AZZA BARAKA

Professor of Clinical Pharmacology

Faculty of Medicine
Alexandria University
Types of Pain
The physical causes of pain have been divided into two types
NOCICEPTIVE PAIN - Examples include bone fractures,
burns, inflammation ,
When nociceptors are activated, they transmit pain signals
(via the peripheral nerves as well as the spinal cord) to the
brain.
The pain is typically
1. well localized, constant, and often with an aching or
throbbing quality.
2. usually time limited, meaning when the tissue damage
heals, the pain typically resolves.
3. tends to respond well to treatment with analgesics.
Types of Pain (Cont..)
2-NEUROPATHIC PAIN - Examples include diabetic neuropathy
.
Neuropathic pain is the result of an injury in the peripheral or
central nervous system.
The pain frequently has burning or electric shock qualities.
Neuropathic pain is frequently chronic, and tends to have a less
response to treatment with analgesics, but may respond well to
other drugs such as anti-seizure and antidepressant medications.
ANALGESICS
Drugs that relieve pain due to multiple causes.
They are classified into 2 major groups:
Opioid or narcotic analgesics .
Non-opioid or analgesic/antipyretics.

Timing of analgesic administration
There is a common Misconception
Patients should wait as long as possible before taking a pain
medication. This abstinence will teach them to have a better
tolerance for pain. Pain that is untreated often escalates.

Without treatment, sensory input from injured tissue reaches
spinal cord neurons and causes subsequent responses to be
enhanced.
Aggressive pain prevention and control that occurs before,
during, and after a painful event such as dental surgery can
yield both short- and long-term benefits. Patients should be
encouraged to use analgesics before pain becomes severe and
difficult to control.
Describes any drug with a primary indication other than pain,
but with analgesic properties in some painful conditions
o Ergot alkaloids (Ergotamine) used for migraine.
o Nitrates (Nitroglycerine) used for angina pectoris.
o Tricyclic antidepressants (Amitriptyline) used in
neuropathic pain.
o Anti-epileptics (Gabapentin/lyrica) used in neuropathic
pain.
oSkeletal muscle relaxants: for musculoskeletal pain
Adjuvant Analgesics
Analgesic Ladder
Bottom of ladder (mild pain): Non opioid +/-adjunctive

Middle of ladder (moderate pain): Weak opioid +/- non
opioid +/- adjuvant

Highest of ladder (severe pain): Strong opioid +/- non opioid
+/- adjuvant
Choice of Analgesics
In choosing analgesics, the severity of pain determines
the choice of agent; the WHO pain ladder specifies mild
analgesics as its first step.
As a general rule, any analgesic regimen should include a
nonopioid drug, even if pain is severe enough to require
the addition of an opioid.
Analgesic choice is also determined by the type of pain:
for neuropathic pain, traditional analgesics are less
effective, and there is often benefit from adjuvant
analgesics.

IMPORTANT NOTE
It is important to note that analgesics do not
have any therapeutic effect on the
underlying disease and they essentially only
act by blocking the pain sensation being
experienced by the patient.
Hence, analgesics should only be adjuncts to
other treatment.
Analgesic Antipyretics
Mild moderate analgesics that works on subcortical
centers, they include:
1. Non-Steroidal Anti-inflammatory Drugs
(NSAIDs)
2. Paracetamol.

Timing of administration
Non-opioid Analgesics are most effective in treating
postprocedural pain when given before the procedure (
or immediately following a short procedure), thus
preventing the synthesis of prostaglandins that quickly
follow the surgical insult.
The delayed use of these analgesics post-procedurally
inhibits the subsequent prostaglandin synthesis and
provides analgesia, but it does not interfere with the
effects of those prostaglandins already produced.
Preoperative administration of NSAIDs delays the onset
of postoperative pain and lessens its severity and
subsequent analgesics requirements.
Classification of Analgesic Antipyretics
Nonselective COX-
inhibitors
Salicylates: Aspirin
Propionic acid derivatives: Ibuprofen
Acetic acid derivatives: Diclofenac
Pyrrolo-pyrrole derivatives: Ketorolac
Oxicam derivatives: Piroxicam
Indole derivatives: Indomethacin
Pyrazolone derivatives:Phenybutazone




Analgesic-antipyretic with no anti-
inflammatory effect
Paracetamol /Acetaminophen
(panadol-abimol-tylenol)



