Eisenberg – Opioid Analgesics – NS Exam 2
Uses
 Pain relief - dull, visceral pain
 Antitussive effects
 Treatment of diarrhea
 Acute pulmonary edema
Morphine & codeine
 Origin
o Phenanthrenes - morphine, codeine, thebaine
o Benzylisoquinolines - papaverine and noscapine
 Structural comparisons
o Morphine  OH
o Heroine  OCOCH3
 deacetylated morphine – crosses BBB 2.5 x faster
o Codeine  OCH3
o Nalorphine  OH
o Naltrexone  OH
 Pharmacological effects
o Mechanism of action - opioid receptors
 Specific opioid receptors in brain and spinal cord - binding sites. Why?
 Endorphins!
 Endogenous ligands
 ß-endorphin – likes all kinds of receptors
 leu/met-enkephalin
 dynorphin
 Neuronal mechanisms are slowly being worked out - possible mechanism
 Spinal sites – pain pathways
o Close voltage-gated Ca++ channels to prevent presynaptic neurotransmitter release
o Hyperpolarizing post-synaptic membranes by opening K+ channels
 Brainstem
 GABA normally inhibits pain inhibitory neurons
 Opioids activate pain inhibitory neurons indirectly by inhibiting GABA activity
 results in enhanced inhibition of nociceptive processing in the dorsal horn
 Supraspinal sites
 exogenous μ-opioids may cause the release of endogenous agents
 endogenous agents may act at ∂ and k-binding sites
 this may result in a change in pain threshold – imp in terminal pts
 There are 7 transmembrane regions and g-protein coupled activity
o Sequence similarities between types of receptors
 differences in the amino terminus region and the 2nd and 3rd extracellular loops suggesting
 specificity in ligand binding
 binding to transmembrane domains is responsible for high affinity binding
 Exogenous ligands
 Name recognition
 Effects on various systems
o CNS
 Analgesia
 dull, visceral pain
 changes in the pain threshold
 codeine has a ceiling effect & there has limitations for more severe pain
 Behavior - euphoria, sedation
o
o
o
o
o
o
o
 dopamine at the nucleus accumbens  pleasure
 patients receiving opiates for acute pain show significantly less euphoria
 Miosis - μ/k effect (parasympathetic effect on the pupil) – heroin addicts always have this
 Respiratory depression - depression of neurogenic, pCO2, pO2 drives
 Chemoreceptor trigger zone
 Causes vomiting!! until tolerance develops
 Apomorthing-dopaminergic agonist
 Probably a vestibular component because ambulation aggravates this
 antitussive effects
 lowers the seizure threshold
 hypothermia
 endocrine
 increases ADH
 decreases ACTH, LH, PIF, and TSH when given chronically (no sex crazed heroin addicts)
Cardiovascular system
 In the healthy, supine patient, there is little effect on HR, BP, or the myocardium
 Orthostatic (change in posture) hypotension
 histamine release - may cause flushing and itching of the blush area
 direct morphine effect on the blood vessels and through the central vasomotor centers
 hypotension is a particular problem if there is reduced blood volume
 Cerebral circulation
 lowered respiration may increase pCO2 and result in cerebral vasodilation and CSF
pressure -may aggravate a head injury
 Useful in MI or in patients with pulmonary edema due to acute left ventricular failure
 pain relief
 peripheral vasodilation is an advantage here – lowers the work load of the heart
 R side heart weakness – not pumping adequately  leg swelling
 L side heart weakness  backup is in lung which is why ppl take diuretics
Gastrointestinal system
 Increased tone: spastic paralysis ( constipation) and decreased peristalsis
 a direct and central action of opioids
 severe constipation - treatment for diarrhea
 treat with a laxative etc
 Increased biliary tract pressure
 meperidine is a better choice for renal colic
Genito-urinary system
 Spasm of the ureter
 Reduced urine production due to ADH release - μ effect
 Sexual activity is depressed
 depression of hypothalamo-pituitary-gonadal axis
 Labor may be retarded and the neonate depressed - little fetal blood-brain barrier to morphine addicted neonate – have to wean them with opium
Immune function
 Generally suppressive - a μ -effect
Chronic effects
 Apparently no long-term pathology due to opioids
Tolerance (cross-tolerance)
 pharmacodynamic: mechanisms behind dev of tolerance – change in neuronal system
 metabolic
 does not occur uniformly to all effects
Dependence (cross-dependence)

o
o
o




withdrawal effects – neurons change to accommodate presence of opioids over time so that
they function normally in presence of this drug. When take opioid away they decomensate!
