Opioid (narcotic) analgesics and antagonists

Question 1

Strong Analgesics (µ agonists)
(drug names)
*10

Answer 1

1. *morphine
2. *codeine
3. *fentanyl
4. *heroin
5. *hydrocodone
6. *hydromorphone
7. *meperidine
8. *methadone
9. *oxycodone
10. *oxymorphone

Question 2

Partial Agonists and Mixed Agonist/Antagonist Analgesics
(drug names)
*5

Answer 2

1. *pentazocine
2. *buprenorphine
3. *butorphanol
4. *tramadol
5. *tapentadol

Question 3

Opioid Antagonists
(drug names)
*5

Answer 3

1. *naloxone
2. *naltrexone
3. *methylnaltrexone
4. *alvimopan
5. *naloxegol

Question 4

Terminology - In common usage, these terms are used interchangeably even
though they, technically, have somewhat different meanings.
Define: Opiate, Opioid, and Narcotic

Answer 4

1. opiate - derived from opium
2. opioid - having properties similar to drugs derived from opium
3. narcotic – technically means “sleep inducing” but is commonly taken to mean “opioid”

Question 5

Opium

Answer 5

is a dried plant resin obtained from the opium poppy

1. source - opium poppy (Papaver somniferum)
2. composition
   -a. benzylisoquinoline alkaloids (no longer used much)
   (1) noscapine - antitussive
   (2) papaverine - smooth muscle
   relaxant

-b. phenanthrene alkaloids - “narcotic analgesics”
(1) morphine - 10% of opium by weight
(2) codeine - 0.5% of opium by weight
(3) thebaine - 0.2% of opium by weight; not an analgesic but can serve as the starting material for the synthesis of
other analgesics.

Question 6

Opioid Drugs - Classification Based On Source

Answer 6

1. natural (morphine)
2. semisynthetic (heroin, hydromorphone, oxycodone, etc..)
3. synthetic (methadone, meperidine, propoxyphene)

Question 7

Mechanism of Analgesic Action:

Pain is a complex experience that consists of two components: _______ and ___________

Answer 7

a. ) pain as a physiological sensation
b. ) pain as an emotional and psychological reaction to a painful sensation

Note: Of these, the emotional and psychological component is the most important, because it represents pain as “suffering”

Question 8

Mechanism of Analgesic Action:

pain as a physiological sensation

Answer 8

The physiologic sensation of pain is produced by excitation of functionally distinct pain receptors or “nociceptors”. The pain sensation is carried by afferent fibers to the dorsal horn of the spinal cord. The spinothalamic pathways then carry sensory impulses to the thalamus, from where the impulses are then sent to the cerebral cortex, reticular formation and limbic system.

Question 9

Mechanism of Analgesic Action:

pain as an emotional and psychological reaction to a painful sensation

Answer 9

The emotional or psychological component of pain involves the reticular activating system, limbic system, periaqueductal gray area and frontal cortex.

Question 10

Mechanism of action of Action for Morphine: Big Picture

-What areas of the body does it act on?

Answer 10

-In most situations morphine acts primarily in the limbic system to modify the patient’s reaction to pain; (ie. the “psychic component” of pain). It also acts in the
spinal cord and thalamus to modify physiological sensation of pain. In addition, there is some evidence that morphine and related agents might decrease the
sensitivity of nociceptor fields in the periphery, although the significance of this peripheral effects are unclear.

Question 11

Mechanism of action of Action for Morphine: Big Picture

-What does it treat?

Answer 11

-Although it alleviates most types of pain, it tends
to be more effective against dull, constant, visceral pain than against sharp, intermittent somatic pain. Following the administration of an effective dose of morphine, pain does not evoke as much anxiety, fear, panic, or suffering. Also, the patient’s ability to tolerate pain is markedly increased without altering the perception of other sensations. Morphine, at moderate therapeutic doses, usually does not cause loss of consciousness. In this respect, morphine differs from other CNS depressants, such as barbiturates, alcohol, etc.. These non-opiate
drugs, in high doses, might cause analgesia, but they will also inhibit or suppress other sensations and cause the loss of consciousness.

Question 12

Mechanism of action of Action for Morphine: Big Picture

-“It is interesting to note that
many patients receiving morphine will report that…?”

Answer 12

-It is interesting to note that many patients receiving morphine will report that “The pain is still present but it does not hurt anymore”, which indicates that morphine mainly affects the patients’ reaction to the pain.

