Analgesics

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Analgesics

• Three classes
• Opiates Opioids or narcotic analgesics
  includes alkaloids of opium poppies,
  semi-synthetic analogs of opium alkaloids and
  totally synthetic agents that may or may not be
  related structurally
• All are Schedule II, III, IV agents due to high
  addictive potential
• Prototypical agent is morphine all agents are
  compared to this standard agent that is a natural
  opium alkaloid
• Central Analgesics site of action is within the
  CNS
• 3. NSAIDS Non-steroidal anti-inflammatory
  drugs NOT narcotics and have no addiction
  potential
• Many have useful antipyretic activity and/or
  anti-inflammatory actions
• When compared to the narcotic agents their
  analgesic activity is relatively weak involving
  primarily peripheral actions with minor centrally
  mediated actions

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Opiates Opioids

• Opioids or narcotic analgesics classified based
  on pharmacology at various receptor subtypes that
  are natural receptors for endogenous peptides
  that demonstrate morphine-like effects
• Endorphins primary peptide is b-endorphin found
  in the hypothalamus and other brain nuclei and
  the anterior pituitary ? released in response to
  stress
• Enkephalins widely distributed in the CNS and
  interneurons especially those mediating pain
  pathways
• Dynorphins widely distributed in the CNS
  associated with spinal cord mediated pain pathways

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Opiates Opioids

• Receptors Many subtypes ALL are
  G-protein-coupled receptors. Most important for
  our discussion
• Mu (m) receptor primarily responsible for
  analgesia, euphoria, respiratory depression and
  physical dependence
• Agonists Endorphins, enkephalins, morphine,
  fentanyl, methadone, meperidine, and others
• Kappa (k) receptor - responsible for
  mixed-action agonists and analgesia at the level
  of the spinal cord, sedation and dysphoria
• Agonists Dynorphins, pentazocine, butorphanol
• Delta (d) receptor - MAY contribute to analgesia
  
• Agonists Enkephalins, endorphins, morphine,
  codeine

See Table 31-2 in Katzung (p 498)
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Opiates Opioids

• Full Agonists
• High efficacy or strong agonists
• Partial Agonists
• Can evoke agonist effects
• Antagonistic ? displace strong agonists
• Antagonists
• Due to different receptor types, some agents may
  be one class at one receptor type and another
  class at a different receptor type.

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m-receptor binding
E endorphans, enkephalins Op Opioids Nx
Naloxone
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Opiates Opioids

• Receptor Mechanisms - alteration of cells leads
  to tolerance to the drug
• Adenylyl cyclase coupled leading to a decrease in
  cAMP, increased K conductance (m and d) and
  decreased Ca2 conductance (k)
• Presynaptic terminal decreased in Ca2
  conductance leads to a decrease in
  neurotransmitter release
• Postsynaptic hyperpolarization and signal
  inhibition via increased K conductance

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B-Adrenergic PathwaySecond Messengers
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Opiates Opioids

• Opiate drug absorption and metabolism
• Often extensive first pass effect when given
  orally unless resistant to conjugation (i.e.
  Codeine)
• Fentanyl most lipophilic v. good transdermal
  abs.
• Labor and delivery BBB is poorly developed in
  infants, can lead to significant respiratory
  depression.
• Metabolism glucuronides, N- and O-demethylation
  (liver) then renal excretion
• Primary indications Analgesia, dyspnea due to
  LVF and resulting pulmonary edema, diarrhea,
  addiction (methadone, ORLAAM)
• Best for severe, constant pain.
• Tolerance a concern

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Opiates Opioids

• CNS Effects
• Analgesia
• Euphoria
• Sedation
• Respiratory depression
• Cough supression
• Miosis
• Truncal rigidity (w/lipid soluble opioids)
• N/V
• PNS Effects
• Smooth muscle (See GI)
• CV Most have no major effects!
• GI Constipation (motility drops, increased
  absorption)
• Renal function decrease
• May prolong labor

