Oleh :

Dimas P.Nugraha
Departemen farmakologi FK UR

Mechanisms of Pain and

Nociception
Nociception is the mechanism
whereby noxious peripheral stimuli
are transmitted to the central
nervous system. Pain is a subjective
experience, not always associated
with nociception.

Mechanisms of Pain and

Nociception
Polymodal nociceptors (PMN) are the
main type of peripheral sensory
neuron that responds to noxious
stimuli. The majority are nonmyelinated C-fibres whose endings
respond to thermal, mechanical and
chemical stimuli.

Pain
mechanis
ms and
pathway
s

Natural painkillers
They

are produced naturally in the

body.
Endorphins and enkephalins are
the natural opiates found in the part
of the brain and the spinal cord that
transmit pain impulses. They are
able to bind to neuro-receptors in the
brain and produce relief from pain.
The temporary loss of pain
immediately after an injury is
associated with the production of

Pain sensation can be influenced or modified as follows:

Elimination of the cause of pain

Non-steroidal anti-inflammatory
drugs (NSAIDs)
An anti-inflammatory action:
(1)The decrease in vasodilator
prostaglandins (PGE2, PGI2) means
less vasodilatation and, indirectly,
less oedema.
(2)The inhibition of activity of
adhesion molecule.
(3) Accumulation of inflammatory
cells is also reduced.

Non-steroidal anti-inflammatory
drugs (NSAIDs)
An analgesic effect: decreased
prostaglandin generation means less
sensitisation of nociceptive nerve
endings to inflammatory mediators
such as bradykinin and 5hydroxytryptamine.
Relief of headache is probably due to
decreased prostaglandin-mediated
vasodilatation.

Non-steroidal anti-inflammatory
drugs (NSAIDs)
An antipyretic effect: this is partly due
to a decrease in the mediator
prostaglandin that is responsible for
elevating the hypothalamic set-point for
temperature control in fever.
Endogenous pyogen(IL-1,TNF,IFN, IL-6)
BBB
CNS(PEG, Na+/Ca2+,
cAMP,CRH)
fever

Categories of NSAIDs
There are two major categories for
non-steroidal anti-inflammatory
drugs
The first is non-selective antiinflammatory drugs.
The second is selective antiinflammatory drugs, COX-2
inhibitors.

Effects of COX Inhibition

by Most NSAIDS
COX-1
Gastric ulcers

COX-2
Reduce inflammation

Bleeding

Reduce pain

Acute renal failure

Reduce fever

NSAIDs : anti-plateletdecreases ability of blood to clot

Pharmacokinetic Variability of
Non-Selective COX-Inhibitors
Name

Time to peak life parent

(hours)
life*active

Aspirin

1-2

Naproxen
Oxaprozin

2-4
3-5

*Sulindac (pro-drug) 2-4

0.25-0.33
(*3-10 L-H)
12-15
42-50

Ketorolac (inj)

.5-1

7.8
(*16.4)
3.8-8.6

Ibuprofen

1-2

1.8-2.5

COX

Expression

Function

Inhibitors

COX-1

organ pain, platelet

constitutively
function, stomach
throughout the body
protection

COX-2

Inducible: inflammation, NSAIDs, COX 2

Inducible and
pain, fever
inhibitors including
constitutively in brain, Constitutive: synaptic celecoxib
kidney
plasticity
(Celobrex )

COX-3

Constitutively, high in pain pathways, not

acetaminophen
inflammation pathways some NSAIDs
brain, heart

NSAIDs including
aspirin

Selective Cox-2
Inhibitors
Greater affinity for cyclooxygenase-2
Decreased incidence of negative effects
associated with non-selective COXinhibitors
Name
Time to peak
life
(hours)
(hours)
Celecoxib
3
11
Rofecoxib

2-3

17

The Salicylates: Aspirin

Aspirin (acetylsalicylic acid) was first
isolated in 1829 by Leroux from willow
bark.
It can cause irreversible inactivation of
cyclo-oxygenase, acting on both COX-1
and COX-2.

Aspirin
Salicylates are given orally and are
rapidly absorbed; 75% metabolized in
the liver.
Excretion: 85% in alkaline urine
5% in acid urine

Pharmacologic effects
(1) Antipyretic action: is rapidly
effective in febrile patients, yet has
little effect on normal body
temperature.
(2) Anti-inflammatory effects: the
primary clinical application is in the
treatment of musculoskeletal
disorders, such as rheumatoid
arthritis, osteoarthritis and
ankylosing spondylitis.

