Pharmacology of the Central Nervous System: Drugs for the Control of Pain

what is pain?

- "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage"

- subjective, personal experience influenced by biological, psychological, and social factors

- a learned concept --> through life experience

function of pain

adaptive - alerts us to danger

may also have adverse effects on function and well-being (moreso in cases of chronic pain)

pain assessment in adults and youth

- numeric rating scale

- used for ppl 8 years of age and up

- pt has to be able to articulate their experience of the pain they are in

mild pain according to the numeric scale

0-4

moderate pain according to the numeric scale

4-6

severe pain according to the numeric scale

7-10

FLACC scale for pain

- face

- legs

- activity

- cry

- consolability

- used for very little kids to gauge their pain

- family/caregivers are the best resource to tell you about what is normal and not for their kid

for pts who cannot verbally communicate, how can we assess pain?

- behavioural cues

FACES scale

- usually used for kids 4-18

- presents faces ranking the severity of pain

- they amended the FACES scale because it had crying faces on it before... kids didn't want to choose those faces because they weren't crying or because they didn't want to seem like a little whiny baby

- meant to measure how bad things hurt, not whether kid is happy or sad so make sure to use words "hurt" and "pain"

acute pain

- intense pain that occurs over a defines period of time (from injury to recovery/repair)

- burn, surgical pain

- linear trajectory of healing

- we understand acute pain because it comes, happens, and goes

- abrupt onset, brief duration, declines in severity as healing begins or pain stimulus is removed

- may need to be managed differently day to day

chronic pain

- pain lasting longer than 6 months, interferes with daily life, high incidence of depression

- not the same as acute, end of life pain, and is not a diagnosis

- further divided into malignant and non-malignant pain (cancer and non cancer chronic pain)

- no set timeline, which is frustrating and discouraging for people

are acute and chronic pain treated the same way?

- no they aren't

- chronic pain may not respond to the same things that normally Tx a pt's pain effectively

nociceptors

sensory nerve receptors that initiate pain transmission when stimulated

nociceptor pain

- most pain

- associated with tissue injury: somatic or visceral

- responds well to analgesics

somatic pain

- sharp, localized pain

visceral pain

- generalized dull, aching/throbbing pain

neuropathic pain

- associated with injury or irritation to nerve tissue; burning, shooting or numbing pain; cause can be difficult to detemine

- responds poorly to traditional analgesics

mediators that bind to nociceptors

- bradykinin

- prostaglandins

- histamine

- these mediators indicate damage

acute pain - injury to experience

- transduction (trauma. Mediators bind nociceptors)

- transmission (afferent neural transmission)

- transmission (spinal cord receptors in substantia gelatinosa)

- reflex sympathetic response to the painful stimulus

- pain perception and modulation (transmission to the brain through the spino-thalamic tract)

pain transduction

release of tissue humoral mediators

- cells release K+, bradykinins, histamine, and cytokines

- Phospholipase A2 activates arachidonic acid pathway

- cyclooxygenases produce prostaglandins that induce inflammation and stimulate nociceptors

pain transmission

afferent neural transmission

afferent impulse transmitted along A delta and C pain fibers synapse at the substantia gelatinosa of the dorsal horn of the spinal cord

pain transmission

spinal cord receptors (substantia gelatinosa)

- substantia gelatinosa is stimmed by substance P released by afferent neurons

- transmits signal via spino-thalamic tracts to cerebral cortex (you become aware of the pain)

Reflex Sympathetic response to the pain stimulus

- reflex arc leads to sympathetic efferent activity to injured area

- blood flow reduced, muscle hypertonicity occurs (stiffness and swelling)

Pain perception and modulation

transmission to the brain (spino-thalamic tract)

- pain is perceived

- descending pathways release endogenous opioids, GABA, 5-HT, and NE, inhibiting the release of substance P from the afferent neurons in the substantia gelatinosa

5 stages of pain transmission

1. transduction

2. transmission in peripheral nerves

3. transmission in spinal tracts

4. perception

5. modulation

multi-modal analgesic therapy

- drug regimens that involve multiple drug classes or multiple routes of administration offering better pain management than single drug therapy

tylenol 3

- acetaminophen, codeine, caffeine

vicodin

hydrocodone and acetaminophen

Acetaminophen

- MOA not completely understood

- activity at CB1 and TRPV1 receptors in the brain

- no direct anti-inflammatory effects

NSAIDs

- given to relieve mild-moderate pain, inflammation, and fever

- inhibits the inflammatory response to tissue injury

- inhibits the activity of cyclooxygenase; enzyme converts arachidonic acid into inflammatory/pain inducing prostaglandins

non-selective NSAIDs

- ASA

- Ibuprofen

- inhibit both COX 1 and COX 2 to stop the conversion of Arachidonic acid into prostaglandins, inhibiting pain at the nociceptor level

