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Analgesics in Dentistry Opioids Pharmacology

Pharmacology & Toxicology College of Pharmacy University of Sulaimani
8/3/12

Hiwa K. Saaed PhD

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Analgesic

Analgesic an agent that selectively relieves pain by acting in the CNS or on peripheral pain mechanisms, without significantly altering the consciousness Pain is:
acute or chronic Consequence of complex neurochemical

processes
Subjective: perceptive and descriptive
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Analgesic

Alleviation of pain depend on its type

Headache, arthritic pain Rx NSAIDs Neurogenic pain Rx TCA Amitriptyline or

SSRI Fluoxetine are DOC

Severe or chronic malignant pain Rx Opiods

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History / Definitions

Ancient Egypt papyrus records reported the use of opium for pain Relief
Opium mixture of alkaloids from the poppy

seed
Opiates naturally occurring alkaloids such

as morphine or codeine obtained from the juice of the opium poppy

Opioid broad term to describe all natural

or synthetic compounds that work at the opioid receptors and produce morphine-like effects 8/3/12 44

Endogenous Opioid peptides neurotransmitters

endorphin, enkephalins & dynorphins Opiods act by binding to specific opioid receptors in the CNS to produce the action of endogenous peptide neurotransmitters

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Opioid Classifications
Chemistry OPIOID RECEPTOR INTRINSIC ACTIVITY
Natural Mu() Agonists Semisynthetic Synthetic Kappa() Antagonists Delta () Mixed Agonists and Antagonists

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Opioid Classifications

Opioids can further be classified by their actions:

agonist, or partial/weak agonist, or antagonist Mixed agonist/antagonist

An agonist has both affinity and efficacy An antagonist has affinity but no efficacy A partial or weak agonist has affinity, but only partial efficacy Compounds can have differing degrees of affinity and efficacy at these various receptors
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Opioid receptors
Mu(), Kappa(), Delta ()

Opioids interact with:

receptors on the membranes of certain

cells in the CNS,

on nerve terminals in the periphery on cells of the gastrointestinal tract and

the anatomic regions urinary bladder.

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Opioid receptors
Analgesic

properties are mediated:

mainly via receptors and receptors of the dorsal horn of the

spinal cord. Enkephalins interact more selectively with the receptors in the periphery.

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Endogenous opioid receptors

Mu Analgesia (supraspinal) Miosis Respiratory depression Euphoria Physical dependence Decrease GIT motility Delta analgesia (spinal & supraspinal) release of growth hormone Affective behavior Present in limbic system Kappa Spinal analgesia Sedation miosis

Sigma# Dysphora Hallucination (both visual & auditory) Respiratory and vasomotor stimulation mydriasis #less specific bind with non opioid agent e.g hallucinogen
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Mechanism of Action
All are G-protein coupled receptors and inhibit adenylate cyclase. They are also involved in postsynaptic hyperpolarization: (increasing K+ efflux) or reducing presynaptic Ca+ + influx;

thus inhibits neuronal activity.

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Receptor distribution
High densities of opioid receptors on peripheral nerve fibers, immune cells and five general areas of the CNS: 1. Brainstem: respiration, cough, nausea & vomiting, BP, papillary diameter and stomach secretion. 2. Medial thalamus: mediating poorly localized deep pain 3. Spinal cord: in the substantia gelatinosa are involved in the receipt & integration on sensory input leading to the attenuation of painful afferent stimuli.
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Receptor distribution
4. Hypothalamus: neuroendocrine secretion. 5. Limbic system: the greatest concentration in the amygdale, a major role in emotional behavior & response and little analgesic effect. 6. Periphery: they inhibit Ca+2 dependent release of excitatory, pro-inflammatory substances (substance P) 7. Immune cells: undetermined.
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Opioids
Strong

Alfentanil Fentanyl Heroin Meperidine Methadone Morphine Oxycodone Remifentanil Sufentanil

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Opioid Agonists

The strongest naturally occurring analgesic drugs are found in opium from the poppy flower, morphine and less potent codeine. These drugs show a high affinity for the receptor and less affinity for the and receptors.

Morphine

Exert its effects through interaction with central & peripheral opioid receptors, binding results in hyperpolarization, inhibition of nerve firing and presynaptic inhibition of transmitter release Acts at the receptors in lamina I & II of the substantia gelatinosa of the cord and decreases the release of substance P, it also inhibits the release of excitatory transmitters from nociceptive nerve terminals centrally and in the cord

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MorphinePharmacological Actions- Analgesia: Opioids cause pain relief by both

raising the pain threshold at the spinal cord level altering the central perception of pain; awareness of pain remains but it loses its unpleasant character Opioids produce a sense of contentment and well being, this may be related to stimulation of the ventral tegmental tract Opioids cause respiratory depression by decreasing the sensitivity of central respiratory neurons to
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Euphoria:

