Opioid Analgesics

Question 1

What are the specific effects associated with opioid receptors?

Answer 1

Supraspinal analgesia - mu, kappa, delta
Spinal analgesia - mu, kappa, delta
Respiratory depression - mu
Reduced GI motility - mu, delta
Psychotomimesis - kappa
Sedation - mu, kappa

• *delta and kappa mainly function as an analgesia at the spinal level
• *mu receptors cause analgesia, euphoria and respiratory depression

Question 2

What is the cellular action of opioids?

Answer 2

1. close VG-Ca2+ channels on presynaptic nerve terminals
2. open K+ channels on postsynaptic neurons
   * Both of these actions reduce NT release [Gi activation]

Question 3

What is the neural mechanism of analgesia by opioids?

Answer 3

1. [spinal] inhibit ascending pain transmission at the spinal analgesia level by inhibiting Ca2+ on presynaptic membrane preventing NT release AND activating K+ channels on post-synaptic membrane preventing secondary afferent neuron
2. [supraspinal] activate descending pain-inhibitory circuits - processes are sent to the spinal cord to inhibit transmission neurons – descending serotonergic and noradrenergic neurons inhibit the presynaptic neurons inhibiting Ca2+ channels preventing NT release
   * supraspinal analgesia - descending pain-inhibitory neurons are inhibited by GABAergic interneurons thereby preventing the inhibition on the presynaptic primary afferent neurons and increasing pain stimuli - these GABAergic interneurons are inhibited by opioids which is how opioids activate the pain-inhibitory descending neurons

**opioids are usually given systemically therefore act at spinal and supraspinal level

Question 4

What are the different classifications of opioid analgesics?

Answer 4

1. pure agonists - higher affinity mu receptors, lower affinity for delta and kappa receptors
2. mixed agonist-antagonist - analgesic ceiling effect, psychotomimetic effects
3. antagonists - all receptors

Question 5

What are the CNS effects of opioids?

Answer 5

1. Analgesia - reduce sensory and emotional components of pain
2. Euphoria - pleasant floating sensation with lessened anxiety and distress
3. Sedation and drowsiness - frequent effect, places ambulatory patients at risk for accident
4. respiratory depression - reduced responsiveness of brainstem respiratory centers to CO2
5. Cough suppression - depression of cough reflex at least in part by a direct effect on a cough center in the medulla
6. Miosis - parasympathetic innervation of pupils, esp during toxic doses of mu agonists, miosis is going to revert to mydriasis during severe respiratory depression
7. Truncal rigidity - results from action at supraspinal level
8. Nausea and vomiting - opioid analgesics activating the brainstem chemoreceptor trigger zone

Question 6

What are the peripheral effects of opioids?

Answer 6

1. Hypotension - opioids inhibit vasomotor center in the brainstem causing peripheral vasodilation; they also inhibit compensatory baroreflexes and increase histamine release
2. GI tract - constipation
3. Biliary tract - opioids contract biliary smooth muscle resulting in biliary colic
4. Genitourinary tract - renal function is depressed due to decreased renal plasma flow
5. Uterus - prolongs labor (mechanism is unclear)
6. Pruritus - flushing, warming of skin, sweating, itching (possibly due to histamine release)

Question 7

Discuss the metabolism of Morphine.

Answer 7

Opioids are converted to glucuronides which are excreted by the kidneys.

Morphine is conjugated to morphine 3-glucuronide (M3G) which has neuroexcitatory properties that are not mediated by opioid receptors.
Morphine to morphine-6-glucuronide (M6G) – M6G is an active metabolite with analgesic potency that is 4-6 times that of its parent compound.

M3G and M6G are polar metabolites that do not contribute significantly to CNS effects of morphine b/c they have limited ability to cross the BBB.

Question 8

How are opioid esters metabolized?

Answer 8

Heroin and remifentanil - rapidly hydrolyzed by tissue esterases

Heroin (diacetylmorphine) is hydrolyzed to monoacetylmorphine and morphine which is then conjugated with glucuronic acid.

