Medications for Pain: Chapters 33-36

Medications for Pain

• Covers chapters 33, 34, and 36

Non-Opioid Analgesics (Chapter 33)

• Two types of non-steroidal anti-inflammatory drugs (NSAIDs)
  • First generation (Classical):
    • Non-selective COX inhibitors
    • Aspirin
    • Ibuprofen
    • Naproxen
    • Inhibit COX-1 & COX-2
    • Increase risk of peptic ulcers
    • Increase risk of bleeding
  • Second-generation (NEW):
    • Selective COX-2 Inhibitors
    • Celecoxib
    • Decrease risk of peptic ulcers
    • Increase risk of clotting

What is COX?

• Cyclooxygenase, an enzyme
• COX 1 & COX 2
• Found in all tissues
• Regulates multiple processes using prostaglandins
  • Stomach COX-1 protects gastric mucosa
  • Platelets COX-1 stimulates aggregation
  • Uterus COX-1 causes contractions for delivery
  • Kidney COX-1 & 2 maintain renal blood flow
  • Tissue injury COX-2 promotes inflammation & pain
  • Vessels COX-2 causes vasodilation
  • Brain COX-2 mediates fever & perception of pain
  • Colon COX-2 promotes colorectal cancer

COX Inhibitors

• Uses:
  • Mild-moderate pain
  • Inflammation
  • Fever
  • Pre-menstrual symptoms
  • Protection against colon cancer
• Two major categories:
  • Anti-inflammatories
    • NSAIDs - aspirin, ibuprofen, naproxen, celecoxib
  • Non anti-inflammatories
    • Acetaminophen

First Gen NSAID - Prototype: Aspirin (ASA)

• Uses: reduction of pain, fever, inflammation, MI prevention
• MOA: irreversibly inhibits COX-1 and COX-2
• Pharmacokinetics:
  • Absorption: PO: plain, buffered, enteric-coated
  • Metabolism: Short T1/2, is quickly converted to salicylic acid (SA), an active metabolite. SA's T1/2 is concentration-dependent.
  • Distribution: SA is highly bound to albumin, crosses all membranes easily
  • Excretion: SA by kidneys; dependent on pH
• Adverse Effects:
  • GI - gastric distress, bleeding, ulcers
  • General excessive bleeding
  • Renal impairment
  • Salicylism Syndrome
  • Hypersensitivity (Do not give ASA to children or pregnant women. Contraindicated in patients with: peptic ulcer disease, bleeding disorders, ASA/NSAID hypersensitivity)
• Interactions:
  • Other anticoagulants (warfarin, heparin)
  • Alcohol
  • Other NSAIDs (antiplatelet effect)
• Toxicities
  • Salicylism Syndrome (develops slowly as ASA levels climb above the therapeutic range, s/sx: tinnitus, sweating, headache, dizziness; withhold aspirin until s/sx resolve, then at a reduced dose)
  • Acute Poisoning (s/sx: respiratory alkalosis, respiratory depression, acidosis, hyperthermia, sweating, dehydration, stupor, coma; an acute medical emergency; death related to respiratory failure; treatment is supportive)

First Gen NSAID - Ibuprofen (Advil, Motrin)

• Non-aspirin NSAID
• MOA: Reversible inhibition of COX-1 and COX-2
• Uses are the same as aspirin except: does not prevent MIs/CVAs; may increase CV risk.
• Good choice for dysmenorrhea; is selective for COX in the uterine muscle
• Less gastric bleeding than aspirin
• Risk of renal impairment

First Gen NSAID - Naproxen (Aleve, Anaprox)

• Another non-aspirin NSAID
• Fairly selective for COX-1, less incidence of GI problems and MI/CVA than other non-ASA NSAIDs
• T1/2 of 12-17 hours, allows less frequent dosing
• Otherwise, same as ibuprofen

Second Gen NSAID - Celecoxib (Celebrex)

• MOA: inhibits COX-2 only
• Uses: arthritis, acute pain, dysmenorrhea
• Less GI problems than 1st-generation NSAIDs
• Increased risk of MIs and CVAs, can impair kidneys
• Use lowest effective dose for shortest possible time
• Not a good option for patients with heart disease

Non-Anti-Inflammatory - Acetaminophen (Tylenol)

• Uses:

  • Analgesia (pain reliever)
  • Antipyretic (fever reducer), preferred for children
  • No anti-inflammatory effects

• MOA: COX inhibition, thought to be limited to the CNS

• Pharmacokinetics:

  • Absorption: PO, PR, IV

• Metabolism: In the liver by two pathways: major and minor;