Pharmacologic effects
(3) Analgesic effects:
(a) is usually effective for low- to
moderate-intensity pain. Integumental
pain is relieved better than the pain from
hollow visceral areas.

Pharmacologic effects
(b) relief of pain occurs through both
peripheral and central mechanisms.
----Peripherally, it inhibits the synthesis of
PGs in inflamed tissues, thus preventing
the sensitization of pain receptors to both
mechanical and chemical stimuli.
----Centrally, the analgesic site exists in
close proximity to the antipyretic region in
the hypothalamus. Its analgesia action is
not associated with mental altertions, such
as hypnosis or changes in sensation other
than pain.

Pharmacologic effects
(4) Respiratory effects:
(a) High doses result in medullary
stimulation, leading to hyperventilation
and a respiratory alkalosis. Compensation
rapidly occurs because the kidney is able
to increase the excretion of bicarbonate,
producing a compensated respiratory
alkalosis.
(b) Toxic doses or very prolonged
administration can depress the medullary
resulting in an uncompensated respiratory
acidosis.

Pharmacologic effects
(5) Cardiovascular effects:
(a)Therapeutic doses have no significant
cardiovascular effect. However, the
prophylactic use of aspirin to reduce
thromboembolic events in coronary and
cerebral circulation has increased. Studies
have demonstrated that such use results
in long-term survival and reduced
frequency of second myocardial
infarctions.

Pharmacologic effects
(5) Cardiovascular effects:
(b) High doses may cause peripheral
vasodilation by exerting a direct effect on
smooth muscle.
(c) Toxic doses depress circulation directly
and by central vasomotor paralysis.
Noncardiogenic pulmonary edema may
occur in older patients on long-term
salicylate therapy.

Pharmacologic effects
(5) Gastrointestinal effects:
(a) It can cause epigastric distress, nausea, and
vomiting by irritating the gastric mucosal lining
and stimulating the chemoreceptor trigger zone
in the CNS.
(b) It may cause a dose-related gastric ulceration,
bleeding, and erosive gastritis because of
inhibiting the formation of PGE2, which inhibits
gastric acid secretion and has a cytoprotective
effect. Salicylate-induced gastric bleeding is
painless and may lead to an iron deficiency
anemia.

Pharmacologic effects
(6) Hepatic effects:
(a) dose-dependent hepatic damage.
Usually, asymptomatic, elevated plasma
transaminase levels are the key indication
of hepatic insult.
(b) more severe and associated with
encephalopathy seen in Reyes syndrome.
Use of salicylates in children with
chickenpox or influenze is contraindicated.

Pharmacologic effects
(7) Hematologic effects:
(1) It inhibits the platelet
aggregation by decreasing the
production of TXA2.
(2) In doses greater than 6g/d,
aspirin may reduce plasma
prothrombin levels.

Pharmacologic effects
(8)Renal effects: It can result in salt
and water retention because of
decreasing renal blood flow.
(9) Metabolic effects: It can produce
hyperglycemia and glycosuria in
large doses.
(10) Endocrine effects: In very large
doses, it can stimulate steroid
secretion by the adrenal cortex.

Therapeutic uses
(1) Aspirin is used in restricted situation for
the symptomatic relief of fever. Because
of an increased incidence of Reyes
syndrome in children who previously were
given aspirin for the relief of viral fevers,
it is now recommended that a child with
any fever be given paracetamol instead,
if medication is required.
(2) It is useful as analgesics for certain
categories of pain, such as headache,
arthritis, dysmenorrhea.

Therapeutic uses
(3) It remains the standard, first-line
drug in the therapy of rheumatoid
arthritis, and can provide relief of
symptoms in acute rheumatic fever.
(4) Some clinicians recommend small
daily doses of aspirin for prophylaxis
of thromboembolism, stroke, or
myocardial infarction because of its
antiplatelet activity.

Adverse effects
(1) Salicylism: usually occurs with repeated
administration of large doses. Characteristic
findings include:
----headache, mental confusion, lassitude, and
drowsiness.
----tinnitus and difficulty in hearing.
----hyperthermia, sweating, thirst,
hyperventilation, vomiting, and diarrhea.
(2) Bronchospasm in aspirin-sensitive
asthmatics.

