• Pharmacological control of pain:
o Analgesic drugs:
Paracetamol:
- Uncertain mechanism.
- Inhibition prostaglandin synthesis within the CNS.
- Oral administration: 60% bioavailability of paracetamol.
- Usual therapeutic dose for adults 1 g.
- Hepatotoxicity more common with exceeded doses.
- Not potent when taken in combination with NSAID, Opioid.
- It is metabolized and in activated in the liver (phase ll conjugation).
- Small proportion metabolized into reactive form NAPQI by cytochrome P.
- NAPQI is deactivated by conjugation with glutathione in liver.
- Stores of glucuronic acid and glutathione can become depleted.
NSAID:
- Exert analgesic and anti-inflammatory effects.
- Inhibit COX-1 & COX-2, responsible for prostaglandin synthesis.
- Both effects make them useful for the treatment of continuous or regular
pain associated with inflammation.
- Analgesic effect seen within a week, anti-inflammatory within 3 weeks.
- Lowest dose of NSAID COX-2 prescribed for the shortest time necessary.
- Concomitant aspirin & anti-platelet drugs increase risk of GIT absit and
decrease the safety of COX-2 inhibitors.
- GRAB mnemonic
Non-opioid analgesic: Nefopam
- Chemically related to orphenadrine and diphenhydramine.
- Not opioid, anti-inflammatory, or antihistamine.
- Unclear mechanism of action
- Not associated with dependence & respiratory depression.
- High numbers of high dose-related side effect and anti-muscarinic actions.
- Useful for asthmatic patients and who cannot tolerate NSAIDs.
- Costly drug
Opioids:
- All opioids act by binding to specific opioid receptors ( µ, κ, δ)
- Mimic the action of endogenous peptides endorphins, enkephalins,
dynorphins.
- Analgesic prosperities are primary mediated by the µ receptors.
- Primary use is to relief intense pain.
natural Semisynthetic Synthetic
Morphine Hydromorphone Fentanyl
Codeine Hydrocodone Meperidine
Oxycodone Methadone
Oxymorphone Tapentadol
Tramadol
▪ Mild to moderate pain:
- Weak opioids either alone or in combination with analgesic drugs.
- Three major drugs: codeine, dihydrocodeine, dextropropoxyphene
1) Codeine:
- Similar to morphine
- 10% of dose is demethylated to morphine.
- Duration 3 hours.
- Powerful antitussive activity as well, being constipating.
- Has been replaced by dextromethorphan, low analgesic action and low
potential for abuse.
2) Dihydrocodeine:
- Available in few countries.
- Chemically similar to codeine.
▪ Severe pain:
- Major analgesic drug: morphine.
- Strong µ receptor agonist.
Morphine:
1) Mechanism of action:
- Interact with opioid receptors on the membrane of CNS,GIT, and urinary
bladder cells.
- Also act at Kappa R, in lamina l & ll of dorsal horn of spinal cord; decrease
release of substance P; modulate pain perception in the spinal cord.
- Inhibit release of many excitatory neurotransmitters carrying nociceptive
stimuli.
2) Action:
a) Analgesia:
- Relief pain without loss of consciousness
- By raising pain threshold at spinal cord level, by altering pain perception.
b) Euphoria:
- Caused by dis-inhibition of dopamine-containing neurons in the brain.
c) Respiration:
- Causes respiratory depression
- By reduction in the sensitivity of respiratory center neurons to CO2.
d) Depression of cough reflex:
- Both morphine and codeine have anti-tussive properties.
e) Miosis:
- Pinpoint; characteristic of morphine use.
- Result from stimulation of mu & kappa receptors.
f) GI tract:
- Constipation
g) Emesis:
- Directly stimulate receptors trigger CTZ causing vomiting.
h) Cardiovascular:
- With large doses
- Hypotension, bradycardia.
i) Histamine release:
- From mast cell
- Causing urticaria, sweating, and vasodilation.
- Bronchoconstriction; contraindicated with asthmatic patients.
j) Hormonal action:
- Increase growth hormone release.
- Enhance prolactin secretion.
- Increase ADH; leads to urinary retention.
k) Labor:
- Prolong the second stage of labor.
- Transiently decreasing the strength, duration, frequency of uterine
contraction.
3) Pharmacokinetics:
a) Administration:
- IM, SC, IV, depend on what u need (rapid action – longer duration)
- Slow absorption from GIT after oral dose
b) Distribution:
- Contraindicated in labor and pregnancy as analgesic.
- Least lipophilic opioid, cuz the ability to cross BBB.
c) Fate:
- Conjugated with glucuronic acid in the liver.
- Excreted primarily in urine, small quantities in bile.
- Duration; 5-6 hours when administered systemically.
▪ Oxycodone & oxymorphone: semisynthetic
1) Oxycodone:
- Derivative of morphine.
- Orally active.
- Sometime formulated with aspirin and acetaminophen.
- Oral analgesic effect twice than morphine.
2) Oxymorphone:
- Opioid analgesic.
- Parenterally ten times potent than morphine.
- Oral formulation has a lower potency; three times potent than oral
morphine.
▪ 3-hydromorphone & hydrocodone:
- Semisynthetic analogs of morphine and codeine.
- Both orally active.
- Oral hydromorphone: 8-10 times potent than morphine.
- Hydrocodone: methyl ether of hydromorphone; weaker analgesic than
hydromorphone.
- Hydrocodone: often combined with acetaminophen or ibuprofen to treat
moderate to severe pain, also as anti-tussive.