  • Major pathway: Acetaminophen converted directly into nontoxic metabolites
  • Minor pathway: CYP450 converts acetaminophen to a toxic metabolite; Glutathione required to then convert toxic metabolite to nontoxic metabolite

• 24-hour max for acetaminophen in adults: 4g

• Watch for acetaminophen in combo medications; Regular alcohol consumption reduces the liver's ability to metabolize excessive doses of acetaminophen

• Acetaminophen Toxicity:

  • Cause of 50% of acute liver failures
  • Manifestations of liver injury (hepatic necrosis) appear 48-72 hours after overdose
  • Early s/sx: N/V/D, sweating, abdominal pain/discomfort are initial signs
  • Late s/sx: Hepatic failure, coma, death
  • Antidote: acetylcysteine (Mucomyst) It substitutes for glutathione; 100% effective if given within 8-10 hours

Drugs for Headaches (Chapter 36)

• Headaches are a very common complaint. Mild, occasional headaches are often improved by over-the-counter (OTC) medications.
• Types of headaches:
  • Tension-type
  • Cluster
  • Migraine

Tension-type Headaches

• Most common type
• "headband", non-throbbing pain, tightness in head & neck
• Abortive: Ibuprofen, naproxen, aspirin-butalbital, acetaminophen
• Preventative: coping & relaxation skills, amitriptyline

Cluster Headaches

• Less common, mostly in males
• Occur in a series of cluster attacks
• Lasts 15 min – 2 hrs
• Unilateral pain near eye, lacrimation, ptosis, nasal congestion, rhinorrhea
• Abortive: Oxygen, sumatriptan
• Preventative: betamethasone, verapamil, lithium

Migraine Headaches

• Throbbing, moderate-severe pain that may be unilateral or bilateral
• May last for days
• Associated with nausea/vomiting, photo/phonophobia
• Aura vs. no aura
• More common & more severe in females
• Very debilitating
• Migraine Patho:
  • Neurovascular problem
  • Vasodilation & inflammation of the cranial blood vessels
  • Many possible triggers
  • Two neurochemicals are involved:
    • Calcitonin gene-related peptide - CGRP (causes migraines?)
    • Serotonin/5-HT (suppresses migraines?)

Abortive Therapy: Triptans (serotonin receptor agonists)

• Prototype: Sumatriptan
• Uses: Migraines & cluster headaches
• MOA: bind to and activate specific subtypes of serotonin receptors in the brain, causing vasoconstriction
• Pharmacokinetics:
  • Absorption: PO, SQ, inhalation
  • Metabolism: hepatic, T 1/2 = 2.5 hours
  • Follow maximum dosing instructions
• Adverse Effects:
  • 50% experience chest "heaviness” – this is not angina pectoris!
  • Coronary vasospasm - this IS angina pectoris!
  • increased risk in patients with CAD risk factors
  • Teratogen
  • Interactions: Ergot Alkaloids cause vasospasm (wait 24 hrs), SSRI/SNRI may cause excessive serotonin syndrome

Abortive Therapy: Ergot Alkaloids

• Prototype: Ergotamine
• Uses: Migraines & cluster headaches
• MOA – several possibilities: activation of serotonin receptors, blockage of cranial inflammation, cranial vasoconstriction
• Pharmacokinetics:
  • Absorption: PO, SL, PR, or inhalation
  • best absorption/distribution with PR and inhalation
  • Metabolism by CYP3A4, T 1/2 = 2 hours
• Adverse Effects:
  • Rare at therapeutic doses
  • Possible nausea/vomiting
  • Risk of dependence
  • Triptans cause vasospastic reactions (wait 24 hrs)
  • CYP3A4 Inhibitors raise levels to dangerous levels to cause vasospasm

Migraines: Preventative Therapy

• In patients who have frequent or severe migraines, ongoing medicine to prevent them may be necessary. Daily dosing
• Three common options:
  • Beta Blockers - propranolol (May cause tiredness, may exacerbate asthma)
  • Antiepileptics - topiramate (May cause fatigue and cognitive dysfunction)
  • Tricyclic Antidepressant - amitriptyline (May cause hypotension and anticholinergic effects)

Opioid Medications (Chapter 34)

• Opioid Analgesics
  • Endogenous opioid peptides: found in the central nervous system (CNS) and in peripheral tissues; serve as neurotransmitters, neurohormones, and neuromodulators
  • Opioids: drugs that have actions similar to endogenous opioid peptides, based on morphine

