Opiods

Question 1

Types of Pain

Answer 1

• Somatic pain ⇒ skin, subcutaneous, or muscle
• Visceral pain ⇒ originates from thoracic or abdominal structures
• Neuropathic pain ⇒ usu. caused by nerve damage

Question 2

Pain Pathways

Answer 2

• Nociceptors are located on primary afferent neurons
  
  • Aδ (fast) neurons ⇒ sense intense, sharp, stinging pain
    
    • Functions to localize pain and in withdrawal reflex
  • C (slow) neurons ⇒ sense dull, burning, aching pain
    
    • Functions to mediate autonomic reflexes, pain memory, and pain discomfort
• Descending inhibitory pathways
  
  • From the periaqueductal grey, raphe nucleus, and locus coeruleus
  • ⊗ ascending spinal thalamic tract neurons
  • Also ⊕ interneurons in spinal cord that release met-enkephalin that ⊗ release of pain mediators
• Sensory a-β fibers arising from peripheral tissues
  
  • ⊕ release of enkephalins from interneurons ⇒ ⊗ pain transmission

Question 3

Endogenous Opioid

Peptides

Answer 3

• Enkephalins ⇒ met- and leu-enkephalin
  
  • Small peptides
  • Released from neurons in periaqueductal grey, medulla and spinal cord
  • Modulate neurotransmission by having an ⊗ effect
• Endorphins and dynorphins
  
  • Larger peptides

Question 4

Endogenous Opioid

Receptors

Answer 4

Three opioid receptors ⇒ μ (mu), δ (delta), and 𝜅 (kappa)

Most of the useful opioid analgesics ⊕ mu receptors

Some of the agonist/antagonist agents also work at kappa receptors

Question 5

Opioid Drugs

Types

Answer 5

• Full agonists
  
  • Strong opioid agonists
    
    • Well-tolerated when given in large doses to relieve pain
  • Moderate opioid agonists
    
    • Cause significant side effects if given at doses large enough to relieve pain
    • Usu. used at submaximal doses along w/ NSAIDS
• Mixed opioid agonist-antagonists
• Opioid antagonists
  
  • Used to counteract adverse effect of overdose

Question 6

General

MOA

Answer 6

Acts through GPCR coupled to G_I

α subunit ⇒ ⊗ adenylate cyclase ⇒ ↓ cAMP

β/𝛾 subunits ⇒ ↑ K⁺ conductance and ↓ Ca²⁺ influx

Actions ⊗ both presynaptic and postsynaptic neurons

Question 7

CNS Effects

Answer 7

• Analgesia ⇒ via action on receptors in spinal cord and CNS
• Sedation, euphoria or dysphoria ⇒ via action on serotonergic, dopaminergic, noradrenergic midbrain nuclei
  
  • Dysphoric reactions lead to behavioral restlessness in some pts
• Miosis ⇒ via ⊕ of Edinger-Westphal nucleus
  
  • Used to dx OD because tolerance does not develop to this effect
• Nausea/vomiting ⇒ by ⊕ the chemo trigger zone
  
  • Issue in ambulatory pts d/t enhanced sensitivity of vestibular organ
• Respiratory depression ⇒ via ⊖ of the medulla
  
  • Usu. the adverse effect that causes death in overdose
  • Due to a reduction in hypercapnic drive w/ no effect on the hypoxic drive
  • Cerebral circulation will respond w/ an ↑ in blood flow leading to ↑ intracranial pressure
• Inhibition of cough reflex ⇒ at site in the medulla
• Truncal rigidity ⇒ intensification of tone in large trunk muscles

Question 8

Cardiovascular Effects

Answer 8

Release of histamine from mast cells ⇒ Vasodilation ⇒ Orthostatic hypotension

Question 9

Gastrointestinal/Urinary Effects

Answer 9

• Constipation ⇒ due to ↑ smooth muscle tone and inhibition of peristalsis
  
  • Mechanism for the antidiarrheal effect
• ↑ tone of biliary sphincter
• ↑ tone of the bladder sphincter ⇒ urinary retention
• ↓ uterine tone ⇒ prolongation of labor
• Dermal flushing, itching, rash
  
  • May not be responsive to antihistamines

Question 10

Tolerance

Answer 10

Defined as a ↓ in pharmacologic effect:

• Mechanism may involve compensatory ↑ in adenylate cyclase, receptor endocytosis/degradation, or receptor uncoupling
• Generally takes 2-3 weeks to develop
  