▪ Fentanyl:
- Synthetic opioid chemically related to meperidine.
- 100-fold the analgesic potency of morphine.
- Used for anesthesia.
- Highly lipophilic.
- Rapid onset and short duration. (15 to 30 min)
- Administered: IV, epidurally, intrathecally.
- Combined with local anesthetics to provide epidural analgesia for labor and
postoperative pain.
- IV fentanyl: used in anesthesia; for its analgesic & sedative effects.
- Oral transmucosal preparation & transdermal patch available.
- Oral transmucosal used for treatment of cancer. (who are tolerant)
- Metabolized to inactive metabolites by CYP450 and eliminated through
urine.
▪ Sufentanil, alfentanil, remifentanil:
- Synthetic opioid agonist related to fentanyl.
- Sufentanil: more potent than fentanyl.
- Other two are less potent and shorter acting.
- The three agents mainly used for their analgesic and sedative properties
during surgical procedures requiring anesthesia.
▪ Methadone:
- Synthetic, orally effective opioid equianalgesic potency to morphine.
- Mu receptors, cause less euphoria & longer duration of action.
- Used to control withdrawal of dependent abuse from opioids and heroin.
- Withdrawal syndrome is milder but more protracted than other opioids.
Pharmacokinetics:
- Absorbed in oral dose and excreted in feces.
- Very lipophilic.
- Half-life from 12 to 40 hours.
- Actual duration 4 to 8.
- Produce physical dependence like that in morphine.
▪ Meperidine:
- Lower-potency synthetic opioids, unrelated to morphine.
- Used for acute pain.
- Act primarily as a kappa agonist, some mu agonist activity.
- Very lipophilic.
- Has anticholinergic effects, resulting in delirium.
▪ Partial & mixed agonist/antagonist:
- PA: bind to opioid receptors but have less intrinsic activity than full agonist.
- M: stimulate one receptor and block another.
- Effects of these drugs depends on previous exposure to opioids.
- Naïve patients: mixed A/A shows agonist activity; used to relief pain.
- Opioid dependent patients: mixed A/A show primary blocking effect.
1) Partial opioids agonist: Buprenorphine
- Act on mu receptors.
- Has long duration due to the tight binding to the receptor.
- Naïve patient: act like morphine.
- Users of morphine & full opioid agonist: precipitate withdrawal
- The major use is in opioid detoxification; cuz shorter and less severe
withdrawal symptoms compare to methadone.
- Causes little sedation, respiratory depression, hypotension in high doses.
- Administered: sublingually, parenterally, transdermally.
- Tablets indicated for opioid dependence and available in a combination.
(buprenorphine and naloxone)
- Naloxone was added to prevent the abuse of buprenorphine via IV.
- Moderate -severe pain: parenteral & once weekly transdermal patch.
- Metabolized by liver & excreted by bile and urine.
- AE: respiratory depression cannot easily be reserved by naloxone.
2) Mixed opioid agonist/antagonist: pentazocine, nalbuphine, butorphanol
a) Pentazocine:
- Agonist at kappa, antagonist at delta & mu.
- Promote analgesia: by activating receptors in the spinal cord.
- used to relief moderate pain.
- Less euphoria compared to morphine.
- In higher doses, it causes respiratory depression and adrenergic effects.
- Does not antagonize the RD of MRF abusers, but precipitate a withdrawal
syndrome.
- Repeated use: tolerance and dependence.
-
# nalbuphine & butorphanol: like pentazocine, play limited role in chronic pain.
b) Butorphanol:
- Available in nasal formulation.
- Has been used for severe headaches.
- Tendency to cause psychotomimetic effect is less than pentazocine.
c) Nalbuphine:
- Does not affect the heart or increase blood pressure in contrast with the
other two.
# All the three medications exhibit a ceiling effect or respiratory depression.
▪ Other analgesics: tramadol
- Centrally acting analgesics.
- Binds to mu opioid receptor.
- Undergo extensive metabolism → active metabolites with much higher
affinity to mu receptors.
- Weakly inhibits reuptake of norepinephrine and serotonin.
- Monoaminergic activity appears to be valuable in the management of
neuropathic pain.
- Used to manage moderate to moderately severe pain.
- Respiratory depressant activity is less than that of morphine.
▪ Opioid antagonist: Naloxone & Naltrexone
- Bind with high affinity to opioid receptors.
- Opioid antagonists produce no profound effects in normal individuals.
- Patients dependent on opioids: antagonist rapidly reserve the agonist.
- Such: morphine of any mu fully agonist.
- Precipitate the symptoms of opioid withdrawal.
a) Naloxone:
- Used to reverse comma and respiratory depression of opioid overdose.
- Rapidly displaces all receptor-bound opioid molecules.
- 30 s of IV: RD and comma of MRF are reserved, causing patient to be
revived and alert.
- Half life 30-80 min, may lapse back into RD.
- Competitive antagonist: mu, kappa, delt, 10 higher in mu and kappa.
- Reserve RD with only minimal reversal of analgesia of analgesia that result
from stimulation of kappa receptors in the spinal cord.
b) Naltrexone:
- Has action similar to naloxone.
- Longer duration.
- Single oral dose block effect of infected heroin up to 24h.
- In combination with clonidine used for rapid opioid detoxification.
- Can lead to hepatotoxicity.
Adjuvants medicines:
1- Antiepileptic
2- Antidepressant
3- Anesthetic agents
4- Skeletal muscle relaxants
5- Steroids
6- Antispasmodics
7- Hormones
8- Bisphosphonate
