Opioid Analgesics/ Anti-inflammatories

Question 1

What is the anatomy of the descending pain modulating system?

Answer 1

1) Projects via the medulla to the spinal cord dorsal horn.
2) High concentrations of endogenous opioid peptides
3) Activated by opiate analgesics (like morphine)
4) Activated by certain kinds of stress

5) Opiates produce analgesia by direct action on the CNS
(Pain receptors = nociceptors)

Question 2

Regarding the descending pain modulating system, how does Systemic administration of opiates produces analgesia ?

Answer 2

By acting at widely distributed sites throughout the CNS (spinal cord and brain)

Question 3

What is the Pain Suppression System?

-Activated by what?

Answer 3

■Starts w/ afferents in higher centers
■Involves serotonin as neurotransmitters
■Partially enkephalin-mediated (endogenous opioids)
■Activated by Noxious stimuli, pain, psychological factors (placebo responders) and opioids

Question 4

What is the Analgesia system?

-Mediated by what?

Answer 4

Analgesia system: areas where opioid analgesics take place
■ Mediated by periaqueductal grey matter (midbrain), nucleus raphe magnus (medulla), pain inhibitory neurons (dorsal horn)

Question 5

What is the role of endorphins in pain modulation?

Answer 5

■ Endogenous morphine (opiate like effect)

■ Involved in blood pressure regulation, temperature regulation & food intake

■ Distributed: brain, arcuate nucleus hypothalamus, pituitary/nucleus tractus solitarii → visceral afferents from facial, glossopharyngeal and vagus n.

■ Acts via mu receptor @ GI tract
1. side effect = constipation (Rx stool softener to prevent)

Question 6

Where are Endorphins found?

Answer 6

Found in gut, sympathetic nervous system, adrenal medullary chromaffin cells, CNS, pancreatic islet cells

Question 7

Endorphins are derived from which precursor molecules?

Answer 7

Precursor molecules:

1. proenkephalin A
2. pro-opiomelanocortin (POMC) = B-endorphin
3. Proenkephalin B (prodynorphin) = dynorphins

Question 8

What is the the role of enkephalins in pain modulation?

Answer 8

■ Mimic opiate activity= weak analgesics
■ Widely distributed

■ Ex: leucine-enkephalin, methionine-enkephalin

■ NT in many brain areas: PAG, RVM, spinal cord laminae

■ May be responsible for producing analgesia in placebo responders & acupuncture
■ Acts via mu & delta

Question 9

Where are Dynorphins found?

Answer 9

In Spinal cord, throughout brain, hypothalamus.

-Acts via Kappa

Question 10

What does the opiate sub-receptor types and the physiological effects depend on?

Answer 10

○ Effects depend on site of binding
■ Recognition site of receptor is highly specific → stereospecific
■ only levo-isomers have biological activity

Question 11

What is the known opiate sub-receptor types and the physiological effects that they produce?

Answer 11

1) Mu- endorphin activated:
■ Best pain relief, but highest risk for addiction (Mu 1)
a. supraspinal analgesia, euphoria, physical dependence
b. dec. affinity of Mu (partial Mu agonist = dec risk of addiction but, dec level of analgesia)
■ Respiratory depression (Mu 2)

2) Delta: enkephalins activated
■ analgesia, emotion, seizures

3) Kappa: dynorphins activated
■ spinal analgesia, miosis (pinpoint pupils), sedation

4) Epsilon:
■ analgesia

5) Sigma: (no longer classified as opioid receptor, no NMDA)
■ Hallucinations, nightmares, anxiety
■ Autonomic stimulation, dysphoria, hallucinations, nightmares, respiratory stimulation, vasomotor stimulation (tachycardia), anxiety

Question 12

What is the distribution of opiate receptors in the body?

Answer 12

1) G protein coupled receptors
2) Location: PAG, dorsal horn of spinal cord, tissues that are not involved in analgesia
3) Strength of attachment of an opioid drug to its binding site (binding affinity) is proportional to its potency

Question 13

What is the concept of tolerance to opioids?

