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Neuro exam 2 > Treatment of pain 1.1 > Flashcards

Treatment of pain 1.1 Flashcards

1
Q

Approach to Pain management: Six major approaches:

A

• Pharmacologic
• Physical medicine – Physical therapy, spinal modulation
• Behavioral medicine - CBT
• Neuromodulation – TENS, Spinal cord stimulation, deep brain stimulation
• Interventional – Direct injection into pain area of substances such as
glucocorticoids or locals
• Surgical
Typically a therapeutic regimen will combine multiple approaches

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2
Q

Pharmacological

A

Non-opioid analgesics: aspirin, acetaminophen, NSAIDs, COX-2 inhibitors,

Opioids: Morphine etc.

Alpha 2 adrenergic
agonists

Antidepressants: TCA, SNRI

Antiepileptic: α2δ drugs, others

Topical local analgesics: Lidocaine, capsaicin

NMDA receptor
antagonists: Ketamine

Muscle relaxants: Baclofen etc.

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3
Q

Non-opioid analgesics Mechanism of

Action:

A

See Santanam lectures in POD for mechanisms and side effects.
Target the inflammatory components of the pain cascade.

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4
Q

Non-opioid analgesics: Uses, Other

A

Uses

  • Mild to moderate pain, particularly of somatic origin
  • Frequently used for soft tissue injury, strains, sprains, headaches, and arthritis.

• Often synergistic when combined with opioids

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5
Q

Non-opioid analgesics: Side Effects, Cautions etc

A

Key ones to remember:
Acetaminophen – hepatotoxic, most common cause of liver failure in US
NSAIDS and Aspirin – Gastric Ulcers, inhibit platelet aggregation

Acetaminophen – liver disease, alcoholics
Avoid NSAIDs in patients on aspirin therapy for CV protection

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6
Q

Opioid receptors: µ-receptor

A

Transduction
Mechanism: Activation of inwardly rectifying K+ channels, inhibition of Ca2+ channels,
inhibition of adenylyl cyclase

Localization:  CNS (neocortex, thalamus,
nucleus accumbens,
hippocampus, amygdala),
myenteric neuons in the gut
and vas deferens, 
Physiological effects:  mediates supraspinal
analgesia, respiratory
depression, euphoria and
dependence, miosis gastric
transit

Key Selective Endogenous Agonists: Endomorphin-1 & 2, enkephalins, β-endorphin

Key Selective Drug Agonists: morphine, fentanyl, methadone, meperidine, buprenorphine

Key Selective Antagonists: Naloxone
Naltrexone

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7
Q

Opioid receptors: δ -receptor

A

Transduction
Mechanism: Activation of inwardly rectifying K+ channels, inhibition of Ca2+ channels,
inhibition of adenylyl cyclase

Localization: Olfactory bulb, nucleus
accumbens, caudate
putamen, neocortex,

Physiological
effects: involved in affective
behaviors

Key Selective Endogenous Agonists: enkephalins

Key Selective Drug Agonists: None

Key Selective Antagonists: Naltrindole

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8
Q

Opioid receptors: κ -receptor

A

Transduction
Mechanism: Activation of inwardly rectifying K+ channels, inhibition of Ca2+ channels,
inhibition of adenylyl cyclase

Localization: Cerebral cortex, nucleus
accumbens, claustrum,
hypothalamus,
Spinal cord

Physiological
effects: mediates spinal cord
analgesia, miosis,
sedation,

Key Selective Endogenous Agonists: dynorphins

Key Selective Drug Agonists: butorphanol,
pentazocine, nalbuphine

Key Selective Antagonists:

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9
Q

Interaction at opioid receptors: Drugs can be:

A 
• Agonist
• Antagonist
• Mixed agonist
• Partial agonist – have
limited agonist like
effects
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10
Q

Opioid Classification: Strong agonists

A

Morphine: Moderate-to-severe acute and chronic pain, treatment of acute pulmonary edema, relief of pain of myocardial infarction

Hydromorphone: severe pain

Methadone: Analgesia, controlled withdrawal form opioids

Heroin Drug of abuse
Oxycodone Moderate – severe pain

Meperidine Acute Analgesia (especially obstetrics)

Fentanyl,Alfentanil, Remifentanil Fentanyl, Sufentanil analogs: Surgery and post-surgical analgesic

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11
Q

Opioid Classification: Moderate to low

agonists

A

Codeine Analgesic, antitussive

Propoxyphene Weak analgesic

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12
Q

Opioid Classification: Mixed agonist /
antagonist
Partial agonists

A

Buprenorphine
(partial µ agonist / κ
antagonist): Opioid withdrawal, detoxification, maintenance