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1. Opiate Agonists
Phenanthrenes Natural products
A-ring
Regular and controlled release tablets and
capsules, solutions, injection and rectal
suppositories for analgesic activity, also used
as an anesthestic agent - preoperative MSIR,
Roxanol, many others Full agonist at the
m-receptor
Less effect as an analgesic and less respiratory
depression and constipation than morphine,
effective anti-tussive 15, 30, 60 mg tablets as
sulfate salt and oral solutions and injectables
as phosphate salts Partial agonist at the
m-receptor
Opium tincture Paregoric a Schedule III agent
camphorated Used in treatment of diarrhea and
as an analgesic (2 mg morphine equiv./5 mL)
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Morphine vs. Heroine
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Heroine
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Analgesics Opiate agonists
Phenanthrenes Semi-synthetic agents
Full agonist at the m-receptor
Full agonist at the m-receptor
Numorphan injection and suppositories
(Refrigerate the suppositories) Pain,
preoperative medication/anesthesia/anxiety Equipot
ent as morphine, weakest anti-tussive agent, MOST
potent respiratory depression and most intense
physical dependence of all the agents Do NOT use
in patients Dilaudid 1,2,3,4,8 mg tablets, liquid, injection
and suppositories Equipotent as an analgesic
(relief of moderate/moderately severe pain) and
less constipating effect, equipotent respiratory
depression Refrigerate the suppositories
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Analgesics Opiate agonists
Phenanthrenes Semi-synthetic agents
Full agonist at the m-receptor
Full agonist at the m-receptor
Less effect as an analgesic and less respiratory
depression than morphine Available as a wide
number of combination products and alone for
anti-tussive effects Iotussin HC syrup also
VicodinTuss Vicodin w/ APAP
Equipotent as morphine as an analgesic and
respiratory depression/constipation Oxycontin
10, 20, 40, 80 and 160 mg controlled release
tablets Roxicodone immediate release tablets and
oral solutions Percodan with ASA
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Analgesics Opiate agonists
Phenanthrenes Semi-synthetic agents
Full agonist at the m-receptor
Levo-Dromoran tablets and injection Pain and
preoperative medication Equipotent as an
analgesic and less constipating effect,
equipotent respiratory depression and
constipation Dextromethorphan Dextrarotatory
stereoisomer of Levorphanol. Produces no
analgesic activity, is less constipating, and is
used in MANY OTC antitussives!
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Analgesics opioids
Demerol - 50 100 mg tablets, syrup injection
or with promethazine (emesis) Less smooth muscle
spasms, constipation and depression of the cough
reflex than morphine Indications oral and
parenteral moderate to severe pain, preoperative
medication, support of anesthesia and obstetrical
analgesia Indications Sublimaze injection -
analgesic action of short duration during
anesthesia and in post-operative pain
relief Transmucosal Lozenges Oralet
pre-operative anesthesia Actiq lozenge on a
stick Breakthrough cancer pain only Transdermal
patches Duragesic 25-100 mcg/hr delivery.
Serious and life threatening hypoventilation
possible
Synthetic Phenylpiperidines
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Analgesics opioids
Synthetic Phenylpiperidines
Very potent agent About 5-7x potency of
Fentanyl injection 1-2 microgram per
kg Indications Analgesic adjunct in intubated
and ventilated patients, major CV or
neuro-surgery as an anesthesia agents, epidural
analgesic agents Exceptional analgesic agent
equal to Remifentanil
Much less potent than Fentanyl Indications
analgesia adjunct in incremental dosing (use
tuberculin syringes) during barbiturate/nitrous
oxide/oxygen anesthesia, primary anesthesia
induction Dosage must be individualized, not
recommended in children with short duration!
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Analgesics opioids
New Drug a phenylpiperidine
Remifentanil HCl - Ultiva An extremely potent
analgesic agent tied with Sufentanil for
potency Indications analgesic agent for use
during induction and maintenance of general
anesthesia for both inpatient and outpatient
procedures, can be continued postoperatively
inpatient only Use caution during interruption of
infusion since this drug is rapidly cleared and
has a very rapid offset of action of 5 minutes Do
not administer into same IV tubing as blood
products due to inactivation of nonspecific
esterases in blood products
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Analgesics opioids
Synthetic Diphenylheptanes
Dolophine and Methadose tablets, dispersable
tablets, solution injection Indications Relief
of severe pain, detoxification and maintenance of
narcotic addiction - i.e. Heroin (only approved
pharmacies as oral dose form). Milder withdrawal
effects. Action similar to morphine ? LONGER
ACTING! Not useful preoperatively to reduce
anxiety or for induction ORLAAM solution Off
shelves by Feb. 2004! Indications Second-line
therapy for opiate dependence. Dispensed no more
than an every other or thrice-weekly basis by an
approved management program Fatal overdosage is
very easy due to drug accumulation if used more
than every other daypeak activity is not
immediate due to prodrug status. LONG half-life!
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Analgesics opioids
Synthetic Diphenylheptanes
Darvon-N as the napsylate salt Darvon as the
HCl salt Indications mild to moderate pain -
weakest of the opiate agonist agents DO NOT use
in patients that are suicidal or addiction prone,
patients using other tranquilizer or
antidepressant medication, do not use with
alcohol - one of the major causes of drug related
deaths Reduce dosage in cases of renal or hepatic
impairment - use this drug cautiously in elderly
patients - consider increasing the dosing interval
LOTS of Combination products available good luck
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2. Partial agonists/antagonists

