Opioid Outline by xV43uA2v


1) Terms
   a) Opiates
      i) Drugs derived from opium
           (1) Morphine
               (a) Alkaloid (plant) extract
               (b) Less lipid soluble & lasts longer
           (2) Codeine
           (3) Why do we have receptors for these exogenous substances?
               (a) We have endogenous substances
   b) Opioids
      i) Naturally occurring & synthetic opioid peptides (morphine-like compounds)
      ii) Receptors found first, then compound
      iii) Used for
           (1) Analgesia
           (2) Physiologic homeostasis
               (a) Blunt stress response
           (3) Hypnosis
               (a) Does not always provide amnesia
2) Endogenous opioid peptides (EOP)
   a) Large peptides
      i) Cleaved by peptidases to:
           (1) Smaller opioids
           (2) Non-opioids
   b) Transcribed & translated to distinct precursor polypeptides
      i) Pro-enkephalins
      ii) Pro-opiomelanocortin (POMC)
      iii) Pro-dynorphin
3) Endorphins
   a) Generic term referring to three families of endogenous opioid peptides
   b) ß-endorphins
      i) Endogenous ligand at the MU (μ)receptor
      ii) Found in:
           (1) Anterior pituitary
           (2) Hypothalamus
      iii) Derived from POMC
           (1) Final 31 amino acids form ß-endorphins
           (2) N-terminus similar to Met-enkephalin
           (3) Stable peptide
               (a) Can circulate in the plasma
           (4) Yields ACTH, MSH, and lipotropins
               (a) ACTH stimulates adrenal cortex
                   (i) Catecholamine release (stress response mediators)
                       1. Dopamine, NE, EPI, Cortisol, ADH
   c) Dynorphins
      i) Endogenous ligand at the KAPPA (κ) receptor
           (1) Role in antinociception at level of spinal cord
      ii) Similar distribution to enkephalins
      iii) Found in:
           (1) Cortex
           (2) Hippocampus
           (3) Hypothalamus
           (4) Posterior pituitary
      iv) Derived from pro-dynorphin gene
           (1) 17 amino acids (dynA) and shorter
               (a) N-terminus similar to Leu-enkephalin
               (b) Readily degraded peptide
                   (i) Does not circulate in plasma
   d) Enkephalins
      i) Endogenous ligand at the DELTA (δ) receptor
      ii) PAG, amygdala, hippocampus, locus ceruleus, and cerebral cortex
      iii) Found in:
           (1) Adrenal medulla
           (2) Catecholamine releasing neurons
      iv) Pentapeptides
           (1) Derived from pro-enkephalin gene
               (a) Readily degraded peptide
                   (i) Does not circulate in plasma
           (2) Try-Gly-Gly-Phe-Met (Met-Enkephalin)
           (3) Try-Gly-Gly-Phe-Leu (Leu-Enkephalin)
           (4) ID’d in 1975
      v) Released from short interneurons (inhibitory)
           within spinal cord
           (1) Laminae I & II
           (2) Act as neurotransmitters (NTs)
           (3) Bind to DELTA receptors on nerve terminals
               containing stimulatory NTs
               (a) Substance P
                   (i) Decrease SP release  decrease pain
4) Receptors
   a) Mu (µ)
      i) Located in brain and spinal cord
      ii) High affinity for ß-endorphins
      iii) Most clinically used opioids bind to Mu
           (1) µ
               (a) Mediates:
                   (i) Sedation
                   (ii) Analgesia
                   (iii) Miosis
                   (iv) Euphoria
                   (v) Constipation
                   (vi) Respiratory depression
           (2) µ1
               (a) Supraspinal analgesia
                   (i) Found in:
                         1. PAG
                         2. Midline Raphe Nuclei
                   (ii) Inhibits ACTH release
                   (iii) Increases prolactin release
           (3) µ2
               (a) Mediates respiratory depression and constipation
               (b) Spinal analgesia
                   (i) Found in:
                         1. Spinal cord
                         2. Dorsal root ganglia
                   (ii) Inhibits DA release
                   (iii) Increases GH release
   b) Kappa (κ) (spinal cord)
      i) Dynorphin-A is endogenous ligand
      ii) Mediates miosis, sedation, respiratory depression and euphoria
           (1) Similar to Mu receptors
      iii) κ
           (1) Mediates:
               (a) Sedation
               (b) Miosis
               (c) Ventilatory depression
               (d) Psychotomimesis
                   (i) Dysphoria
               (e) GIT inhibition
      iv) κ1
           (1) Mediates:
               (a) Diuresis
           (2) Spinal
               (a) Analgesia
      v) κ3
           (1) Mediates:
               (a) Supraspinal analgesia
c) Delta (δ) (vas deferens)
   i) Enkephalins are endogenous ligands
   ii) β-endorphins bind equally well
   iii) Mediates analgesia supraspinally and in spinal cord
        (1) Spinal system is more robust
            (a) Stronger effect in spinal cord
        (2) δ
            (a) Inhibits DA release
            (b) Increase GH release
        (3) δ1
            (a) Supraspinal analgesia
        (4) δ2
            (a) Spinal and Supraspinal analgesia
5) Mechanism of action (C & Aδ fibers)
   a) Opioid receptors are G-protein coupled receptors
   b) Gi / Go – coupled superfamily
      i) Inhibits adenylyl cyclase (AC)
           (1) Decrease cAMP
      i) Membrane hyperpolarization  IPSPs
      ii) Reduced excitability
      iii) Reduced NT release
      i) Reduce intracellular calcium  reduced NT
      i) Decrease cAMP levels
           (1) Inhibits transmitter release
               (a) ACh
               (b) NE
               (c) GABA
               (d) Substance P
      ii) Reduce activity of cAMP activated enzymes
      iii) Alter expression of cAMP activated genes
6) CNS effects of Opioids
   a) Analgesia
      i) Reduction in severity of perceived pain without
           loss of consciousness
   b) Drowsiness
   c) Sedation
   d) Mood changes
   e) Mental clouding
   f) Euphoria
   g) High doses produce seizures (in animal models)
      i) Excitation of hippocampal pyramidal cells
           (1) Inhibits GABA release
   h) CBF
      i) No direct effect
   i) CMRO2
      i) Little to no change
   j) ICP
      i) Little to no effect
           (1) Opioid-induced muscle rigidity may increase ICP
   k) Miosis
      i) Most Mu & Kappa agonists cause pupillary constriction
           (1) Stimulation of nucleus of Edinger-Westphal (CN III)
   l) Nausea
      i) Direct stimulation of
           Chemoreceptor Trigger Zone (CTZ)
           (1) Area postrema of medulla
           (2) Vestibular component
   m) Antitussive
      i) Depression of cough reflex
           (1) Inhibition of medullary cough
           (2) Dextroisomers most effective
               (a) Heroin
               (b) Codeine
           (3) Dextromethorphan does not
               have analgesic or addictive
   n) Motor effects
      i) Lab animal study
           (1) Rigid immobility (catatonia)
           (2) Stereotyped behaviors in rats (licking, chewing)
           (3) Skeletal muscle rigidity with rapid administration of opioids
               (a) “Mahogany chest”
                   (i) Paralyze to treat
               (b) Seen in short latency opioids
                   (i) Fentanyl, Alfentanil, Remifentanil
               (c) Central effect on basal ganglia – fine motor functioning
   o) Excitation
      i) High doses of morphine or fentanyl can produce seizure activity in lab animals
   p) Mood effects