  • Occurs rapidly when large doses are given over a short interval
  • Minimized by giving small doses at longer intervals
• Marked tolerance develops to analgesic, sedating, and respiratory depressant effects
• Tolerance also develops to antidiuretic, emetic and hypotensive effects but not to the miotic and constipating actions
• No tolerance to the pure antagonists
• Cross tolerance particularly to those agents that ⊕ mu receptors
  
  • Can be incomplete
  • Opioids can be “rotated” to maintain analgesia in cancer pts
• Another agent can be used to enhance opioid receptor function in tolerant individuals
  
  • NMDA receptor antagonist
• Use ultra low doses of an opioid antagonist to prevent tolerance

Question 11

Physical Dependence

Answer 11

Manifested when the discontinuation of the drug results in withdrawal sx

Continued use of the drug required for pt’s well-being

Question 12

Withdrawal

Overview

Answer 12

• Onset, intensity, and duration of sx depend on opioid used
  
  • Time of onset depends on T_½ of the drug
  • Morphine withdrawal sx ⇒ peak in 36-48 hours
  • Methadone withdrawal sx ⇒ may take several days to reach the peak
    
    • May persist for as long as 2 weeks
• Antagonists like naloxone can precipitate a transient and explosive withdrawal within 3 mins
  
  • Used to dx an OD or reverse severe respiratory depression
• Clonidine ⇒ used to tx some of the autonomic sx of withdrawal

Question 13

Withdrawal Symptoms

Answer 13

• Rhinorrhea
• Lacrimation
• Yawning
• Chills
• Piloerection
• Hyperventilation
• Hyperthermia
• Mydriasis
• Muscular aches
• Vomiting
• Diarrhea
• Anxiety and hostility

Question 14

Psychological Dependence

Answer 14

• Euphoria, indifference to stimuli, and sedation promote compulsive use
• Also cause intense pleasure (“rush”) often compared w/ sexual orgasm
• Main reason for opioid’s abuse liability coupled w/ the need to administer the drug to avoid withdrawal sx
• Despite the risk of abuse, adequate pain relief should never be withheld

Question 15

Drug Interactions

Answer 15

• Sedative hypnotics ⇒ ↑ respiratory depression
• Antipsychotic, tricyclic antidepressants ⇒ ↑ sedation, potential for ↑ cardiovascular effects
• Monoamine oxidase inhibitors ⇒ potential for serotonin syndrome
  
  • Cognitive, autonomic and somatic sx

Question 16

Overdose

Answer 16

Respiratory depression, miosis, coma

Diagnose w/ naloxone

Question 17

Opiod

Contraindications

Answer 17

• Pulmonary dysfunction (except pulmonary edema)
• Closed head injuries
• Hepatic or renal dysfunction
• Adrenal or thyroid deficiencies
• Pregnancy
• Partial agonists could precipitate withdrawal in pts tolerant to a full agonist

Question 18

Strong Opioid Agonists

Answer 18

1. Morphine
2. Fentanyl
3. Meperidine
4. Methadone
5. Oxycodone

Question 19

Morphine

Answer 19

• Principal alkaloid of opium
• Diacetic acid ester of morphine ⇒ heroin
• Well-absorbed orally
• Significant 1st pass metabolism → 3-glucuronide metabolite (inactive)
• Significant amount metabolized to 6-glucuronide
  
  • More active than morphine and has a longer half-life
• Standard to which other drugs are compared
• Indications:
  
  • Severe pain of trauma
  • MI ⇒ coronary vasodilation and ↓ oxygen demand

Question 20

Fentanyl and Sufentanil

Answer 20

• Synthetic opioid agonists
• The most potent agonists available
• Fentanyl formulated into a long-acting transdermal skin patch for severe chronic pain
• Used parenterally preoperatively and postoperatively and as an adjunct to general anesthesia
  
  • Under these circumstances it can cause truncal rigidity

Question 21

Meperidine

Answer 21

• Synthetic opioid agonist
• Has antimuscarinic properties ⇒ may cause the pupils to dilate
• Effects on smooth muscle are less pronounced than morphine
• Indications:
  
  • Can be used for analgesia in obstetrics
  • Used orally in the outpatient setting for short-term treatment of moderate to severe pain
• Long term treatment is not recommended because the drug has a neurotoxic metabolite called normeperidine
  