Question 13

Mechanism of action of Action for Morphine: Big Picture

-How does it act at the cellular and molecular level?

Answer 13

-At the cellular and molecular levels, morphine primarily acts as an agonist at receptors for endogenous opioid peptides (endorphins and enkephalins) and thereby modifies the processing of pain information in the CNS.

Question 14

Mechanism of action of Action for Morphine: Big Picture

-The families of opioid peptides?

Answer 14

-The families of opioid peptides include the: enkephalins, dynorphins and endorphins. These peptides are derived from precursor polypeptides having distinct chemical
compositions and anatomical distributions in the CNS.

Question 15

Mechanism of action of Action for Morphine: Big Picture

-The opioid peptides function as neurotransmitters. Explain.

Answer 15

-The opioid peptides function as neurotransmitters particularly in areas of the limbic system (arcuate nucleus, raphe nuclei, thalamus, hypothalamus, amygdala, hippocampus) and in the spinal cord (dorsal horn). They play an especially important role in modulating pain pathways and the emotional responses to pain. At the molecular level opioid agonists tend to inhibit the Ca2+-dependent release of neurotransmitters including substance P, GABA and others that play a role in modulating the processing of pain information.

Question 16

Activation of presynaptic opioid receptors (particularly of the mu type)

Answer 16

Activation of presynaptic opioid receptors (particularly of the mu type) in the dorsal horn of the spinal cord

-inhibits release of substance P and other primary transmitters by the afferent pain fiber. This disrupts the transmission of the afferent pain signal. Similar effects occur in areas of the limbic system (such as the peri-aqueductal grey area) which leads to alterations in the awareness and emotional responses to pain. With respect to signaling mechanisms, opioid receptors are: linked to a variety of signaling pathways inhibition of adenylate cyclase, inhibition of voltage-gated calcium channels and modulation of potassium channels. The effects on calcium signaling are especially important because they lead to inhibition of transmitter release. It is also important to note that the actions of opioids also involve pathways that utilize a variety of other neurotransmitters including glutamate, aspartate, GABA, norepinephrine and serotonin. Drugs that act on these other transmitters can influence the responses to opioids and are often used as adjuvant drugs in pain management.

Question 17

Like other neurotransmitters, the opioid peptides produce their effects by interacting with
specific receptors. Although many subtypes of opioid receptors have been characterized, the
three most important are the µ (mu) and κ (kappa)

-Where are they located and what do they do?

Answer 17

µ receptors (MOP): located primarily in the brainstem, spinal cord, and limbic areas and are thought to mediate supraspinal analgesia, some spinal analgesia, sedation,
respiratory depression, euphoria and dependence. There is now solid evidence that they are also located in the periphery and modulate the sensitivity of nociceptors.

κ receptors (KOP): located mainly in the brainstem and spinal cord, and to a lesser extent, the limbic system. They are thought to mediate some spinal analgesia, some supraspinal analgesia, meiosis, sedation, and dysphoria.

Question 18

The various classes of opioid drugs can act as agonists, partial agonists, or antagonists at the various types of opioid receptors.

-What does Morphine, Pentazocine, and Naloxone do in relation to this?

Answer 18

• Morphine and most classic opioid analgesics are strong agonists at µ receptors, moderate agonists at κ receptors
• Pentazocine and related drugs act as agonists at κ receptors, but only as partial agonists or antagonists at µ receptors.
• Naloxone acts as an antagonist at all types of opioid receptors.

(+)=agonist, (-)=antagonist
Receptor Types
Drug µ (mu) κ (kappa)

Morphine             +++         +
Hydromorphine   +++         +
Pentazocine         +/-          ++
Buprenorphine     ++          -
Naloxone              ---           -

Question 19

Pharmacologic Actions of Morphine: (14 of them)

Answer 19

1. ) Analgesia
2. ) Sedation and mental clouding
3. ) Relief of anxiety and apprehension
4. ) Euphoria (usually) - Dysphoria (occasionally)
5. ) Nausea
6. ) Depression of respiration
7. ) Constriction of pupils
8. ) Antitussive effect
9. ) Lowering of seizure threshold
10. ) Endocrine Disturbances
11. ) Effects on Smooth Muscle
12. ) CV effects
13. ) Skeletal muscle rigidity
14. ) Immunosuppression

Question 20

Pharmacologic Actions of Morphine:

-Analgesia

Answer 20

already described but here it is again

-Although it alleviates most types of pain, it tends
to be more effective against dull, constant, visceral pain than against sharp, intermittent somatic pain. Following the administration of an effective dose of morphine, pain does not evoke as much anxiety, fear, panic, or suffering. Also, the patient’s ability to tolerate pain is markedly increased without altering the perception of other sensations. Morphine, at moderate therapeutic doses,
usually does not cause loss of consciousness. In this respect, morphine differs from other CNS depressants, such as barbiturates, alcohol, etc.. These non-opiate
drugs, in high doses, might cause analgesia, but they will also inhibit or suppress other sensations and cause the loss of consciousness.

