7/23/2014

PHARMACOLOGIC
MANAGEMENT OF PAIN

Kalungia A.C. BPharm

BPharm,, MSc, MSc, Rhodes Scholar

Cavendish University Zambia

Faculty of Medicine

Learning Objectives:
At the end of this session, YOU should be able to
to::
1. Describe the pathophysiology of pain and the role
of analgesia;

2. Discuss the pharmacology of the various classes

of analgesic drugs;

3. Describe the WHO analgesic ladder;

4. Outline the clinical management of pain
disorders.

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What is Pain?

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Introduction
Pain:
 An unpleasant sensory sensation ranging from mild discomfort
to agonizing distress associated with actual or potential tissue
damage, or described in terms of such damage (Merskey et al, 1979)

 A response to impulses from peripheral nerves in damaged

tissues, which pass to nerves in the spinal cord, where they are
subject to control by a gateway mechanism (Oxford Medical Dictionary, 6th
ed, 2003)

Analgesia is the relief of pain without the loss of consciousness.

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Pathophysiology of Pain
• Noxious stimuli detected physiologically by
sensory nerve endings and nociceptors;
• Two types of nociceptive impulse conductors:
1) C-fibers: - unmyelinated axons, very rapid conduction
velocity (0.2–2ms); respond to chemical stimuli (H+, K+,
histamine, bradykinin, etc.) arising from tissue trauma

2) Aδ-fibers: - myelinated axons, conduction velocity 10–

30ms, respond to heat &intense pressure.

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Role of Analgesia
Mechanisms by which pain sensation can be
influenced or modified include:
1. Eliminating the cause of pain;

2. Lowering the sensitivity of nociceptors (e.g. using

antipyretic analgesics, local anesthetics, etc);

3. Interrupting nociceptive conduction in sensory

nerves (e.g. local anesthetics);

4. Suppressing transmission of nociceptive impulses in

the spinal medulla (e.g. opioids);
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5. Inhibiting pain perception centrally (e.g. opioids,

general anesthetics,etc);

6. Altering emotional responses to pain (e.g.

antidepressants as adjuvant analgesics, opioids)

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ANALGESICS
These are drugs used to relieve pain due to
multiple causes
causes..

 Note:
Drugs that:
i. relieve pain due to a single cause, or
ii. relieve pain due to a specific pain syndrome only, (e.g.
ergotamine, GTN, carbamazepine, etc), or
iii. suppress pain of inflammation of any cause (e.g. Corticostroids,
etc),

are NOT classified as Analgesics

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Classification of Analgesics

Used in Mild to Used as Adjuvants Used in Moderate to

Moderate Pain E.g. TCAs, Severe Pain
E.g. NSAIDs, Anticonvulsants, etc E.g. Morphine,
Paracetamol Pethidine, etc

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Non-opioid Analgesics

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Non--Steroidal Anti-
Non Anti-inflammatory Drugs
(NSAIDs)
• A group of heterogeneous agents that share in
common the capacity to induce:
 Anti-inflammatory,
 Analgesic, and
 Antipyretic effects;
• A sub-class of selective cyclo-oxygenase (COX)
inhibitors.
 Paracetamol is selective for COX
COX--3 in CNS
CNS;; has antipyretic
antipyretic--
analgesic activity but devoid of anti
anti--inflammatory activity
activity..
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NSAIDS: Effects on Prostaglandin Biosynthesis

• Cellular damage associated with inflammation

stimulates:
 Leukocyte release;
 Precursor release i.e. Arachidonic acid;
 Eicosanoid synthesis;

• NSAIDs inhibit cyclo-oxygenase (COX) enzyme that

catalyses conversion of Arachidonic acid to
Endoperoxides that synthesize Eicosanoids (i.e.
Prostaglandins, Prostacyclin and Thromboxanes)

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NSAIDs

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Luellmann, Color Atlas of Pharmacology, 6th ed

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Three main types of COX enzymes:

1) COX-1 is constitutive (i.e. normally present in tissues
regulating its physiological functions); responsible
for synthesis of protective PGs in GIT and Kidney;
2) COX-2 is inducible (i.e. formed during inflammatory
response);
3) COX-3 is active in CNS; target for Paracetamol

