1. OPIOID ANALGESICS
Roy Krishna, PhD, FCP.

2. Opioids
Narcotic – a drug with addictive properties that can produce analgesic and sedative effects.
Opiate – a drug naturally derived from opium (morphine and codeine)
Opioid – a drug, natural or synthetic, with morphine- like qualities
Collectively called Opioid Analgesics

3. Classification of Opioids
Agonist
Strong
Moderate
Weak
Antagonist
Agonist / Antagonist
Other

4. Indications for Opioids
Analgesic
Anesthetic
Antitussive
Antidiarrheal

5. Strong Opioid Agonists
Fentanyl (Sublimaze, Duragesic)
Alfentanil, Remifentanil, Sufentanil
related to Fentanyl but use for anesthesia
Hydromorphone (Dilaudid)
Meperidine (Demerol)
Methadone (Methadose, Dolophine)
Morphine sulfate (MS Contin)
Oxycodone (Oxycontin)
Heroin

6. Moderate Opioid Agonists
Codeine (Robitussin AC)
Hydrocodone
Combination Meds
Tylenol #2, 3, 4 (acetaminophen/codeine)
Vicodin, Lortab (acetaminophen/hydrocodone)
Vicoprofen (ibuprofen/hydrocodone)
Percocet (acetaminophen/oxycodone)
class II schedule

7. Weak Opioid Agonists Other Loperamide (Imodium)
Diphenoxylate – (Lomotil) Combined with atropine
Propoxyphene (Darvon)
Combined with acetaminophen-marketed as Darvocet (acetaminophen/propoxyphene)
Dextromethorphan (Delsym, Robitussin DM)
Other
Tramodol (Ultram)
Tapentadol (Nucynta)

8. Opioid Agonist / Antagonist (Mixed-Acting)
Pentazocine (Talwin)
Nalbuphine (Nubain)
Butorphanol (Stadol)
Opioid Antagonist
Naloxone (Narcan)
Naltrexone (Revia)

9. Schedule of Controlled Substances
Criteria
Examples I
No medical use; high addiction potential
heroin II
Medical use; high addiction potential
strong and moderate opioid agonists
III
Medical use; moderate potential for dependence
Lortab, Tylenol #3 IV
Medical use; low abuse potential
weak opioid agonists

10. Opioid Receptors mu “REAP” kappa “SAM” delta (epsilon) (sigma)
Respiratory depression
Euphoria
Analgesia
Physical dependence
kappa “SAM”
Sedation
Miosis
delta
(epsilon)
(sigma)

11. Endogenous Opioids Endorphins Dynorphins Enkephalins
neurohormones (ACTH)
mediates pain
memory
mood
appetite
(thirst, hunger, sex)
Dynorphins
neurotransmitters
Enkephalins
Adrenocorticotropic hormone

12. Opioid Receptor locations in the CNS
(highest to lowest concentration)
1. cerebral cortex
2. amygdala
3. septum
4. thalamus
5. hypothalamus
6. midbrain
7. spinal cord

13. CNS pain pathways
Opioids have 3 primary sites of action for their analgesic effects:
Spinal cord - opioids inhibit release of neurotransmitters from the afferents
Thalamus and limbic system – opioids block the perception of pain and reaction to pain
Brainstem – opioids activate descending inhibitory systems to modulate pain

14. Mechanism of Action of Opioids
Inhibitory G-Protein (Gi) signaling→ ↓ cAMP ↓ Inhibition of presynaptic firing in the spinal cord and postsynaptic firing in the brain ↓ Hyperpolarization of neurons Diminished or blocked pain perception

15. Morphine Contraindications Adverse Effects PAIN
severe
chronic
used in acute pulmonary edema
Palliative measures
Contraindications
respiratory compromise
asthma
intracranial injuries (increased intracranial pressure)
paralytic ileus
Adverse Effects
euphoria and dysphoria, respiratory depression, nausea, constipation, sedation, pruritus, urticaria, bronchospasms, urinary retention, anxiety, hypotension, miosis

16. Peripheral effects of morphine
Cardiovascular – vasodilation, decreases blood pressure, some negative inotropic response
Skin – histamine release to cause itchiness
Pulmonary – bronchospasm
GI – decreases secretions and motility of gut.