Question 21

Pharmacologic Actions of Morphine:

-Sedation and mental clouding

Answer 21

Note: Although morphine does produce sedation and cause drowsiness, the effects are qualitatively different from those produced by other CNS depressants
(benzodiazepines, barbiturates, alcohol. etc.). Therapeutic doses of morphine produce a floating, dream-like state from which the patient normally can be aroused. However, in overdose situations, morphine and other opioids can cause the graded depression of cortical function: Mental Clouding and Sedation →
Hypnosis or Stupor → Coma → Death

Question 22

Pharmacologic Actions of Morphine:

-Relief of anxiety and apprehension

Answer 22

particularly in individuals with pain.

Question 23

Pharmacologic Actions of Morphine:

-Euphoria (usually) - Dysphoria (occasionally)

Answer 23

• Subjectively, the effects of morphine are usually perceived as pleasant, particularly in individuals with pain. The drug causes analgesia and produces a floating dream-like state of tranquility. The individual may drift in and out of a pleasant sleep from which they can easily be aroused. Although the effects of morphine are generally perceived as pleasant, some individuals may experience unpleasant subjective effects (dysphoria). These individuals may experience fear, anxiety, restlessness, hallucinations, and nausea. It is worth noting that these adverse reactions tend to be more common in females. In certain species (particularly cats), morphine can cause excitement and even rage reactions.

Question 24

Pharmacologic Actions of Morphine:

-Nausea

Answer 24

a. ) due to stimulation of the chemoreceptor trigger zone (CRTZ) in medulla, also may involve vestibular system.
b. ) more common in ambulatory patients than in recumbent patients
c. ) tolerance develops - with chronic use, the CRTZ may actually become desensitized

Question 25

Pharmacologic Actions of Morphine:

-Depression of respiration

Answer 25

***a.) major toxic effect - usual cause of death in opioid poisoning

b. ) decreased sensitivity to CO2 at chemoreceptors in medulla – effect involves activation of µ receptors.
c. ) use with caution in patients with impaired respiratory function

Note: One beneficial effect of respiratory depression by morphine is applicable in the treatment of pulmonary edema with its frightening and unpleasant symptoms or air hunger. In this condition, the struggle to breath aggravates the pathophysiology of the edema. Morphine gives partial relief in acute pulmonary edema by alleviating the patient’s conscious awareness of respiratory distress. After a moderately large dose of
morphine, the patient will not struggle to breath. This actually improves the patient’s physiologic state and is beneficial. In addition, morphine causes peripheral vasodilation. This decreases both preload and afterload on the heart, which is also beneficial to the patient.

Question 26

Pharmacologic Actions of Morphine:

-Constriction of pupils

Answer 26

a.) due to an action in the nucleus of Edinger - Westfall

***b.) “Pin point” pupils is one of the tell-tale signs of opioid poisoning!

c.) tolerance does not usually develop to this effect

Question 27

Pharmacologic Actions of Morphine:

-Antitussive effect

Answer 27

***a.) depression of cough control center in the medulla

b.) opioids, particularly codeine and its analogs, are widely used as antitussives

Note: Systemically administered (oral, IV, IM, SC, transdermal) morphine and related opioids cause the release of histamine and may aggravate asthma or
obstructive pulmonary disease. Opioids should be used only with extreme caution in such patients. They also can cause itching of the skin. H-1 histamine antagonists such as diphenhydramine (Benadryl) can alleviate this effect. Very severe itching of the trunk and face can occur after spinal morphine administration. This situation involves mechanisms other than simple histamine release. In such situations, diphendyramine is often not effective, but
naloxone may be beneficial.