Question 9

How is fentanyl metabolized?

Answer 9

CYP3A4 in the liver

There are no active metabolites to fentanyl.

Question 10

How are codeine, oxycodone and hydrocodone metabolized?

Answer 10

In the liver via CYP2D6 resulting in the production of metabolites of greater potency.

Ex. codeine is converted/metabolized to morphine

Question 11

What are the uses of opioid analgesics?

Answer 11

1. Analgesia - moderate to severe pain
2. Acute pulmonary edema - reduced anxiety, reduced cardiac preload, reduced cardiac afterload
3. cough - antitussive (dextrmetorphan, codeine)
4. Control of diarrhea - loperamide and diphenoxylate

Question 12

In what manners are opioids given in the application of anesthesia?

Answer 12

1. premedicant drugs - before anesthesia and surgery due to their sedative, anxiolytic and analgesic properties
2. intraoperatively - as adjunct or primary component of anesthetic regimen
3. regional analgesics - intraspinal administration

Question 13

What are the adverse effects of opioids?

Answer 13

1. nausea [most common]
2. vomiting [most common]
3. sedation [most common]
4. itching [most common]
5. constipation [most common]
6. urinary retention
7. hypotension
8. respiratory depression

Question 14

What is the difference b/t addiction and physical dependence?

Answer 14

Physical dependence - common when opioids are used for therapeutic purpose
Addiction - drug seeking behavior most likely due to euphoria

Question 15

What is the result of giving a pure opioid agonists with weak partial opioid agonists?

Answer 15

Weak partial agonist is given to a pt receiving a pure (strong) agonist - there is a risk of diminishing analgesia inducing a possible state of withdrawal

Question 16

What is the effect of using opioids in pts with head injuries, who are pregnant, have impaired pulmonary function, impaired hepatic function, impaired renal function, endocrine disease?

Answer 16

Head injury - opioids cause respiratory depression and CO2 retention resulting in cerebral vasodilation. In pts with elevated intracranial pressure, this may lead to lethal alterations in brain function.

Pregnant - fetus may become dependent

Impaired pulmonary function - depressant properties may lead to acute respiratory failure

Impaired hepatic function - metabolism primarily occurs in the liver

Impaired renal function - most opioids are excreted by the kidney therefore with impaired renal function the half-life of the opioid is prolonged

Endocrine disease - pts with adrenal insufficiency or hypothyroidism may have prolonged and exaggerated responses to opioids

Question 17

What is the drug interaction of opioids with hypnotics?

Answer 17

Hypnotics are sedatives just like opioids increasing CNS depression (esp respiratory depression).

Question 18

What is the drug interaction of opioids with antipsychotics?

Answer 18

1. Increased sedation
2. variable effects on respiratory depression
3. accentuation of CV effects (antimuscarinic and a-blocking action)

Question 19

What is the drug interaction of opioids with MAO inhibitors?

Answer 19

Concurrent use of Meperidine or tramadol with MAOI may lead to a potentially life-threatening reaction - serotonin syndrome. (weak serotonin re-uptake inhibitors)

Question 20

What is morphine?

Answer 20

Strong opioid agonist that has high affinity for mu receptors and low affinity for delta and kappa receptors.

Question 21

What are hydromorphone and oxymorphone?

Answer 21

Strong opioid agonists used to treat severe pain.

Question 22

What is Heroin?

Answer 22

Heroin is a strong opioid agonist that gets rapidly hydrolyzed to 6-MAM which is then hydrolyzed to morphine. Both heroin and 6-MAM are more liposoluble than morphine and pass through the BBB more readily.

Question 23

What is meperidine?