17. Morphine’s effect on smooth muscle
biliary tract
10 fold increase over normal pressure (normal is 20 mm H20 pressure)
increase due to contraction of Sphincter of Odi
urinary bladder
tone of detrusor muscle increased
feel urinary urgency
have urinary retention due to increased muscle tone where sphincter closed off
bronchial muscle
bronchoconstriction
uterus
Reduced uterine tone- can prolong labor

18. Primarily renal excretion-dosage adjustment in renal dysfunction.
Morphine
Undergoes conjugation to active metabolites: morphine 6β glucoronide and morphine 3β glucoronide .
Primarily renal excretion-dosage adjustment in renal dysfunction.
PO-10-30mg q4h, IV mg q4h
IM/SC- 5-20mg q4h

19. Fentanyl (Sublimaze, Duragesic)
80 to 100 times more potent than morphine
rapid onset of action (peaks in 5 min)
short acting (30 min)
IV form used as preoperative medication
Also commonly used for epidurals
Transdermal form excellent in chronic patients
Onset of action is 12 hours
replace patch every 72 hours

20. Meperidine (Demerol)
Synthesized to normeperidine – excess accumulation can cause seizures
Normeperidine inhibits reuptake of serotonin- serotonin syndrome.
Avoid in renal dysfunction patients
PO/SC/IM/IV mg q4h, prn

21. Methadone (Methadose, Dolophine)
pharmacological activity and potency similar to morphine
powerful pain reliever
long duration of activity, half life of up to 24 hours
absorbed well orally
less addiction liability
used in maintenance program for narcotic dependence treatment
PO/SC/IM mg q 3-4h

22. Heroin the diacetyl derivative of morphine
Most lipophilic and thus enhanced capability to enter the brain
3 times more potent
than morphine
No medicinal value
recreational drug that is commonly injected, snorted, or smoked

23. Moderate Opioid Agonists
Codeine (Robitussin AC)
Hydrocodone
Combination Meds
Tylenol #1, 2, 3, 4 (acetaminophen/codeine)
Vicodin, Lortab (acetaminophen/hydrocodone)
Vicoprofen (ibuprofen/hydrocodone)
Percocet (acetaminophen/oxycodone)
class II schedule

24. Codeine 1/10th the potency of morphine excellent antitussive
good analgesic
low potential for abuse and rarely produces dependence
usually combined with acetaminophen
PO/IM/SC 15-60mg bid

25. Weak Opioid Agonists Other Propoxyphene (Darvon) Tramodol (Ultram)
(acetaminophen/propoxyphene)
Other
Tramodol (Ultram)
Loperamide (Imodium)
Diphenoxylate – (Lomotil) Combined with atropine
Dextromethorphan (Delsym, Robitussin DM)

26. Propoxyphene a derivative of methadone 1/20th the potency of morphine
Given alone, analgesic effect similar to aspirin
Usually combined with acetaminophen (Darvocet)
PO-65mg q4h

27. Dextromethorphan mu, kappa, sigma receptor activity
used as an antitussive
(Delsym, Robitussin DM)
Opioids with indications for the treatment of cough:
codeine
hydrocodone
hydromorphone

28. Antidiarrheals Loperamide (Imodium)-GI effects only
Diphenoxylate – (Lomotil) Combined with atropine- GI and CNS effects
has very little analgesic properties at therapeutic dose
no antitussive effect
causes respiratory depression and euphoria at high doses
Loperamide: PO 4mg, followed by 2mg

29. Opioid Agonist / Antagonist
Pentazocine (Talwin)
Nalbuphine (Nubain)
Butorphanol (Stadol)
Does not cause serious respiratory depression
Partial Agonist
Buprenorphine (Subutex )
used for outpatient opioid detoxification

30. Opioid Antagonists Naloxone (narcan) Naltrexone (Revia)
Binds with high affinity to opioid receptors
Displaces opioids from receptor site
Completely and dramatically reverses the effects of opioids

31. Naloxone (Narcan) Administered via IV push
Rapidly displaces all bound opioid molecules
Binds to mu, kappa, and delta receptors
But has a 10 fold affinity to the mu receptor.
Respiratory depression and sedation are reversed in less than 30 seconds
Short duration of 1-2 hours.
Repeat doses may have to be given because of the longer durations of action of the opioid agonists
IV mg

32. Naltrexone (Revia) Same pharmacodynamics as naloxone
Slightly different pharmacokinetics
Naltrexone comes in an oral form
Unlike naloxone, it has a long half life
One single 100mg dose can block the effects of injected heroin for up to 48 hours.
Patient gets no euphoric effect from heroin so person gets off heroin (negative reinforcement)
Approved for use by the FDA
Also used for treatment of alcoholism 
Highly hepatotoxic
PO 25mg

33. Opioid Dependence Tolerance with repeated administration
Cellular tolerance/receptor desensitization
Abstinent withdrawal-drug seeking behavior, autonomic hyperexcitability-goose bumps, CNS originating pain, lacrimation, yawning, irritability
Pered withdrawal is recommended.
Precipitated withdrawal-induced by administration of opioid antagonist

34. Opioids-Drug Interactions
Side effects exacerbated-CNS depression, respiratory depression, sedation, dizziness
First generation antihistamines
Barbiturates
Alcohol
TCA’s
MAO’s
Antiepileptics