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NSAIDs: Mechanism of Action

• Aspirin (Acetyl Salicylic acid) - the prototype
NSAID;
• Induces irreversible inhibition (acetylation) of both
COX-1 and COX-2 enzymes in peripheral tissues;

• Other NSAIDs cause competitive reversible inhibition

of COX enzymes;

• Selective COX-2 inhibitors (‘Coxibs’):

Celecoxib, Rofecoxib, Nimesulide, etc. – more
antinflammatory than analgesic

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Pharmacological Actions &

Therapeutic Uses of Aspirin
I. Anti-
Anti-inflammatory
inflammatory::
1)Decreases vasodilator PGE2 and PGI2 thus
reducing the vasodilatation and oedema of
inflammation;
2)Anti-oxidant effect (free radical scavenger).

Therapeutic Uses:
 Rheumatic fever, Rheumatoid arthritis, Bursitis,
pain due to inflammation
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II. Analgesic effect

1) Peripheral effect: Its anti-inflammatory effect
decreases PGs which sensitize nerve endings to
Kinins  increases the pain threshold;
2) Central effect: Decreases PGs thus inhibiting
pain stimuli at sub-cortical sites.
Therapeutic Uses:
 Mild to moderate pain secondary to inflammation;
 Rheumatoid arthritis;
 Dental pain;
 Headache (decreases cerebral vasodilator effect of PGs);
 Dysmenorrhea and Postpartum pain.
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III. Antipyretic effect

effect::
Decreases PGE2 (generated in response to
inflammatory pyrogens e.g. IL-1) that is
responsible for elevating the hypothalamic set
point for temperature control.

Therapeutic Uses:
 Antipyretic (Lowers body temperature) in fever

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Adverse Effects
• GIT side effects: - Dyspepsia, nausea,
vomiting, gastritis, ulceration with risk of
haemorrhage (due to direct irritant effect on the mucosa
and decreased protective PGs).

• Renal side effects: Analgesic nephropathy - due

to decreased renal vasodilator PGs.

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Adverse Effects
• Hypersensitivity reactions: Skin rash, Rhinitis,
Asthma especially in asthmatics and patients
with nasal polyps (Aspirin diverts arachidonate
metabolism from cyclo-oxygenase to lipoxygenase pathway
increasing chemotactic LTB4 and spasmogenic LTs).

• Hyperuricemia in patients with Gout: Aspirin

competes with uric acid for excretion by organic acid secretory
mechanism in renal tubules.

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Adverse Effects
• Reye’s syndrome (Encephalopathy and liver damage) in
children with fever due to viral infection.

• Increased bleeding tendency: due to Anti-platelet

effect.

• Salicylism (in chronic toxicity): Large doses used for long

periods lead to dizziness, tinnitus and gastric upset.

• Acute toxicity: Respiratory alkalosis (hyperpnoea with

washing out of CO2) followed by respiratory acidosis due to
respiratory depression and metabolic acidosis (due to
accumulation of acidic metabolites).
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Other NSAIDs
Diclofenac
• very potent antinflammatory, analgesic and
antipyretic effect;
• Actively and reversibly inhibits COX-1 and COX-2;
• Rapid oral absorption, extensive protein binding,
short t1/2, first-pass effect (~50%);
Therapeutic use in
in::
 Long
Long--term treatment of chronic inflammatory
musculoskeletal disorders e.g.Rheumatoid arthritis,
Osteoarthritis and Ankylosing Spondylitis
Spondylitis..
 Renal colic and Post
Post--operative pain
pain..
 Post
ost--operative inflammation
inflammation..
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Ibuprofen
• Non-selective reversible COX inhibitor;
• Effective and better tolerated;
• Doses: 200-800mg TDS or QID depending on
indication;
• Rapidly absorbed, protein bound, 90% hepatic
metabolism; t1/2 ~ 2hrs;
• First choice for mild
mild--moderate pain and in
inflammatory joint disease

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Naproxen

• related to Ibuprofen but longer acting; more

potent with moderate risk of side effects;
• 100% oral absorption (accelerated by NaHCO3
but delayed by food, Fe3+, Mg2+); Also
absorbed rectally;
• Crosses placenta and secreted in breast milk.

