Analgesics

 Safe and effective management of acute
dental pain can be accomplished with
nonopioid and opioid analgesics.
 To formulate regimens properly, it is
essential to appreciate basic pharmacological
principles and appropriate dosage strategies
for each of the available analgesic classes.
 Conventional analgesics either
1. interrupt ascending nociceptive impulses
2. depress their interpretation within the
central nervous system (CNS).

 Formerly, it was believed that opioids acted
only within the brain and spinal cord, but the
action of nonopioids was confined to the
periphery (ie, the site of injury).
 This explanation is no longer tenable,
however; both are known to act centrally
and peripherally.
 In fact, the feature that best distinguishes
these analgesic classes is their mechanism of
action.
 Opioids activate specific receptors in a
manner identical to opiates, such as
morphine.
 Nonopioids interrupt prostaglandin synthesis,
thereby resembling aspirin in action.

 include acetaminophen(APAP) and the
nonsteroidal anti-inflammatory drugs(NSAIDs).
 The analgesic efficacy of these agents is typically
underestimated.
 However, they generally are equivalent or
superior to opioids for managing musculoskeletal
pain, and they produce a lower incidence of side
effects, including the potential for abuse.
 Dental pain is included in the musculoskeletal
category, and for decades studies have
repeatedly found that NSAIDs are generally
superior to opioids at conventional dosages.

 All of the NSAIDs and paracetamol act by inhibiting
the synthesis of prostaglandins.
 Prostaglandins and related compounds are produced
in minute quantities by virtually all tissues.
 They generally act locally on the tissues in which they
are synthesized, and they are rapidly metabolized to
inactive products at their sites of action.
 Therefore, the prostaglandins do not circulate in the
blood in significant concentrations.
 Thromboxanes, leukotrienes are related lipids,
synthesized from the same precursors as the
prostaglandins, and use interrelated pathways.
 These compounds are sometimes referred to as
eicosanoids

 Arachidonic acid,is the primary precursor of
the prostaglandins and related compounds.
 Arachidonic acid is present as a component of
the phospholipids of cell membranes primarily
phosphatidylinositol and other complex lipids.
 Free arachidonic acid is released from tissue
phospholipids by the action of phospholipase A2
via a process controlled by hormones and other
stimuli.
 There are two major pathways in the synthesis
of the eicosanoids from arachidonic acid.

 All eicosanoids with ring structures that is, the
prostaglandins, thromboxanes, and
prostacyclins are synthesized via the
cyclooxygenase pathway.
 Two related isoforms of the cyclooxygenase
enzymes have been described.
1- Cyclooxygenase-1 (COX-1) is responsible for
the physiologic production of Prostanoids.
2- cyclooxygenase-2 (COX-2) causes the elevated
production of prostanoids that occurs in sites of
disease and inflammation.

 COX-1 is described as a Housekeeping enzyme
that regulates normal cellular processes, such as
gastric cytoprotection, vascular homeostasis,
platelet aggregation, and kidney function.
 COX-2 is constitutively expressed in tissues such
as the brain, kidney, and bone. Its expression at
other sites is increased during states of
inflammation.
 two enzymes share 60 percent homology in
amino acid sequence. However, the
conformation for the substrate-binding sites and
catalytic regions are slightly different.
 Another distinguishing characteristic of COX-2 is
that its expression is inhibited by
glucocorticoids.

 Alternatively, several lipoxygenases can act
on arachidonic acid to form leukotrienes or
lipoxins, depending on the tissue.
 Leukotrienes cause bronchospasm.
 Antileukotriene drugs, such as zileuton,
zafirlukast, and montelukast, are useful for
the treatment of moderate to severe allergic
asthma

 Many of the actions of prostaglandins are
mediated by their binding to a wide variety
of distinct cell membrane receptors that
operate via G proteins, which subsequently
activate or inhibit adenylyl cyclase or
stimulate phospholipase C.
 Their functions vary widely, depending on
the tissue.
 For example, the release of TXA2 from
platelets triggers the recruitment of new
platelets for aggregation

 They are also responsible for protection of
gastric mucosa.
 Prostaglandins are also among the chemical
mediators that are released in allergic and
inflammatory processes, increasing body
temprature, and pain sensation.