Question 28

Pharmacologic Actions of Morphine:

-Lowering of Seizure Threshold

Answer 28

Use with caution in seizure-prone patients

Question 29

Pharmacologic Actions of Morphine:
-Endocrine disturbances
(2 things)

Answer 29

a. ) decreased secretion of gonadotropins, corticosteroids and prolactin
b. ) menstrual disturbances in females and impotence in males are common in chronic opioid users

Question 30

Pharmacologic Actions of Morphine:
-Effects on smooth muscle
(5 things)

Answer 30

• increased tone of circular smooth muscle, decrease
  in propulsive movements of longitudinal muscle – effects are mediated by
  opioid receptors

a. ) decreased intestinal motility - constipation is a common side effect
b. ) urine retention - often have to catheterize patients who received opioids
c. ) bronchoconstriction - may cause serious problems in asthmatics and patients with obstructive pulmonary disease.
d. ) increased biliary pressure due to constriction of the bile duct
e. ) some inhibition of uterine contractions may prolong labor

Question 31

Pharmacologic Actions of Morphine:
-Cardiovascular effects
(3 things)

Answer 31

a. ) postural (orthostatic) hypotension due to release of histamine and interference with hemostatic reflexes
b. ) cutaneous vasodilation - due to release of histamine, causes a warm flushing of the skin. Some patients may experience pruritus that can be alleviated by H-1 histamine antagonists.
c. ) increased CSF pressure

- (1) due to buildup of CO2 and resulting cerebral vasodilation * **- (2) use only with caution in patients with head injuries

Question 32

Pharmacologic Actions of Morphine:

-Skeletal Muscle Rigidity

Answer 32

occurs at high doses and may cause problems when opioids are used as adjuncts for surgical anesthesia.

Question 33

Pharmacologic Actions of Morphine:

-Immunosuppression

Answer 33

a. ) seen especially with chronic usage
b. ) may complicate use of opioids in immunocompromised patients or may contribute to the pathogenesis of immune disorders such as AIDS.

Question 34

Pharmacokinetics of Morphine:

-Route of Administration

Answer 34

usually IV, IM or SC or by spinal routes although oral
preparations are widely used for severe pain. In addition, morphine and related agents such as heroin are sometimes “snorted” for abuse purposes.

Question 35

“first pass” effect with Morphine

Answer 35

Morphine is considerably less potent orally because of significant “first pass” effect. (i.e. about 75% of the dose is metabolized during its passage through the liver). Still can be given orally in high doses for the management of chronic, severe pain. Because of marked individual variations in the first-pass metabolism of morphine, establishing appropriate oral dosing of morphine can be difficult.

Question 36

Because of marked individual variations in the “first-pass” metabolism of morphine, establishing appropriate oral dosing of morphine can be difficult. What variations contribute to having this impact?
(6 things)

Answer 36

1. ) rapid onset after parenteral administration; maximal analgesic action within one hour of injection.
2. ) duration of analgesia is approximately 4-6 hours.
3. ) t½ = 2-3 hours: may be longer in elderly patients.
4. ) metabolism in the liver (glucuronide formation)
5. ) excretion - 90% in the urine primarily as metabolites in 24 hours. 7-10% in the feces.
6. ) morphine and other opioids readily cross the placental barrier and can affect the fetus resulting in respiratory depression or even drug dependence with chronic use.

Question 37

Standard Therapeutic dose of morphine

Answer 37

10 mg SC or IM. This is the dose to which all other analgesic drugs are compared. Typical IV doses are 1-5 mg

Question 38

Major Drug Interactions of Morphine (6 things)

Answer 38

1. ) additive effects with other CNS depressants (alcohol, barbiturates, benzodiazepines, antipsychotics, antidepressants, antihistamines)
2. ) MAO inhibitors - reports of severe hyperpyrexia and coma, especially with meperidine (Demerol) but it can occur with all opioids.
3. ) abuse with amphetamines and cocaine - mixture is called a “speedball”.
4. ) Some opioids are used in combinations with other analgesics (e.g. aspirin, acetaminophen or ibuprofen) - By acting through different mechanisms, the drugs in combination produce an enhanced analgesic effect.

5.) Certain antihistamines (e.g. hydroxyzine (Vistaril) can enhance the analgesic effects of opioids. A drug combination that was popular many years ago, but
which has fallen out of favor is meperidine plus hydroxyzine (Demerol + Vistaril)

6.) Tricyclic and SNRI antidepressants can enhance the analgesic effects of opioids and are sometimes included in the regimens for the management of chronic, severe pain.