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Piroxicam
• Enolic acid derivative that inhibits COX non-
selectively; has antinflammatory, analgesic and
antipyretic effect;
• Can inhibit activation of neutrophils independent
of COX inhibition;
• Potent and long acting (t1/2 = 45 hours); given
once daily;
• Therapeutic use in Rheumatoid arthritis &
osteoarthritis;
• Approx. 20% of patients develop side effects e.g.
GIT bleeding.
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Ketorolac
• Potent analgesic effect but moderate systemic
antinflammatory effect;
• Rapid onset of action, extensive protein binding,
short duration of action (given I.V. for acute pain)
• Doses: 30-60mg (IM), 15-30mg (IV), 5-30mg (PO)
• Therapeutic Use:
 Moderate
Moderate--severe pain as short term alternative to opioids
opioids;;
 Post
Post--operative analgesia (except obsterics
obsterics))

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Paracetamol
• Analgesic-Antipyretic with No Anti-inflammatory
action.
• Preferred to NSAIDs in:
1)Patients allergic to NSAIDs.
2)Peptic ulcer disease (No GIT disturbances).
3)Gout (NSAIDs may exacerbate hyperuricemia).
4)Viral infection in children (to avoid Reye’s syndrome
with Aspirin).
5)Bleeding disorders (does not affect platelet function).

• Adult Dose:
Dose: 0.5g – 1g PO t.d.s or PRN.
• Pediatric Dose: 125 – 500mg t.d.s or PRN
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• Paracetamol can be ineffective in high fever

because excess free radicals generated by
leucocytes antagonize Antipyretic effect of
Paracetamol.
• Metabolized in the liver; potentially toxic in
high doses

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Paracetamol toxicity
• Toxic doses of Paracetamol (>200mg/kg dose or
8g/day);
• Cause acute severe & potentially fatal liver damage due
to generation of a toxic metabolite: N-acetyl-p-
benzoquinone imine (NAPBQI);

• If toxic metabolite is not inactivated by conjugation with

Glutathione, it reacts with cellular proteins triggering
apoptosis of hepatocytes  liver damage

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Treatment of acute toxicity:

 Activated Charcoal 1g/kg within 4hr post-
ingestion
 Agents which increase Glutathione (e.g. N-
acetylcysteine PO Loading dose: 140 mg/kg PO,
Maintenance: 70 mg/kg PO q4hr upto 17 doses
(Can also be given I.V);
 Agents which increase conjugation reaction
(e.g. Methionine) can prevent liver damage if
given early.

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Opioid
Analgesics

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Types of Opioid Analgesics:

• Natural opioids (from opium poppy plant): e.g.

Morphine, Codeine;
• Synthetic opioids
opioids:: e.g. Fentanyl, Methadone,
Pethidine, Diamorphine (Heroin), Nalorphine,
Levallorphine, Naloxone, Sufentanil, Pentazocine,
Cyclazocine and Dextropropoxyphene, etc;
• Semi
Semi--synthetic derivatives
derivatives:: e.g. Buprenorphine;
Etorphine
• Endogenous Opioid Peptides
Peptides:: e.g. -Endorphin,
Encephalins, Dynorphins (released in conditions of stress)
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Transmission of pain stimuli

• Nociceptive stimuli
transmitted through
afferent fibres in dorsal
horn of spinal cord;
• From dorsal horn,
nociceptive stimuli
transmitted to the
thalamus.
• Opioids interfere with
pain perception in the
thalamic centres
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Opioid receptors
-receptors -receptors -receptors
(mu-receptors) (kappa receptors) (delta receptors)
Analgesia Analgesia (spinal level) More important in the
periphery – contribute to
analgesia