 The NSAIDs are a group of chemically dissimilar
agents that differ in their antipyretic,
analgesic, and anti-inflammatory activities.
 They act primarily by inhibiting the
cyclooxygenase enzymes that catalyze the first
step in prostanoid biosynthesis.
 This leads to decreased prostaglandin synthesis
with both beneficial and unwanted effects.

 Ibuprofen is conventionally regarded as the
prototype of this large group of synthetic
compounds known for their analgesic,
antipyretic, and anti-inflammatory efficacy.
 These therapeutic effects and their most
notable side effects can be explained almost
entirely by their ability to inhibit the
cyclooxygenase (COX) required for synthesis
of various families of prostanoids

 Analgesic (CNS and peripheral effect) may
involve non-PG related effects
 Antipyretic (CNS effect)
 Anti-inflammatory (except acetaminophen)
due mainly to PG inhibition.
Some shown to inhibit activation, aggregation,
adhesion of neutrophils & release of lysosomal
enzymes
 Some are Uricosuric

 Clinical use of NSAIDs is predicated on their
ability to reduce the synthesis of
prostaglandins implicated in pain, fever, and
inflammation.
 However, these agents are hardly selective in
this goal and also inhibit the production of
additional prostanoids that perform useful
physiological functions.
 This accounts for potential side effects and
contraindications.

 The most frequent side effects of NSAIDs are related
to their gastrointestinal (GI ) toxicity. Prostaglandins
stimulate the production of a mucous lining that
protects the stomach and small intestine. The erosive
and ulcerative side effects common to NSAIDs are
attributed to their inhibiting the synthesis of these
particular prostaglandins.
 This action not only occurs locally as orally
administered drug lies in contact with gastric
mucosa but also follows absorption and systemic
distribution to the GI mucosa.
 Parenteral administration does not preclude a
risk for GI erosions and ulcerations.

 The ability of NSAIDs to inhibit
cyclooxygenases in platelets reduces the
synthesis of thromboxane A2, which normally
contributes to platelet aggregation.
 This accounts for the so-called antiplatelet
effect of these agents and is a consideration
following surgical procedures.
 However, aspirin is the only NSAID that has
proven effective in preventing thrombotic
events such as acute coronary syndromes or
stroke.
 This is so because the antiplatelet action of
aspirin is irreversible, lasting the life span of
the platelet (up to 14 days).

 Other NSAIDs bind weakly and reversibly to
platelet cyclooxygenases, which results in
loss of their mild antiplatelet influence after
drug elimination.
 Although nonaspirin NSAIDs all prolong
bleeding times to some degree, this does not
correlate with significant clinical bleeding
following minor surgical procedures.
 However, nonaspirin NSAIDs generally are
withheld before major thoracic, abdominal,
or orthopedic procedures.
 If aspirin is medically necessary for patients,
such as those with endovascular stents who
are at risk for life threatening clot
formation, it should not be withdrawn.

 NSAIDs should be avoided in patients suffer
bleeding disorders and in those taking
anticoagulants such as warfarin and powerful
antiplatelet drugs such as clopidogrel (Plavix).
 Patients receiving monotherapy with low-dose
aspirin are not as great a concern but should
be considered.
 The issue with NSAIDs is due not so much to
their antiplatelet action but to NSAID-induced
injury of GI mucosa that may bleed far more
profusely in this patient population.
 NSAIDs increase the risk for GI bleeding
twofold to threefold in patients medicated
with clopidogrel (Plavix) and fourfold to
fivefold in those taking warfarin

 By inhibiting cyclooxygenase, NSAIDs shunt the
arachidonic pathway toward leukotriene
synthesisre .
 Leukotrienes mediate a variety of tissue
responses,including those associated with
bronchospasm and anaphylaxis.
 Certain individuals may be extremely
sensitive to even subtle elevation in
leukotriene synthesis, which may result in
signs and symptoms of allergic response.
 Acetaminophen is the conventional alternative
for patients reporting an allergic reaction to
any NSAID, unless the patient can identify a
particular product that he or she has tolerated
without problem in the past.

 Prostaglandins play an essential role in renal
perfusion, and diminished levels of these are
believed to account for reported cases of
nephrotoxicity after longterm NSAID use.
 In the healthy patient, nephrotoxicity
attributed to NSAIDs requires high doses for
extended periods (eg, a year or longer).
 However, a patient with compromised renal
function relies more heavily on prostaglandins
for adequate function, and acute renal failure
can occur within hours of NSAID administration.
 NSAIDs must never be prescribed for patients
who have known or questionable renal function.