Respiration:

Morphine PharmacologicalActionsSuppression of cough reflex:

Antitussive

properties do not correlate with analgesic or respiratory depression effects; this appears mediated via a different receptor complex

Miosis:
Results

from stimulation of and receptors located in the Edinger 18 8/3/12

Emesis:

Morphine Pharmacological Actions-

Opioids

directly stimulate the chemoreceptor trigger zone in the area postrema that causes vomiting relieve diarrhea by decreasing gut motility and increasing the tone of intestinal smooth muscle is also resistant to
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GI tract:
Opioids

Constipation

tolerance

Histamine release:
Morphine

Morphine Pharmacological Actions-

causes mast cell degranulation, the release of histamine causing urticaria, itching, diaphoresis and vasodilation asthmatics it may precipitate bronchospasm the release of GnRH, CRH

In

Hormonal Actions:o
inhibits and
8/3/12 20 deceases the release of LH, FSH &

Morphine Therapeutic Uses

Analgesia:
Few drugs are as effective as morphine for

the relief of pain

Treatment

of Diarrhea

Anti tussive:

codeine and dextromethorphanare

Acute

congeners with greater antitussive effects

Pulmonary Edema:

IV morphine dramatically relieves the 8/3/12 21

Morphine Pharmacokinetics
Administration:

Morphine is poorly absorbed orally; codeine

is a much more effective oral analgesic

Both undergo extensive first pass

metabolism in the liver. Inhalation is an effective route but has found favor only with nonmedicinal administration
Implantable morphine pumps are also now

use for chronic pain

Distribution:

Morphine readily enters all body tissues 8/3/12 22

Morphine Pharmacokinetics
Metabolism:

Conjugated in the liver, morphine6glucuronide is a much more

potent analgesic;
however morphine3glucuronide is less

analgesic

Both are excreted in the urine with small amounts excreted in the bile Hepatic & renal dysfunction both prolong
8/3/12 23 the normal 46 hour duration of action

Morphine Pharmacokinetics
Note:

A patient's age can influence the response to morphine. patients are more sensitive to the analgesic effects of the drug, possibly due to decreased metabolism or other factors, such as decreased lean body mass, renal function, etc. They should be treated with lower doses. should not receive morphine because of their low conjugating 8/3/12 24

Elderly

Neonates

Morphine Adverse Effects

Severe

respiratory depression ( , and receptors) (variable, and receptors)

Constipation Nausea

and vomiting constriction ( / receptors)

Pupillary Caution

must be exercised when opiates are used in those with liver or renal failure 8/3/12 25

Morphine Adverse Effects

In

BPH, morphine cause acute urinary retension with adrenal insufficiency or myxedema may experience extended and increased effects from the opioids. Morphine should be used with cautiously in patients with bronchial asthma or liver failure. Many of the effects above can be inhibited by opioid receptor antagonists 8/3/12 26

Patients

Note:

 Repeated

use produces tolerance to the effects of respiratory depression, analgesia, euphoria and sedation does not develop to miosis and constipation & psychological dependence readily occurs induces a syndrome associated with autonomic, motor and 8/3/12 psychological responses that are 27

Morphine Tolerance & Physical Dependence

Tolerance Physical

Withdrawal

Opioid withdrawal syndrome

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comparison of the maximum Efficacy versus Addiction/ Abuse Potential of Various Opioids
Detoxification

of heroinor morphine-dependent individuals is usually accomplished through the oral administration of

methadone, buprenorphine, or clonidine.
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Drug interactions:
The

depressant actions of morphine are enhanced by phenothiazines, MAOIs, and TCAs. doses of amphetamine inexplicably enhance analgesia, as does hydroxyzine.

Low

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synthetic opioid structurally unrelated to morphine

It binds to receptors with some binding

Meperidine Pethidine (, )

Mechanism:

at receptors

Actions:

Causes respiratory depression similar to

morphine, but less urine retention

no significant CV effect when given orally. IV administration produces a decrease in 8/3/12 31

Meperidine
Therapeutic

uses:

Severe acute pain Lacks antitussive activity No anti diarrhea; Obstetrics; Produces less smooth muscle

contraction/ spasm than morphine

Pharmacokinetics:

Well absorbed form the GI tract; it is most

often given IM

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With large repeated doses normeperidine (demethylated meperidine) accumulates causing

anxiety, Causes

Meperidine-Adverse effects:

muscle tremors and convulsions

papillary dilation (vs. miosis with morphine) in large doses reflexes hypotension when admin.
8/3/12 33 enhanced depression

Hyperactive Severe

postop.
+neuroleptics:

Methadone ()
This

is a synthetic orally effective opioid

that
is equipotent to morphine but induces less euphoria has a longer duration of action
Mechanism Actions:

of action:

Binds to the receptor.