Question 39

Opioid Poisoning:
-Symptoms
(3 things)

Answer 39

• characteristic triad*
  a. ) CNS depression - stupor or coma
  b. ) depressed depth and rate of respiration
  c. ) pin point pupils

Note: If the patient is severely hypoxic (i.e. very close to death) the pupils may be dilated.

Question 40

Opioid Poisoning:
-Treatment
(2 things)

Answer 40

a. ) Support respiration - be prepared to mechanically ventilate the patient. Be aware that administration of O2 may remove the hypoxic drive for respiration and cause apnea.
b. ) Administer a narcotic antagonist such as naloxone .

Question 41

Common Uses of Morphine and Related Drugs

7 things

Answer 41

1. ) Moderate - severe acute pain
2. ) Treatment of chronic pain
3. ) Adjuncts to surgical anesthesia
4. ) Antitussives
5. ) Antidiarrheals
6. ) Dyspnea of left heart failure and pulmonary edema
7. ) Abuse

Question 42

Strong Analgesics (µ agonists):
-Morphine

Answer 42

1. ) route of administration - absorbed from GI tract, but not as effective orally because of first pass metabolism; however, oral forms are available. Morphine can be given subcutaneously, IM or IV. In addition it is now widely used for various types of spinal analgesia.
2. ) usual dose is 1-5 mg IV, 10 mg SC or IM; or 10-30 mg P.O., although with severe, chronic pain, higher doses may be needed.
3. ) used for more severe pain
4. ) The ways in which morphine and related opioids are used have changed dramatically in the past few years. Three of the most important developments are:a.) infusion and autoinjector
   systemsb.) PCA (patient controlled
   analgesia)c.) spinal analgesia

Question 43

Strong Analgesics (µ agonists):
-Codeine

Answer 43

1. ) route of administration - orally effective
2. ) dose - 1/12 the potency of morphine; common doses are 30-60 mg P.O.
3. ) uses:
   (a. ) analgesic for mild-moderate pain
   (b. ) antitussive

4.) The codeine molecule has only weak opioid agonist activity. However, in most patients, a small percentage of codeine is demethylated to form morphine, which
then produces its effects. Genetic polymorphisms in metabolic enzymes may explain why some people are more or less sensitive to opioid effects of codeine than others.

Question 44

Strong Analgesics (µ agonists):
-Hydromorphone

Answer 44

-similar to morphine but more potent

Question 45

Strong Analgesics (µ agonists):
-Oxycodone

Answer 45

– sort of a cross between morphine and codeine. Used orally (alone or in combination with acetaminophen) for moderate-severe pain. OxyContin is a sustained release oral preparation for the management of severe chronic pain.

Question 46

Strong Analgesics (µ agonists):
-Hydrocodone

Answer 46

-similar both to codeine and oxycodone; used orally in combination with acetaminophen for mild-moderate pain and as an antitussive; is currently one of the most widely prescribed opioids. Zohydro ER is an extended release product that contains hydrocodone alone, without acetaminophen.

Question 47

Strong Analgesics (µ agonists):
-Meperidine

Answer 47

1. ) synthetic drug
2. ) route of administration - oral and parenteral
3. ) 1/10 the potency of morphine
4. ) reputed to have weaker effects on smooth muscle than morphine - less constipation and urine retention, although the evidence to support this is weak.
5. ) used for moderate to severe pain
6. ) have been commonly used in obstetrics - may cause less respiratory depression in the newborn than morphine
7. ) relatively short acting 1-3 hours; not appropriate for chronic pain because of the buildup of an active metabolite (normeperidine) that can cause seizures.
8. ) falling into disfavor in many circles, but still widely used.

Question 48

Strong Analgesics (µ agonists):
-Heroin

Answer 48

1. ) more potent and more euphoric than morphine; duration of action about 4-6 hours.
2. ) available for medical use in some countries, but not in the US
3. ) abuse
4. ) commonly taken by injection, snorting or smoking

Question 49

Strong Analgesics (µ agonists):
-Methadone

Answer 49

1. ) less euphoric and longer duration of action (12-24 hours) than heroin (4-6 hours) or morphine (4-6 hours)
2. ) used as an analgesic and in treating opioid addiction
3. ) dosing can be tricky and needs to be done carefully, with close monitoring of the patient.
   * Note: When used acutely as an analgesic, methadone has a duration of action of 4-6 hours. However, when used chronically (as in methadone maintenance for the treatment of opioid dependence, or for the management of chronic pain), it has a duration of action of 12-24 hours.*

