Pain Meds

• What meds are available for pain management

  • Opioid Agonists: Morphine, Codeine, Oxycodone, Hydrocodone, Hydromorphone, Fentanyl, Methadone, Meperidine
  • Mixed Agonist/Antagonist: Buprenorphine
  • Opioid Antagonists: Naloxone, Naltrexone
  • Other: Tramadol
  • Skeletal Muscle Relaxants: Tizanidine, Baclofen, Cyclobenzaparine
• Opioids overall MOA

  • Effects mediated by 3 G protein-coupled receptors (mu, kappa, delta), analgesic properties primarily mediated by mu receptors, but kappa receptor also contribute, interact w/ opioid receptors in CNS, GI tract, urinary bladder
  • Bind w/ receptors on presynaptic neurons (lead to decrease of both influx of Ca 2+ and release of excitatory NTs (glutamate)) and postsynaptic neurons (leads to increase in K+ efflux and decreased response to excitatory transmitters
• Opioids overall adverse effects

  • Respiratory depression, increased ICP (so DONT use in head injury), hypotension, bradycardia, n/v, constipation, sedation, pruritus (leads to release of histamine), addictive potential, opioid-induced neurotoxicity, allergy
• Opioids overall

  • Interact with drugs metabolized by CYP450, watch for drugs w/ additive CNS depressant effects 
  • Morphine leads to euphoria, analgesia, depression of cough reflex, respiratory depression, miosis, emesis, GI tract (constipation, n/v), CV (hypotension, bradycardia)
  • Used for analgesia w/o loss of consciousness, diarrhea, cough relief, tx acute pulmonary edema, anesthesia
• Morphine

  • Prototype strong mu receptor, major analgesic drug contained in crude opium
  • Pharmacokinetics
  • Least lipophilic of common opioids (very little crosses BBB)
  • Crosses placenta (should NOT be used in labor)
  • Oral, IV, rectal, subcutaneous, intrathecal, sublingual
  • 2 main metabolites: morphine 6 glucuronide (leads to analgesic effect) and morphine 3 glucuronide (can lead to neurotoxicity w/ high doses and/or in renal insufficiency)
• Codeine

  • Present in crude opium in lower concentration than morphine
  • Prototype of weak opioid agonists
  • Only effective for mild to moderate pain (often used in combination with acetaminophen)
  • Effective as an antitussive at low doses
  • Gets converted to morphine via CYP450 2D6
  • Some patients are rapid metabolizers → toxicity can occur
  • Drug interactions (CYP450 2D6) can lead to toxicity
• Oxycodone (Oxycontin)


  • Semi-synthetic derivative of morphine
  • Oral analgesic effect about twice the amount of morphine
  • May be combined with aspirin or acetaminophen
  • Excreted via kidney
  • Metabolized by CYP450 2D6 and 3A4
• Hydromorphone (Dilaudid)


  • Orally active, semisynthetic analog of morphine
  • 8-10 x more potent than morphine
  • Preferred over morphine in renal dysfunction
• Hydrocodone

  • Orally active, semisynthetic analog of codeine
  • Weaker analgesic effects than hydromorphone
  • Often combined with acetaminophen or ibuprofen for moderate to severe pain
  • Also used as antitussive
  • Metabolized via CYP450 2D6 pathway
• Fentanyl

  • Synthetic opioid related to meperidine
  • 100-fold analgesic potency of morphine
  • Also used for anesthesia
  • Pharmacokinetics:
  • Highly lipophilic
  • Rapid onset of action and short duration of action (10 to 30 mins)
  • Metabolized via CYP450 3A4 system 
  • Available IV, epidural, intrathecal, oral transmucosal, sublingual, buccal, nasal, transdermal (delayed onset, can lead to hypoventilation and death, never use in opioid-naive patients or for acute/post-op pain)
• Methadone

  • Synthetic, orally effective opioid
  • Acts as agonist on mu receptors, acts as antagonist on NMDA receptor, inhibits norepinephrine and serotonin reuptake
  • Variable potency compared to morphine
  • Induces less euphoria and has longer duration of action
  • Effective for nociceptive and neuropathic pain, used in controlled withdrawal of opioids and heroin
  • Should be used by experienced clinicians only b/c long half life (12-40 hours, up to 150 hours), can lead to accumulation and possible toxicity/overdose
• Meperidine

  • Low potency, synthetic opioid structurally unrelated to morphine
  • Acts primarily as kappa agonist w/ some mu agonist activity, also exhibits anticholinergic effects (results in higher incidence of delirium)
  • Used for acute pain, NOT for use longer than 48 hours
  • Can lead to delirium, hyperreflexia, myoclonus, possible seizure
  • Avoid use in elderly patients, renal insufficiency, hepatic impairment, pre-existing respiratory compromise, concomitant/recent use of MAOIs
• Buprenorphine

  • Mu opioid agonist, weak kappa antagonist, exhibits morphine-like (analgesic) effects in opioid naive patients but may precipitate withdrawal in patients previously exposed to opioid via receptor blocking effects
  • Used for analgesia, opioid detoxification (b/c it has shorter and less severe withdrawal sx compared to methadone), combine w/ naloxone for opioid dependence (combo aka suboxone)
• Opioid antagonists MOA: Naloxone and Naltrexone

  Binds w/ high affinity to opioid receptors but fail to activate the receptor-mediated response, in opioid naive → no clinical effect, in opioid exposed → precipitate sx of withdrawal
• Naloxone

  • For opioid overdose and reversal of coma/respiratory depression d/t opioid overdose
  • Can reverse effects of morphine within 30 seconds of IV injection
  • Half life of 30-81 minutes (relapse of respiratory depression can occur)
  • Rapid reversal of respiratory depression, minimal reversal of analgesic effects
  • Not active orally, has been formulated in combination w/ oral opioids to help deter IV drug abuse
• Naltrexone

  • For opioid dependence and alcohol dependence
  • Acts similar to naloxone but ORALLY active
  • Longer duration of action than naloxone → one dose can block effects of injected heroin for up to 24 hours
  • Used in combo w/ clonidine for rapid opioid detoxification
  • Can lead to hepatotoxicity
• Tramadol(Ultram)


  • Centrally acting analgesic, binds to mu opioid receptor, metabolized to active metabolic w/ stronger affinity for mu opioid receptors, weakly inhibits reuptake of serotonin and norepinephrine
  • Less respiratory depression than morphine, can decrease seizure threshold, overdose and drug interactions can lead to toxicity (CNS excitation/seizures)
  • Used for moderate to moderately severe pain
• Tizanidine

  • Centrally acting alpha 2 adrenoceptor agonist, leading to blockage of nerve impulses through presynaptic inhibition of motor neurons
  • Also for tx of MS symptoms
  • Produces more drowsiness and sedation than baclofen but it is NOT associated w/ the muscle weakness which can occur w/ baclofen
• Baclofen

  • GABA B receptor agonist, leading to reduction of motor neuron excitability
  • Also used for tx of neurodegenerative disease symptoms, particularly in MS but may contribute to muscle weakness
• Cyclobenzaparine (Flexeril)

  • MOA not clearly defined
  • Indicated for short term treatment of muscle spasms caused by acute painful, MSK conditions
  • NOT useful in tx of CNS neurodegenerative disease