An equipotent analgesic to morphine 8/3/12

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Methadone
Therapeutic

uses:

Used for controlled withdrawal from heroin

& morphine

Self addictive but the withdrawal syndrome

is somewhat milder but more protracted than with other opioids

Pharmacokinetics:

Readily absorbed orally, t1/2 24hrs Highly protein bound so remains in tissues

for a prolonged period.

8/3/12 by Transformed in the liver and excreted 35

Fentanyl
Chemically

related to meperidine but

miosis
has

100 times the analgesic potency of morphine; used in anesthesia and as analgesia postop & during labor lipophilic: elimination halflife is longer than morphines as redistribution occurs onset of action and a short duration (1530 minutes)
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Highly

Rapid

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Fentanyl
Like

morphine fentanyl causes miosis (vs. mydriasis) risk of the transmucosal or transdermal routes is respiratory depression; these delivery routes create a reservoir of drug in the skin or mucosa. Hence, the onset is delayed 12 hours, and the offset is prolonged is often used during cardiac surgery because of its negligible effects 8/3/12 37

Particular

Fentanyl

Fentanyl derivative
Adverse

effects of fentanyl are similar to those of other -receptor agonists. of life-threatening hypoventilation, the fentanyl patch is contraindicated in the management of acute and postoperative pain or pain that can be ameliorated with other analgesics. Alfentanil & Remifentanil are related to fentanyl they differ in their potency and metabolic disposition. 38 8/3/12

Because

Sufentanil,

Heroin
Heroin

is produced by the diacetylation of morphine which results in a three fold increase in its potency allows it to cross the BBB much more rapidly yielding a more pronounced euphoria be used IV or smoked, both allow for rapid distribution, is metabolized to morphine medical indication for its use in the 8/3/12 39

Acetylation

May

heroin No

oxycodone
is It

a semisynthetic derivative of morphine. is orally active and is sometimes formulated with aspirin or acetaminophen. is used to treat moderate to severe pain and has many properties in common with morphine. is metabolized to products with lower analgesic activity.
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It

Oxycodone

Moderate/WeakAgonists
Codeine Converted Much Less

to morphine thus:

less analgesic than morphine

euphoria and has much lower abuse potential and rarely produces physical dependence effective oral analgesic possess significant antitussive effects at subanalgesic doses
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An

Does

Often

Moderate/WeakAgonists

Propoxyphene
Derivative of methadone, dextro isomer is analgesic, levo isomer is antitussive Used for mild to moderate pain; its opioid dose equipotency is about half of codeine (require twice dose) Often formulated with another overthecounter analgesic; combination has greater effect than either drug alone Toxic doses may produce cardio and pulmonary toxicity particularly when taken in combination with alcohol and/or sedatives in addition to CNS depression
8/3/12 42 Opioid antagonists can reverse the pulmonary and

Mixed AgonistsAntagonists & Partial Agonists

Pentazocine Buprenorphine Butorphanol Nalbuphine

Drugs that stimulate one receptor but

block another

Effects of these drugs depend on previous

exposure to opioids

Nave patients drugs act as agonists; 8/3/12 43

Pentazocine
Pentazocine

acts as an agonist on k receptors and is a weak antagonist at and delta receptors. promotes analgesia by activating receptors in the spinal cord, and it is used to relieve moderate pain. may be administered either orally or parenterally. produces less euphoria compared to morphine. 8/3/12 44

Pentazocine

It

Pentazocine

Pentazocine
In

angina, pentazocine increases the mean aortic pressure and pulmonary arterial pressure and, thus, increases the work of the heart. drug decreases renal plasma flow. its antagonist action, pentazocine does not antagonize the respiratory depression of morphine, it can precipitate a withdrawal syndrome in a morphine abuser. 8/3/12 Tolerance and dependence develop 45 on

The

Despite

but

Mixed Agonists Antagonists & Partial Agonists

Buprenorphine A

partial agonist at receptors producing morphinelike effects in nave users but precipitating withdrawal in morphine dependents in the liver and excreted in the urine and bile be taken sublingually or parenteral and possess a long duration of action
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Metabolized May

Buprenorphine
Main

use is in opioid detoxification as its withdrawal syndrome appears less severe and of shorter duration than methadone outside of the specialized clinic allowed to dispense methadone for opiate withdrawal

Available

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Antagonists
Bind

with high affinity to the , & receptors but fail to activate the receptor normal individuals, these agents produce no effect but in those with opiates present, they induce an acute withdrawal syndrome the coma and respiratory depression associated with opioid
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In

Naloxone Reverses

48

Antagonists
Naltrexone (hepatotoxic)
Similar

actions as naloxone but an oral agent with a much longer duration of action dose able to antagonize the effects of heroin for up to 48 hours a parenteral opioid antagonist with actions similar to that of naloxone and 8/3/12 49 naltrexone.

Single

Nalmefene
is

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