      i) Mu agonists activate dopaminergic neurons in the nucleus accumbens
      ii) Related to euphoric effects
           (1) VTANucleus accumbensPrefrontal cortexeuphoria effects
      iii) Euphoric effects are related to abuse
7) Respiratory effects of Opioids
   a) Ventilatory depression
      i) May be mediated by mu2 receptors
      ii) Main cause of death associated with opioid administration
      iii) High concentrations of opioid receptors in medullary respiratory centers
      iv) Reduction in response to CO2
           (1) Shifts response curve to the right
               (a) Require a higher CO2 level to stimulate a breath
      v) Dose dependent respiratory depression of brainstem respiratory centers
           (1) After large doses, pts will breath IF instructed to
      vi) Decreased minute volume VE
      vii) Decreased rate (f)
           (1) Slight increase in VT
      viii)Effects reduced by:
           (1) Administration of antagonists
           (2) Development of tolerance
           (3) Pain may counter the ventilatory depression
8) CV effects of Opioids
    a) Cardiac stability
       i) Ideal for ischemic patients or patients in failure
            (1) Slow HR
            (2) Peripheral vasodilation
            (3) Minimal direct effects on myocardium
    b) Attenuates increase HR during induction/intubation
    c) Decreases IV anesthetic requirements
    d) Attenuate or prevent increases in HR that accompany use of inhaled anesthetic agents
    e) Cause hypotension in patients with high sympathetic activity
       i) Hypovolemia
       ii) Pts with low catecholamine reserve
       iii) Acute MI or CHF
    f) Produce bradycardia thru vagal stimulation in the brainstem
       i) Increases in vagal tone may cause prolonged AV conduction
       ii) Treat with atropine or glycopyrulate
       iii) Asystole may follow
            (1) Alfentanil and sufentanil
            (2) Attenuated by antimuscarinic (anticholinergic) drugs
    g) May be direct depression of SA node
    h) Opioids have anti-dysrhythmic effects
    i) No significant effects on inotropy
9) Peripheral vascular effects of Opioids
    a) Peripheral vasodilation
       i) Depression of vasomotor center in medulla
       ii) Affects resistance and capacitance vessels
       iii) Release histamine
            (1) Morphine
            (2) Meperidine (Demerol)
       iv) Possible direct effect on vascular smooth muscle
       v) Decreases CNS sympathetic outflow
10) GI effects of Opioids
    a) Decreases lower esophageal sphincter tone (LES)
    b) Delays gastric emptying
       i) Central effect
            (1) Vagally mediated
       ii) Peripheral effect
            (1) Myenteric plexus
    c) Inhibits peristalsis
       i) Anti-diarrheal agents
            (1) Loperamide (Lomotil)
            (2) Diphenoxylate (Immodium)
    d) Increases biliary duct pressure (biliary spasm)
       i) Increases sphincter of Oddi tone
            (1) Morphine causes greatest constriction
                (a) Reversible with naloxone (Narcan) or glucagon
11) Other effects of Opioids
    a) Renal
       i) Inhibition of micturation and the voiding reflex
            (1) Urinary retention most common after intrathecal use
       ii) Relaxes bladder smooth muscle (detrussor muscle)
    b) Pruritus
       i) Receptor mediated
            (1) Not histamine related
       ii) Narcan can reverse effects
       iii) “Scratching center” in medulla in animals
            (1) Unknown human correlations
       iv) Peri-facial itching is common
    c) Histamine release
       i) Morphine and meperidine can stimulate release of histamine
            (1) Vasodilation and hypotension
       ii) Fentanyl family doesn’t stimulate release of histamine
1) Morphine and Related Opioids
   a) Several alkaloids are extracted from poppy
   b) Alkaloids fall into one of two categories
      i) Phenanthrenes
           (1) Morphine
           (2) Codeine
               (a) Methylmorphine
           (3) Thebaine
               (a) Poor analgesic
               (b) Precursor to etorphine
                   (i) >1000 times more potent as morphine
               (c) Precursor naloxone and oxycodone
      ii) Benzylisoquinolines
           (1) Papaverine – smooth muscle relaxant
           (2) Noscapine – antitussive
   c) Morphine
      i) Least lipid soluble
      ii) 25-35% plasma protein bound
           (1) Bound to albumin and alpha1 – acidic glycoprotein
      iii) Weak base
           (1) pKa: 8.0
           (2) Ionized at physiologic pH
      iv) Hepatic biotransformation
           (1) Conjugated to m-6-glucuronide (M6G)  m-3-glucuronide (M3G)  excreted in urine
           (2) M6G may play a significant role in patients chronically receiving morphine
               (a) Can’t convert to M3G
           (3) Elimination of metabolites in renal patients may make them more prone to respiratory
               depression with small doses of MSO4
           (4) Formulation of glucuronide conjugates may be impaired in pts with MAOI
               (a) May get exaggerated effects with MSO4
      v) t1/2ß (elimination) may be prolonged in elderly, renal patients, and neonates
      vi) Prototype that opioids are compared
      vii) MSO4 increases pain threshold and modifies perception of noxious stimuli
      viii)Analgesia most prominent when given BEFORE painful stimuli (pre-emptive analgesia)
           (1) PO dose unpredictable
               (a) Decreased bioavailability
           (2) IM: onset 15-30 min with duration 4hrs
           (3) IV onset in 5 min; peak effect 15-30min
               (a) <0.1% enters CNS
      ix) CV effects of morphine
           (1) Decreases SNS tone and compensatory SNS responses
               (a) Decreased venous return, decreased CO, decreased BP
               (b) Can induce hypotension by drug-induced bradycardia and histamine release
               (c) BZs + opioids results in decrease in SVR and BP
                   (i) Due to vagal nuclei stimulation
d) Codeine (3-methoxymorphine)
   i) Methyl group on #3 carbon limits first-pass hepatic metabolism
   ii) Effective with oral and parenteral administration
   iii) 10% is demethylated to form morphine
        (1) Ineffective binding with opioid receptors
        (2) Analgesic effect due to morphine conversion (approx. 10%)
   iv) Antitussive effects from binding to distinct receptors
        (1) Dextromethorphan
   v) 60 mg codeine ~ 650 mg aspirin
   vi) 120 mg codeine IM ~ 10 mg MSO4
   vii) Minimal sedation, N/V, and constipation
   viii)Use with neuro pts
        (1) Preserve ability to assess mental status
   ix) Avoid IV administration
        (1) Histamine release
            (a) Induces hypotension
e) Diacetylmorphine (Heroin)
   i) Acetylation at the #3 & #6 carbons
   ii) Synthesized from MSO4
   iii) Rapidly accumulated in brain after IV dose
        (1) “Rush” sought by addicts
   iv) 2.5 times analgesic potency of MSO4
   v) Metabolized to 6-monoacetylmorphine  morphine
f) Meperidine (Demerol, Pethidine)
   i) “Dirty” drug
   ii) Phenylpiperidine
   iii) Mu agonist
   iv) Atropine-like agent, may increase HR
        (1) Synthesized in Germany in 1939
   v) Onset 10-15min
        (1) Peak: one hour
        (2) Duration: 2-4hrs
   vi) May interact with MAOI
        (1) Get respiratory depression, excitation, delirium
   vii) Toxic doses may cause CNS excitation and convulsions
        (1) Normeperidine is an active metabolite
   viii)1/10th potency of MSO4
        (1) 100 mg Demerol = 10 mg MSO4
        (2) Better absorbed than MSO4
