Pain: Barker Flashcards
What are the classifications of pain?
- Acute and Chronic
What is Acute pain?
- Refers to an injury or post-operative faire
What is Chronic pain?
- Pain that last more than 3 months
- Nociceptive [Somatic; Inflammatory], Neuropathic, Visceral [Inflammatory], Mixed
what is the basic function of pain?
- Bodies warning system [1st warning]
- Aid in repair [Hypersensitivity]
- Can be maladaptive [further damage]
How does pain act as an alarm system?
- Tissue Damage: releases cytokines and chemical mediators that increase vascularization and sensitizes somatosensory
What is Allodynia?
- Spontnaeuos or breakthroug pain
What are some way that we can characterize pain?
- Temporal [WHEN?], Intensity, Location [WHERE?], Quality [HOW DOES IT FEEL?]
What is Referred Pain?
- Pain that is in one area that can lead to other areas of the body
What are some of the ways the chronic pain may appear?
- Inflammatory Pain [Arthritis], Neuropathic Pain [Diabetes], Verceral Pain [Cancer], Breakthrough Pain, Fibromyalgia [Allodynia], Migraine, Phantom [Amputation]
What is the etiology of Chronic pain?
- Tissue Injury leading to the release of Active factors [PG, BK, K]
- Persistent activiation and sensitization of Ay/C
-Activity in ascending pathway [Peripheral sensitization] - Output for the input
- Ongoing pain [Central sensitization]
What are the peripheral receptors and channels that are involved in pain signaling?
- Temperature, Acid, Chemical Irritant Sensitive
What are the Temperature Sensitive receptors for pain?
- Transient receptor Potential Cation Channel
- TRPV = Hot
- TRPM = Cold
What are the Acid Sensitive receptors for pain?
- Acid Sensing Ion channels [ASIC]
- Activated by H+ and Conducts Na+
What are the Chemical irritant receptors for pain?
- Histamine and Bradykinin
What are the three different pain fibers?
- Ab - Fibers
- Ay - Fibers
- C - Fibers
What are the Ab - Fibers?
- Bigger and More Myelinated [Fastest]
- Non-noxious [Touch and Pressure]
What are the Ay - Fibers?
- Less myelinated
- Pain and Cold
- “First Pain” [Sharp and Prickly]
What are the C - Fibers?
- Unmyelinated
- Pain, Temperature, Touch, Pressure
- “Second Pain” [Dull, Aching]
How does Substance P play an important role in heightening pain responses?
- Repeated Stimuli that reduces the firing treshold
- Causes: vasodilation, Degranulation, Histamine Release, Inflammation
- Increase expression of pain
How is a sunburn temporary peripheral pain?
- UV radation damages the skin = Inflammation
- Involves TRPV4 [Temperature Sensitive]
- Allodynia occurs
What is the pathway for spinal pain?
- The release of Substance p and glutamte from the primary neuron to the secondary neuron
What is found within the pain ciruitray of the brain?
- High expression of opioid receptors along the descending pathway [Opioids, GABA, NA, & 5-HT]
- Mu Receptors
What are the two type of alkaloids found witin opioids?
- Phenanthrenes [Morphine] & Benzylisoquinolines
What are Opiates?
- Opioids that are naturally occurring
What are the structure relationships of Phenanthrenes in opioids?
- 3 Position: substitution decreases potency [Codeine]
- 6 Position: Increases activity [Hydromorphone or Hydrocodone from Codeine]
- 14 Position: OH increases potency [Oxycodone]
- N-allyl: Antagonist [Narcan]
What are the Pharmacokinetics or Morphine [Phenanthrenes]?
- Metabolized in the Liver [Hepatic]
- Bioavailability 25%
- 2D6 and 3A4
- Glucuronidation at 3’ and 6’
What are some of the Administration routes for Opioids?
- IV, Intra-axial, IM, Oral, Topical
Which opioids create active metabolites?