- "blood thinner" bc block platelet aggregation

what is arachidonic acid made of?

arachidonal esters converted into arachidonic acid by phospholipase A2

selective COX-2 inhibitor

- celecoxib

- just for pain

why should all analgesic regimens include a non-opioid drug?

because non-opioids can reduce requirement of opioids by ~30%

endogenous opioids

- beta-endorphins, enkephalins, and more

- modulate transmission of pain to the brain and spinal cord

- they tell your pain receptors to shut up

- descending inhibitory activity

(endogenous) opioid receptor activation at the postsynaptic neuron:

- open K+ channels, causing membrane hyperpolarization, inhibiting neuronal activity

(endogenous) opioid receptor activation at the presynaptic neuron:

- closes Ca2+ channels, inhibiting release of excitatory neurotransmitters; Ach, Substance P, and glutamate

how do opioid drugs exert their effects?

- stimulation of mu and kappa opioid receptors in the brain and spinal cord

mu opioid receptor effects:

- analgesia

- decreased GI motility

- respiratory depression

- sedation

- physical dependence

- euphoria

kappa opioid receptor effects:

- analgesia

- decreased GI motility

- sedation

- miosis

when do we use opioid analgesics?

- treatment of moderate to severe visceral pain

- severe diarrhea, antitussive therapy, sedation

example of a pure opioid antagonist

naloxone

examples of mixed opioid agonists

burprenorphine (blocks kappa)

pentazocine (blocks mu)

example of a pure opioid agonist

morphine, codeine

Canadian Guidelines for Opioids for Chronic Non-Cancer Pain

- optimization of non-opioid drug therapy and nonpharmacological therapy before trying opioids

- stabilizing any psychiatric disorder(s) before considering opioids

- do not use opioids in clients with an active substance use disorder (not recommended due to increased risk of dependence)

how do we discontinue the use of opioid medications?

slowly! we have to wean people off of these drugs to mitigate the risk of experiencing withdrawals

adverse effects of opioid drugs

- constipation

- N/V

- itching like you wouldn't believe

- sedation

- respiratory depression

- delirium

pharmacokinetics of opioids

- metabolized by the liver, excreted in the urine; pharmacokinetics change with age and dysfunction

- active metabolites (ex: phase 1 metab: codeine --> morphine)

Tx for opioid overdose

naloxone --> binds to every single opioid receptor in the body, reverses the OD

opioid withdrawals

- unpleasant, but not life threatening

- last about 7 days in cases of abrupt stopping of opioid therapy

symptoms of opioid withdrawals

- runny nose

- lacrimation

- chills

- muscle aches

- cramping

- vomiting

- diarrhea

- anxiety

buprenorphine/naloxone

suboxone

- given together in a tab

- can't crush this it has to be taken PO whole

- if crushed, the naloxone will work, not the buprenorphine

- for dependence, slowly taper off the buprenorphine, naloxone given to help them not abuse the buprenorphine

what is an adjuvant in pain management?

something that improves analgesia effects

local anesthetics as adjuvants to pain management

block afferent nerve transmission of pain (like nerve blocks)

GABA receptor agonists as adjuvants to pain management

endogenous pain suppression pathways release GABA; benzodiazepines act on GABA receptors and increase the effect of GABA at its receptor

corticosteroids as adjuvants to pain management

bone pain and nerve compression; dexamethasone, prednisone

Cannabis as an adjuvant to pain management

may be helpful in chronic pain management

serotonin agonists as adjuvants to pain management

- endogenous pain suppression pathway releases serotonin

- few pure serotonin agents have a robust analgesic effect; SSRI anti-depressant drugs have little nociceptive effect

- mixed agents such as tricyclic antidepressants augment analgesia and improve neuropathic pain

- SSRIs do nothing for neuropathic pain

- triptans bind to 5-HT1b and 5-HT1d receptors; effective in the tx of migraines, vasoconstrictive effect on intracranial vessels, inhibits release of substance p

mixed agents (antidepressants/serotonin agonists) as adjuvants to pain management

- mixed agents such as tricyclic antidepressants augment analgesia and improve neuropathic pain

- SSRIs do nothing for neuropathic pain

triptans as adjuvants to pain management

- triptans (serotonin agonist) bind to 5-HT1b and 5-HT1d receptors; effective in the tx of migraines, vasoconstrictive effect on intracranial vessels, inhibits release of substance p

anticonvulsant and antiepileptic drugs as adjuvants to pain management

- phenytoin, gabapentin, pregabalin

- neuropathic pain

nonpharmacological methods as adjuvants to pain management

- acupuncture, acupressure

- PT and OT

- massage

- heat or cold