   ix) 90% hepatically metabolized to normeperidine
        (1) ½ as potent as meperidine
        (2) Can produce CNS stimulation
   x) Primary Urine elimination
        (1) Increased t ½ ß (elimination) with renal disease
        (2) Accumulation can result in myoclonus and seizures from long term exposure
            (a) PCA use > 72 hrs
   xi) Maybe responsible for delirium (confusion and hallucinations)
   xii) Primarily used for L&D, post-op pain
   xiii)Suppressing post-op shivering
        (1) May stimulate kappa receptors (10% of its activity)
        (2) Butorphanol (Stadol)
            (a) kappa receptor agonist-antagonist
            (b) Used for shivering
   xiv) Not used in high doses b/c of its significant (-) inotropic effects + histamine release
        (1) Decreased myocardial contractility (unlike other opioids)
   xv) No antitussive effects
   xvi) Atropine-like effects
        (1) Mydriasis (pupil dilation)
            (a) Others cause constriction
        (2) Dry mouth
        (3) Increased HR
g) Fentanyl Citrate (Sublimaze)
   i) Synthetic related to phenylpiperidines
   ii) Primarily Mu agonist
        (1) 80-100 times more potent than MSO4
   iii) High doses may cause muscular rigidity
        (1) May be effect of dopaminergic stimulation in striatum
            (a) Basal ganglia
   iv) Historically used with droperidol in neuroleptanesthesia (Innovar)
        (1) Catatonic stupor
   v) Undergoes hepatic metabolism
   vi) Extremely fat soluble
        (1) Accounts for rapid onset and short duration
   vii) Fentanyl easily crosses BBB
        (1) Peak: 3-5min
   viii)Vd = 4L / kg
   ix) Analgesic dose
        (1) ~ 1 - 2 mcg / kg
        (2) ~2 - 20 mcg / kg to blunt SNS
   x) Larger doses (>20mcg / kg)
        (1) Redistribution is insufficient to drop plasma levels
   xi) Rapid onset and shorter duration than morphine
   xii) Blood to brain time is 6-8 mins
   xiii)Short duration of action
        (1) t½ α (distribution)
   xiv) Lungs serve as a large inactive storage site
        (1) 75% initial dose undergoes “1st pass” pulmonary uptake
   xv) Metabolized to N-demethylation  norfentanyl (<potent)
   xvi) Excreted by kidneys
   xvii) Long terminal half-life
   xviii) Greater t½ ß than morphine b/c increased lipid solubility
        (1) Prolonged in elderly from decrease in hepatic blood flow
   xix) Increased context-sensitive half-time b/c saturation of inactive tissue sites and return to
        plasma from peripheral sites
   xx) Can give transmucosal and transdermal
   xxi) Side effects
        (1) Respiratory depression, decreased carotid sinus baroreflex
   xxii) Synergistic with BZ to cause increased respiratory depression and cardiac depression
h) Sufentanil
   i) 7-10 times more potent than fentanyl
   ii) 1000 time more potent than morphine
   iii) Parallels increased affinity to Mu receptor
   iv) pKa: 8.0
   v) Effect-site equilibration time = 6.2 min
        (1) Similar to fentanyl = 6.8 min
   vi) Twice as lipophilic as fentanyl
        (1) Increased BBB penetration
   vii) Short t½ß (elimination)
   viii)Undergoes hepatic metabolism
        (1) Via N-dealkylation and O-demethylation
   ix) Increased renal absorption and increased access to microsomal enzymes
   x) Increased respiratory depression in CRF with increased plasma concentrations
   xi) Redistribution to inactive tissue sites
   xii) 60% initial dose goes thru “1st Pass” pulmonary uptake
   xiii)Highly protein bound (93%)
        (1) Increased protein binding = 92.5% vs. fentanyl = 79-87%
            (a) Decreased Vd
   xiv) Good for continuous infusions
        (1) Short context-sensitive half-time
        (2) Good steady-state with HR & BP
   xv) Good for decreasing coughing & bucking
        (1) Use with
            (a) Abdominal cases
            (b) Neuro
                (i) Increased ICP
            (c) ENT
i) Alfentanil
   i) 1/3 potency of fentanyl
   ii) Shorter acting with 1/3 duration
   iii) Less lipid soluble than fentanyl
        (1) Highly protein bound by AAG
   iv) Undergoes hepatic metabolism
   v) Increased Nausea and vomiting
   vi) Rapid effect-site equilibration = 1.4 min
   vii) Low pKa, 90% unionized to cross BBB
   viii)Smaller Vd
   ix) Metabolized by liver
        (1) N-dealkylation
        (2) Metabolism 96% efficient in 60 mins
        (3) Unpredictable infusion relating to P4503A4 activity variability
            (a) Erythromycin may prolong effects of alfentanil
   x) Great for one time SNS stimulants
        (1) Direct laryngoscopy
   xi) Short cases
        (1) EENT
        (2) Reductions
        (3) Biopsy
j) Remifentanil
   i) Ultra short acting
        (1) Newest opioid in clinical practice
   ii) Unique pharm profile
   iii) Undergoes extrahepatic hydrolysis
        (1) Non-specific plasma and tissue esterases (NOT psuedocholinesterases)
            (a) Found everywhere
   iv) Context-sensitive half life
        (1) Less than 5 min (regardless of duration
            of infusion)
   v) Similar potency as fentanyl
   vi) Blood-brain effect-site equilibration (1.1min)
        is similar to Alfentanil
   vii) Ester hydrolysis by non-specific plasma and
        tissue esterases to inactive metabolites
        (1) NOT pseudocholinesterase
   viii)Brief action, precise titration b/c quick on
        and off
        (1) Very little accumulation effects, rapid
   ix) Decreased Vd, rapid clearance and low
   x) Metabolism not altered in liver disease
k) Clinical Correlations
   i) Levorotatory isomers are most active
   ii) Fen, suf, remi, alf have higher potency and rate of equilibration between plasma and site of
        drug action
   iii) Peripheral effects, i.e. presynaptic inhibition when give intra-articular Morphine
   iv) Severe pain may be resistant to κ receptor activation
   v) Electrical stimulation of brain sites or mechanical stimulation (acupuncture) most likely
        reflect release of Endorphins
   vi) Avoid inducing intraoperative hypocarbia to maintain adequate ventilatory drive postop
        (1) May stimulate pt to breathe with slightly higher ETCO2 parameters in OR
   vii) κ and μ receptors share several effects
        (1) Analgesia, sedation, respiratory. depression
   viii)Opioid analgesic effects probably results from actions at several levels of neural processing
   ix) Opioids do NOT produce amnesia
   x) All opioids produce equal respiratory. depression at equivalent doses
   xi) Histamine releasers: Morphine, Codeine, Demerol
        (1) Local histamine reactions occur, but true allergies rare
   xii) Produce vomiting by stimulating the CTZ which activates vomiting center
   xiii)Large IV doses of opioids can cause generalized skeletal muscle hypertonia
        (1) Most common with Fentanyl family
   xiv) Systemic absorption of epidural opioids can affect neonate
   xv) Maternal opioid addiction can cause baby to have withdrawal symptoms
   xvi) Morphine analgesia effects peak 15-30min after IV dose
 l) Neuraxial Opioids (spinal cord)
     i) Can decrease MAC for volatile anesthetics, reducing dose requirements
     ii) Penetration of dura (CSF level) is reflected by lipid solubility
         (1) Fentanyl peaks at 20min
         (2) Sufentanil peaks at 6min
         (3) Morphine
             (a) Least lipophilic opioid
             (b) Peaks 1-4hrs
             (c) Approximately 3% crosses BBB
             (d) Can have delays in distribution from epidural/SAB admin to brain- rostral sites of
             (e) Stays in CSF longer so bulk flow can reach 4th and lateral ventricles in 3-6hrs.