- Herion, Codeine, Tramadol = Prodrugs
[Morphine, O-Hydroxy-oxymorphone, Morphine] - Fentanyl and Methadone DO NOT
What does CYP3A4 make within Opioids?
- Makes the “NOR”
What does CYP2D6 make within Opioids?
- Other active metabolites
What are the metabolizers for 2D6?
- PM, IM, EM, UM
- UM: Higher blood concentration; higher SE
- PM: NO therapeutic effect
What are the types fo opioid receptors?
- G Protein [Gi, GRIK], Mu [Morphine], Kappa [Ketocyclazocine], Delta [Defernes], Nociceptin, Sigma [NOT opioid]
What is the signal transduction within the opioids receptors?
- Presynpatic: Inhibition of Ca2+ channel [Gi] decreases the neurotransmitters release
- Postsynaptic: Activation of GIRK channels [Gby] causing an efflux of K+ =>hyperpolarization
What are the endogenous opioids contained within the human genome?
- Pro-opiomelanocortin [POMC]
- Preproenkephalin
- Preprodynorphin
- Nociceptin/Orphanin FQ
What is important to know for the MU opioids receptors?
- Linked to Beta-Endorphins
- Uses: Analgesia [NOT Chronic], Sedation, Antitussive [Suppression of cough]
What are some of the opioid induced side effects?
- ON TARGET EFFECTS
- Respiratory depression, Constipation, Itch [NOT allergic reaction], Addiction, Urinary retention, Nausea & Vomiting, Miosis
What is important to know about the KAPPA opioid receptors?
- Linked to Dynorphins
- Activation is dysphoric [Negative feelings]
- Treatment for addiction [Decreases dopamine]
What is important to know about the DELTA opioid receptor?
- Linked to Enkephalins
- Reduces Anxiety, depression
- Treats Alcoholism
- SEIZURES
What is opioid induced hyperalgesia and how is it different than tolerance?
- Tolerance: INCREASE in dose to get the same effect
- Hyperalgesia: INCREASED sensitivity toward pain; increasing the does makes that pain worsen
What are some of the clinically used opioids for?
- Cough/antitussive & Anti-Diarrheal
What are some of the Cough/Antitussive opioids used?
- Codeine [C-II]
- Dextrometorphan [Limited Opioid activity; opens receptors in the brain stem]
What are some of the Anti-Diarrheal opioids that are used?
- Diphenoxylate with atropine [Lomotil]
- Loperamide [Strong P-glycoprotein; pumps out of brain]
- Eluxadoline [Mu/Kappa Agonist, Delta Antagonist
What opioids are used within the hospital setting?
- ALL ARE C-II
- Agonist: Sufentanil, Remifentanil, Alfentanil [Breakdown by plasma esterases]; Fentanyl, [lollipop], Hydromorphone, Oxymorphone, Morphine, Hydrocodone, oxycodone
What are the Non-Phenanthrene opioids?
- Tramadol, Tapentadol [SNRI like; 5HT & NET inhibitor]
- Meperidine [Toxic Metabolite: Normeperidine]
What opioids are able to block the NMDA receptors?
- Methadone [used for opioids dependence; QTc PROLONGATION, NMDA antagonist]
What are some of the opioids that are used in MOR and KOR?
- Pentazocine [k agoinst, mu antagonism]
- Nalbuphine [Full k agonist, mu antagonist]
- Buprenorphine [Partial mu agonist, weak k agonist & y antagonist]
What are the types of NASIDS?
- Salicylates [Aspirin]
- Arylpropionic Acids [Ibuprofen, Naproxen]
- Arylacetic Acids [Indomethain, Diclfenac…]
- Enlic Acids [Piroxicam, Meloxicam]
What is the therapeutic applications for NSAIDs?
- Analgesic [Chronic Pain, Inflammatory Pain]
- Anti-Inflammatory [Arthritis]
- Antipyretic [Fever]
- Reduce Myocardial Infarction
What contributes to the Inflammatory pain?
- Eicosanoids
What are the Eicosanoids that are recruited in Inflammatory cells?