 Decreased synthesis of prostaglandins can
result in retention of sodium and water and
may cause edema and hyperkalemia in some
patients Interstitial nephritis can also occur
with all NSAIDs except aspirin.

Also should be avoided during pregnancy because
prostaglandins maintain patency of the ductus
arteriosus during fetal development.
Although this concern is most relevant during the
third trimester, NSAIDs generally should be avoided
throughout pregnancy.
In all cases where NSAIDs are contraindicated,
acetaminophen is the conventional nonopioid
alternative.

 Celecoxib (Celebrex) is representative of agents
that selectively inhibit COX-2; it reduces pain and
inflammation with little or no influence on gastric
mucosa.
 However, this selective inhibition may promote
greater synthesis of prostanoids derived from COX-1,
including thromboxane-mediated effects leading to
possible thrombotic events (eg, myocardial
infarction, stroke).
 Detection of serious cardiovascular events
associated with COX-2 inhibitors have led to
withdrawal of rofecoxib and valdecoxib from the
market (celecoxib is still available for use in
patients with RA).

 Additionally, the U.S. Food and Drug Administration
(FDA) has required that the labeling of the traditional
NSAIDs and celecoxib be updated to include the
following:
1) a warning of the potential risks of serious
cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal;
additionally, a warning that the risk may increase
with duration of use and that patients with
cardiovascular disease or risk factors may be at
greater risk; for celecoxib
2) a warning that use is contraindicated for the
treatment of perioperative pain in the setting of
coronary artery bypass graft surgery; for both.
3) a notice that there is increased risk of serious
gastrointestinal (GI) adverse events, including
bleeding, ulceration, and perforation of the
stomach or intestines, which can be fatal. For
NSAIDs; traditional

 These events can occur at any time during use and
without warning symptoms.
 Elderly patients are at greater risk for serious GI
events.
 Aspirin, however, has proven to be beneficial in
patients for the primary and secondary
prevention of cardiovascular events and is most
commonly used for this purpose rather than for
pain control.

 In summary, NSAIDs are contraindicated for
patients who have:
1. a current history of nephropathy
2. erosive or ulcerative conditions of the GI
mucosa
3. anticoagulant therapy
4. hemorrhagic disorders
5. intolerance or allergy to any NSAID;
Symptoms of true allergy include urticaria,
bronchoconstriction, or angioedema. Fatal
anaphylactic shock is rare.

 Aspirin is the prototype of traditional NSAIDs.
 Analgesic action: Prostaglandin E2 (PGE2) is
thought to sensitize nerve endings to the action of
bradykinin, histamine, and other chemical
mediators released locally by the inflammatory
process.
 Thus, by decreasing PGE2 synthesis, aspirin and
other NSAIDs repress the sensation of pain.
 The salicylates are used mainly for the
management of pain of low to moderate intensity
arising from musculoskeletal disorders rather than
that arising from the viscera.

 Antipyretic action:
 Fever occurs when the set-point of the anterior
hypothalamic thermoregulatory center is elevated.
 This can be caused by PGE2 synthesis, which is
stimulated when an endogenous fever-producing
agent (pyrogen), such as a cytokine, is released from
white cells that are activated by infection,
hypersensitivity, malignancy, or inflammation.
 The salicylates lower body temperature in patients
with fever by impeding PGE2 synthesis and release.
Aspirin resets the thermostat toward normal, and it
rapidly lowers the body temperature of febrile
patients by increasing heat dissipation as a result of
peripheral vasodilation and sweating.
 Aspirin has no effect on normal body temperature.

 Duration of action ~ 4 hr.
 Orally taken.
 Weak acid (pKa ~ 3.5); so, non-ionized in
stomach  easily absorbed.
 Hydrolyzed by esterases in tissues and blood
to salicylate (active) and acetic acid.
 Most salicylate is converted in liver to H2O-sol
conjugates that are rapidly excreted by
kidneys.