             (f) Side effects:
                 (i) Pruritus – Trigeminal nucleus
                 (ii) N/V
                 (iii) Urinary retention
                       1. Sacral PNS inhibition??
                 (iv) Respiratory depression occurs within 2 hrs for 1% of population
                       1. Delayed respiratory depression up to 12-24 hrs later due to migration and
                           action on receptors in ventral medulla
                           a. Monitor pt for at least 24 hrs after administration
             (g) Naloxone drip (0.25μg/kg/hr) to relieve N/V and pruritus effects
      Opioid         Intrathecal Duration of           Epidural       Duration of  Cont. gtt Dose
                                    action 1 shot                    action 1 shot    (epidural)
                                       (spinal)                        (epidural)
       MSO4            .1-.3 mg        8-24 hrs          1-6 mg         6-24 hrs      .1-1 mg/hr
    Fentanyl           5-25 ug          2-4 hrs        25-100 ug        1.5-3 hrs   25-100 ug/hr
    Sufentanil         5-10 ug          2-4 hrs         10-60 ug         2-4 hrs     10-50 ug/hr

  Opioid       Perioperative        General         Induction Dose       Continuous       Histamine
                Analgesia        Anesthesia                               Drip Dose        Release
                   Dose            (Nitrous-
                                Narcotic) Dose
  MSO4          .05-.2 mg/kg      .2-.3 mg/kg          1-2 mg/kg                               Y
Meperidine       .5-2 mg/kg        2-3 mg/kg                                                   Y
 Fentanyl        .5-2 ug/kg        2-8 ug/kg          50-150 ug/kg                             N
 Sufentanil                       .2-.8 ug/kg          10-30 ug/kg      .25-1 ug/kg/hr         N
 Alfentanil                      10-75 ug/kg                            .5-3 ug/kg/min         N
Remifentanil                                          1 ug/kg/min            .5-20             N
                                                     Loading Dose*        ug/kg/min
1) Opioid Antagonists
   a) Drug that blocks some or all opioid receptor subtypes
   b) Minor structural changes to opioid agonists can form antagonists
   c) Pure μ receptor antagonists, no agonist activity
   d) May need to re-administer dose after 30-45 min (naloxone, naltrexone, nalmefene)
      i) Re-sedation
   e) Give low dose slowly to decrease N/V & pruritus
   f) Low dose can reverse SNS effects
      i) May not effect analgesia
   g) May have increase in SNS response after admin
   h) Major clinical use
      i) Manage acute opioid overdose
   i) Naloxone (Narcan)
      i) 0.4-0.8mg, IV
      ii) Onset 1-2 min
      iii) Short duration 1-4hrs
      iv) ↑RR, ↓sedation
      v) May precipitate non-cardiogenic pulmonary edema
           (1) Naloxone induced pulmonary edema
           (2) d/t rebound catecholamine release
      vi) No discernable effects in absence of opioids
      vii) At high dosages (>0.3mg/kg)
           (1) Can have ↑ SBP
           (2) Poor performance of memory tasks
      viii)May require multiple doses
   j) Naltrexone (Revia)
      i) Long t1/2 (8-12 hrs)
      ii) Duration 24-48 hrs
      iii) Given PO
           (1) Patient must be compliant
      iv) Used in dependency programs
           (1) Alcohol, heroin, opioid addiction
   k) Nalmefene (Revex)
      i) Analogue to Naltrexone
      ii) Longer duration of action
           (1) Can treat delayed respiratory depression from opioids
   l) Methylnaltraxone
      i) Quaternary opioid receptor antagonist
      ii) Highly ionized
      iii) Can not cross BBB
           (1) Peripheral effects without CNS effects
           (2) Used to treat constipation
1) Mixed Partial Agonist/Competitive Antagonists
   a) Drugs that activate some opioid receptor
      subtypes and block other subtypes
   b) κ and δ receptor partial agonists (most often κ)
   c) μ receptor partial agonist or competitive
   d) Structurally similar to morphine
      i) Used to treat moderate to severe pain
      ii) Produce drowsiness and mood effects
           different from pure agonists
           (1) “Apathetic sedation”
           (2) Dysphoria possible instead of euphoria
   e) Ceiling on toxic effects
      i) More drug does not produce higher effect
      ii) Respiratory depressant
      iii) Analgesia
   f) Pentazocaine (Talwin)
      i) Opioid agonist
           (1) Moderate pain relief
           (2) Can be antagonized by Naloxone
           (3) Gives rapid analgesia when used
               for epidural (κ receptor in spinal
           (4) ↑ dysphoria with higher doses
           (5) ↑HR and BP
      ii) Weak antagonist
           (1) Can cause withdrawal effect
   g) Nalbuphine (Nubain)
      i) Chemically similar to Naloxone
      ii) Opioid partial agonist
           (1) Affinity for κ receptors
           (2) Ceiling effect on respiratory depression
           (3) Sedation common
           (4) No ↑HR or BP
      iii) Antagonist
           (1) Effects from binding to μ receptor
           (2) Preop use may interfere with opioid admin intraoperatively
           (3) Can antagonize respiratory depression postop but leave analgesia intact
               (a) 10-20mg IV reverses Fentanyl as described
   h) Butorphanol (Stadol)
      i) Actions resemble Pentazocaine
      ii) Opioid partial agonist
           (1) Moderate affinity for κ receptors
           (2) Causes analgesia, anti-shivering
           (3) Side effects: nausea, sedation, diaphoresis
           (4) Respiratory depression similar to equal doses Morphine
           (5) ↑HR and BP
      iii) Weak antagonist
           (1) Can reverse some opioid agonist effects (careful use in chronic cancer pts.)
           (2) Low affinity for μ receptors
               (a) Binds when agonist released
i) Buprenorphine (Buprenex)
   i) Derivative of Thebaine
   ii) Partial agonist
        (1) Potent analgesic 0.3mg = 10mg Morphine
        (2) Higher μ affinity than Morphine (50X)
        (3) Resistant to Naloxone antagonism
            (a) Does not want to leave receptor, Naloxone can not bind
        (4) Moderate to severe pain treatment
            (a) Higher pain control requires higher doses pure agonist
        (5) Ceiling respiratory effects also
   iii) Antagonist
        (1) Can cause withdrawal symptoms in opioid dependent pts.
