1 & 2 - Pain & Pain Management Flashcards
Can pain be perceived differently across ethnic origins and gender?
Yes
What is the relationship between pain sensitivity and COMT activity? What does this mean?
- Low pain sensitivity has higher levels of COMT activity
- Therefore, COMT activity has inverse relationship to pain sensitivity
- This means there is a genetic difference in how people perceive pain
How can pain be classified?
- Based on duration
1) Acute - mild to severe; most intense at time of injury; generally decreases upon healing or removal of source
2) Chronic - lasting more than 6 months; persists when initial cause removed or medically resolved; may not have underlying cause; very difficult to treat
Which types of pain are generally acute?
- Nociceptive (somatic or visceral)
- Post-op or post-traumatic pain
- Burn
- Childbirth
- Acute headache
What can chronic pain be classified into?
1) Malignant - cancer, HIV/AIDS, MS, organ failure
2) Non-malignant - lower back pain, chronic degenerative arthritis, OA, RA, migraine
What are the 3 main types of pain, classified by source?
1) Physiological
2) Neuropathic
3) Inflammatory
What is physiological pain?
- Cutaneous, somatic, and visceral
- Cutaneous = skin and surface tissue
- Somatic = ligaments, tendons, bones, blood vessels; often described as dull or aching; generally able to point directly to pain location
- Visceral = body organs, internal cavities; described as throbbing or gnawing/aching pain; difficult to locate; may be distant from source
What is nociceptive pain?
- Directly caused by the stimulation of pain nerve endings to tissue injury or disease infiltration
- Pain resulting as a consequence of peripheral nerve damage
- Can result from limb amputation, spinal surgery, viral infections (shingles), or worsening disease states (diabetes, AIDS, MS)
What are the first line treatments for neuropathic pain (based on table 4 of reference)?
- Tricyclic antidepressants
- Calcium channel alpha2-beta ligands (gabapentin and pregabalin)
- SSNRIs (duloxetine and venlafaxine), only based on NeuPSIG guidelines
What is inflammatory pain?
- Originates from infection or inflammation as a result of initial tissue or organ damage (NSAIDs)
- Can be further defined as pain arising from tissue damage and infiltration of immune cells
What category of pain does cancer fall under?
Sometimes classified separately, b/c can have both nociceptive and neuropathic components, palliative and breakthrough pain
Describe the WHO guideline for pain management
1) Pain persisting or increasing – non opioid +/- adjuvant
2) Pain persisting or increasing – opioid for mild to moderate pain +/- non opioid and +/- adjuvant
3) Freedom from cancer pain – opioid for moderate to severe pain +/- non opioid and +/- adjuvant
What are the classes of drugs used in pain management?
- Acetaminophen
- NSAIDs and coxibs (selective COX inhibitors)
- Opioids
- Opioid substitution therapy (methadone, buprenorphine)
- Tramadol and tapentadol (open-chain opioids)
- Antidepressants
- Anti-epileptics
- 5-HT1 agonists (triptans, headache, migraines)
- Local anesthetics (topical = lidocaine)
- Capsaicin
What is one of the oldest recorded medications?
Juice or latex from unripe seed pods of the poppy Papaver Somniferum
When was morphine first introduced?
- Early 1800’s
- The first total synthesis of the alkaloid morphine was performed in 1952
What is diacetylmorphine? When was it first marketed and as what?
- Heroin
- Marketed in 1898 as the first non-addictive analgesic, anti-diarrheal, and anti-tussive agent
What is an opioid?
All agonists and antagonists, either natural or synthetic
What is an opiate?
Drugs derived from opium, poppy plants
What is an opioid receptor?
Group of G-protein-coupled receptors w/ opioid ligands
What is a narcotic?
All drugs of abuse, not just opioids
What are side effects of opioid analgesics?
- Addictive “narcotic effects”
- Euphoria
- Excessive sedation
- Respiratory depression
- Withdrawal sx
What are the 3 families of endogenous opioid peptides?
- Enkephalin
- Endorphin
- Dynorphin
What is the principle effect of opioids?
Inhibition of adenylate cyclase which decreases cAMP production and simultaneously lowers overall perception of pain
Do opioids bind directly to adenylate cyclase?
No, bind to a GPCR which downregulates adenylate cyclase
What is the hypothesis for the cause of tolerance?
Receptors uncouple from G-protein, causing a need for higher doses b/c opioid can’t have an effect on adenylate cyclase
What is the hypothesis for the cause of addiction?
Chronic decrease in cAMP triggers compensatory increase in adenylate cyclase synthesis (enzyme induction) => increased cAMP concentration in brain
Is the mechanism of opiate addiction the same as other drugs?
No
What is the hypothesis for the cause of withdrawal?