Answer 13

1) With continued exposure of tissues to high concentrations of opioid agonists, potency of drug declines so that progressively higher concentrations are required to produce same degree of analgesia
2) Characteristic of all opioids
3) Cross-tolerance develops to other opioid analgesics as well

Question 14

What is the desired clinical effects produced by all opiate drugs?

Answer 14

1) Potent analgesia
2) Sedation and euphoria
3) Cough suppression
4) GI effects
■ Increase smooth muscle tone
■ Decrease propulsion and motility= constipation
■ Used for tx of diarrhea

Question 15

Describe common adverse effects produced by all opiate drugs

Answer 15

1) Severity of side effects is proportional to efficacy
2) Physical addiction
3) Respiratory depression (dose-related)

■ Decreases brainstem sensitivity to carbon dioxide

4) Nausea & vomiting (emesis)
■ Directly stimulates chemoreceptor trigger zone in medulla
■ Regular, repeated dosing prevents vomiting by depressing vomiting center (floor of 4th ventricle)

5) Constipation

6) Miosis (pinpoint pupils)
■ Diagnostic of addiction

7) Urinary retention
■ Stimulate ADH; increase smooth muscle tone
■ Watch if prostate problem

Question 16

What are the CNS and Cardiovascular effects produced by all opiate drugs?

Answer 16

CNS effects:
■ Occasionally, stimulatory effects: anxiety, restlessness, nervousness, dysphoria

Cardiovascular:
■ Depress vasomotor center & stimulate vagus nerve = at high doses, postural hypotension, bradycardia, syncope

Question 17

What are other common adverse effects produced produced by all opiate drugs?

Answer 17

1) Biliary tract constriction
■ Biliary colic (watch in patients with gallstones)

2) Histamine release
■ itching/urticaria (at injection site and at remote sites)

3) Pregnancy and lactation
■ Prolong labor; depress fetal respiration if given near term
■ Infants born to addicts have marked depressed respiration & experience withdrawal
■ Cross into breast milk
a. morphine & codeine = FDA Pregnancy category “C”

4) Physical dependency/addiction

5) Tolerance
■ Tolerance readily develops = cross-tolerance
■ Cross-addiction can be produced

Question 18

What is the overdose and withdrawal produced by all opiate drugs?

Answer 18

1) Pharmacologic effect may also be an adverse reaction
■ May like sedation to help sleep w/ pain

2) Overdose
■	Major symptom: respiratory depression
■	Pinpoint pupils
■	Coma
■	Treated w/ antagonist = naloxone

3) Withdrawal
■ Occurs after abrupt discontinuation of drug
■ Yawning, lacrimation, perspiration, rhinorrhea, gooseflesh & piloerection (“cold turkey”), irritability, nausea, vomiting, tachycardia, tremors, chills

Question 19

What is the life-threatening adverse event associated with opiate overdose.

Answer 19

○ Respiratory depression

Question 20

What are 2 pure opiate antagonists and their clinical use in medicine and dentistry?

Answer 20

1) naltrexone (Depade, ReVia, Vivitrol)
■	Antidote given orally or IM
■	Reverse exogenously administered opioids
■	Also used for alcohol abstinence
■	Long duration of action

2) naloxone (Narcan)
■ antidote- IV to reverse overdose of fentanyl and meperidine (sedation)

Question 21

What is the origin of opium alkaloid drugs and give 2 examples of derivatives used in dentistry?

Answer 21

1) Opium = dried juice obtained from unripe seed capsules of poppy plant

2) Drugs used in dentistry are derivatives from these molecules:
■ morphine
■ codeine
3) Heroin= synthesized morphine product

Question 22

What are the common opioids used in dentistry according to potency and indications for use. (ranked highest to lowest)

Answer 22

○ fentanyl = 100 times more potent than morphine; 500 times more potent than meperidine
○ morphine = oxycodone
○ meperidine
○ hydrocodone = 3 times more potent than codeine
○ codeine = 1/6th the potency of morphine
○ dihydrocodeine = codeine

Question 23

What is the CODEINE preparations used in dentistry, with an emphasis on dosage availability of popular combination products?

-How does dihydrocodeine compare to Codeine?