        (2) Can displace pure opioid agonists from μ receptors
        (3) If Mu receptors occupied
            (a) Give κ agonist for pain relief
j) Dezocine (Dalgan)
1) Non-Opioid Analgesics
   a) Tramadol
      i) Centrally acting analgesic
      ii) Synthetic analog of Codeine
      iii) Low affinity for μ receptors
      iv) Racemic mixture:
           (1) (L) enantiomer weakly inhibits NE reuptake
           (2) Other enantiomer weakly inhibits reuptake of 5HT, has μ receptor affinity
      v) Partially antagonized by naloxone (30%)
      vi) Opioid like side effect
           (1) Nausea
   b) Other receptors
      i) Sigma (σ) receptors (psycho)
           (1) Not in opioid family
           (2) Not antagonized by Naloxone
           (3) Ketamine is σ agonist
      ii) Orphan receptors (ORL-1)
           (1) High degree of homology with other opioid receptors (in rats, mice & men)
           (2) Non-selective opioid ligands have low affinity
           (3) This receptor’s ligand similar to dynorphin
   c) Clinical Correlations of Agonist-Antagonists
      i) Careful opioid use so antagonist use is rare
      ii) Carefully titrate from low dose to specific effect
      iii) Treat/prevent some opioid side effects
      iv) Respiratory depression is difficult to reverse without reversing analgesia
1) Pain Mechanisms
   a) Afferent nociceptive pathways end in post-central gyrus/ somatosensory area
   b) Pain fibers: Aδ and C-fibers
   c) Opiates work at receptor sites in:
      i) Periphery (ie. intra-articular)
      ii) Dorsal Horn, Laminae I & II
      iii) PAG- Periaqueductal Gray Horn of the Midbrain
2) Afferent (ascending) pathway
   a) Primary afferents
      i) Cell body in dorsal root ganglia
      ii) Info transmitted to spinal cord
   b) Spinothalamic Tract (most prominent pain pathway)
      i) Lateral thalamic nuclei
      ii) Medial thalamic nuclei
   c) Spinoreticular tract
      i) Pontine reticular formation
   d) Spinomesencephalic tract
      i) Mesencephalic reticular formation
      ii) PAG
3) Descending pathway
   a) Endogenous opioid peptides involved in
      ascending & descending inhibitory pathways
   b) Exogenous opioids act to mimic these
   c) Most are mediated by activation of mu
   d) PAG  ventral medulla  dorsolateral
      funiculus  dorsal horn (laminae I & II)
      i) Electrical stimulation can produce
           (1) Where TENS works
   e) Injury response
   f) Peripheral sensitization
      i) Triple response
           (1) Flare (increased blood flow)
           (2) Wheal (edema)
           (3) Sensitization of nociceptors (hyperalgia)
      ii) Release of chemical mediators
           (1) BK, 5HT, PG
           (2) Stimulation of C-fibers and A delta fibers  dorsal horn
g) Central mechanism
   i) Secondary hyperalgesia
        (1) Reflects sensitization in the
            dorsal horn
        (2) Plasticity changes
            (a) Increased pain after
                removal of noxious stimuli
   ii) Manifestations include
        (1) Increased pain intensity
        (2) Allodynia
            (a) Pain from non-noxious
        (3) Flexion reflexes (splinting)
        (4) Alterations in regional
            sympathetic tone
h) Neuroendocrine responses
   i) Stress response to injury
        (1) Hyperglycemia
        (2) Increases glucagon, cortisol, GH, catecholamines
        (3) Inhibition of anabolic mediators
            (a) Insulin & testosterone
        (4) Increased in gluconeogenesis and glycogenolysis
            (a) Increased proteolysis
i) Symathoadrenal response
   i) Stimulation of sympathetic preganglionic neurons in anterior lateral horn
   ii) Increased release of EPI and NE
   iii) Dramatically affects key organ systems
        (1) Increased chronotropy and inotropy
        (2) Changes in vascular resistance and coagulability
        (3) Increased RR and decreased VT
j) Factors affecting perception
   i) Previous experience
   ii) Observational learning, models for pain and reinforcement
   iii) Cultural factor
k) Cognitive factors
   i) Pain beliefs and meaning of pain
   ii) Anxiety and fear
   iii) Depression
   iv) Anger, irritability, & frustration
l) Coping styles and strategies
   i) Active vs. avoidant
   ii) Internal vs. external locus of control
   iii) Negative thinking and catastrophizing
   iv) Family and social influences
4) Pain assessment
   a) Patient self report: very reliable, but not universal
   b) Numerical or VAS
      i) Verbal pain scales
      ii) McGill Pain Questionnaire (MPQ)
   c) Tools must be appropriate for cognitive status
5) Pain management principles
   a) Assessment requires rapport
   b) Unrelieved pain has negative effects
   c) All pain will not be eliminated
      i) Explain that meds will take the “edge” off of the pain, but may not completely remove pain
   d) Prevention is better thank treatment
   e) Communication problems require special attention
   f) Unexpected intense pain raises suspicion
6) Goal of pain management
   a) Educate patients, family and staff
   b) Reduce incidence & severity of pain
   c) Enhance patient comfort and satisfaction
   d) Reduce post-op complications
7) Treatment Modalities
   a) Pharmacologic interventions
      i) Opioids
           (1) Central
               (a) Act on brain & spinal cord
           (2) Peripheral
               (a) Blocks C & Aδ fibers
      ii) NSAIDS
           (1) COX-2 Inhibitors
           (2) Blocks prostaglandin production
      iii) Local Anesthetics
           (1) Blocks C & Aδ fibers
      iv) Psychotropic Drugs
           (1) Antidepressants
               (a) Lithium Carbonate
           (2) Antianxiety agents
           (3) Inhibit reuptake of neurotransmitters that modulate pain
           (4) Adjunct for chronic pain
   b) Surgical Techniques to alleviate pain
      i) Central neurosurgery
           (1) Cordotomy – ablation of spinal cord areas
           (2) Lesioning dorsal root entry zone (DREZ)
           (3) Tractotomy – lesion part of ascending tract
               (a) Bulbar and pontine spinothalamic
   c) TENS – transcutaneous electrical nerve stimulation
      i) Releases endogenous β-endorphins
d)   Vibration
e)   Acupuncture
f)   Placebo
g)   Cognitive and

  Neurotransmitter             Receptor          Effect on Nociception
      Substance P                NK-1                   Excitatory
Calcitonin Gene related                                 Excitatory
       Glutamate          NMDA, AMPA, kainite,         Excitatory
      Aspartate           NMDA, AMPA, kainite,         Excitatory
         ATP                    P1, P2                 Excitatory
    Somatostatin                                       Inhibitory
    Acetylcholine              Muscarinic              Inhibitory
    Enkephalins                  µ,δ,κ                 Inhibitory
    β - Endorphin                µ,δ,κ                 Inhibitory
   Norepinephrine                 α2                   Inhibitory
     Adenosine                    A1                   Inhibitory
      Serotonin                  5-HT                  Inhibitory
       GABA                       A,B                  Inhibitory
       Glycine                                         Inhibitory

     Substance                   Acute                 Chronic
       Opioids                     ↓                      ↑
     Barbiturates                  ↓                      ↑
       Alcohol                     ↓                      ↑
      Marijuana                    ↓                      X
   Benzodiazepines                 ↓                      ↑
    Amphetamines                   ↑                      ↓
      Cocaine                      ↑                      X
    Phencyclidine                  ↓                      ?
1) Drug Addiction, Abuse, Tolerance and Dependence
   a) Tolerance
      i) Occurs when a standard dose of drug, administered repeatedly, produces progressively
           smaller effect; or when an increased dose of drug is required to produce the same intensity
           of effect after repeated administration
   b) Cross Tolerance
      i) Tolerance to other agents acting through the same mechanism (usually through a specific
           receptor) as the tolerance inducing drug
   c) Sensitization
      i) Occurs when a standard dose of drug, administered repeatedly, produces progressively
           greater effect; or when a reduced dose of the drug is required to produce the same
           intensity of effect after repeated administration
   d) Physical Dependence
      i) The state that develops as a result of resetting of homeostatic mechanisms in response to
           repeated drug use; normal physiologic function now requires the continued presence of the
   e) Withdrawal or Abstinence Syndrome
      i) A pattern of symptoms that develops after cessation of drug administration in a physically-
           dependent subject
           (1) Withdrawal syndrome indicates the subject is physically dependent
      ii) Withdrawal syndrome can be suppressed by re-administration of the dependent drug
           (1) May give pharmacologically related agent
               (a) Cross-dependence
   f) Drug Dependence
      i) Syndrome in which the use of a drug is given a much higher priority than other behaviors
           that once had higher value