Question 50

Strong Analgesics (µ agonists):
-Fentanyl

Answer 50

very potent mu agonist (about 100 x more potent than
morphine) - given parenterally to supplement surgical anesthesia. A transdermal preparation (Duragesic) is available for the management of chronic pain. Fentanyl is
often used either alone or in combination with IV anesthetics such as propofol to provide pain relief and sedation for acute, unpleasant procedures, such as endoscopies, colonoscopies, reducing fractures, etc. A Lozenge preparation (Actiq) is available for the treatment of “breakthrough” pain. Adminisration of fentanyl plus droperidol can induce a state called neuroleptic analgesia. In this state, various diagnostic or minor surgical procedures may be carried out even though the patient might not completely lose consciousness. Administering nitrous oxide in conjunction with fentanyl and droperidol will produce a state called neuroleptic anesthesia.

Question 51

Opioid Combination Preparations

Answer 51

Most contain either codeine, hydrocodone or oxycodone, in combination with either aspirin, acetaminophen or ibuprofen. Note that when these combination products are used at very high doses needed to control severe pain, the patient may be exposed to potentially toxic doses of acetaminophen, aspirin or ibuprofen.
Some examples are:

1. ) Codeine/Acetaminophen (Tylenol with Codeine and generic preparations.
2. ) Codeine/Aspirin (Empirin and generics)
3. ) Hydrocodone/Acetaminophen (Vicodin, Norco, Lortab, others)
4. ) Hydrocodone/Ibuprofen (Vicoprofen)
5. ) Oxycodone/Acetaminophen (Percocet, Percodan, Tylox, and others)

Question 52

Abuse – Deterrent Opioid Formulations

Answer 52

As a result of the growing concerns about the abuse of prescription opioids, many companies have developed “abuse – deterrent” opioid formulations. Some of the products contain agents which cause the formation of
viscous gels when the tablets or capsules are crushed and “dissolved” for abuse purposes. Some such products include hydrocodone (Zohydro ER) and oxycodone (Oxycontin ER). Another strategy involves making drug particles resistant to chewing or crushing. An example is oxycodone (Xtampza ER). The other approach is to include naloxone in the product to prevent IV abuse. Examples of such products include Suboxone (buprenorphine plus naloxone) and Embeda (morphine plus naloxone). New products that entail the use of multiple strategies are being developed.

Question 53

Opium Extracts

Answer 53

Paregoric “comphorated tincture of opium” – old medication that contained about 2 mg morphine per 5 ml; had been used for treatment of diarrhea

Question 54

Opioid Antagonists and Mixed Agonist/Antagonists:
-Types of Antagonists
(2 types)

Answer 54

1. ) “pure” antagonists - block all types of opioid receptors.
2. ) mixed agonist antagonists - block some types of opioid receptors but act as agonists or partial agonists at others.

Question 55

Mixed Agonist-Antagonists:

-Pentazocine

Answer 55

a. ) agonist effects are dominant - acts as an agonist at κ (kappa) receptors, but only as a partial agonist at µ (mu) receptors; it acts as a µ antagonist at high doses.
b. ) less effective than morphine for severe pain
c. ) sedation and respiratory depression are less than with morphine
d. ) CNS stimulation and hallucinations are more common than with morphine
e. ) with chronic use, the potential for physical dependence is less than morphine, but still significant
f. ) can precipitate withdrawal syndrome in opioid addicts
g. ) Talwin Nx is a preparation that contains petazocine and naloxone. The latter is included to reduce the potential for IV abuse.

Question 56

Other Agents Similar to Pentazocine

Answer 56

• butorphanol

* Note: must be given parenterally although butorphanol can be given intranasally.*

Question 57

Mixed Agonist-Antagonists:

-Buprenorphine

Answer 57

a. ) acts as a partial agonist at µ-receptors; very high does have μ antagonist actions.
b. ) Although its analgesic effects may be slightly less than that of morphine, its abuse potential is reported to be much lower.
c. ) It has been reported to reduce drug craving in heroin addicts and is being used in the treatment of heroin addiction. Suboxone is a new combination product containing buprenorphine plus nalaxone designed for sublingual use. When taken as directed, the naloxone does not reach a therapeutic blood level and the buprenorphine can produce its effects. However, if the user tries to inject the drug to achieve a high, the naloxone will block the effects of the buprenorphine.
d. ) Usually given by injection, sublingually or intranasally.
e. ) Buprenorphine is the primary agent used for the so-called “office based” treatment of opioid addiction (This will be explained in class!).