- Arachidonic Acid Metabolites
- Prostaglandins [Redness, Heat, Pain]
- Thromboxanes
- Leukotrienes [Swelling]
- Cytokines [Pain]
What are the two pathways for Arachidonic Acid?
- COX-1 & COX-2
What happens COX-1 pathway?
- Induces platelet activity - TXA2
- Protects the Stomach lining
What happens COX-2 pathway?
- Induces the anti-platelet activity - PGI2
What is important to know about Aspirin in regards to COX?
- IRREVERSIBLY COX-1/2 Inhibitor
- Low Dose = COX-1 & High Dose = COX-2
What is important to know about Other NSAIDs in regards to COX?
- REVERSIBLE COX-1/2 Inhibitors
- anti-flammatory too
What is Aspirin’s main use?
- Prophylactic for Anti-coagulation
- NO tolerance development to analgesic effects
- DO NOT use in children - Reye’s Syndrome
What are the Pharmacokinetic Properties of Aspirin [Salicylates]?
- Absorption: Rapidly Absorbed
- Distribution: Most tissues and Fluids
- Metabolism & Excretion: Half-life 6-20 hour; increased excretion with increased urinary pH
What are some of the side effects that relate to Aspirin [Salicyism] Posioning?
- Vertigo, Tinnitus, Respiratory Alakalosis [hyperventilating], Metabolic Acidosis [lowering blood pH]
What is the treatment for Aspirin [Salicyism] Poisoning?
- REDUCE salicylate load
- Will cause an increase in urinary excretion
What is important to know about the Enolic Acids NSAIDs?
- Used to treat ARTHRITIS
- Meloxicam at low doses is COX-2
What are some of the adverse effects for NSAIDs?
- Renal function: Decrease PGE2 = Edema
- Inhibition of Platelets = Increase bleeding
- Inhibition of Uterine Motility
What is the therapeutic use of Acetaminophen?
- Highly effective analgesic and antipryretic
- NO GI TOXICITY
- Could lead to Hepatic Necrosis
What are the side effects of Acetaminophen?
- Renal Toxicity > aspirin
- Hepatic Necrosis [High risk with alcohol] because of an increase in toxic acetaminophen metabolites [NAPQI]
What are some of the contraindications for NSAIDs?
- AVOID: chronic kidney disease, poptic uler disease, history of GI Bleeds
- Cardiovascular risks [with CAD]
- Interfere with Bone Healing [high doses]
- Cause Asthma Exacerbations [COX-2 less likely]
What is another way that we are able to get analgesic effects?
- Blocking sodium channels - NaV1.7`
What are some Psychiatric drugs that are also NaV1.7 Blockers?
- Lamotrigine, Cabamazepine, Amitriptyline
What are some SNRIs that are also NaV1.7 Blockers?
- Increase Norepi [acting on a2A-Adrenergic]
- Duloxtine, Venlafaxine, Milnacipran [lacking]
What are the controlled substance drug classifications?
- C-I: NO MEDICAL USE [Marjiuana, THC, LSD…]
- C-II: High Abuse [Cocaine, PCP…]
- C-III: Moderate Abuse [Marinol; THC oil]
- C-IV: Low Abuse [Benzos]
- C-V: Cough Suppressant with small amout of codeine or Lomotil
What are some substances of abuse that act INDIRECTLY on GCPRs?
- Cocaine, Amphetamine [block DAT]
- MDMA/Ecstasy [block DAT & SERT]
- Alcohol
What are some substance of abuse that act on Ion channels?
- Nicotine [Acetylcholine: Agonist]
- PCP, Ketamine [NMDA; Antagonist]
- Benzo [GABAa; allosteric modulators]
What are some of the important ares of the brain that drugs can affect causings abuse?
- Frontal Cortex: Decision Making
- Striatum: Reward
- NUCLEUS ACCUMBENS: Pleasure
- VTA: Dopamine Source
- Hippocampus: Memory Learning