Answer 23

Strong opioid agonist that binds ONLY the mu receptor. It is no longer recommended for treatment of chronic pain due to concerns over metabolite toxicity.
Meperidine alone has a half-life of 3 hours, and its metabolite normeperidine has a half-life of 15-20 hours. Therefore large doses of meperidine repeated at short intervals produce tremors, muscle twitches, dilated pupils and convulsions – all of these symptoms are due to the accumulation of normeperidine.

Meperidine also blocks reuptake of serotonin therefore can lead to “serotonin syndrome” that exhibits delirium, hyperthermia, headache, hyper- or hypotension, rigidity, convulsions, coma and death. Because of this Meperidine should not be used in patients taking other serotonergic agents such as MAO inhibitors.

Question 24

What is fentanyl?

Answer 24

Fentanyl is a strong opioid agonist that acts on the mu receptors. It has a rapid onset and a short duration of action (15-30 minutes). Fentanyl is 100 times more potent than morphine.

Question 25

What is Methadone?

Answer 25

Methadone is a strong opioid agonist that has approximately equal potency to morphine but exhibits less euphoria and has a longer duration of action. Methadone is a ….

1. mu receptor agonist
2. NMDA receptor antagonist
3. serotonin and norepinephrine reuptake inhibitor [so don’t give with MAOI!]

AE - QT prolongation possibly leading to torsades de pointes and possible death (very rare)

Question 26

What is the role of methadone substitution?

Answer 26

Methadone substitution is the preferred method of managing opioid withdrawal for addicted patients due to its long half-life and less effect of sedation and euphoria. Methadone treatment maintains a pt going through heroin detox in the normal range, rather than falling b/t the sick to high, then to sick, then to high range of withdrawal seen with heroin.

Question 27

What is codeine, oxycodone and hydrocodone?

Answer 27

These are mild to moderate agonists that are less efficacious than morphine. They are rarely used alone and usually combined with aspirin, acetaminophen or other drugs.

Codeine has a low affinity for opioid receptors. [codeine to morphine via CYP2D6]

Question 28

What is tramadol?

Answer 28

mild to moderate opioid agonist that acts as a weak mu agonist as well as a NE and serotonin reuptake inhibitor. It is very useful in the tx of neuropathic pain.

AE - increased risk of seizures as it lowers seizure threshold, serotonin syndrome

Question 29

What are pentazocine, butorphanol, nalbuphine, and buprenorphine?

Answer 29

These are mixed opioid agonists and antagonists that are potent analgesics in opioid-naive patients to treat mild to moderate pain. These drugs are given to opioid dependent pts to precipitate withdrawal - developed to reduce the addiction potential of the opioids

Pentazocine - kappa agonists, mu antagonist or partial agonist [may cause psychotomimetic effects]

Butorphanol - kappa agonist, mu antagonist or partial agonist [may cause psychotomimetic effects]

Nalbuphine - kappa agonist, mu antagonist [may cause psychotomimetic effects]

Buprenorphine - partial my agonists, kappa antagonist [used in the management of opioid addiction]

Question 30

What is the ceiling effect?

Answer 30

There is a dose large enough where there will be no increase in therapeutic benefit or action. This may be caused by mixed agonist-antagonists (pentazocine, butorphanol, nalbuphine, buprenorphine).

Question 31

What are Naloxone and Naltrexone?

Answer 31

Opioid antagonists against mu, delta and kappa receptors.

Naloxone - antidote for tx of acute opioid overdose

Naltrexone - opioid addiction, helps decrease craving for alcohol in chronic alcoholics

Question 32

What are dextrometorphan and codeine?

Answer 32

These are opioid analgesics used as antitussives (cough suppression). Low doses of these drugs help relieve cough, but higher cause analgesic effects.
Receptors involved in the antitussive effect appear to differ from those associated with other actions of opioids.

Question 33

What are diphenoxylate and loperamide?

Answer 33

These are widely used antimotility agents used in the treatment of diarrhea. They bind mu and delta receptors on the enteric nerves, epithelial cells and muscle. At normal prescribed doses there is a lack of analgesic effect.