Question 58

Mixed Agonist-Antagonists:

-Tramadol

Answer 58

a. ) use in mild-moderate pain.
b. ) It supposedly is a weak mu agonist. In addition, it inhibits the synaptic reuptake of norepinephrine and serotonin, much like the tricyclic antidepressants and SNRI’s.
c. ) It supposedly produces effective analgesia, with only mild side effects. It has been reported to be good for treating so called neurologic/neuropathic pain. In general, the side effects resemble those of other opioids (dizziness, sedation, nausea, constipation), but are less severe. It is more likely to trigger seizures than other opioids.
d. ) The manufacturer has claimed that the drug has a very low abuse and addiction potential. However, there are a large number of reports indicating that the drug has at least modest opioid-like abuse potential.

Question 59

Mixed Agonist-Antagonists:

-Tapentadol

Answer 59

a. ) newer drug similar to tramadol, except that it has significantly greater activity at mu receptors. Like tramadol, it inhibits NE and 5-HT reuptake.
b. ) Use for moderate to severe pain – Schedule 2 with significant abuse potential.
c. ) Place in therapy is evolving.

Question 60

“Pure” Opioid Antagonists

Answer 60

block most opioid effects, can precipitate a withdrawal syndrome in addicts

Question 61

Opioid Antagonists:

-Naloxone

Answer 61

drug of choice for opioid poisoning, can reverse the
respiratory depressant effects of opioids

a. ) not effective orally, because of first pass metabolism, must be given parenterally; occasionally given intranasally by “first responders”.
b. ) sometimes included in combination with oral narcotic analgesics to prevent abuse (i.e. injection of the drug)
c. ) relatively short duration of action (i.e. only about 1-2 hours)
d. ) can precipitate withdrawal in addicts, which greatly complicates use of the drug. Patients who become agitated after receiving naloxone may have to be sedated, usually with benzodiazepines (diazepam or lorazepam)
e. ) Evzio is a new auto-injector preparation of naloxone intended for emergency treatment of opioid overdose by non-medical personnel

Question 62

Opioid Antagonists:

-Naltrexone

Answer 62

a. ) orally effective, long acting antagonist (24 hours)
b. ) originally used in “immunizing” addicts (ie. preventing the high produced by opioid agonists)
c. ) risk of hepatotoxicity is a drawback
d. ) its effectiveness in the long-term treatment of opioid dependence is not clear
e. ) patient compliance is a major problem
f. ) It can induce a state of hyper-algesia in some patients and complicate the treatment of pain.
g. ) Keep in mind that an opioid addict must first be detoxified (ie. brought through withdrawal) before naltrexone therapy can be initiated.
h. ) It has been shown to decrease the craving for alcohol in alcoholics and is approved for use in the treatment of alcoholism.

Question 63

Opioid Antagonists:

-Methylnaltrexone

Answer 63

a. ) quaternary salt of naltrexone approved for the treatment/prevention of opioid-induced constipation.
b. ) must be given parenterally (subcutaneously) and is only appropriate for serious constipation resulting from opioid use in more severe types of pain.
c. ) also may be useful for treatment of post-operative paralytic ileus.

Question 64

Opioid Antagonists:

-Alvimopan and Naloxegol

Answer 64

a. ) similar to methylnatrexone but better oral efficacy
b. ) both are approved for preventing/treating opioid-induced constipation. Naloxegol is being heavily marketed.
c. ) Alvimopan – now one of the preferred drugs for treatment of postoperative paralytic ileus.

Question 65

Therapeutic Uses of Opioid Antagonists

4 of them

Answer 65

1. ) To treat opioid induced overdose toxicity - (respiratory depression) in adults as well as in neonates.
2. ) To diagnose opioid physical dependence
3. ) To treat compulsive opioid abusers (Naltrexone)
4. ) To reduce craving for alcohol in recovering alcoholics (Naltrexone)

Question 66

Opioid Dependence and Addiction:
-Physical Dependence
(2 things)

Answer 66

1.) tolerance - develops to some effects more than others. For example, there can be a high degree of tolerance to the analgesic, euphoric sedative and respiratory
depressant effects of opioids, whereas there is usually little tolerance to opioid induced meiosis or constipation.