Selective COX-2 inhibitors
Celecoxib
I. Non-steroidal anti-
inflammatory drugs NSAIDs
NSAIDs are group of drugs that share in
common the capacity to induce:
Analgesic effect.
Antipyretic effect.
Anti-inflammatory effect.
Aspirin only has antiplatelet action
Non-steroidal anti-inflammatory
drugs NSAIDs
Classification of NSAIDs:
Non-selective COX inhibitors
Selective COX-2 inhibitors

Mechanism of action of NSAIDs:
NSAIDs cause competitive reversible inhibition of
COX enzymes.
Acetyl salicylic acid is the only NSAID that causes
irreversible inhibition of COX.
Celecoxib is a selective COX-2 inhibitor.
NSAIDs
NSAIDs
Non-selective COX inhibitors
1. Salicylates, e.g. acetyl salicylic acid (Aspirin).
2- Other NSAIDs: e.g.
Ibuprofen & naproxen.
piroxicam (Feldene)
Diclofenac sodium (Voltaren)
Diclofenac potassium (Cataflam).
Indomethacin (Indocid).
Ketorolac (Ketolac)
Absorption: well absorbed after oral administration but
delayed with food.
Onset of analgesia occurs rapidly with all NSAIDs,
usually within one hour.
Diclofenac potassium (Cataflam) is very rapidly
absorbed thus provides rapid analgesic relief
compared to diclofenac sodium (Voltaren),a
characteristic essential in the management of acute
pain.

Pharmacokinetics of NSAIDs








Variable first-pass metabolism,
consequently have different bioavailability
(diclofenac 50% vs ibuprofen 100%)

Distribution:- Extensively protein bound
SO DRUG INTERACTIONS FREQUENT.
Elimination: mainly in liver.
Inter-patient differences in the metabolic clearances
of individual NSAIDs can be large leading to
considerable variability in plasma levels.
Renal Excretion:- Small component of the elimination of
NSAIDs

NSAIDs difference in potency &
elimination half life
Low potency & short elimination half life (even in patients
with liver or renal disease) used for transient inflammatory
pain : ibuprofen (low incidence of GIT AR bec more selective
for COX 2 compared to COX 1)
High potency & short elimination half life : diclofenac (low
incidence of GIT AR but low oral bioavailability ) ,
ketoprofen, indomethacin, ketorolac (v high potency but
high incidence of GIT AR)
High potency & long elimination half life (slow metabolism
& slow elimination)used for persistent inflammatory pain
but carries a high incidence of GIT & renal AR : piroxicam
Topical NSAIDs
Topical application leads to relatively high NSAID
concentrations in the dermis.
Concentrations achieved in the muscle tissue below the
ite of application are variable.
NSAIDs applied topically reach the synovial fluid, but
in a small amount.
Topical NSAIDs
There are five components to the successful use of topical
therapies:
Correct diagnosis
Type of lesion being treated
Vehicle (the base in which the active medication is delivered)
Method used to apply the medication
Topical NSAIDs(Cont..)
1-Vehicle used
If the correct medication but the wrong vehicle is
used, the response to therapy may be delayed,
inadequate, or in some cases, worsened.
As examples,
1- Use of gel on skin inflammation (dermatitis) and
fissures will cause increased pain and stinging due to
the alcohol base of the gel.
2- Treating a moist lesion with an ointment may cause
folliculitis secondary to its occlusive properties.

Types of vehicles
Ointments
Ointments consist of water suspended in oil.
This type of vehicle decreases transepidermal water loss,
provides enhanced medication absorption, and is
semiocclusive. They are generally the most potent vehicles
due to their occlusive effect.
Patient acceptance may be low because they are greasy, and
they are not useful in hairy areas.

Creams
Creams are semisolid emulsions of oil in water and can be
washed off with water. They are the most cosmetically
appealing vehicle type for delivering topical medications.
Creams are less potent than ointments.