Respiratory depression Sedation GIT effects

Euphoria Dysphoria
Sedation Pupillary constriction

Dependence Decrease GIT motility

Pupillary constriction

Decrease GIT motility

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Mechanism of Analgesia
1. Activate the descending pathways from the midbrain
and brainstem that exert a strong inhibitory effect on
dorsal horn transmission;
2. Inhibits neuronal transmission in the dorsal horn;
3. Inhibits excitation of sensory nerve terminals in the
periphery

Neuronal inhibition occurs through:

a) Inhibition of Ca2+ entry decreasing release of excitatory
neurotransmitters e.g. Substance-P
b) Stimulation of K+ outflux  hyperpolarization of neuronal
membrane potential

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Mechanism of action at Opioid receptors

• Opioid receptors are GPCRs present in CNS and

periphery (e.g. GIT);
• Mechanisms at these receptors include:
 Inhibition of adenylate cyclase
 Opening of K+ channels
 Inhibiting Ca2+ channel opening  inhibits
excitatory neurotransmitter release (e.g.
Substance-P)

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Pharmacodynamic Profile of Opioid Analgesics:

Classification Examples
Pure Agonist Morphine, Codeine, Oxymorphine,
Dextropropoxyphene, Methadone, Pethidine,
Torphine, Fentanyl, Sufentanil, Bremazocine

Partial agonists (mixed Pentazocine, Nalbuphine, Nalorphine,

agonists/antagonists) Buprenorphine

Pure antagonists Naloxone, Naltrexone

High efficacy (for severe pain) Morphine, Diamorphine, Buprenorphine,
Pethidine, Methadone

Low efficacy (for mild to Codeine, Dihydrocodeine, Dextropropoxyphene,

moderate pain) Nalbuphine, Pentazocine

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Pharmacological effects of opioids

(Morphine is prototype)

On CNS:
• Analgesia, sedation & euphoria (decreases emotional
response to pain and inducing euphoria)
• Respiratory depression (reduced sensitivity of respiratory center
to pCO2)

• Depression of cough reflex (antitussive effect)

• Nausea and vomiting (stimulates the CRTZ)
• Pupillary constriction  miosis (due to stimulation of the
oculomotor nucleus)

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Pharmacological effects of opioids

(Morphine is prototype)

On GIT:
• Increase GI smooth muscle tone and reduced GIT
motility constipation;
• Increase pressure in biliary tract (contraction of gall
bladder and constriction of biliary sphincter)

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Pharmacological effects of opioids

(Morphine is prototype)

On CVS:
• Impairs sympathetic vascular reflexes  veno- and
arteriolar dilatation;
• Stimulates vagal center  Bradycardia

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Pharmacological effects of opioids

(Morphine is prototype)

Other Effects:
• Histamine release (unrelated to opioid receptors) 
urticaria, itching, bronchoconstriction, hypotension;
• Piloerection & sweating;
• Stimulates ADH release;
• Immunosuppressant with long-term use

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Opioid Analgesics: Properties & Clinical Uses

Drug Name Properties Uses
Morphine Prototype opioid; Given IV, IM, •Severe pain
SC, PO •Anaesthesia medication
•Acute MI
Fentanyl More potent than Morphine; •Severe Pain
Short acting; Given IV •Anaesthesia medication
Pethidine Less potent & less adverse •Moderate to severe pain
effects than Morphine; Short-
acting; Does not delay labor;
Has anti-muscarinic effects
Methadone Longer acting; Given PO; Less •Severe pain
sedating; •Treatment of Opioid
addicts
Codeine Metabolized to morphine; Less •Mild pain
potent & less efficacious; More •Antitussive
antitussive •Gut hypermotility
(alternative to Loperamide)
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Opioid Analgesics: Properties & Clinical Uses

Drug Name Properties Uses
Sufentanil Similar to Fentanyl •Severe Pain
•Anaesthesia medication

Buprenorphine Partial agonist at σ-receptors •Severe pain

and antagonist at κ-receptors; •Opioid addiction
Less abuse liability than
morphine; Long acting

Pentazocine Mixed agonist-antagonist; •Similar to Morphine

Used at low doses
Dextropropoxyphene Similar to codeine but longer •Antitussive
acting
Propoxyphene Weak opioid; Given PO •Mild to moderate pain
(in combination with
Paracetamol)