2.) withdrawal syndrome

Question 67

Opioid Dependence and Addiction:
-Characteristics of the Acute Withdrawal Syndrome (opposite of drug effects)
(8 of them)

Answer 67

1. ) yawning, rhinorrhea, sweating
2. ) craving for drug
3. ) anxiety, hostility, insomnia, hyperventilation
4. ) dilation of pupils
5. ) GI hypermotility (diarrhea, nausea, vomiting, cramping)
6. ) hypertension, tachycardia
7. ) “goose flesh”, chills, “cold sweats”
8. ) hyperalgesia, muscle aches, GI pain

Question 68

Opioid Dependence and Addiction:
-Duration and Intensity of Acute Withdrawal
(2 of them)

Answer 68

1. ) short acting drug (e.g. heroin) - intense symptoms, short duration (3-7 days)
2. ) long acting drug (e.g. methadone) - moderate symptoms, long duration (1-2 weeks)

Note: The acute withdrawal phase is often followed by prolonged syndrome consisting of anxiety, irritability, sleep disturbances and autonomic excitability and drug craving that may last for several months.

Question 69

Biochemical Basis of Dependence

Answer 69

Physical dependence to opioids is currently thought to result from compensatory changes in opioid receptors or closely related systems, although the exact nature of the changes are not fully-understood.

One explantation involves depletion of endogenous stores of enkephalins/endorphins in response to chronic exposure to opioid agonists and the following description:
a.) Specialized neurons release enkephalins and endorphins which act on opioid receptors on target cells and the person “feels good”. There are also presynaptic receptors on the enkephalin/endorphin neurons. These receptors function as a negative feedback mechanism to inhibit the further release of enkephalins/endorphins.

b.) Opioid agonists (D) bind to and stimulate the post synaptic opioid receptors to produce the drug-induced high. They also interact with the presynaptic receptors to inhibit the release of endogenous enkephalins/endorphins.

c.) With chronic exposure to the opioid agonist, the enkephalin/endorphin neuron down regulates the synthesis of enkephalins/endorphins and
eventually becomes depleted of the transmitter. If use of the opioid agonist is abruptly stopped, there is not enough enkephalin/endorphin to stimulate the post synaptic receptors and the person feels bad (i.e. the withdrawal syndrome).

It is now clear that the above explanation for opioid tolerance and dependence is overly-simplistic. Most current theories are focused on the effects of chronic opioid exposure on the coupling between opioid receptors and their signal transduction pathways, or on the cycling (i.e. inactivation and reactivation) of the receptors. A central tenet of all of these theories is that the receptors and their associated signaling pathways adapt to minimize the effects of chronic drug exposure.

Question 70

Treatment of Dependence

7 things

Answer 70

1. ) “cold turkey”
2. ) weaning patient off the drug

3.) methadone
(a.) substitution - wean
patient off drug
(b.) maintenance -
maintain patient on drug

4. ) buphenorphine is an alternative to methadone that is more readily available through “office-based” treatment programs.
5. ) naltrexone (ReVia, Vivitrol) - long acting opioid antagonist; Vivitrol is a very long acting (3-4 weeks) depot injection preparation.
6. ) clonidine (Catapres) - will reduce the severity of some withdrawal symptoms (tachycardia, hypertension) and may also decrease craving for the drug.
7. ) antidepressants

Note: Opioid addiction in the street setting remains an extremely difficult problem to treat. In general, the overall prognosis for the hard core heroin addict is not good.
Abuse of prescription opioids is an increasing problem. Although methadone maintenance programs have been shown to be effective, they remain controversial. Buprenorphine is being widely touted as a more accessible alternative. The single most important factor for the success of any program appears to be the motivation of the addict.

Question 71

Opioid Dependence in a Hospital Setting

Answer 71

In a medical setting, patients may become dependent while chronically receiving opioids for medically valid reasons. Under such conditions, they receive known doses of pure drug under strictly controlled conditions. With appropriate medical management, the patient can be weaned off the drug with minimal discomfort and reduced potential for continuing dependence.

Question 72

Opioid Dependence in a Street Setting.

Answer 72

In a street setting, the drug abuser actively seeks an illegal drug for its mind altering effects. Often, the pattern of addict involves the taking of unknown doses of impure drugs under very unsanitary conditions. In addition, the addict must often resort to crime or prostitution to support their habit.

Question 73

Health Hazards associated with the street use of Opioids

3 of them

Answer 73

a. ) hepatitis
b. ) miscellaneous infections (abscesses, endocarditis, tuberculosis, etc.)
c. ) AIDS

drug purity and dosages are questionable. There is also socioeconomic aspects of the problem