This substance can be converted industrially into a variety of compounds including oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and etorphine.

Thebaine

*not used therapeutically

*The main alkaloid extracted from papaver bracteatum.

Synthetic opioids contain the _______ nucleus of morphine.

Synthetic opioids are manufactured by _______ rather than modification off morphine.

They are agonist at the opioid receptors located in the  Presynaptic and Postsynaptic sites of the CNS

(periaqueductalgray matter of the brainstem, amigdala, hypothalamus, spinal cord), and peripheral tissue.

Three endogenous peptide opioids ligands-enkephalins, endorphins, and dynorphins.

Activation causes a decreases in the neurotransmission of Acetylcholine, Dopamine, Norepinephrine, and Substance P.

Largely presynaptic but some postsynaptic by either increase of potassium conductance or Ca Channel inactivation or both.

1. Alter responsiveness of afferent nerve endings to 

    noxious stimulation.

2. Impair conduction of nerver impulses along peripheral

    nerves.

Spinal and Supraspinal Analgesia

Euphoria-profound sense of wellbeing

Miosis-constriction of the pupil

*known as morphine-preferring receptors*

Adenyl cyclase-this in turn decrease the conductance of voltage-gated calcium channels or opens inward flowing potassium channels.

Net result decreased neuronal activity.

Spinal Analgesia (low)

Decreased Ventilation

Physical Dependence

Constipation

Spinal and supraspinal Analgesia (low)

Dysphoria

Sedation

Miosis

Agonist-Antagonist functions

Diuresis

Respiratory depression is much less with kappa receptor activation.

Respond to Dynorphins-resulting in inhibition of neurotrasmitter release via type N calcium channels.

Analgesia

Hypovenilation

Physical Dependance

Urinary Retention

Modulate activity of Mu receptors

Respond to enkephalines

No clinical advantage

ex. fentanyl, sufentanil

Morphine-a poorly lipid soluble opioid have a slower onset of analgesia but a longer duration when administered via the neuraxial route.

Lipid Solubility and Molecular Weight

Epinephrine added to the solution decreased the systemic absorption and enhances the effect of morphine solutions. Epinephrine does not influence diffusion of morphine across the dura.

Analgesia is more prominent when administered ______ the painful stimulus occurs.

parenterally, orally, intrathecally, and as epidural preparations.

Minimally absorbed into the CNS because of:

1. Poor lipid solubility

2. high degree of ionization at physiologic pH

    (alkalization of blood will increase the nonionized

    fraction of morphine and enhance passage into CNS.)

3. Protein Binding

4. Rapid conjugation with glucuronic acid.

    75-85% form morphine 3 glucuronide-inactive

     5-10% morphine 6 glucuronide (analgesia, 

     depressed ventilations)

• Primary metabolic pathway conjugation in the liver
• Metabolites eliminated principally in the urine   

Analgesia 

Euphoria 

Sedation 

Diminished ability to concentrate

Peri-operative analgesia

PCA for post-op pain control

Epidural admin. (Pres. Free Duramorph)

2.5-5mg/kg

ONSET:

DURATION: 4 Hrs

HALF LIFE: 2-4 Hrs

• Intermediate acting opioid that can be used intraoperatively but also postoperatively.
• Active metabolite M6G contributes to analgesia paticularly in patients with renal disease.

• Synthetic opioid agonist at mu and kappa receptors
• Principal pharm. effect ressembles morphine
• Tertiary amine, ester group, lipophylic phenol
  • similar to lidocaine
• One tenth as potent as morphine
• Very active metabolite Normeperidine

• Analgesia
  • toxicity  manifested as myoclonus and seizures is due to prolonged admin i.e..PCA. and accumulation of normeperidine which causes CNS stimulation.
• Suppression of post-op shivering (kappa & alpha 2 receptor stimulation)

12.5mg IV to reduce shivering in adults

*not inidicated for use in children*

Duration: 2-4hrs

Half Life: 3-5hrs Normeperidine elim. half life 15hrs.

Warning: Serotonin syndrome 

• HTN-Hyperthermia
• Tachycardia-cofusion
• Diaphoresis-Agitation
• Neuromuscular changes
• Coma-Seizures
• Coagulopathy-etc.

In patients taking MAO inhibitors

inin

• Synthetic agonist opioid related to meperidine
• 75-125 times more potent than morphine
• Rapid onset, Short DOA
• Metabolized in the liver
  • norfentanyl is similar to normeperidine

Low dose:  2mcg/kg-minor painful procedure

• side effects opioid naive patients at risk for respiratory depression 

Mod. dose: 2-20mcg/kg-Major Surgical procedures to reduce stress response.

• likely to cause respiratory depression-need for monitoring post-op r/t resp. depression.

High dose: 20-50mcg/kg-Cardiac or Neuro procedures requiring a decrease in stress response.