1. Because salicylates are excreted in breast milk,
aspirin should be avoided during pregnancy and
while breast-feeding.

 Reye's syndrome: Aspirin and other salicylates
given during viral infections has been associated
with an increased incidence of Reye's syndrome,
which is an often fatal, fulminating hepatitis
with cerebral edema. This is especially
encountered in children, who therefore should
be given acetaminophen instead of aspirin when
such medication is required to reduce fever.
Ibuprofen is also appropriate.
 Children who have received live varicella virus
vaccine should
 avoid aspirin for at least 6 weeks after
vaccination to prevent Reye's syndrome.

 Drug interactions: Concomitant administration
of salicylates with many classes of drugs may
produce undesirable side effects.
 Because aspirin is found in many over-the-
counter agents, patients should be counseled to
read labels to verify aspirin content to avoid
overdose.
 Salicylate is 90 to 95 percent protein bound and
can be displaced from its protein-binding sites,
resulting in increased concentration of free
salicylate; alternatively, aspirin could displace
other highly protein-bound drugs, such as
warfarin, phenytoin, or valproic acid, resulting
in higher free concentrations of the other agent.

 Diflunisal is three- to four-fold more potent
than aspirin as an analgesic and an anti-
inflammatory agent, but it has no antipyretic
properties.
 Diflunisal does not reduce fever, because it
does not cross the blood-brain barrier.

 Ibuprofen [eye-byoo-PROE-fen] was the first in
this class of agents to become available.
 It has been joined by naproxen [nah-PROX-en],
fenoprofen [fen-oh-PROE-fen], ketoprofen [key-
toe-PROE-fen], flurbiprofen [flur-bye-PROE-
fen], and oxaprozin [ox-ah-PROE-zin].
 All these drugs possess anti-inflammatory,
analgesic, and antipyretic activity; additionally,
they can can alter platelet function and prolong
bleeding time.
 their GI effects are generally less intense than
those of aspirin.

 All are well absorbed on oral administration
and are almost totally bound to serum
albumin.
 Oxaprozin has the longest half-life and is
administered once daily.
 They undergo hepatic metabolism and are
excreted by the kidney.
 The most common adverse effects are GI,
ranging from dyspepsia to bleeding.
 Side effects involving the central nervous
system (CNS), such as headache, tinnitus,
and dizziness, have also been reported.

 This group of drugs includes indomethacin [in-doe-METH-
a-sin], sulindac [sul-IN-dak], and etodolac [eh-TOEdoh-
lak].
 All have anti-inflammatory, analgesic, and antipyretic
activity.
 They are generally not used to lower fever.
 Despite its potency as an anti-inflammatory agent, the
toxicity of indomethacin limits its use to the treatment of
acute gouty arthritis, ankylosing spondylitis, and
osteoarthritis of the hip.
 Sulindac is an inactive prodrug that is closely related to
indomethacin. The adverse reactions caused by sulindac
are similar to, but less severe than, those of the other
NSAIDs, including indomethacin.
 Etodolac has effects similar to those of the other NSAIDs.
GI problems are less common.

 Piroxicam [peer-OX-i-kam] and meloxicam [mel-
OX-i-kam] are used to treat RA, ankylosing
spondylitis, and osteoarthritis.
 They have long half-lives, which permit once-
daily administration.
 Meloxicam inhibits both COX-1 and COX-2, with
preferential binding for COX-2, and at low to
moderate doses shows less GI irritation than
piroxicam.
 However, at high doses, meloxicam is a
nonselective NSAID, inhibiting both COX-1 and
COX-2.

 Diclofenac [dye-KLO-feh-nak] and tolmetin
[tole-MEN-tin] are approved for long-term
use in the treatment of RA, osteoarthritis,
and ankylosing spondylitis.
 Diclofenac is more potent than indomethacin
or naproxen.

 Ketorolac [key-toe-ROLE-ak] is a potent analgesic but
has moderate anti-inflammatory effects.
 It is available for oral administration, for
intramuscular use in the treatment of postoperative
pain.
 Ketorolac undergoes hepatic metabolism, and the
drug and its metabolites are eliminated via the urine.
 Ketorolac is indicated for short-term relief of
moderate to severe pain for up to 5 days after the
first dose is administered via IV or intramuscular
dosing at the doctor's office or in a hospital.
 This agent is to be avoided in pediatric patients;
patients with mild pain, and those with chronic
conditions, the dose should not exceed 40 mg/day.
 Ketorolac can cause fatal peptic ulcers as well as GI
bleeding and/or perforation of the stomach or
intestines.