• Opioid Agonist/Antagonists lower abuse
  potential than other narcotics due to
  antagonistic properties.
• Compete with other agents at the mu (m) receptor
  level which mediate morphine-like supraspinal
  analgesia, euphoria and respiratory and physical
  depression
• Large N-substitutions cause antagonistic
  activity!
• Pure antagonists have only N-allyl substitution
  NALOXONE!!!

Opiate antagonist IndicationsTreatment of acute
morphine overdose. Can be used to offset effects
of common i.v. or epidural opoid administration
(itching, N/V, etc.) VERY short duration of
action patient relapse after appearing
normal May have use in alcoholism (decreases
cravings!)
Naloxone - Narcan
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Partial agonists/antagonists
Partial opiate agonist which is capable of
displacing other agents thereby giving it
antagonistic activity equipotent to naloxone
(Narcan) Indications moderate to severe pain
by injection, onset 15 minutes which peaks at 60
minutes and lasts 6 hours duration 0.3 mg 10 mg
morphine Hepatic metabolism, can produce
withdrawl in addicted patients
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Partial agonists/antagonists
Indications Nasal spray treatment of migraine
headaches, Injection pain management
post-operatively and during labor, preoperative/
preanesthesia medication. k agonist, 5x
morphine Antagonistic activity 1/40th of
naloxone, onset morphine Indications relief of moderate to
severe pain as injection only Aminotetralin
chemical series (non-opiate agent) comparable to
morphine in strength 66 excreted in urine
unchanged, 34 as the glucuronide, onset 15-30
minutes with a peak in 30 minutes and a 4 hour
duration Antagonistic activity 1/120th naloxone
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Partial agonists/antagonists
Indications relief of moderate to severe pain,
pre- and post-operative analgesia by injection
including labor and delivery Equipotent to
morphine, 2nd weakest antagonist, onset 15
minutes with a 3-6 hour duration, use
caution Indications injection and oral
relief of moderate to severe pain, injection only
- pre- and post-operative analgesia Use as a
heroin substitute in combo with tripelennamine
Ts and Blues Use caution in renal and hepatic
failure Combo with ASA Talwin Compound Combo
with APAP Talacen Combo with naloxone Talwin
NX Use together to prevent IV abuse
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Central Analgesic Agents
Agents that produce analgesia not mediated by
opiate receptors but via other neuronal mechanisms
Orally used as an anti-hypertensive agent Given
as epidural for analgesia. Used in combination
with opiates when opiates alone are
ineffective NOT recommended for obstetrical,
post-partum or peri-operative pain
management MOA produces analgesia at both
presynaptic and postjunctional a2-adrenoceptors
in the spinal cord that are responsible for pain
transmission to the brain
Methotrimeprazine - Levoprome Indications
relief of moderate to marked pain in
non-ambulatory patients, obstetrical analgesia
and sedation in order to avoid respiratory
depression in the infants and mother,
pre-anesthetic anti-anxiety agent MOA increases
pain threshold and produces amnesia, possesses
antihistaminic, anticholinergic and
antiadrenergic effects
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Central Analgesic Agents
Non-schedule agent with narcotic agonistic
activity Indications moderate pain as 50 mg
tablets MOA binds m-receptors and prevents
reuptake of norepinephrine and serotonin in the
CNS Hepatic metabolism and renal excretion
modify dose interval if creatinine clearance is
Ultracet Indications Useful alternative as an
analgesic-antipyretic in aspirin allergy,
patients taking anti-coagulants or bleeding
disorders, upper GI disease such as
ulcer,toothache, colds, flu, other viral
illnesses MOA antipyretic activity direct
inhibition of hypothalamic heat-regulating
centers, pain - inhibits prostaglandin synthase
in the CNS with minimal peripheral
inhibition Tablets, suppositories, caplets,
gelcaps, drops, elixir, liquid Tylenol also
w/codeine
APAP