Previously inhibited adenylate cyclase produces a flood of cAMP, leading to loss of appetite, muscle spasms, tremors, and even death
What is the biochemical effect of opioid peptides?
Function as NTs/modulators and co-exist w/ other NTs, making it difficult to elucidate biological function
What is proenkephalin A a precursor for?
Met- and Leu-enkephalin
What is proenkephalin B (prodynorphin) a precursor for?
Dynorphin and alpha-neoendorphin
What is proopiomelanocortin (POMC) a percursor for?
Beta-endorphin
What is pronociceptin a precursor for?
Nociceptin (orphan opioid receptor)
What is the amino acid sequence of Met-enkephalin?
Tyr-Gly-Gly-Phe-Met
What is the amino acid sequence of Leu-enkephalin?
Tyr-Gly-Gly-Phe-Leu
What is the amino acid sequence of dynorphin (dyn 1-13)?
Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys
What is the amino acid sequence of beta-endorphin?
Tyr-Gly-Gly-Phe-Met-Thr-Ser-24 amino acids
What are the 3 major types of opioid receptors?
Mu, kappa, and delta
What is the definition of an opioid?
A substance which produces biological effects through interaction w/ opioid receptor subtypes, and whose actions are reversed by naloxone
What are some selective agonists for the Mu opioid receptor?
- Morphine
- Sufentanil
- Meptazinol
- Etonitazene
What are some selective antagonists for the Mu opioid receptor?
- Naloxone
- Naltrexone
- Cyprodime
- Naloxonazine
What are properties of Mu opioid receptor agonists?
- Analgesia
- Euphoria
- Increase GI transit time
- Immune suppression
- Respiratory depression
- Tolerance
- Physical dependence
What allows enkephalins to form cyclic structures? What does this cause?
- Intramolecular H bonds
- Cause beta bends (180 degree turn)
For opioid analgesics, the tyrosine residue is analogous to _____
Tyramine residue
What is the difference between tyrosine and tyramine?
Tyramine is tyrosine attached to NH3+
What are the requirements for the T-binding region and 2-hydrophobic regions of opioid analgesics?
- T-binding region must have a group capable of forming H bonds
- 2-hydrophobic regions must be equidistant apart (Gly-Gly)
- Also must have ionic binding region
Which type of enkephalins need to fit into all 3 sites? Which do not?
Naturally occurring enkephalins will fit into all 3 sites, but synthetically derived ones don’t need to
What affect does the addition of a halogen have on an opioid peptide? Which halogen has the greatest effect?
- Increases potency
- Increases selectivity if added to phenyl group in 6 position
- Bromine has greatest effect; fluorine has smallest
What are the 3 distinct regions of a 31-amino acid residue of a beta-endorphin?
1) N-terminus has a Met-enkephalin unit
2) Hydrophobic region in middle (Pro13 to Phe18)
3) C-terminal amphiphilic alpha-helix (AA 14-31)
What does amphiphilic mean?
Compound possesses hydrophilic and lipophilic properties
How many chiral centers does morphine have? How many optical isomers?
- 5 chiral centers
- 16 optical isomers
Does morphine have good oral bioavailability?
No, extensive first pass metabolism (primarily glucuronidation at 3-OH position in liver)
What percent of an oral dose of codeine is metabolized to morphine?
10%
What happens if a px w/ no CYP2D6 is given codeine?
Will not metabolize it to morphine, so will not experience analgesia
How is codeine metabolized to morphine?
O-demethylation by CYP2D6
What metabolism does morphine undergo?
- N-demethylation to normorphine, which has decreased activity
- 6-glucuronidation to active metabolite
- 3-glucuronidation to inactive metabolite
- Oxidation to high analgesic activity
What is the difference btwn meperidine and morphine?
Meperidine has rapid onset, short duration, less constipation, and less cough than morphine
What is the duration of fentanyl?
1-2 hours (short)
Does fentanyl or sufentanil have a faster onset and a longer duration?
- Sufentanil has faster onset
- Fentanyl has longer duration
What is important to note about remifentanil?
IV onset = 1-3 minutes and offset = 3-5 minutes (rapid hydrolysis)
What effects does embutramide have?
- Strong sedative
- Produces respiratory depression
- Produces ventricular arrhythmia
What does a binding assay measure?
- Binding affinity for certain receptors
- Measures how good your compound is at displacing another ligand, which measures its affinity for that particular receptor
What does an inhibition assay measure?
How well your molecule inhibits a certain process from occurring
When comparing IC50 of different compound, which compound will be the most potent?
The one w/ the lowest IC50
When comparing binding ratio for different receptors (ex: mu receptor/delta receptor), which compound will be more selective for the mu receptor?
The one w/ the highest ratio
Which halogens produce better potency and why?
Fluorine and chlorine because more electronegative
Which halogen is more selective and why?
Iodine b/c larger size