Gels
Gels Gels are oil-in-water emulsion with alcohol in
the base, and they dry in a thin, greaseless,
nonstaining film.
Gel formulations combine therapeutic advantages of
ointments with the cosmetic advantages of creams.
Gels are transparent, colorless, semisolid emulsions
that liquefy on contact with the skin.
They are an efficient method for delivering
medications to hair-bearing areas

Lotions
Lotions (as well as aerosols) are the least potent topical
therapies, but are useful in hairy areas and in conditions
where large areas have to be treated.
They consist of powder-in-water; thus, patients must
shake the container before each application to receive the
desired therapeutic concentration (and therefore the
desired effect).
As lotions evaporate, they provide a cooling and drying
effect, making them useful for treating moist dermatoses
and/or pruritus.

Topical NSAIDs(Cont..)
2-Type of lesion
"If a lesion is wet, use agents to make it dry, and "If a lesion
is dry, make it wet" (eg, use an ointment base to increase
hydration to the affected area).
Thus, for acute exudative dermatoses, treatments in liquid
vehicles (eg, lotions) are generally recommended. In
contrast, when treating dry lesions, therapeutic agents
incorporated into ointments ( or creams) may help to retain
native moisture and provide relief to dry, pruritic skin.

Topical NSAIDs(Cont..)
3-Method of application
Topical drug penetration into the skin is determined by the
method of topical application.
For optimal absorption of most topical drugs, apply them to
moist skin either immediately after bathing or after wet
soaks.
Occlusive dressings will also enhance drug absorption, often
by a factor of 10.
The site of an application is also important as variations in
the epidermal layer will alter the extent of drug absorption.

Side effects & Toxicity:
GIT: Gastric irritation, bleeding & ulceration.
Hypersensitivity:
(Inhibition of COX & shift to LTs)
bronchoconstriction, urticaria,...
Kidney : Nephropathy.
Aspirin might cause Reye's syndrome: severe
hepatic injury & encephalopathy in case of viral
infections in both children and adolescents.

The most common risk of NSAIDs
GIT side effects include: N, V, D , gastric ulceration.
Risk of ulceration with duration of therapy and with higher doses.

Enteric coated products ,injectable or suppository formulations
do not eliminate the problem of gastric mucosal damage.
use the lowest effective dose for the shortest period of time.
take with food or directly after a meal.
Misoprostol (PG analogue) or drugs that decrease gastric acidity
(H 2 blockers) are used for prophylaxis against ulcers.
Recommended in high risk patients if NSAIDS cannot be avoided.

Ketorolac, Indomethacin, ketoprofen
and piroxicam appear to have the highest
prevalence of gastric ADRs, while
ibuprofen (lower doses) and diclofenac
appear to have lower rates.
Nephrotoxicity
Nephrotoxicity from NSAIDs is rare in healthy patients
because both renal blood flow and glomerular filtration
do not depend on prostaglandin levels,
But the risk of nephrotoxicity increases for patients
who are volume depleted, who have congestive heart
failure, or who have hepatic cirrhosis, because these
patients rely on renal prostaglandin synthesis to
ensure sufficient renal blood flow and to maintain an
adequate GFR.
Signs of nephrotoxicity include development of oliguria
with sodium and water retention.

Can be a drug effect or a class effect.
There is marked cross-sensitivity between most NSAIDs
even where they are structurally dissimilar
AERD
Aspirin exacerbated respiratory disease(AERD) is a clinical
entity characterized by aspirin- and NSAID-induced respiratory
reactions in patients with chronic rhinosinusitis and asthma.
Administration of NSAID leads to inhibition of COX-1 , thus
arachidonic acid is preferentially metabolized in the 5-
lipoxygenase pathway, resulting in increased production of
leukotrienes.
All routes of administration can precipitate bronchospasm in
sensitive asthmatics even ophthalmic drops.
Selective COX-2 inhibitors do not cause reactions in patients
with AERD and can be taken safely.


Selective COX-2 Inhibitors
Celecoxib (Celebrex)
A selective COX-2 inhibitor that spares COX-1, thus does not
inhibit synthesis of protective PGs in the gut. Hence, associated
with less GI adverse effects.
-But there are concerns regarding cardiovascular side effects(due to
alterating the balance of antithrombotic and prothrombotic
pathways in a way that promotes thrombogenesis )
- due to inhibition of COX-2 in endothelium responsible for
synthesis of PGI2( a PG responsible for inhibiting platelet
aggregation) . Decreased formation of PGI2 increase chance for
platelet aggregation.
-Thus, it is advised not to prescribe COX-2 inhibitors to patients
who have a history of myocardial infarction or ischemic stroke.

