Pharmacology of Analgesia

Pain

• response to an intense or noxious stimulus

• end perceptual consequence of the neural processing of particular sensory info

Physiologic pain

“ouch”

early warning and for protection

Neuropathic pain

• caused by diabetes, amputation

• due to nerve damage (primary afferent neuron)

• Na_v1.3 up-regulated

  • Na+ up-regulated

  • higher depolarization → more action potentials

• treated by carbamazepine and oxcarbazepine (trigeminal neuralgia)

  • GABAnergic or glycinergic inhibitor

• excitotoxicity from loss of inhibitory neurons; contributes to heighten pain sensitivity

Inflammatory pain

includes rheumatoid arthritis

Pathologic pain

due to irreversible alterations in structures and functions in nervous system

ex. dysfunctional pain:tension-type headache, fibramyalgia, IBS

Pain treatment should

target specific mechanism rather than just suppresses the symptoms

MOA of pain drugs

• interference with the response of primary sensory neurons to somatic or visceral sensory stimuli

• inhibition of the relaying of pain information to the brain

• blockade of the perceptual response to a painful stimulus

Nocioreceptor

• pain receptor

• responds to noxious stimuli

TRPV1

• detects noxious heat

• thermosensitive nonselective cation channel

• active in response to:

  • low extracellular ph

  • vanilloid chemical ligands (capsaicin: chili pepper)

  • heat over 42C

TRPM8

detects cold

also activated by menthol

TRPA1

detects intense cold

also activated by allyl isothiocyanate (mustard and wasabi)

Mechanonociceptors

excited by relatively intense mechanical stimuli (pinch, pinprick)

Chemical activators

chemical agents that directly excite peripheral terminals

Sensitizing agents

chemical agents that increase the sensitivity of the peripheral terminals

Other nocireceptor stimuli

• low pH

• ATP

• Kinin peptides

Major inhibitory neurotransmitters

• opioid peptides

  • B-endorphin

  • enkephalins

  • dynorphins

• NE

• 5-HT

• GABA

Opoid receptor classes

1. mu

   1. mediate morphine-induced analgesia

2. delta

3. kappa

   all GCPR

Are the endogenous opioid peptides receptor selective?

Yes

dynorphins → K receptors

enkephalins and B-endorphin → mu and delta receptors

Allodynia

normally innocuous stimuli perceived as painful

Hyperalgesia

high-intensity stimuli perceived as more painful and longer lasting than usual at the site of injury

What can cause Allodynia and Hyperalgesia?

peripherally released sensitizing agents activate signal transduction that can increase sensitivity of the peripheral nerve terminal

Central Sensitization

• hyperalgesia and allodynia usually extend beyond primary area of inflammation/damage

• usually slowly subsides, but chronic injury cna produce persisting state of central sensitization

What can prevent induction and maintenance of central sensitization?

NMDA blockade

Migraine

• disorder consisting of headache attacks that last for up to 3 days, typically associated with light and sound avoidance and nausea

• considered acute manifestation of abnormal intermittent peripheral and central excitability

Familial hemiplegic migraine

• rare autosomal dominant disorder that consists of migrane

Centrally acting agents

• opioid receptor agonists

• opioid antagonists

• neuropathic analgesics

• antimigraine drugs

Peripherally acting agents

• NSAIDs

• Acetaminophen

• Monoclonal Antobodies for Rheumatoid Arthritis

• Drugs for treatment of gout

• local anesthetics

Opioid Receptor Agonists

• mediate analgesia by decreasing presynaptive Ca2+, increasing postsynaptic K+ conductance, and decreasing postsynaptic response to excitatory neurotransmission

• at spinal or supraspinal sites

• act on mu-opiod receptors

mu receptors are responsive to

enkephalins and B-endorphins

delta receptors are responsive to

enkephalins and b-endorphins

Kappa receptors are responsive to

dynorphins

Essential structural feature of all opioids

• basic amine

• forms electrostatic bond with Asp residue in all GPCRs

Common Adverse Effects of Opioids

• hypotension

• sedation

• dysphoria and euphoria

• development of tolerance and physical dependence

• addiction leading to drug abuse

• respiratory effects are major, dose-limiting adverse effect

Difference between morphine and codeine

codeine has a ether instead of a hydroyl (added methyl group)

Most widely used opioids for pain control

• morphine

• codeine (methylmorphine)

• semisynthetic derivatives

More potent analogues of codeine (Semi-synthetics)

oxycodone and hydrocodone

Oxycodome metabolism

• by CYP450

• to highly potent opioid oxymorphone and less potent metabolite noroxycodone

Hydrocodone metablism

• CYP

Synthetic Agnonists

• Meperidine

• Methadone

• Fentanyl

• Sufentanil

Partial and Mixed Agonist Agents

• Buprenorphine (partial mu-agonist)

• Nalbuphine (kappa-agonist with mu-antagonist activity)

Opioid receptor antagonist

• Naloxone and Naltrexone

• used to reverse life-threatening adverse effects of opioid admin, specifically respiratory depression

• antagonists to all opioid receptors

• reverse effects of agonists, will precipitate symptoms of opiate withdrawal

• used to reverse coma and respiratory depression of opioid overdose (within 30 seconds of iv)

NMDA receptor antagonists

ketamine and dextromethorphan

Adrenergic agonists

clonidine

NSAIDs inhibit

• COX-1 and COX-2

  • actual target is COX-2, but COX-1 also blocked

  • COX-1 blocking → GI upset

• do NOT involve mu-opioid receptor

• inhibit prostaglandin production by COX enzymes

  • decrease inflammatory hyperalgesia and allodynia

• decrease recruitment of leukocytes and production of leukocyte-derived inflammatory mediators

• NSAIDs that cross BBB prevent generation of prostaglandins that act as pain producing neuromodulators in the spinal cord dorsal horn

Acetaminophen target

• does not involve mu receptor

• targets CNS but not PNS

  • reduces central prostaglandin synthesis

  • uncertain mech, probably COX-2

• analgesic and antipyresis but little anti-inflammatory efficacy

  • reduce pain, reduce fever, NOT inflammation

• low TI

• frequently combined with weak opioids for treatment of moderate pain

NSAID-opioid and acetaminophen-opioid combos can

act synergistically to reduce pain