 a NON-ISSUE in the terminally ill
Mechanisms for tolerance/dependence
 Dysfunction between the opiate receptor and the G-protein complex so the opioid is less
effective
 A change in the NMDA receptor action - a learning phenomenon involving the interaction
between pre- and post-synaptic events
 antagonism of the receptor with ketamine prevents tolerance development
Uncoupling of the μ/Δ dual receptor complex - complex appears necessary opioid action
Tolerance to chronic effects:
 Something new on the horizon - an opiate pain-reliever without tolerance and physical
dependence?
 Using a μ-agonist and a Δ-antagonist provides pain relief without tolerance/dependence
 mice without Δ-opioid receptors don’t show tolerance/dependence
 Drug combinations are being developed for trials
Absorption, distribution, metabolism, excretion
o Absorption is rapid by all parenteral routes
 morphine - 15-49% is available when given orally - first pass metabolism
 codeine - 70% available, much higher oral/parenteral ration
o Blood-brain-barrier is significant for morphine
 heroin (diacetyl-morphine) crosses
o Metabolic breakdown
 conjugation occurs mainly in the liver
 heroin is deacetylated after passage into the brain - converted to morphine
o Most is excreted in 24 hours
Side/toxic effects
o Common: dizziness, dysphoria, nausea, vomiting, constipation,
o Possible: biliary colic
o Allergic reactions
o Hypotensive reactions
 an antihistamine is sometimes included in a vial for IM administration
o Respiratory problems
 caution - pre-existing conditions
o Opioid overdose – naloxone, nalmefene (longer acting)
Drug interactions
o tricyclic antidepressants, phenothiazines, and barbiturates enhance respiration depression
Tramadol - Ultram
o A synthetic codeine analog approved for mild to moderate pain, used in Europe for many years
o Mechanisms
 binds weakly to μ-opioid receptors
 inhibits biogenic amine reuptake
 enhances serotonergic neurotransmission
o Good orally, active half-life of drug and one metabolite is 5-9 hrs..
o Causes less nausea and constipation than morphine
o Morphine was still rated superior
o CNS side effects: nausea, dizziness, constipation, sedation, and headache
 Associated with seizures, contraindicated where there is a history of epilepsy
o No more effective than codeine with aspirin/acetaminophen, and expensive
o Since pain relief may be independent of opioid receptors, it may be useful in chronic neuropathic pain
o Post-marketing survey shows an abuse liability


o A metabolite of tramadol has μ-agonist activity and will substitute for morphine to prevent withdrawal
o High doses (200-400mg) are required for this effect
Methadone and prophoxyphene
o Methadone (DOLOPHINE)
 properties and uses
 good oral long-acting analgesic - currently expanding in use
 extended duration of action (8+ hrs)
 withdrawal effects are less severe - useful in heroin detoxification
 well absorbed by all routes
 side effects are similar to morphine
 tolerance develops more slowly
 LAAM - long-acting, recently approved methadone analog (2-3 day dosing)
o Prophoxyphene (DARVON)
 properties and uses
 dextro form has analgesic activity
 about half as potent as codeine for analgesia
 well absorbed by all routes
 toxic doses produce CNS and respiratory depression
 abuse potential is lower than codeine - pleasurable effects are different
Meperidine (Demerol) and analogs
o Comparison with morphine
 good oral/parenteral ratio
 shorter duration of action 2-4 hrs
o Pharmacologic actions
 CNS actions are similar to morphine
 equivalent analgesia
 shorter duration
 CV effects
 antimuscarinic effects may cause tachycardia
 negative inotropic effect has been reported
 Smooth muscle effects
 less constipation (diphenoxylate and loperamide are commonly used)
 less spasm of the biliary tract and ureter
 Absorption, fate, and excretion
 Absorption is rapid by all routes
 Metabolism occurs mainly in the liver
 60% is excreted in the urine
 Side/toxic effects
 Side effects are like morphine plus atropine-like effects
 Normeperidine accumulation causes seizures
o when given in high doses
o in patients with renal compromise
o responsible for the gravitation from meperidine to morphine in the ER
 Drug interactions
 tricyclic antidepressants, phenothiazines, and barbiturates enhance respiration
depression
 CNS excitation with MAO inhibitors - probably due to an increase of normeperidine
 Therapeutic uses
 Indications are similar to morphine for analgesia
 Fentanyl and analogs (sufentanil, alfentanil, and remifentanil) are used for short-term
anesthesia and for chronic treatment in the terminally ill
o patches or lollipops are newer approaches to maintain adequate blood levels
o new buccal tablet for “breakthrough” pain acts very rapidly
Opioid antagonists
 Properties of naloxone, naltrexone, and nalmefene
o pretreatment prevents the action of the agonist
o administration of antagonist in a chronic user will precipitate withdrawal
 Used in heroin overdose - naloxone (t.= 1-2 hrs.), naltrexone and nalmefene (t.≈10 hrs.)