           (1) Job, family, sex, friends
           (2) Dependence on a drug per se is not necessarily cause for concern (e.g., caffeine)–Low
               toxicity and inexpensive
           (3) Hazard of using drugs that alter mood and feeling–Intensity of the “need” may vary–Mild
               desire to craving or compulsion
   g) Withdrawal syndromes
      i) Occur when a drug is abruptly removed from a physically dependent person
           (1) CNS hyperarousal due to re-adaptation in the absence of the drug
      ii) Symptoms characteristic of a given drug usually have opposite effects of the original drug
   h) Addiction
      i) A life characterized by an overwhelming involvement in the use of a drug (Compulsive)
   i) Craving
      i) An intense need to take more of a previously used drug
           (1) Often a major factor in relapse in former addicted individuals
   j) Reinforcement
      i) The property of a drug that facilitates (supports) self-administration behavior
           (1) Drug is said to be “reinforcing”
           (2) Presumed to be “rewarding” to the user
      ii) Positive
           (1) They feel good after taking the drug
               (a) Drug is “rewarding”
               (b) Gives user a “rush”
      iii) Negative
           (1) The drug alleviates anxiety or depression
           (2) The drug alleviates a withdrawal syndrome
k) Drug abuse (Behavioral Syndrome)
   i) The use, usually by self-administration, of any drug in a manner that deviates from the
        approved medical or social patterns within a given culture
   ii) Drug abuse does not necessarily imply drug dependence
   iii) Drug abuse conveys the notion of social disapproval, and it is not necessarily descriptive of
        any particular pattern of drug use or its potential adverse consequences
l) Drug Addiction (Behavioral Syndrome)
   i) Compulsive drug use
   ii) Substance dependence syndrome as defined in DSM IV (Diagnostic and Statistical
   iii) Difference exists between physical dependence and psychological dependence
   iv) Animals given continuous access show patterns of self-administration that are often
        strikingly similar to those exhibited by human users of the same drug
m) Legal vs. Illegal Substances
   i) Prescription
        (1) Benzodiazepines
   ii) Nonprescription
        (1) ETOH
        (2) Nicotine
   iii) Illegal
        (1) Heroin
        (2) Cocaine
        (3) Mary Jane
        (4) LSD
n) Pharmacology of Drug Addiction & Tolerance
   i) CNS
      (1) Disulfiram (Antabuse)
          (a) Used in the rubber industry as an antioxidant
          (b) Workers exposed to disulfiram developed a
              hypersensitivity to ethanol
          (c) Two Danish physicians took disulfiram became
              ill while investigating its potential Antihelminthic
              (worm killing) properties
          (d) Realized that the compound altered ETOH
          (e) Causes the blood acetaldehyde concentration to
              increase 5 to 10 times
          (f) Produced as a result of the initial oxidation of
              ethanol by the alcohol
              (i) dehydrogenase of the liver
          (g) Acetaldehyde does not accumulate in the
              tissues because it is further oxidized almost
              instantly, primarily by the enzyme aldehyde
          (h) With Disulfiram, aldehyde dehydrogenase
              becomes irreversibly inactivated, and the
              concentration of acetaldehyde increases
          (i) Ingestion of alcohol by individuals treated with disulfiram gives rise to marked Signs
              and Symptoms
          (j) Symptoms are attributable to the increase in the concentration of acetaldehyde in
              the body
              (i) Referred to as the acetaldehyde syndrome
                   1. Face feels hot and it is flushed in appearance
                   2. Vasodilation spreads over the whole body
                   3. Nausea, vomiting, sweating, thirst, hypotension, orthostatic syncope, marked
                       uneasiness, weakness
                   4. 7 ml of alcohol will cause mild symptoms in sensitive persons
                   5. Effects last between 30 min and several hours
                   6. Individuals must learn to avoid disguised forms of alcohol
                       a. Cough syrups and other drugs, and even aftershaves
      (2) Ethanol
          (a) Heavy consumers become tolerant
              (i) Drinking in the am
              (ii) Waking in the middle of the night for a drink
          (b) Alcohol withdrawal syndrome
              (i) Depends on size of daily dose of ETOH
              (ii) Not usually life-threatening
ii) Other substances of abuse
     (1) BZs
         (a) Most commonly prescribed drug worldwide
         (b) Used to treat insomnia and anxiety disorders
         (c) Patients should be weaned
         (d) Buspirone (5HT1A agonist)
         (e) Carbamazepine or phenobarbital
     (2) Flumazenil (Romazicon®)
         (a) Antagonist of BZ modulatory site of GABAA receptors
             (i) Watch for withdraw syndromes
     (3) Barbiturates
         (a) Use has declined
             (i) Replace by BZ’s
         (b) Frequently prescribed for patients with insomnia
             (i) Insomnia is often a symptom of chronic underlying problem
                 1. Depression
iii) Nicotine Abuse
     (1) Bupropion (Zyban®)
         (a) Originally approved by the FDA in December 1985
         (b) Removed from marketing due to concern over drug-induced seizures
         (c) Reintroduced in July 1989 as an antidepressant (Wellbutrin®)
         (d) Another sustained-release oral dosage form, Zyban®, was approved for the
             management of smoking cessation on May 14, 1997
     (2) Mechanism of Action
         (a) Bupropion inhibits the neuronal reuptake of dopamine
             (i) Significantly more potent than the tricyclic antidepressants in this regard
         (b) Blocks NE and serotonin reuptake as well
             (i) Not as potently as the tricyclic antidepressants
         (c) Increased dopamine at neuronal sites may reduce nicotine cravings and the urge to
iv) Opioid Abuse
    (1) Used to treat pain
    (2) Euphoric state
    (3) Major risk of abuse
        (a) Headaches
        (b) Backaches
        (c) Peripheral neuropathies
    (4) Tolerance takes 2-3 wks
        (a) Miotic and constipating actions persist, but tolerance to resp depression develops
        (b) Physical dependence of morphine usually takes 25 days
        (c) Withdrawal syndrome occurs within 15-20 hrs,
        (d) Peak in 2 to 3 days and remission in 10-14 days.
            (i) Yawning, diaphoresis,
                  lacrimation, or coryza,
                  insomnia, restlessness, N/V,
                  abdominal cramps,diarrhea.
            (ii) Terminate syndrome by
                  modest opioid dose
    (5) Mechanism of tolerance and
        dependence has not been
        conclusively determined
        (a) Could reflect chronic opioid
            induced inhibition of ACh release
        (b) Withdrawal leads to increased
            levels of cAMP and brain SNS
        (c) Tolerance:
            (i) no change in opioid drug metabolism
            (ii) µ opioid receptor may be desensitized
            (iii) opioid regulated neurons become less sensitive to drug
        (d) Compensatory changes:
            (i) signal transduction pathways modified
            (ii) patterns of gene expression altered
        (e) Dependence:
            (i) compensatory changes are “unmasked” when drug is withdrawn or removed from
                  receptor by an antagonist
            (ii) withdrawal symptoms are often opposite to the acute effects of the opioid drug
                  1. pain
                  2. diarrhea
                  3. agitation
    (6) Clonidine, centrally acting α2 adrenergic agonist
        (a) Decreases SNS transmission in sympathetic pathways in the CNS
        (b) Effective drug in suppressing withdrawal signs in dependent people.
    (7) Tolerance is not do to enzyme induction b/c no increases in rate of metabolism of opioid
        (a) agonists occurs
          (8) Heroin
              (a) Most important abused drug
                  (i) Produces a rush
                        1. Compared to sexual orgasm
              (b) Tolerance builds to euphoric effects
                  (i) Also to analgesic, respiratory depressant, sedative, and emetic properties
              (c) Opioid withdrawal syndrome is unpleasant
                  (i) Not usually life-threatening
              (d) Risks associated with IV use of heroin:
                  (i) overdose
                  (ii) infections - HIV, bacterial endocarditis, hepatitis
                  (iii) psychological consequences
                  (iv) social consequences
              (e) Features of dependent state:
                  (i) Reduced effect of all opioids - cross-tolerance
                  (ii) Little cross-tolerance to other centrally acting drugs
                  (iii) Physical dependence - withdrawal syndrome after:
                        1. Discontinuation of opioid drug
                        2. Administration of an opioid antagonist (e.g. naloxone)
o)   Detoxification
     i) “Cold Turkey”
          (1) Not recommended!