 Celecoxib [sel-eh-COCKS-ib] is significantly more
selective for inhibition of COX-2 than of COX-1.
 Unlike aspirin, celecoxib does not inhibit platelet
aggregation and does not increase bleeding time.
 Celecoxib has similar efficacy to NSAIDs in the
treatment of pain.
 Celecoxib, when used without concomitant
aspirin therapy, has been shown to be associated
with less GI bleeding and dyspepsia; however, this
benefit is lost when aspirin is added to celecoxib
therapy.
 In patients at high risk for ulcers (that is, history
of peptic ulcer disease), use of PPIs with
celecoxib and aspirin may be necessary to avoid
gastric ulcers.

Pharmacokinetics:
 Celecoxib is readily absorbed, reaching a peak
concentration in about 3 hours.
 It is extensively metabolized in the liver by
cytochrome P450 (CYP2C9) and is excreted in the
feces and urine.
 Its half-life is about 11 hours; thus, the drug is
usually taken once a day but can be administered
as divided doses twice daily.
 The daily recommended dose should be reduced
by 50 percent in those with moderate hepatic
impairment,
 celecoxib should be avoided in patients with
severe hepatic and renal disease.
 Celecoxib is contraindicated in patients who are
allergic to sulfonamides.

 After prolonged use, NSAIDs may interfere with
the effectiveness of most classes of
antihypertensive medications; calcium channel
blockers are a notable exception.
 The precise mechanism for this interaction is
unknown but is believed to be related to
diminished vasodilator actions attributed to
renal prostaglandins.
 In the rare event that postoperative analgesics
must be continued for longer than 5 days,
hypertensive patients should return to the
office for blood pressure assessment. If pressure
has elevated more than 8% above baseline, it
would be wise to replace the NSAID with
acetaminophen.

 serum levels of lithium and methotrexate
are elevated during concurrent consumption
of NSAIDs. To prevent toxicity, NSAIDs should
be avoided in patients medicated with these
agents, particularly those taking high-dose
regimens.

 In general, no convincing evidence indicates that a
particular NSAID is more effective or safer than other
members of this drug class.
 Selective COX-2 inhibitors such as celecoxib produce less
GI toxicity after short-term use, but this advantage wanes
as consumption continues.
 Patients vary considerably in their clinical response and GI
tolerance to a particular agent. Given its efficacy and low
side effect profile and cost, ibuprofen is generally a sound
initial choice. Regardless of the agent selected, however,
an optimal dosing schedule should be maintained for 2 to3
days before an alternative agent is prescribed.
 usually antiniflammtory effect requires higher dose than
that for pain relief.

 Compared with NSAIDs, the mechanism of action of
acetaminophen is less clear but is believed to involve an
inhibition of prostaglandin synthesis within the CNS.
 It has little influence on peripheral prostaglandin
synthesis, especially within inflamed tissues.
 This is a likely explanation for its lacking anti-
inflammatory efficacy and sharing none of the
peripheral side effects attributed to NSAIDs.
 However, it is an ideal analgesic for patients who
present any contraindications to NSAIDs. As an analgesic
and antipyretic, acetaminophen is equal in potency and
efficacy to aspirin and presumably may be somewhat
inferior to ibuprofen and other NSAIDs as well.

 Hepatotoxicity is the most significant
adverse effect of acetaminophen.
 The dose may be less for patients who are
poorly nourished, who have liver
dysfunction, or who are being treated with
other hepatotoxic medications.
 For example, in contrast to the 4 g/d
allowed healthy patients, those suspected of
chronic alcoholism should limit their
maximum daily intake to 2 grams.

 Most cases of postoperative dental pain include an
inflammatory component. For this reason, NSAIDs
are the most rational first-line agents often
superior to conventional dosages of opioids.
 Should a patient present a contraindication to
NSAIDs, acetaminophen is the only alternative.
 Nonopioids exhibit a ceiling to their analgesic
response, but optimal doses should be established
before it is assumed that the NSAID has failed.
 Furthermore, the combination of a NSAID with
acetaminophen provides greater analgesic efficacy
than does either agent alone, and this strategy
may obviate the need for opioids.