• Respiratory depression likely
• Respiratory muscle rigidity more likely 

Onset: Almost immediately

Duration of action: 0.5-1hr

Half Life: 2-4hrs        

1. analgesia-blunts circulatory response to painful stimulation
2. provide surgical anesthesia
3. intrathecal analgesia
4. transdermal analgesia

Sufentanil Characteristics:

• Analgesic potency
• 5-10 times more than fentanylRapid Onset
• High lipid solubility
• Shorter DOA than fentanyl smaller Vd
• Metabolized in the liver
• Marked trunk rigidity

• Dose: 1-2mcg/kg
  • major sugical procedures requiring a decrease in the stress response.
  • Respiratory depression likely
  • Rigidity of respiratory muscles more likely
• Onset of Action: almost immediate
• Duration: ??
• Half-Life: 2-4hrs

• Perioperative analgesia
• Cardiac anesthesia
• Epidural and intrathecal analgesia

• Analogue of Fentanyl
• Less potent-one fifth to one tenth due to low lipid solubility.
• More rapid onset of action (low pK)
• Short elimimnation half-time (low Vd)
• Metabolized in the liver
• Excreted in the urine

8-20mcg/kg

• major surgical procedures requiring a decrease in stress response
• alfentanil is more likely to cause hypotension than fentanil
• Respiratory depression likely

• analgesic potency similar to fentanyl
• chemically similar to fentanyl with the addition of an ester linkage
• hydrolyzed to nonspecific plasma and tissue esterases to inactive metabolites
• rapidly titratable effect due to rapid onset
• brevity of action
• rapid offset-low Vd
• rapid recovery after discontinuation

Dose: o.1-1mcg/kg/min

Onset: Almost immediate

Duration: 5-10min

Half Life: 10-20min

• major surgical procedures requiring a decrease in stress response
• respiratory depression likely
• Rigidity of respiratory muscles likely

Remifentanil Uses:

• PCA
• IV infusion
• Consider administering a longer acting opioid after remi therapy is terminated.
• Intrathecal or epidural administration is not recommended.
• Acute opioid tolerance
• Delayed hyperalgesia

Decreased SBP due to bradycardia and/or histamine release.

• Dose-dependent ventilatory depression
  • Mu 2 receptor activation
• Decreasd responsiveness of ventilation centers to CO2.
• Interferes wit ventilation centers that regulate breathing rhythm
• APNEA
• Cough suppression-medullary cough centers
• Thoracic and abdominal muscle rigidity-resulting in possible inadequate ventilation of the lungs and attempts to ventilate can lead to airway pressures that interfere with venous return.
  • more common with fentanyl, sufentanil and depends on the dose used and the rate of administration

• Decreased CBF
• Miosis-antagonized by atropine
• Sedation
• Caution in patients with head injury related to:
  • Associated effects on wakefulness
  • production of miosis
  • depression of ventilation associated with increased ICP if the PaCO2 becomes increased.
  • Head injury may impair the BBB and increase sensitivity to opioids.
• Opioids do not alter responses to NMB drugs.

• Spasm of GI smooth muscle
  • constipation
  • biliary colic-naloxone will relieve pain of spasm but not MI. Nitro will relieve pain of both.
  • delayed gastric emptying
• Enhanced tone of the pyloric sphincter, ileocecal valve, and the sphincter
• Narrowing or closure of the sphincter of Oddi-misinterpreted as a common bile duct stone on xray. Glucagon 2mgIV will reverse the spasm without antagonizing the effects of  the opioid.
• Nausea and vomiting
  • stimulation of the CTZ

• Increased tone and peristaltic activity of the ureter
• Urinary urgency
• Increased tone of vesicle sphincter make voiding difficult.

• dilated cutaneous blood vessels
  • histamine release
• Erythema and pruritus
  • especially around the eyes, nose, and lips

State of adaptation in which exposure to a drug induces changes that result in a diminution on one or more of the drug's effects over time.

• leads to greater does of opioids to provide analgesia 

State of adaptation that is manifested by drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood levels of the drug an/or administration of an antagonist.

• gradually decreae the dose of the opioid to avoid this

Addiction is a primary, chronic, neurobiologic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm or craving.

Meperidine

Morphine

Hydromorphone

Fentanyl

Sufentanil

Alfentanil

Remifentanil

Butorphanol (Stadol)

Nalbuphine (Nubain)

Pentazocine (Talwin)

Buprenorphine (Buprenex)

Nalorphine (Nalline)

Naloxone (Narcan)

Nalmefene (Revex)

Naltrexone (Trexan)-oral only 

compared to morphine

Meperidine (Demerol)                              0.1

Morphine (astromorph, duramorph)            1

Nalbuphine (Nubain)                               1

Butorphanol (Stadol)                               3-7

Hydromorphine (Dilaudid)                         8

Alfentanil (Alfenta)                                  10

Fentanyl (sublimaze)                               100-125

Remifentanil (Ultiva)                                100

Sufentanil (Sufenta)                                 1000

Meperidine        0.5-2mg/kg

Morphine          0.03-0.15mg/kg

Hydromorphine  0.01-0.04mg/kg

           Opioid Induction\Maintenance Doses: 

             Induction Dose        Maintenance Dose 

Fentanyl:              5-40ug/kg           0.025-0.25ug/kg/min

Alfentanil             50-300ug/kg            0.5-15ug/kg/min

Sufentanil              2-10ug/kg               0.1-0.5ug/kg/min

Remifentanil        0.5-1.0ug/kg/min      0.25-0.4ug/kg/min