Pentazocine
(κ-agonist, µ/δ- antagonist)
Moderate pain

Butorphanol
(κ-agonist, µ/δ- antagonist)

Nalbuphine
(κ-agonist, µ- antagonist)

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13
Q

Opioid Classification: Antagonists

A

Naloxone
(µ/κ/δ- antagonist): Opioid overdose

Naltrexone
(µ/κ/δ- antagonist)
Opioid detoxification, alcoholism

Nalmefene
(µ/κ/δ- antagonist)

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14
Q

Morphine: Mechanism

A

Act at µ receptors with high affinity
• Activation of µ receptors → ↓ spontaneous activity of gut/CNS neurons
• Act on areas involved in respiration, pain perception, mood, emotion
• Act at κ-receptors in spinal cord
• Prevents substance P release

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15
Q

Morphine: CNS Effects, Pupil

A
  • Analgesia without loss of consciousness
  • Drowsiness, Itchy nose
  • Euphoria/Dysphoria
  • Nausea & vomiting

Miosis: due to excitation at the Edinger-Westphal nucleus of the oculomotor nerve
Pathognomonic of opiate intoxication

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16
Q

Morphine: Respiration, Cardiovascular

A

Major adverse effect, Usually cause of death in overdose
Respiration depressed by direct effect on brain stem
↓ sensitivity to CO2

Minor effect
Peripheral vasodilation, reduced peripheral resistance
Inhibition of baroreceptor reflexes
Orthostatic hypotension and fainting

Respiratory depression main cause of OD death
Regulation of pain perception good for analgesia
Helps in pain perception, but also a factor in abuse potential

17
Q

Morphine: Gastrointestinal,

A 
Prominent side effect; mediated by µ and δ receptors
↓ stomach motility
↑ duodenal tone
↓ propulsive intestinal movement
↑ anal sphincter tone
↑ pressure in biliary tract
↓ intestinal secretions
CONSTIPATION
Antidiarrheal opioids with no
CNS activity:
Diphenoxylate (Lomotil)
Loperamide (Imodium A-D).  Can lead to “Biliary pain”
18
Q

Morphine: Endocrine:

A

↓ plasma levels of luteinizing hormone
↓ plasma levels of testosterone
Menstrual cycle irregularities
Male sexual impotence

19
Q

Morphine: Tolerance and
Dependence:

A
  • Development is characteristic of the opioids
  • Opioids demonstrate cross tolerance
  • Tolerance does not develop to miosis / constipation / respiratory effects
20
Q

Morphine: Withdrawal:

A
  • Many signs and symptoms of withdrawal indicate a “rebound phenomenon”
  • Increased sensitivity to noxious stimuli (hyperalgesia)
  • Hyperventilation
  • Dilatation of pupils, Diarrhea, Dysphoria
21
Q

Morphine: Drug Interactions

A

Opiate action potentiated by:
• Phenothiazines, MAO inhibitors, tricyclic antidepressants
• Phenothiazines can ↑ sedative effects of opiates while ↓ analgesic effects
• Amphetamine has mood elevating and analgesic effects, enhances analgesia

22
Q

Morphine: Opioid Poisoning:

A

Symptoms include coma, pinpoint pupils, depressed respiration
• Treatment: ventilation, i.v. opiate antagonist

23
Q

Contraindication

A
  • Hepatic insufficiency
  • Respiratory insufficiency (emphysema, severe obesity, etc.)
  • Head injury patients
24
Q

Morphine DESCRIPTION AND SOURCE, Structure:

A

• Gold standard for comparison among opioids
• Relief of moderate-to-severe acute and chronic
pain; pulmonary edema; preanesthetic
medication
Source:
• From poppy plant, Papaver somniferum
• Milky substance from seed capsule which is dried
and powdered to make opium
• Opium contains several alkaloids:
• morphine, codeine, papaverine

Structure
• Many semisynthetic compounds made by modification of
morphine molecule

25
Q

Morphine: Other effects:

A

• Antitussive effects: prevent cough by action in medulla
• Codeine/hydrocodone used for cough suppression
o ↓ sensitivity of CNS cough centers to peripheral stimuli
o ↓ mucosal secretion
o action occurs at doses less than that for analgesia
o antagonized by naloxone

26
Q

Morphine: Pharmacokinetics:

A

• Route of administration: s.c./i.m./ oral / suppository /pump
• Low bioavailability of oral formulation (17-30%) due to 1st pass
effect
• Readily absorbed from GI tract, nasal mucosa, lung
• Metabolism: glucuronide conjugation with urinary excretion
• Active metabolites

CYP2D6 codeine to morphine

27
Q

Hydromorphone (Dilaudid)

A

• Hydrogenated ketone of morphine
• 7x more potent than oral morphine, used for
severe pain
• Less active metabolites than morphine
• Oral, IV, IM and extended release formulations

28
Q

Methadone (Dolophine)

A

• Effective analgesic; as potent as morphine
• No Kappa activity
• Constipation; biliary spasms are predominant side effects
• Long t1/2 ∼ 1-1.5 days
• Used in treatment of opiate withdrawal/heroin users;
chronic pain
• “Methadone Maintenance”
• Tolerance develops slower with methadone than to
morphine
• Major overdose issue in Appalachia, potentially via altered
metabolism by CYP SNPs?