          (2) Abrupt discontinuation of drug administration(with some symptomatic relief by drugs)
     ii) Methadone detoxification (medically supervised withdrawal)
          (1) E.g. replacement of heroin with methadone
          (2) Buprenorphine may also be used for a scheduled withdrawal
     iii) Clonidine detoxification
          (1) Suppression of symptoms by alpha-2 receptor activation (inhibits firing of locus ceruleus
     iv) Antagonist-accelerated withdrawal
          (1) Naltrexone-precipitated withdrawal induces a rapid transition to the non-dependent state
p)   Heroin maintenance (not available in USA)
     i) Replace illegal heroin with legally supplied heroin
          (1) Pure, controlled supply from non-criminal elements)
q)   Methadone maintenance
          (1) Substitute illegal heroin with legally supplied methadone
r)   Antagonist therapy
     i) After detoxification, give long-term naltrexone to block the effects of any self-administered
          opioid drug
     ii) Buprenorphine (a mixed agonist-antagonist) also blocks opioid effects, but in addition
          induces a mild “high” by itself
s)   Methadone synthetic mµ opioid agonist
     i) (NMDA –weak noncompetitive antagonist)
t)   Methadone maintenance
     i) Highly effective orally
     ii) Prolonged duration of action
     iii) Prolonged t½β (elimination) = 35 hrs
     iv) Side effects same as morphine
     v) Less sedative and euphoric actions seem less than morphine
u) Three approaches to withdrawal
   i) Cross-tolerance
        (1) Switch to long-acting opioid
            (a) Methadone
        (2) Switch to clonidine
            (a) α2 agonist
            (b) Alleviates many of the ANS symptoms
        (3) Activation of endogenous opioid system
            (a) TENS or acupuncture(Not practical)•
   ii) Opioid receptor antagonists
        (1) Naltrexone (Trexan®, Revia®), Naloxone (Narcan®)
v) Psychostimulants
   i) Cocaine
        (1) Inhibits reuptake of DA, NE, and 5-HT
   ii) Amphetamine and related agents
        (1) Stimulates pre-synaptic release of DA and NE
   iii) Caffeine
        (1) Increase NE secretion
        (2) Competitive antagonist at adenosine receptors
            (a) Adenosine is a neuromodulator in the CNS
w) Cannabinoids (marijuana)
   i) Arachadonic acid derivative (anandamide)
        (1) Identified as an endogenous ligand
   ii) Cannabinoid receptors (CB1and CB2) have been cloned
        (1) Coupled to a Gi/o type of G protein effector
x) Psychedelic Agents
   i) Hallucinogens & psychotomimetics
        (1) LSD (d-lysergic acid diethylamide)
            (a) Discriminative stimulus effects appear to be mediated by activation of 5-HT2A
            (b) Act as partial or full agonists at 5-HT2A and 5-HT2C receptors
y) Other Agents
                (i) MDMA (methylenedioxymethamphetamine) (“Ecstasy”)
                (ii) Arylcyclohexylamines
                      1. PCP (phencyclidine)
                (iii) NMDA receptor antagonist
                      1. Action at σ receptors
                (iv) Inhalants
                      1. Toluene
                      2. Fluorocarbon propellants
                      3. Amyl nitrate
                      4. Nitrous oxide
            (b) Clinical Correlations
                (i) Drug abusers may have increased skin
                      infections, thrombophlebitis, blood
                      borne diseases
                (ii) Avoid withdrawal perioperatively
                      1. Any pure opioid can be used
                      2. Avoid agonist-antagonist
                      3. Consider regional anesthesia
                (iii) Use BZs with alcohol abuse
1) Herbal Medicine (nutraceuticals)
   a) Basic pharmacologic principles & predictability
      i) Tight control of traditional meds
      ii) No quality control over herbal supplements
           (1) All are unreliable
           (2) No FDA control
           (3) Variability in dosing
               (a) Due to compounding & concentration
               (b) Inconsistency in amount of active ingredients
           (4) Can lead to serious health related problems
   b) Nutraceuticals
      i) Include vitamins & herbal remedies
      ii) 1/3 of chiropractic pts take nutraceuticals
      iii) 380% increase (1990-1997)
      iv) 35-56% of pts do not report use
      v) Greater than 20,000 products
      vi) 1994 regulated by Dietary Supplement Health & Education Act (DSHEA)
           (1) But no burden of proof
           (2) Recognizes dietary supplements as separate from food & drugs
           (3) Ingredients not approved by FDA
           (4) Lack of reliable info
           (5) Claims are questionable
               (a) Cannot claim to treat, cure or prevent a disease
      vii) Important for HCP to be aware of potentially dangerous supplements
   c) FDA dangerous herbs
      i) Chaparral
           (1) Liver disease
      ii) Comfrey
           (1) Liver disease & toxicity
      iii) Germander
           (1) Liver disease & toxicity
      iv) Yohimbe
           (1) HTN
           (2) Tachycardia
           (3) Paralysis
      v) Kavakava
           (1) Liver toxicity
      vi) Willow bark
           (1) Reye syndrome
      vii) Lobelia
           (1) Respiratory depression
           (2) Coma
           (3) Possible death
           (1) Carcinogenic
d) Ephedra ( Ma Huang)
   i) Claims
        (1) Stimulates CNS
        (2) Suppresses appetite
        (3) Decongestant
        (4) Asthma reliever
        (5) Ergogenic aid
   ii) Warnings
        (1) Banned by FDA
            (a) >40 deaths & >800 adverse reactions
        (2) Side effects
            (a) Dizziness
            (b) Jitters
            (c) Insomnia
            (d) Heart palpitations
            (e) Increased BP & HR
            (f) Decrease peripheral catecholamines
                (i) Caution using ephedrine during anesthesia with these patients
e) St. John’s Wart (Hypericum)
   i) Clinical trials shown effective in mild to moderate depression
        (1) Blocks reuptake of Monoamine neurotransmitter
            (a) 5HT
            (b) NE
            (c) DA
        (2) Inhibition via GABAA affinity
   ii) Claims
        (1) Boosts mood
        (2) Suppresses appetite
        (3) Improves wound healing (topically)
   iii) Warnings
        (1) Possible interactions with other antidepressants
            (a) MAOIs & SSRIs
                (i) Serotonin syndrome (too much serotonin)
                      1. Aggression, hyperpyrexia, myoclonus, death
        (2) May induce hepatic P450 enzymes
            (a) Lowers concentration of several drugs
                (i) Cyclosporine
                (ii) Theophylline
                (iii) Digoxin
        (3) Avoid with pregnancy
            (a) Hypertonic uterus
        (4) Side effects
            (a) GI irritation
            (b) Sensitivity to sun
            (c) Fatigue
            (d) Dizziness
            (e) Itching
            (f) Autonomic arousal
                (i) From decreased reuptake of monoamines
f) Saw Palmetto
   i) For BPH
        (1) No clinical proof
   ii) Side effects
        (1) GI irritation
        (2) HTN
        (3) Urinary retention
        (4) Headache
   iii) No drug interactions noted
g) Ginko Biloba
   i) Shown to increase blood flow & reduce blood viscosity
        (1) May enhance endogenous nitric oxide
   ii) Claims
        (1) Memory booster
        (2) Decrease progression Alzheimer’s
            (a) Increases
                (i) Muscarinic
                (ii) Alpha 2
                (iii) 5HT1a
        (3) Improves blood flow & intermittent claudication
        (4) Anti-platelet
        (5) Treatment for asthma
        (6) Decongestant
        (7) Antioxidant
            (a) Decrease free radicals which cause cell damage
            (b) May be protective in ischemic injury
   iii) Warnings
        (1) Caution with blood thinners (coumadin), vit E, omega-3-fatty acids, aspirin
            (a) Case reports of subdural hematomas & bleeding
        (2) May be epileptogenic
            (a) Avoid in pts with seizures
        (3) Side effects
            (a) Nausea
            (b) Headache
            (c) Rash