  • Can cause CNS excitation, convulsions and tremors

Question 22

Methadone

Answer 22

• Synthetic opioid agonist
• Most often used orally for opioid dependence or chronic pain
  
  • Can prevent the craving for heroin
  • Does not cause significant euphoria or other reinforcing side effects
  • Called the “methadone maintenance program”
• Long half-life - administered once a day

Question 23

Oxycodone

Answer 23

• Semisynthetic opioid morphine derivative
• Used w/ an NSAID to treat moderate to severe pain
• Sustained-release preparation is called oxycontin
  
  • Has caused several deaths b/c dependent persons have crushed the pill and injected it

Question 24

Moderate Opioid Agonists

Answer 24

Do not produce maximal analgesia at tolerable doses

Used at lower doses in fixed dose combo w/ acetaminophen, aspirin, or ibuprofen

Drugs include:

Codeine

Propoxyphene

Question 25

Codeine

Answer 25

• Naturally occurring opioid
• Has a methyl group at the 3-position
  
  • Principal site at which morphine is conjugated
  • PO doses undergo less first-pass metabolism than morphine
• Codeine → morphine via cytochrome CYP2D6
  
  • Responsible for significant portion of analgesic effect
  • Genetic polymorphisms can result in ∆ analgesic effect
• Used in combo w/ an NSAID to treat mild to moderate pain
• Also used in cough syrups as anti-tussive, but not in children

Question 26

Propoxyphene

Answer 26

• Half the analgesic potency of codeine
• Recently taken off the market
  
  • Risk of potentially serious or even fatal heart rhythm abnormalities
  • FDA concluded that the risks did not outweigh the benefits

Question 27

Tramadol

Answer 27

• MOA:
  
  • Weak agonist at mu receptors
  • ⊗ serotonin and norepinephrine reuptake
    
    • Uptake ⊗ may potentiate actions of descending inhibitory pathways
    • May also be part of mech for use of tricyclic antidepressants in pain
• Used for moderate pain and in chronic pain syndromes
• Abuse potential

Question 28

Dextromethorphan

Answer 28

• Analogue of codeine
• Used as an anti-tussive
• Minimal analgesic and abuse properties
• Abuse of its purified (powdered) form has been reported
• Use in children less than 6 y/o has been banned by the FDA d/t reports of death

Question 29

Diphenoxylate

Answer 29

• Used for diarrhea in combination w/ atropine
• Atropine is at too low a dose to have a therapeutic effect
  
  • Thought to reduce to likelihood of abuse
• Abuse potential is low

Question 30

Loperamide

Answer 30

Activates mu receptors in the periphery, not in the CNS

Potential for abuse is low, so it is available OTC

Used as an anti-diarrheal

Question 31

Mixed Opioid Agonist-Antagonists

&

Partial Agonists

Answer 31

• Produce less respiratory depression at high doses
  
  • Safer in overdose
• Less abuse potential
• Less constipation
• Partial agonists can precipitate withdrawal in a pt who is dependent on a full agonist
• Drugs include:
  
  • Buprenorphine
  • Butorphanol
  • Pentazocine

Question 32

Buprenorphine

Answer 32

• MOA:
  
  • Partial agonist at mu receptors
  • Antagonist at kappa and delta receptors
• Slow dissociation from mu receptors ⇒ longer duration of action
• Causes less respiratory depression than morphine
• Its effects cannot be readily reversed by naloxone
• Adverse effects: sedation, nausea
• Also available orally and sublingually in combo w/ naloxone to prevent IV abuse
• Approved for outpatient treatment of opioid abuse
• Relief of moderate to severe pain, also use postoperatively

Question 33

Butorphanol

Answer 33

• MOA:
  
  • Mu antagonist/partial agonist
  • kappa agonist
• Adverse effects: sedation, nausea, sweating
• Used for acute pain relief
• Available in IV form or intranasally

Question 34

Pentazocine

Answer 34

• MOA:
  
  • Mu antagonist/partial agonist
  • Kappa agonist
• Adverse effects:
  
  • Stimulation of sigma receptors ⇒ ± anxiety, nightmares, and psychotomimetic effects
  • Nausea and sweating
• Indications:
  
  • Oral (contains naloxone) used for moderate to severe pain
  • IV used as a pre-anesthetic or as a supplement to surgical anesthesia