 Naltrexone (oral) is available to prevent a relapse into drug-taking behavior in high risk patients
 mu-receptor antagonist that doesn’t cross BBB
o Methylnaltrexone (Relistor) for pts getting pallitave care
 given sc every other day
 reduces constipation – produces GI side effects: abd pain, flatulence, diarrhea
o Alvimopan (entereg) to relieve postop ileus (bowel obstruction b/c peristalsis stops) floow partial large
or small bowl resection
Partial agonists
 Effects depend on administration
o agonist effects when given alone
o antagonist properties when administered after an opioid agonist
 Differential actions on specific opioid receptors
 Nalorphine
o Effects
 k-opioid effects - analgesia, miosis, respiratory depression, dysphoria when given primarily
 precipitate withdrawal in chronic users when given secondarily because it blocks mu-receptors
o Used to diagnose physical dependence
 Pentazocine (TALWIN)
o May increase HR and BP
o Uses and effects
 good oral, low level analgesic
 drug of choice if addiction problem exists
 does not substitute for other opioids to sustain dependence
 may precipitate withdrawal in chronic abusers
 oral form is combined with naloxone to prevent dependence relapse>
 Newer partial agonists
o Butorphanol (STADOL)
 actions are similar to pentazocine (increase in HR and BP)
 morphine is preferred in patients with cardiac problems
 for moderate to severe pain
 low abuse/dependence liability
 better for acute rather than chronic pain
 causes dysphoria and has limited potency
o Nalbuphine (NUBAINE)
 also has shown some success as an analgesic
 causes dysphoria and has limited potency
 abrupt removal will result in characteristic withdrawal signs
 may precipitate withdrawal in an individual already taking a low dose of morphine
 no cardiovascular stimulation as with pentazocine and no hypotension as with morphine
o Buprenorphine (BUPRENEX)
 can be used as an analgesic because of μ-agonist activity
 will antagonize the action of morphine if given secondarily
 because of high μ-agonist affinity but low intrinsic activity it can serve as a good substitute in
heroin maintenance
 has been found to be useful in reducing craving for heroin or cocaine during the withdrawal
period -a major advance in treatment
 now available in combination with naloxone – SUBOXONE
Antitussive agents
 Codeine or an analog
 Dextromethorphan
o d-isomer of methoxylated levorphanol
 Benzonatate
o a polyglycol derivative related to procaine
o may act on cough or stretch receptors in the lung, and by a central mechanism
Therapeutic use of opioids
 Guidelines
o what is the biggest recent advance in pain treatment? - pain level is now a routine vital sign
o administration for pain, cough or diarrhea is only symptomatic treatment
o adequate post-operative pain treatment yields a better outcome
o concern for dependence development is overdone - surveys suggest undermedication (especially true
of children)
o chronic use is undesirable
o alternative treatments for chronic pain conditions should be sought
o dependence in the terminally ill should NOT be a consideration
 good maintenance doses provide for smaller step increases
 patient-controlled medication
 Selecting a drug
o for moderate pain choose codeine
 good orally- sustained-release forms of morphine and oxycodone are available
 often combined with aspirin or acetaminophen
o meperidine is the drug of choice for biliary/renal colic
o select a short-acting drug when required for diagnostic procedures
o methadone is widely used as a substitute for heroin
o naloxone or nalmefene i.v. to reverse respiratory depression in opioid overdose
o dyspnea due to left ventricular failure is relieved by morphine
o loperamide or diphenoxylate for diarrhea