Answer 23

■ Many GI side effects
■ ⅙ the potency of morphine
■ 60 mg is optimum dose
-no effect after this but increased adverse events

■	Used in combination with:
a) 	aspirin
b) 	acetaminophen
■	for moderate to moderately severe pain
■	Drug of choice for cough suppression
■	Codeine containing preparations are identified by “numbers” that reflect the mg concentration
1.	#1= 8 mg (canada only)
2.	#2= 15 mg
3.	#3= 30 mg
4.	#4= 60 mg

■ Tylenol w/ codeine (#1,2,3,4) Class 3 & 4
-Tylenol 3 most widely prescribed codeine product in dentistry

Note: dihydrocodeine
■ SAME efficacy/ potency as codeine!

Question 24

What is the HYDROCODONE preparations used in dentistry, with an emphasis on dosage availability of popular combination products?

Answer 24

■ 3 times more potent than codeine
■ Drug examples with acetaminophen:
1. Vicodin (5/500 mg or 7.5/500 mg)
2. Lorcet/Lortab (5/500 mg; 7.5/500 mg)

hydrocodone with ibuprofen:
■ does not have enough ibuprofen for anti-inflammatory response use OTC to supplement

Question 25

What is the norco preparations used in dentistry, with an emphasis on dosage availability of popular combination products?

Answer 25

■ 10 mg hydrocodone with 325 mg acetaminophen

■ uses lower dose of acetaminophen but still strong opiate dose

Question 26

What is the oxycodone (Schedule 2) preparations used in dentistry, with an emphasis on dosage availability of popular combination products?

Answer 26

■	HIGHLY addictive
■	as potent as morphine
■	more potent than codeine
■	more side effects
■	severe pain 

■ Examples:

1. Percocet
2. Tylox
3. Percodan
4. Roxicet

Question 27

What is the most widely prescribed codeine preparation by dentists?

Answer 27

■ Used in combination with acetaminophen or aspirin

■ Tylenol #3

Question 28

What is the most widely used hydrocodone preparation by dentists?

Answer 28

■hydrocodone with acetaminophen (Vicodin or Lorcet)

Question 29

What is the indication for use of meperidine (Demerol) in dentistry?

Answer 29

meperidine (Demerol): 
■	IV sedation (conscious sedation)
1.	NOT as potent as fentanyl
2.	NOT as much risk for respiratory depression as with fentanyl (Unless patient is an addict)
3.	WIDER margin of safety
4.	25 mg IV dose
5.	May cause nausea

■ Orally for moderate to severe pain

1. 50-100 mg orally q 4 hours as needed
2. 3-4 hour duration of action

Question 30

What is the indication for use of fentanyl in dentistry?

Answer 30

■	CONSCIOUS sedation only!
1.	IV
2.	Transdermal
3.	Lollipop
■	100 times more potent than morphine
■	500 times more potent than meperidine

Question 31

What are the prescribing considerations associated w/ tramadol and ketorolac when given to patients to manage dental pain?

Answer 31

○ tramadol (Ultram):
■ Use for ≤ 5 days for ACUTE dental pain (short term)
■ INHIBITS reuptake of norepinephrine & serotonin
■ Associated w/ seizures (Anaphylaxis is RARE)
■ Rapid release & absorption of extended release formula if broken, crushed or chewed can lead to potentially lethal overdose

○ ketorolac (Toradol):
■ NSAID but gives pain relief at opioid level
■ Watch for bleeding & GI complications
■ SHORT term use: ≤ 5 days only

Question 32

What are important patient variables to take into consideration when selecting an analgesic drug to manage dental pain?

Answer 32

○ oxycodone w/ acetaminophen is used to treat the more SEVERE degrees of pain
○ meperidine (Demerol) is useful for patients w/ a history of codeine ALLERGY
○ morphine & hydromorphone (Dilaudid) are NOT indicated as analgesics in any dental situation

○ Whenever possible, an NSAID is PREFERRED to an opiate agent for pain management
■ opiates DON’T reduce inflammation
■ treating inflammation will DECREASE pain

○ All opiates will cause NAUSEA in MOST patients
○ Constipation
○ Elderly patients: use CAUTION