Adverse effects
(3) Gastrointestinal disturbances.
(4) Prolongation of bleed time or reduce
prothrombin level.
(5) Other: skin eruption, hepatic effects,
Reyes syndrome.

Salicylates

Treatment of Aspirin
poisoning
(1)Inducing emesis or administering
gastric lavage.
(2)Appropriate infusion measures to
correct abnormal electrolyte
balance and dehydration.
(3)Alkalinization of the urine.
(4)Dialysis as required.

Paracetamol
Pharmacologic effects:
Paracetamol has analgesic and antipyretic
actions but only weak anti-inflammatory
effects.
It appears to be an inhibitor of PG synthesis
in the brain, thus accounting for its analgesic
and antipyretic activity.
It is much less effective than aspirin as an
inhibitor of the peripherally located PG
biosynthetic enzyme system that plays such
an important role in inflammation.

Paracetamol
Pharmacologic effects:
It exerts little or no pharmacologic effect on
the cardiovascular, respiratory, or
gastrointestinal systems, on acid-base
regulation, or on platelet function.

Therapeutic uses
Paracetamol provides an effective
alternative when aspirin is
contraindicated (e.g., in patients with
peptic ulcer or hemophilia) and when
the anti-inflammtory action of aspirin
is not required.

Adverse effects
At therapeutic doses, paracetamol is well
tolerated; however, adverse effects
include:
-----Skin rash and drug fever.
-----Rare instances of blood dyscrasias.
-----Renal tubular necrosis and renal failure.
-----Hypoglycemic coma
At overdose, it can result in severe
hepatotoxicity, resulting in centrilobular
hepatic necrosis.

Indomethacin
Pharmacologic effects :
(1)Inhibit COX nonselectively .
(2)Inhibit phospholipase A and C.
(3)Reduce PMN migration.
(4)Decrease T cell and B cell
proliferation.
(10-40 time more potent antiinflammatory than aspirin)

Indomethacin

Therapeutic uses:
Because of its toxicity and side
effect, it is not routinely used for
analgesia or antipyresis.
The major uses of indomethacin are
in the treatment of rheumatoid
arthritis, ankylosing spondylitis,
osteoarthritis, and acute gout.

Indomethacin
Adverse effect:
(1)Gastrointestinal complaint:
(2)CNS effects: 25%-50%
(3)Hematologic reactions:
(4)Hypersensitivity reactions: asthma
(aspirin- sensitive patients may
exhibit cross-reactions to
indomethacin).

Naproxen and Ibuprofen

They have prominent anti-inflammatory
action.
Therapeutic uses: rheumatoid arthritis,
osteoarthritis, ankylosing spondylitis,
acute tendinitis, dysmenorrhea, et al.
Adverse effect: gastrointestinal effects,
dermatologic problems, thrombocytopenia.
apply to long-term treatment because
they are better-tolerated.

Selective COX-2 inhibitor

Celecoxib, Meloxicam and Rofenxib
more selective for COX-2 than for
COX-1.
Adverse effects are slighter than
other NSADs.
Long-term studies of the incidence of
clinically significant gastrointestinal
ulcers and bleeding are not yet
completed.

Clinical uses of the NSAIDs

For analgesia in painful conditions (e.g.
headache, dysmenorrhoea, backache,
bony metastases of cancers, postoperative
pain):
The drugs of choice for short-term analgesia
are aspirin, paracetamol and ibuprofen; more
potent, longer-acting drugs (diflunisal,
naproxen, piroxicam) are useful for chronic
pain.
The requirement for narcotic analgesics can be
markedly reduced by NSAIDs in some patients
with bony metastases or postoperative pain.

Clinical uses of the NSAIDs

For anti-inflammatory effects in chronic or
acute inflammatory conditions (e.g. rheumatoid
arthritis and related connective tissue
disorders, gout and soft tissue diseases).
With many NSAIDs, the dosage required for
chronic inflammatory disorders is usually
greater than for simple analgesia and treatment
may need to be continued for long periods;
Treatment could be initiated with an agent
known to have a low incidence of side-effects. If
this proves unsatisfactory, more potent agents
should be used.

Clinical uses of the NSAIDs

To lower temperature. Paracetamol is
preferred because it lacks gastrointestinal
side-effects and, unlike aspirin, has not
been associated with Reyes syndrome in
children.
There is substantial individual variation in
clinical response to NSAIDs and
considerable unpredictable patient
preference for one drug rather than
another.