 Opioids are natural or synthetic compounds that produce
morphine-like effects. [The term opiate is reserved for
drugs, such as morphine and codeine, obtained from the
juice of the opium poppy.]
 All drugs in this category act by binding to specific opioid
receptors in the CNS to produce effects that mimic the
action of endogenous peptide neurotransmitters (for
example, endorphins, enkephalins, and dynorphins).
 Although the opioids have a broad range of effects, their
primary use is to relieve intense pain and the anxiety that
accompanies it, whether that pain is from surgery or a
result of injury or disease, such as cancer.
 However, their widespread availability has led to abuse of
those opioids with euphoric properties. [Dependence is
seldom a problem in patients being treated for severe
pain with these agents, as in cancer or acute pain in
terminally ill patients.]
 Antagonists that can reverse the actions of opioids are
also very important clinically for use in cases of overdose.

 Opioids interact stereospecifically with protein
receptors on the membranes of certain cells in the
CNS, on nerve terminals in the periphery, and on
cells of the gastrointestinal tract and other anatomic
regions.
 The major effects of the opioids are mediated by
three major receptor families. μ (mu), κ(kappa), and
δ (delta). Each receptor family exhibits a different
specificity for the drug(s) it binds.
 All three opioid receptors are members of the G
protein coupled receptor family and inhibit adenylyl
cyclase.
 They are also associated with ion channels,
increasing postsynaptic K+ efflux (hyperpolarization)
or reducing presynaptic Ca2+ influx, thus impeding
neuronal firing and transmitter release.

High densities of opioid receptors known to be involved in integrating
information about pain are present in five general areas of the CNS. They
have also been identified on the peripheral sensory nerve fibers and on
immune cells.
1. Brainstem: Opioid receptors influence respiration, cough, nausea and
vomiting, blood pressure, pupillary diameter, and control of stomach
secretions.
2. Medial thalamus:
3. Spinal cord: involved with the receipt and integration of incoming
sensory information, leading to the attenuation of painful afferent
stimuli.
4. Hypothalamus: Receptors here affect neuroendocrine secretion.
5. Limbic system: These receptors probably do not exert analgesic
action, but they may influence emotional behavior.
6. Periphery: Opioids also bind to peripheral sensory nerve fibers and
their terminals. As in the CNS, they inhibit Ca2+-dependent release of
excitatory, proinflammatory substances (for example, substance P)
from these nerve endings.
7. Immune cells: The role of these receptors in has not been
determined.

 Opioids produce most of their therapeutic and adverse
effects by acting as agonists at opioid receptors.
 Morphine produces its effects by acting as an agonist at
both mu and kappa receptors
 The mu receptor is responsible for mediating analgesia
and 2 of the most undesirable side effects attributed to
opioids: respiratory depression and dependence. Mu
effects have unlimited intensity
 Like mu receptors, the kappa receptor mediates
analgesia and respiratory depression, but efficacy at this
receptor is limited
 When high doses of opioids are used, selective
kappa agonists are viewed as safer, but less
analgesic, compared with traditional mu agonists.

 Mu
Located throughout CNS
Responsible for:
 respiratory depression
 analgesia
 nausea and vomitting
 Miosis
 constipation
 euphoria

 Only modest analgesia
 Little or no respiratory depression
 Little or no dependence
 Dysphoric effects

 Analgesia
 Possible role in emotional response

 Analgesia
 Euphoria may affect dompaminergic receptors and mu receptors

 Sedation and anxiolysis but level not as CNS depressants
 Drowsiness and lethargy
 Apathy
 Cognitive impairment
 Depression of respiration
Reduce response of respiratory center to high level of carbon monoxide
 Main cause of death from opioid overdose
 Combination of opioids and alcohol is especially dangerous
 Cough suppression
 Opioids suppress the “cough center” in the brainstem
 Pupillary constriction
 pupillary constriction in the presence of analgesics is characteristic
of opioid use

 Nausea and vomiting
 Stimulation of receptors in an area of the
medulla called the chemoreceptor trigger zone
causes nausea and vomiting
 Unpleasant side effect, but not life threatening
 Gastrointestinal symptoms
 Opioids relieve diarrhea as a result of their
direct actions on the intestines
 Other effects
 Opioids can release histamines causing itching
or more severe allergic reactions including
bronchoconstriction
 Opioids can affect white blood cell function and
immune function