            (d) Dizziness
h) Ginseng
   i) Active compound believed to be ginsenosides
   ii) No solid evidence regarding clinical benefits
   iii) Claims
        (1) Protect against tissue damage
        (2) Increases energy
        (3) Increases sex drive
        (4) Anti-inflammatory
        (5) Anti-stress
        (6) Analgesia
        (7) Anti-platelet
        (8) Anti-cancer
   iv) Warnings
        (1) Caution with blood thinners (coumadin), vit E, omega-3-fatty acids, aspirin
        (2) HTN pts should not use ginseng
        (3) Varying concentrations of root extract
            (a) Not always pure
        (4) Avoid in immunocompromised pts and autoimmune diseases
        (5) Side effects
            (a) Headache
            (b) Insomnia
            (c) Rash
            (d) Steven-Johnson’s Syndrome
                (i) Sloughing of skin
                    1. Especially palms of hands & soles of feet
            (e) Anxiety
            (f) Diarrhea
            (g) Mastalgia (breast pain)
            (h) HTN
i) Ginger
   i) Claims
        (1) Anticoagulant
            (a) Inhibition of thromboxane synthase
        (2) Antiemetic
            (a) Seasickness
   ii) Warnings
        (1) May raise BP
        (2) Caution in bleeding disorders
        (3) Avoid in pts on anticoagulants & anti-platelet drugs
j) Echinacea
   i) Shown to increase phagocytosis
   ii) In vitro enhancement of NK cells
   iii) In vitro anti-inflammatory properties
        (1) May be from inhibition of cyclooxygenase & lipoxygenase enzymes
            (a) Decrease prostaglandins
   iv) Claims
        (1) Immune booster
        (2) Prevent & relieve cold & flu symptoms
        (3) Used topically to heal wounds
   v) Warnings
        (1) May inhibit hepatic P450 enzymes
            (a) May potentiate Phenytoin & Phenobarbital toxicity
        (2) May be contraindicated in:
            (a) Lupus
            (b) HIV
            (c) MS
            (d) Organ transplant
k) Valerian
   i) Claims
        (1) Mild sedative, anxiolysis, sleep aid
            (a) Suggested to inhibit degradation of GABA
   ii) Warnings
        (1) Not to be used with other sedative or anxiolytics
        (2) May increase effects of alcohol or other CNS depressants
l) Kava
   i) Studies have shown significant improvements in pts with anxiety
   ii) Shown to have mild anticonvulsant effects
   iii) No effects on opioid receptor
   iv) May have cyclooxygenase inhibiting effects
   v) Resembles BZs
        (1) May interact with GABAa
   vi) Claims
        (1) Relaxation with intact memory
   vii) Warnings
        (1) Potentiation of other CNS depressants
        (2) Inhibition of hepatic P450 enzymes
        (3) Avoid in pregnancy
            (a) Alters uterine tone
        (4) Kava induced hepatitis
            (a) Hepatotoxic
            (b) Caused removal from market in Germany, Canada & Australia
        (5) Side effects
            (a) GI upset
            (b) Sedation
            (c) Euphoria
            (d) Ataxia
            (e) Muscle relaxation
m) Cayenne
   i) Claims
       (1) Help muscle spasms & soreness
       (2) Help GI tract disorders
   ii) Warnings
       (1) Side effects
           (a) When used more than 2 days
               (i) Potential skin sores & blisters
           (b) OD can cause hypothermia
n) Grapefruit
   i) Claims
       (1) Decreases cholesterol
   ii) Warnings
       (1) Inhibition of hepatic P450 enzymes
           (a) 3A4
o) Feverfew
   i) Claims
       (1) Migraine HA prophylaxis
           (a) May be due to inhibition of 5HT from platelets
           (b) Weak evidence
       (2) Rheumatoid arthritis (RA)
           (a) Anti-inflammatory
           (b) Shown to inhibit prostaglandin & prostanoid synthesis in vitro
               (i) No reliable studies confirming effectiveness in RA
   ii) Warnings
       (1) Increased effectiveness of platelet inhibitors
           (a) Lead to bleeding
       (2) Mouth ulcerations
       (3) Increases histamine release from mast cells
       (4) Smooth muscle contraction
       (5) Antimicrobial effects
p) Garlic
   i) Claims
       (1) Anti-hypertensive
           (a) Allicin
       (2) Anti-platelet
       (3) Anti-lipid
           (a) Inhibition of HMG-CoA reductase
               (i) Important in cholesterol synthesis
       (4) Antimicrobial
       (5) Anti-neoplastic
   ii) Warnings
       (1) Increases effects of platelet inhibitors
           (a) Increased bleeding
           (b) Monitor BP
       (2) Few case reports of periop bleeding
q) Passionflower
   i) Mechanism of action
        (1) May be BZ receptor
   ii) Claims
        (1) Anti-anxiety
   iii) Warnings
        (1) Potentiation of other CNS depressants
r) Lavender
   i) Claims
        (1) Antidepressant
        (2) Sedative
        (3) Analgesic properties
        (4) Local anesthetic properties
        (5) Anticonvulsive properties
   ii) Warnings
        (1) Potentiation of other CNS depressants
s) DHEA (dehydroepiandrosterone)
   i) No scientific data
   ii) Hormone in body, converted to androstenedione, testosterone & aldosterone
        (1) Decreased with age
   iii) Claims
        (1) Boosts immune system
        (2) Slows aging
        (3) Weight loss
        (4) Cure-all for everything from impotence to cancer
   iv) Warnings
        (1) OTC strength & purity not regulated
        (2) Untested in long-term clinical trials
        (3) Avoid in prostatic cancer
        (4) May be OK for DHEA deficiency
            (a) Take under care of Dr.
        (5) Not recommended by National Institute of Aging
        (6) Side effects
            (a) Acne
            (b) Insomnia
            (c) Increased HR
            (d) Increased heart palpitations
            (e) Decreased HDL
            (f) Increased testosterone level
                (i) Aggressive behavior
            (g) Facial hair in women taking high doses
t) Glucosamine chondroitin
   i) Helps joints
u) Chromium
   i) Claims
        (1) Increases muscle mass
        (2) Decreases body fat
        (3) Alternative to steroids
        (4) Helps maintain normal blood sugar levels
            (a) May be effective for diabetics
   ii) Warnings
        (1) Side effects
            (a) Mega doses may lead to zinc & iron deficiencies
v) Amino acids
   i) Claims
        (1) Repair & build muscle
        (2) Increases strength
   ii) Warnings
        (1) Increased risk for dehydration
        (2) Increased stress on kidneys
        (3) Excess protein stored as fat
w) Creatine
   i) Research states
        (1) Improves anaerobic activities
        (2) No effect on aerobic activities
        (3) Excess is excreted
        (4) Vegetarians demonstrate greater uptake
        (5) Not studied long-term
   ii) Claims
        (1) Increases energy & muscular strength
        (2) Burns fat
        (3) Improves endurance
        (4) Delays fatigue
   iii) Warnings
        (1) Side effects
            (a) Wt gain
            (b) Muscle cramps
            (c) Nausea
            (d) Diarrhea
            (e) Kidney problems
x) HMB (beta-hydroxy-betamethylbutyrate)
   i) Metabolite of leucine (essential AA)
   ii) Literature is weak
   iii) Acts as anti-catabolic agent
        (1) Minimizes protein breakdown from intense exercise
   iv) Claims
        (1) Enhances gains in strength & lean body mass
            (a) Mechanism unknown
y) Androstenedione
   i) Limited research
   ii) Anabolic steroid produced by body
   iii) Claims
        (1) Increases strength
        (2) Increases testosterone levels
   iv) Warnings
        (1) Side effects
            (a) Acne
            (b) Increased aggressiveness
            (c) Increased LDL
            (d) Decreased HDL
            (e) Decreased sperm production
            (f) Stroke
            (g) Heart attack
            (h) Heart muscle damage
            (i) Stunted growth in teens
z) Safety tips
   i) Do your research
   ii) Buy nationally known brands
   iii) Start with small dose
   iv) Use single herbal supplements
   v) Don’t give to children
   vi) Don’t take if pregnant or breastfeeding
   vii) Tell HCP what you’re taking
   viii)Stop 2-3 weeks before surgery

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