Important Note
High levels of COX-2 are detected in activated and
proliferating vascular tissues, for example angiogenic
microvessels, atherosclerotic lesions, and inflamed
tissues.
High levels of COX-2 are expressed in certain disease;
Alzheimers disease, cancer where PGs are responsible
for angiogenesis & invasion of tumor, thus NSAIDs are
recently reported to protect against certain cancers &
Alzheimers disease.
Analgesic Antipyretics
It effectively inhibits PG synthesis in the
nervous system resulting in analgesic &
antipyretic effects
But does not inhibit COX in peripheral
tissue thus has no anti-inflammatory
effect.
II. Paracetamol
Mechanism of action:
Paracetamol

Analgesic, antipyretic: as it inhibits
COX enzyme centrally.
No anti-inflammatory action (doesnt
inhibit COX peripherally)
No antiplatelet action

- Peptic ulcers (it causes no GIT disturbances)
- Bleeding tendency (it does not affect platelet function)
- Allergy to salicylates.
- Viral infections in children (to avoid Reyes
syndrome).
- Pregnancy.
Paracetamol

Commonly used instead of NSAIDs in
cases of:

- Of particular significance to older people is the use of
paracetamol in the management of osteoarthritis
where it is recommended as first-line treatment
Paracetamol

An Important Therapeutic Use
Paracetamol

Its protein binding is insignificant
The usual dosage for adults is 500 mg every four to six
hours as needed.
No more than 4 g should be taken in 24 hours, to
avoid toxicity in the form of: Liver damage (with acute
over dosage).
Since paracetamol is metabolized in the liver, patients
with liver disease need to take care. ( given half dose)
Considerations during therapy with NSAIDs
1. Consider drug interactions between NSAIDs &
anticoagulants, hypoglycemics.
2. Anti-inflammatory activity often requires a week or more to
become established. For this reason, an adequate trial of 1-2
weeks should be allowed before increasing the dose or
changing to another NSAID.
3. Combining NSAIDs is NOT recommended as it has no
additive effect and increases risk of toxicity. But
combination of NSAIDs with paracetamol increases pain
relief compared with NSAIDs alone.
4. NSAIDs differ in analgesic potency: NSAIDs of considerable
analgesic potency are ketorolac & diclofenac.
5. Remain upright 30 minutes after administration of NSAID
to reduce gastric irritation or ulcer formation.




4. Patients who can tolerate NSAIDs should be first given
maximally effective doses before adding or shifting to an
opioid.
5. In patients who have CVD, studies have found that
concomitant intake of NSAIDs decrease the
cardioprotective effects of aspirin
6. Combining NSAID with aspirin interferes with the
antiplatelet action of aspirin.
7. Because nonselective NSAIDs interfere with normal
bleeding time, they should be discontinued several days to
one week before any surgical procedure. Cox-2 NSAIDs
do not decrease platelet aggregation. As a result, Celebrex
may be used perioperatively
8. NSADs blunt the effect of some antihypertensive drugs.




NSAIDs blunt antihypertensive effect
Monitor blood pressure in hypertensive patients using
NSAIDs chronically. Adjust antihypertensive drugs as
necessary.
Recommend a calcium channel blocker if a patient
needs an antihypertensive thats less affected by
NSAIDs
Case Study(I)
A 70-year-old woman has been treated for diabetes mellitus
for the past 10 years. She complains of burning pain in both
feet. The pain is severe enough that she reports substantial
limitations in her physical activities and severe disruption of
her sleep. She has undergone electrodiagnostic testing,
which demonstrated abnormalities consistent with diabetic
polyneuropathy. The patients general medical status is
noteworthy in that she had a mild myocardial infarction 3
years ago, with subsequent angioplasty. The patient has a
history of hypertension adequately controlled with
Lisinopril. What are the analgesic(s) that this patient can be
advised to take??

Case Study(II)
Mr A is a 52-year-old patient suffering from osteoarthritis(OA). He is
currently experiencing lumbosacral back pain. He takes 600mg of
Ibuprofen twice daily for his OA.
An analgesic that is better to be given to this patient is:
1. Paracetamol
2. NSAID
3. COX-2 inhibitor
4. Opioid
5. None of the above
An adjuvant analgesic that can be given to this patient is:
1. Anticonvulsant
2. TCA
3. Skeletal muscle relaxant
4. None of the above