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Adverse Effects of Opioids

• Sedation and narcosis

• Drug dependence
• Respiratory depression
• Nausea and vomiting
• Miosis  blurred vision
• Constipation and urine retention
• Hypotension, itching and bronchospasm (due to Histamine
release)
• Delayed labor and Asphyxia neonatorum (Respiratory
depression in the newborn)
• Mask the diagnosis of acute abdomen (masks pain)
• Biliary spasm.
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Contraindications of Opioids

• Avoid in Acute undiagnosed abdomen (masks pain)

• Avoid in Head injury (Opioids cause respiratory depression leading to
increased CO2 resulting in cerebral vasodilatation with increased
intracranial tension)
• Avoid in Bronchial asthma (Opioids cause Histamine release).
• Avoid in Biliary colic (Opioids increase intra-biliary pressure and
aggravate the colic).
• Avoid in patients with prostate hyperplasia (Opioids decrease
motility of the bladder wall and cause urine retention).
• Extremes of age, Hypothyroidism and liver dysfunction
(decreased Opioid metabolism).

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Adjuvant
Analgesics

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Neuropathic Pain
• Undifferentiated pain (non-
visceral, non-somatic)
• Peripheral or central nerve
injury
• ‘Burning, tingling, shooting
pain’
• Poor response to conventional
analgesics, responds better to
adjuvants

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Adjuvant Analgesics
• These are drugs with other therapeutic indications
that may be analgesic in specific circumstances (and
at specified doses);
• Numerous drugs in diverse classes are used;
• Usually less effective acutely;
• Indications include:
 Neuropathic pain
 Bone pain
 Muscle spasm
 Cancer pain
 Refractory headache
 Musculoskeletal pain, etc
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Adjuvant Analgesics
Drug Class Mechanism Examples Uses
Anticonvulsants ??Block Na+ Carbamazepine, -Neuropathic pain
channels; Valproate, -Trigeminal
??Modulate Ca2+ Lamotrigine, neuralgia
influx Topiramate, -Phantom limb pain
Gabapentin -Refractory pain
Antidepressants Inhibit 5HT and NE Amitryptylline, -Neuropathic pain
reuptake in CNS Desipramine, -Diabetic
Duloxetine, nephropathy
Trazodone, -Post-herpetic
Bupropione, neuralgia
Maprotiline -Refractory
headache
Local Anaesthetics Block Na+ channels Lignocaine, - Neuropathic pain
Bipuvacaine
Antiarrhythmics Block Na+ channels Mexiletine, - Neuropathic pain
Class 1 Procainamide,
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Adjuvant Analgesics
Drug Class Mechanism Examples Uses
Alpha2 Not elucidated Clonidine, Tizanidine, -Diabetic
Adrenergic Dexmedatomidine neuropathy
Agonists -Chronic pain
Corticosteroids Anti-inflammatory Prednisolone, -Nerve compression
Dexamethazone -Bone pain
-Soft tissue injury
-Raised ICP
NMDA receptor Block VG-NMDA Ketamine, Amantadine, -Refractory pain
antagonists receptor Dextromethorphan
Cannabinoids CB1 and CB2 THC, Cannabidiol, -Cancer pain
agonists Nobilone -Sclerosis pain
-Fibromylgia
Miscellaneous Various Capsiasin, Calcitonin, -Neuralgia
Baclofen, Prigabalin, -Bone pain
Bisphosphonates,
Radiopharmaceuticals
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WHO Analgesic Ladder

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Reading List:
1. Brunton L, Parker K, Blumenthal D, Buxton I. (eds). 2008. Goodman &
Gilman’s Manual of Pharmacology & Therapeutics. The McGraw-Hill
Companies Inc.

2. Katzung B. 2006. Basic & Clinical Pharmacology, 10th ed. The McGraw-Hill
Companies Inc.

3. American Pain Society. Principles of Analgesic Use in Management of

Acute Pain and Cancer Pain. 4th ed. American Pain Society. 1999.

4. American Pain Society. Pain: Current Understanding of Assessment,

Management & Treatments. 2004.

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