oral)

- methylnaltrexone (SQ)

- naloxegol (oral)

What is the clinical use of naloxone?

Reversal of overdose.

This drug has *no oral bioavailability*, but may be added to oral dosage forms of other drugs to prevent misuse (no effect if taken orally, but can precipitate withdrawals if used parenterally like crushed and dissolved in solution for injection or snorted)

What is the clinical use of naltrexone?

Addiction recovery/abstinence

Used in both opioid and alcohol use disorder.

What is the use of methylnaltrexone and naloxegol?

Prevention of opioid-induced constipation

These agents are *peripherally restricted*. Because of the positive charge on methylnaltrexone and the pegylation of naloxegol, they are too large to cross the BBB. These antagonists will block the constipating effects of opioids, but will allow opioids to still have the centrally-acting pain relief effects (these cannot act on mu receptors in the CNS)

What does it mean if a person is opioid naive?

For this class, *has NOT had an opioid prescription before this opioid prescription*

In reality, just means not having received opioids during the previous designated time frame. For Medicare, this means the last 60 days. Can also mean not chronically used prior to this prescription (but may have had a previous Rx for 3 days after surgery or other non-chronic use).

What is the definition of non-naive?

- current use, prior to the prescription written/given today/current appointment

- chronic use

These patients are more complex because they will have some tolerance and will need a different dosing plan.

What is required for a person to be tolerant to opioids?

- use for 1 week or longer

- 60mg morphine equivalent

What targets are specific to neuropathic pain?

- voltage-gated sodium channels (NaV): important for decreasing nerve impulses that are inappropriate due to nerve damage

- voltage-gated calcium channel (VGCC): important for vesicular release

What agents used for neuropathic pain act on voltage-gated sodium channels (NaV)?

- SSRIs

- amitriptyline

- carbamazepine (also potentiates GABA)

- lamotrigine

- oxcarbazepine

- topiramate (also potentiates GABA-A and blocks AMPA-K glutamate receptors)

What agents used for neuropathic pain act on voltage-gated calcium channels?

- opioids (via G-by)

- gabapentin

- pregabalin (alpha-2-delta targeted)

Which antidepressants can be used for neuropathic pain?

- desipramine

- nortriptyline

- duloxetine