Comparison of
antipyretic
analgesics
with a
nonsteroidal
antiinflammatory
drug

NSAIDs

13

NSAIDs

14

Summary of Nonsteroidal antiinflammatory agents (NSAIDs)

OPIOIDS (MORPHINE-LIKE) ANALGESICS

AND ANTAGONISTS
Opioids
natural or synthetic; produce morphine-like effects.
They act by binding to specific opioid receptors in the CNS
effects mimic the action of endogenous peptide neurotransmitters
(e.g., leu- and met-enkephalins).
They relieve severe pain - essential in treatment of major diseases,
trauma, and surgery.
Danger of the drug abuse.
Although the opioids have a broad range of effects, their primary use
is to relieve intense pain and the anxiety that accompanies it.
Antagonists they can reverse actions of opioids, important
clinically treatment of overdose.

History of Opioids
Opium is extracted from poppy seeds
(Paper somniforum)
Used for thousands of years to
produce:
Euphoria
Analgesia
Sedation
Relief from diarrhea
Cough suppression

Terminology
opium is a Greek word meaning
juice, or the exudate from the
poppy
opiate is a drug extracted from the
exudate of the poppy
opioid is a natural or synthetic drug
that binds to opioid receptors
producing agonist effects

OPIOID ANALGESICS AND ANTAGONISTS

STRONG AGONISTS

Alfentanil
Fentanyl
Heroin
Meperidine
Methadone
Morphine
Remifentanil
Sufentanil
MODERATE/LOW AGONISTS
Codeine
Oxycodone
Propoxyphene
MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS
Buprenorphine
Butorphanol
Nalbuphine
Pentazocine
ANTAGONISTS
Naloxone
Naltrexone
(according to
OTHER ANALGESICS
Lippincotts
Tramadol
Pharmacology, 2006

 morphine analogues: closely related in structure to morphine; often

synthesized from it: they may be agonists (e.g. morphine, diamorphine
(heroin) and codeine), partial agonists (e.g. nalorphine and
levallorphan) or antagonists (e.g. naloxone)
synthetic derivatives with structures unrelated to morphine:
phenylpiperidine series, e.g. pethidine, fentanyl
methadone series, e.g. methadone, dextropropoxyphene
benzomorphan series, e.g. pentazocine, cyclazocine
semisynthetic thebaine derivatives, e.g. etorphine,
buprenorphine.
Loperamide - an opiate but it does not enter the CNS - it lacks analgesic
activity. However, like other opiates it inhibits peristalsis - used to
control diarrhea.

Opioid Receptors
-receptors are thought to be responsible for most
of the analgesic effects of opioids, and for some
major unwanted effects (e.g. respiratory
depression, euphoria, sedation and dependence).
Most of the analgesic opioids are -receptor
agonists.
-receptors are probably more important in the
periphery, but may also contribute to analgesia.
-receptors contribute to analgesia at the spinal
level, and may elicit sedation and dysphoria, but
produce relatively few unwanted effects, and do
not contribute to dependence. Some analgesics
are relatively -selective.

Mu and Kappa Receptor Activation

Response
Analgesia
Respiratory
Depression
Euphoria
Dysphoria
Decrease GI
motility
Physical
Dependence

Mu-1

Mu-2

Kappa

Division (in relation to the activity)

1. Strong agonists (e.g. morphine, meperidine=pethidine,
methadone, fentanyl, sufentanil, alfentanil, remifentanil)
2. Moderate agonists (e.g. propoxyphene, codein, oxycodone)
3. Mixed agonist-antagonists (e.g. pentazocine, buprenorphine,
nalbuphine, butorphanol)
4. Other analgesics ( tramadol)
5. Antagonists (naloxone, naltrexone)

Morphine
Pharmacological effects and
Mechanisms
CNS effects
Analgesia: increasing tolerance of
pain are the most prominent effects.
Therefore, help patients to eliminate
dysphoria, anxiety. Consciousness is
not lost, and the patient can usually
still locate the source of pain.

Morphine
CNS effects
Respiratory depression and
suppression of cough: reducing the
responsiveness of the respiratory
centers in the brain stem to blood
levels of carbon dioxide and inhibiting
directly the respiratory center.

