Treatment of pain 1.1 Flashcards
Approach to Pain management: Six major approaches:
• 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
Pharmacological
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.
Non-opioid analgesics Mechanism of
Action:
See Santanam lectures in POD for mechanisms and side effects.
Target the inflammatory components of the pain cascade.
Non-opioid analgesics: Uses, Other
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
Non-opioid analgesics: Side Effects, Cautions etc
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
Opioid receptors: µ-receptor
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
Opioid receptors: δ -receptor
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
Opioid receptors: κ -receptor
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:
Interaction at opioid receptors: Drugs can be:
• Agonist • Antagonist • Mixed agonist • Partial agonist – have limited agonist like effects
Opioid Classification: Strong agonists
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
Opioid Classification: Moderate to low
agonists
Codeine Analgesic, antitussive
Propoxyphene Weak analgesic
Opioid Classification: Mixed agonist /
antagonist
Partial agonists
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)
Opioid Classification: Antagonists
Naloxone
(µ/κ/δ- antagonist): Opioid overdose
Naltrexone
(µ/κ/δ- antagonist)
Opioid detoxification, alcoholism
Nalmefene
(µ/κ/δ- antagonist)
Morphine: Mechanism
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
Morphine: CNS Effects, Pupil
- 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
Morphine: Respiration, Cardiovascular
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
Morphine: Gastrointestinal,
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”
Morphine: Endocrine:
↓ plasma levels of luteinizing hormone
↓ plasma levels of testosterone
Menstrual cycle irregularities
Male sexual impotence
Morphine: Tolerance and
Dependence:
- Development is characteristic of the opioids
- Opioids demonstrate cross tolerance
- Tolerance does not develop to miosis / constipation / respiratory effects
Morphine: Withdrawal:
- Many signs and symptoms of withdrawal indicate a “rebound phenomenon”
- Increased sensitivity to noxious stimuli (hyperalgesia)
- Hyperventilation
- Dilatation of pupils, Diarrhea, Dysphoria
Morphine: Drug Interactions
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
Morphine: Opioid Poisoning:
Symptoms include coma, pinpoint pupils, depressed respiration
• Treatment: ventilation, i.v. opiate antagonist
Contraindication
- Hepatic insufficiency
- Respiratory insufficiency (emphysema, severe obesity, etc.)
- Head injury patients
Morphine DESCRIPTION AND SOURCE, Structure:
• 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