29
Q

“Methadone Maintenance”

A

• Used in Rx for opiate withdrawal
• 1x/day at higher dose than for analgesia
• Tolerance develops
• Opioid craving is met without need for IV drug use
• If opiate such as heroin is taken while on methadone, effects are
greatly reduced due to “cross tolerance”

30
Q

Heroin

A

• Only used for recreational purposes in US
• Diacetylmorphine metabolized to 6- monoacetylmorphine then morphine
• Both Diacetylmorphine and 6- monoacetylmorphine have higher BBB
penetration than morphine
• Effect due to both 6-monoacetylmorphine and
morphine
• 6-monoacetylmorphine specific heroin
metabolite detectable in urine tests

31
Q

Hydrocodone + acetaminophen

(Lortab, Vicodin):

A 
• Orally equipotent to morphine
• Moderate to severe pain, cough
• New mono formulation of extended release
hydrocodone (Zohydro) is now available.
– Major concerns for abuse and OD
32
Q

Oxycodone

A

• Management of moderate-to-severe pain, normally
used in combination with non-opioid analgesics
• Orally active semi synthetic analog of morphine
• Oxycontin Delayed release formulation has large
potential for abuse, can crush tablet and ingest all at
once (drug abuse lecture)
Combined formulations:
• Oxycodone/ibuprofen:
• Oxycodone/aspirin:
• Oxycodone/acetaminophen:

33
Q

Synthetic Derivatives: Phenylpiperidine Analgesics

A 
Phenylpiperidine Analgesics
• Meperidine
• Fentanyl
• Sufentanyl
• Alfentanil
• Remifantanil
34
Q

Meperidine (Demerol)

A

• µ- opioid agonist
• Less potent than morphine
• Excitement caused at toxic doses due to metabolite, normeperidine (CNS
stimulant); not blocked by naloxone
• Respiration depressed
• Cardiovascular effects: postural hypotension
• Doesn’t suppress cough
• Causes variable effects on pupil size
• Side effects similar to morphine with less constipation and urinary
retention
• MAO inhibitors + Meperidine Possibly severe reaction: excitation,
delirium, hyperpyrexia, convulsions, respiratory depression
• Better bioavailability than morphine
• Tolerance develops slower than with morphine
• Dependence also develops

35
Q

Fentanyl (Duragesic)

A

µ opioid agonist:
• Meperidine analog
• 80 x as potent as morphine – now major abuse
substance
• Available as patch for chronic pain, or as lozenge
(sucker) for breakthrough pain in opioid tolerant
patients, including cancer patients.
• I.V. administration for pre and post-surgery
analgesia, rapid onset short duration
• Produces less nausea in comparison to morphine

36
Q

Fentanyl derivatives: Sufentanil (Sufenta) – µ opioid agonist:

A

• 6000 x as potent as morphine
• I.V. administration; anesthesia adjunct; post-op anesthesia
• Less hemodynamic instability, respiratory depression, chest
wall rigidity
• Costly

37
Q

Fentanyl derivatives: Alfentanil-μ-opioid agonist:, Remifentanil- μ opioid agonist:

A

Remifentanil- μ opioid agonist:
• short acting
• 20x more potent than alfentanil

38
Q

Codeine

A
  • Less potent analgesic than morphine
  • Used in conjunction with non-opioid analgesics
  • Codeine is component of cough syrups to alleviate/prevent coughing
Therapeutic Uses:
• Pain Control
• Acute relief of pain
• Chronic treatment of pain
• Terminal illness
• Cough
• To produce constipation
• Opium tincture/paregoric

Pharmacogenomics:
• Codeine (inactive for analgesia) metabolized to morphine by CYP2D6
• CYP2D6 is highly polymorphic, with over 90 known allelic variants
• Can result in:
o Slow metabolizers – codeine ineffective analgesic
o High metabolizers – fast conversion to morphine - overdose
Precursor for “Krokodil” (drug abuse lecture)

39
Q

Propoxyphene (Darvon)

A 
• Weak potency µ-agonist
• Analgesic-used in combination with
acetaminophen or aspirin for treatment of
mild to moderate pain
• Less potential for dependence

Neuro exam 2 (35 decks)

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