Morphine
CNS effects
Nausea and vomiting: stimulating the
chemoreceptor trigger zone. In most
cases, after therapeutic dose,
subsequent doses of morphine do not
produce vomiting.
Miosis: pinpoint pupils are indicative
of toxic dosage prior to asphyxia. It
can be block with atropine.

Morphine
Cardiovascular effects:
Orthostatic hypotention can occur
due to vasomotor medullary
depression and histamine release.

Gastrointestinal effect:
Reduces gastrointestinal motility,
causing constipation
Decreases biliary and pancreatic
secretions.
Constriction at the spincter of Oddi
causes an increase in biliary pressure.

Morphine
Other systemic effects:
Increases detrusor muscle tone in the
urinary bladder, producing a feeling of
urinary. Vesical sphincter tone is also
increased, making voiding
Inhibits the cellular immunity and
humoral immunity, which is significant
in withdrawal syndrome and tolerant in
chronic administration.

Pharmacokinetics of
Morphine
Is well absorbed from the gastrointestinal
tract. However, the analgesic effect is
greater when drug is administered
intramuscularly or intrvenously. It has a
significant first-pass effect.
Morphine is metabolised to morphine-6glucuronide, which is more potent as an
analgesic.
Ninety percent of a given dose is excreted
in the urine; the remaining 10% is
excreted in the feces.

Therapeutic uses
Analgesia, such as the relief of pain from
myocardial infaction, terminal illness,
surgery, biliary colic and renal colic
(combined with atropine).
Dyspnea due to pulmonary edema
because of sedative, vascular dilataltion
and inhibition of the respiratory centers
responsiveness to CO2 .
Treating severe diarrhea because of
constipating effects.
Treating cough (usually insteaded by
codeine).

Adverse effects
Respiratory depression is the most important effect.

Contraindications and
cautions
Use in patients with head injures
Use during pregnancy
Use in patients with impaired
pulmonary function
Use in patients with impaired
hepatic or renal function

Codeine
Although the pharmacologic effects of
codeine are similar to those of morphine, it
has about one-twelfth the analgesic
potency of morphine.
Be used mainly for cough suppressant and
milder pain.
It produces less sedation, respiratory
depression, fewer gastrointestinal effects,
and less addiction and withdrawal.

Synthetic analgesic:
Pethidine
It is very similar to morphine (one-seventh to onetenth potent) in pharmacologic effects by receptor agonists.
Therapeutic uses: analgesic, cardiac asthma,
sedation (decrease the dosage of anesthetic )and
artificial hibernation.
It has no gastrointestinal or antitussive action
because of shorter-acting.
Adverse effect: also causes respiratory depression
and possesses addiction liability, although
withdrawal effects are less severe than with
morphine.

Methadone
It is widely used as a means of
treating morphine and diamorphine
addiction because of its chronic and
insignificant addiction.

Opioid Antagonists
Pure antagonists include naloxone
(short-acting) and naltrexone (longacting). They block -, - and -
receptors more-or-less equally.
Naloxone does not affect pain
threshold normally, but blocks stressinduced analgesia, and can
exacerbate clinical pain.

Opioid Antagonists
Naloxone rapidly reverses opioidinduced analgesia and respiratory
depression, and is used mainly to
treat opioid overdose or to improve
breathing in newborn babies affected
by opioids given to the mother.
Naloxone precipitates withdrawal
symptoms in morphine-dependent
patients or animals.

Clinical Use of Analgesic

Drugs
The choice and route of
administration of analgesic drugs
depends on the nature and duration
of the pain.
A progressive approach is often used,
starting with nonsteroidal antiinflammatory drugs, supplemented
first by weak opioid analgesics, and
then by strong opioids.

Clinical Use of Analgesic

Drugs
In general, severe acute pain (e.g. trauma, burns,
post-operative pain) is treated with strong opioid
drugs (e.g. morphine, fentanyl) given by
injection.
Mild inflammatory pain (e.g. arthritis) is treated
with non-steroidal anti-inflammatory drugs (e.g.
aspirin) supplemented by weak opioid drugs
(codeine, pentazocine) given orally if required.
Severe pain (e.g. cancer pain, severe arthritis or
back pain) is treated with strong opioids given
orally, intrathecally, epidurally or by
subcutaneous injection.

Clinical Use of Analgesic

Drugs
Chronic neuropathic pain is often
unresponsive to opioids, and treated
with tricyclic antidepressants (e.g.
amitriptyline), or other drugs, such
as carbamazepine.

ALHAMDULILLAH.