Question 35

Opioid Antagonists

Answer 35

• Analogues of morphine w/ chemical ∆ which allows the molecule to bind the receptor but prevents activation
• Drugs are used to treat overdose and treat opioid as well as other drug dependencies
• Drugs include:
  
  • Naloxone
  • Naltrexone

Question 36

Naloxone

Answer 36

• Used IV to block respiratory depression of the opioid agonist
  
  • Works within 30 seconds
  • May need to be repeated if opioid agonist is long lasting
• Used in oral preparations of opioid agonists to prevent IV abuse
  
  • Is not well absorbed orally
  • Does not block the effect of the orally administered opioid agonist

Question 37

Naltrexone

Answer 37

• Used to treat opioid dependence and alcoholism
• Oral and transdermal preparations
• Longer duration of action than naloxone
  
  • Up to 48 hours
• Adverse effects: Hepatotoxicity, nausea, sedation, and headache

Question 38

Drug Choice

Answer 38

• Mild pain – non-opioid analgesic
• Moderate to severe pain – codeine, hydrocodone, or oxycodone in combo w/ an NSAID
• Severe pain – fentanyl, meperidine, methadone, morphine
  
  • Meperidine should not be used for more than a few days because of the toxic metabolite

Question 39

Acute Pain

Management

Answer 39

• Caused by trauma, surgery
• Risk of producing dependence in these pts is low
• During initial stages, analgesic should be given at regular intervals
  
  • Dose should control the pain while minimizing sedation and other side effects
• Pt-controlled analgesia
  
  • Allows pt to self-admin a preset amount of opioid (fentanyl) via a pump interfaced w/ a timing device
  • Allows the pt to balance pain control w/ sedation

Question 40

Chronic Pain

Management

Answer 40

• Caused by a number of different conditions
• Usu. treated w/ a combination:
  
  • Opioid and non-opioid analgesics
  • Co-analgesics
  • Physical therapy
  • Transcutaneous nerve stimulation
  • Local anesthetics
  • Capsaicin
• Risk a drug dependence and tolerance in these pts
  
  • Care must be taken when using opioid analgesics
  • Set up strict guidelines for refills
  • Make a “contract” w/ the pt

Question 41

Neuropathic Pain

Management

Answer 41

• Occurs when pain is present for a long time
  
  • ↑ in pain perception and memory
  • Reflects some type of neuronal alteration
• Tx requires many agents or modalities:
  
  • Transcutaneous electrical nerve stimulation (tens) therapy, acupuncture, physical therapy
  • Antiepileptic drugs ⇒ carbamazepine, gabapentin, phenytoin, valproate
    
    • Probably works by ⊗ nerve conduction
    • Used to tx sharp piercing pain ⇒ trigeminal neuralgia and postherpetic neuralgia
    • Works for continuous burning pain
  • Tricyclic antidepressants ⇒ amitriptyline and desipramine
    
    • Used for postherpetic neuralgia, diabetic neuropathy, migraine, and other neuropathic pain
  • Duloxetine ⇒ diabetic neuropathy
• Tramadol – used for chronic pain syndrome See above

Question 42

Cancer Pain

Management

Answer 42

• Most pts managed w/ oral agents:
  
  • Opioids
  • NSAIDS
  • Neuropathic drugs
• In severe cancer pain:
  
  • Necessary to use strong opioid agonists continuously via sustained release preparations or skin patches

Question 43

Acute Pulmonary Edema

Management

Answer 43

• Opiods used for relief of dyspnea caused by pulmonary edema
• Maybe due to:
  
  • Reduced anxiety
  • Reduced cardiac preload and afterload due to histamine release
• Use of morphine for this condition has been called into question
  
  • Studies indicate that it may cause harm to these pts

Question 44

Cough Management

Answer 44

• Effect is manifest at lower doses than those required to achieve analgesia
• Mediated by other receptors than those that cause analgesia
• Dextromethorphan has reduced abuse potential
• Codeine is also used

Question 45

Diarrhea Treatment

Answer 45

Diphenoxylate or Loperamide

Question 46

Anesthesia Uses

Answer 46

• Used as pre-medicant before surgery because of their sedative, anxiolytic, and analgesic properties
• Also used intraoperatively
• Most commonly used during cardiac surgery ⇒ does not cause as much cardiac depression as anesthetics
• May be injected along w/ local anesthetics in the epidural space for spinal anesthesia

Question 47

Drugs Summary

Answer 47