 Pure agonists:
These opoids have high affinity for
receptor binding plus high efficacy used in
management of sever pains. They all have
high affinity for Mμ receptors and
generally lower affinity for δ and κ sites.
They always cause both physical and
psychological dependence.
Morphine
Heroin 3 times more potent than morphine
Methadone effective analgesia, orally
effective, long duration
fentanyl
Codeine 110 activity of morphine
Oxymorphone 6-8 times as morphine
Naglaa El-Orabi, Ph D

 Partial agonist
Buprenorphine:
low ceiling
Analgesic
Euphoric
Respiratory depressant
Long duration of action : more than 22 hours

 mixed agonist-antagonists:
These drugs may produce agonist effects
at some opiate receptors and antagonist
effects at another opiate receptors
e.g Pentazocine, Nalbuphine,
Nalorphine, and Dezocine.
Nalbuphine is agonist on -receptor
and potent anatagonist at m-receptor but
weak antagonist at -receptors.
Pentazocine is antagonist at μ-
receptors but partial agonists on - and -
receptors.
Toxicityof opiates

 These so-called agonist-antagonists are not
constipating, produce less respiratory
depression at higher doses, and have less
potential for abuse, but their limited analgesic
efficacy diminishes their value when
postoperative pain is severe.
 Higher doses are no more effective than
conventional doses. Because they act as
antagonists at mu receptors, agonist-
antagonists
 may precipitate a withdrawal syndrome in
patients dependent on opioids.

 Antagonist
Naloxone and Naltrexone
Used in acute opioid toxicity.

Therapeutic uses of Opiates :
i. Pain management:
- Relief of moderate to severe acute pain (Like
postoperative pain, pain associated with
orthopedic manipulations, myocardial infarction
pain, cancer pain, renal colic)
- To induce brief tranqullizing effect with
analgesia in serious and frightening conditions
accompanied by pain (e.g. multiple traumas )
ii. Preanesthetic medication to reduce pain
sensation and anxiety ( e.g Fentany,
Pethidine)
iii. Cough Suppression (e.g. codeine,
dextromethorphan)
iv. Symptomatic treatment of sever diarrhea
and dysentery (e.g. Diphenoxylate,
Loperamide)

- Opiates have
many legal
medicinal uses in
addition to high
potential of
abuses.
- Members of
opiates family are
listed in different
drug schedules.
s
Narcotic Drug Most Common
Uses
Heroin Abuse
Morphine Analgesia
Methadone Treat narcotic
dependence
Meperidine Analgesia
Oxycodone Analgesia
Propoxyphene Analgesia
Codeine Analgesia,
antitussive
Loperamide Antidiarrheal
Diphenoxylate Antidiarrheal
Opium tincture Antidiarrheal

 LATENCY TO ONSET
*oral (-30 minutes)
*intranasal (2-3 minutes)
*intravenous (30 seconds)
*pulmonary-inhalation (6-11 seconds)
 DURATION OF ACTION – anywhere between 4 and 72
hours depending on the substance in question.
 Metabolism –
hepatic via phase 1 and phase 2 biotransformations to
form a diverse array of metabolites ( eg., morphine to
morphine-6-glucuronide).
 Opiate metabolites are excreted in the urine. Impaired
renal function can lead to toxic effects from
accumulated drug or active metabolites (eg,
normeperidine).

 Precautions: Opiates should be avoided to
be used in patients with the following
pathologic disorders:
i. Decreased impaired respiratory functions
e.g. emphysema, asthma and CPOD.
ii. Biliary colic
iii. Head injury (increase in ICP)
iv. Reduced blood volume
v. Hepatic and renal insufficiency
vi. During pregnancy and labor.

 Dependence occurs when the body
accommodates to the influences of a drug
and, upon sudden discontinuation,the
patient experiences a withdrawal syndrome
that generally includes reactions opposite
those produced by the particular drug. For
example, opioids produce sedation, and
constipation. A patient who is experiencing
opioid withdrawal becomes excited and
experiences diarrhea.