Opioid Receptors

• Mu - activation causes analgesia (pain relief), respiratory depression, euphoria, sedation, decreased GI motility, and eventual physical dependence
• Kappa - activation causes analgesia, sedation, and decreased GI motility
• Delta - no significant effects

Classifications of Opioid Drugs

• Pure Agonists: agonists for Mu and Kappa receptors (morphine, fentanyl, codeine, meperidine (Demerol), etc)
• Agonist-Antagonists: antagonist for Mu, agonist for Kappa receptors (Pentazocine (Talwin), nalbuphine (Nubain))
• Pure Antagonists: antagonists for Mu and Kappa (Naloxone (Narcan), naltrexone)

Strong Opioid Agonists

• Common drugs: morphine, hydromorphone, fentanyl, meperidine (Demerol), heroin, methadone
• Morphine is the prototype
• MOA: mimics endogenous opioids, activating mu and kappa receptors
• Clinical uses: relief of moderate to severe pain (postoperative, cancer-related, labor/delivery, Mls)

Strong Opioid Agonist: morphine

• Pharmacokinetics/Distribution: can be given practically any route; onset and duration differ; small amount crosses BBB, best with scheduled administration depending on pain severity

• Metabolism: affected by first-pass effect, liver inactivation

• Adverse Effects:

  • Respiratory depression
  • Constipation (common)
  • Orthostatic hypotension
  • Urinary retention
  • Nausea/vomiting
  • Cough suppression
  • Toxicity: coma, respiratory depression, pinpoint

• Drug Interactions

  • other CNS depressants
  • Anticholinergics
  • Antihypertensives
  • Agonist-antagonists
  • Antagonists

• Physical Dependence

• Intensity and duration of withdrawal syndrome depend on T 1/2 and degree of dependence on drug

• Morphine short half-life means withdrawal is intense (7-10 days)

• Initial reactions include yawning, rhinorrhea, sweating

• Anorexia, irritability, tremor, gooseflesh, violent sneezing, N/V/D, abd cramping, bone & muscle pain, kicking movts

Strong Opioid Agonist: fentanyl (Duragesic)

• Strong opioid, about 100x more potent than morphine
• Parenteral administration: for induction and maintenance of anesthesia
• Transdermal administration: for persistent severe pain; usually reserved for patients tolerant
• Metabolism: hepatic, by CYP3A4
• Adverse effects same as morphine

Moderate-Strong Opioid Agonists

• Examples: codeine, oxycodone, hydrocodone
• MOA is same as strong opioid agonists
• Main difference: less analgesia and respiratory depression; less abuse potential than strong agonists
• Many are co-formulated with APAP

Moderate-Strong Agonist: Codeine

• Uses: relief of mild to moderate pain, often co-formulated with acetaminophen; cough suppressant
• Pharmacokinetics/Metabolism:
  • Absorption: PO most common method
  • Metabolism: liver metabolizes 10% of codeine to morphine
• Adverse Effects: similar to morphine, increases with higher dosages, high dosages required for significant pain relief = dangerous side effects

Agonist-Antagonist Opioids

• Activate kappa receptors and block mu receptors
• Provide analgesia without as many side effects as pure agonists
• Less potential for abuse
• If used to replace a long-term opioid agonist, could cause withdrawal symptoms

Agonist-Antagonist: Pentazocine (Talwin)

• MOA: Activates kappa receptors causing analgesia, sedation, and limited respiratory depression
• Pharmacokinetics:
  • Absorption: PO administration
  • Metabolism: short T1/2; frequent dosing
• Adverse Effects: many similar to morphine, but less respiratory depression; Increases cardiac workload; not a good choice for pain related to myocardial infarction
• Physical dependence can develop but withdrawal is mild compared to pure opioid agonists

Opioid Antagonists

• MOA: block the opioid receptors
• Uses: reversal of opioid overdose, relief of opioid-related constipation, and treatment of opioid addiction
• No effect on their own; only used in combination with an opioid agonist

Opioid Antagonist: Naloxone (Narcan)

• Pharmacokinetics: 
  • Absorption highly affected by first-pass effect
• given parenterally or intranasally
• longer effects when given IM/SC
• Metabolism: hepatic, T1/2 about hours
• Adverse Effects: None on its own; if given to a person physically dependent on opioids, will cause immediate/severe withdrawal problems

The Opioid Epidemic- Nursing Considerations

• Nursing goals to minimize physical dependence and abuse of opioids
• Assess pain and dosage sufficient to relieve pain
• Administer lowest effective dose for shortest time needed
• As pain diminishes, opioid dosages should be reduced
• Switch patient to nonopioid analgesic as soon as possible