 After repeated administration, patients
develop tolerance to opioids. This is to say
that greater doses are required to produce
the same intensity of effect formerly
provided by a smaller dose.
 Tolerance to analgesia, sedation, and
respiratory depression occurs simultaneously,
but it is curious that no tolerance occurs to
the constipating or miotic effects of opioids.
Constipation may become severe and night
vision becomes impaired.

 Addiction is distinct from dependence or
tolerance. It is a compulsive behavior centered on
seeking a drug and its effects for nonmedical
reasons generally for pleasure. It It is a complexp
sychiatric phenomenon, but it should not be
attributed to the drug.
 Opioids produce dependence, even after as little
as 5^7 days of therapy, and this may require
institution of a tapering dosage schedule.
 However, opioids do not produce addiction; they
should not be withheld on the presumption that
the patient will become ‘‘addicted.’’
 Obviously, opioids must be prescribed cautiously
for patients who demonstrate addictive
personality.

 Codeine has very little affinity for the mu receptor
and may be considered a prodrug because 11% of the
parent drug is converted to morphine by cytochrome
P450 CYP2D6.The morphine metabolite accounts for
its entire analgesic effect.
 Altered activity of CYP2D6 offers one explanation for
varied responses to codeine and to its derivatives
 Roughly 5- 9% of the Caucasian population
metabolizes codeine poorly because these individuals
have inherited nonfunctional CYP2D6. For them,
analgesia resulting from codeine will be less than
expected with the general population.
 Likewise, a variety of drugs that a patient may be
taking concurrently have the ability to inhibit or
induce CYP2D6 activity. For example, the SSRI
antidepressants are CYP2D6 inhibitors, making
codeine less effective. This is established for
fluoxetine (Prozac) and paroxetine (Paxil)

 Hydrocodone is demethylated to hydromorphone
 For this reason, hydrocodone shares the same
considerations regarding demethylation
addressed previously for codeine.
 In contrast, the analgesic effect of oxycodone is
almost entirely attributedto the parent drug
because only scant amounts are demethylated
to oxymorphone.
 This makes it the better choice for patients
taking medications known to inhibit CYP2D6.
 Their potency allows for lower doses of these
agents and reduces the incidence of nausea
compared with codeine

 Meperidine: A significant portion of an IM dose of
meperidine is converted to normeperidine, a
metabolite that has no analgesic properties but is a
noted cardiovascular and CNS stimulant.
 Furthermore, this metabolite has a 17 hours half life.
 For hospitalized patients, meperidine is used for only a
day or 2; otherwise, normeperidine will accumulate. In
fact, many hospitals have deleted it from their
formularies.
 Pentazocine: Pentazocine is the only oral agonist
antagonist analgesic available in the United States.
 It produces its analgesic effect by acting as an agonist
at kappa receptors but is an antagonist at mu
receptors.
 Therefore it reverses all effects of traditional mu
agonist opioids if taken concurrently.
 Additionally, pentazocine is available compounded with
APAP.

 Tramadol. Tramadol is a centrally acting analgesic with
binary action.
 The parent drug inhibits the reuptake of norepinephrine
and serotonin. This resembles the action of tricyclic
antidepressants and potentiates descending neural
pathways that inhibit incoming nociceptive impulses. This
action has proven efficacy in the management of chronic
pain.
 The principal metabolite of tramadol, O-
desmethyltramadol (M1), demonstrate agonist action on
mu receptors, providing analgesic efficacy approximating
that of codeine.
 Formation of this metabolite is provided by CYP2D6
enzymes and introduces the identical risk for drug
interactions described earlier for codeine.

 Tramadol is not recommended for patients
with a tendency toward opioid abuse or
dependence.
 It is available in combination with
acetaminophen but is no more effective than
codeine-acetaminophen combinations

 Mild to moderate pain generally can be managed by
using optimal doses of nonopioids: ibuprofen 400^
800 mg, acetaminophen 1000 mg, or a combination of
the two.
 Although it is unwise to combine NSAIDs,the addition
of acetaminophen to an NSAID is reasonable.
 Regardless of pain severity, one should seek to
optimize ‘‘around-the-clock’’ dosages of these agents
and then, if necessary, add an opioid to the regimen
as needed for breakthrough pain.
 This practice generally will reduce the amount of
opioid required, sometimes to only a fraction of the
maximum doses .
 It is irrational to prescribe opioid combinations
routinely as ‘‘first-line’’ analgesics

Analgesics

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