Analgesics

Dr. Amit T. Suryawanshi

Oral and Maxillofacial Surgeon
Pune, India

Contact details :
Email ID - amitsuryawanshi999@gmail.com
Mobile No - 9405622455
 Contents
 Introduction
– Pain
– Analgesia
 Analgesics
 Classification of analgesics
 NSAID’s
– History
– Classification of NSAID’s
– Mechanism of action
– Adverse effects
– Individual drugs
 Contents
 Opioids
– Classification of opioids
– Individual drugs
– Opioid receptors
– Complex action opioids and opioid antagonists
- Opioids in dental pain
 Analgesics and Medical conditions
 Adjuvant drugs
 Future of Analgesics
 References
 Introduction
Pain -
“ An unpleasant emotional experience usually
initiated by a noxious stimulus and transmitted over
a specialized neural network to the central nervous
system where it is interpreted as such ”
- Monheim’s

“Pain is whatever the experiencing person says it is

and exists whenever he says it does.”
 Goals of pain management

 To relieve suffering
 To increase functional capacity
 To improve quality of life
 Methods of pain control

1. Removing the cause

2. Blocking the pathway of painful impulses
3. Raising the pain threshold
4. Preventing pain reaction by cortical depression
5. Using psychosomatic methods
 What is Analgesia?
The word analgesia is derived from Greek word
analgetos (an – without ; algesia – pain )

‘Analgesia simply means the absence of pain without

losing consciousness’

 “Theanalgesia system is mediated by 3 major

components :
1. Periaquaductal grey matter
2. Nucleus raphe magnus
3. Pain inhibitory neurons
 Analgesics

Definition -
“Analgesics are drugs that selectively relieve
pain by acting in the CNS or on the peripheral
pain mechanisms, without altering
consciousness”
 History of Analgesics
 BC: Ancient Greeks and Romans used salicylate
extracts derived from willow leaves as analgesics
and antipyretics

 Middle Ages: Medicinal herb gardens featured

salicylate containing wintergreen and meadowsweet
plants

 1763: Edward Stone reported on use of willow bark

powder as an anti-inflammatory agent.

 1853: Von Gerhardt synthesized a crude form of

aspirin (acetylsalicylic acid)

 1860: Felix Hoffman synthesized pure aspirin

 continued
 Opiatesare one of the oldest types of drugs in history
 Opium is extracted from poppy seeds (Paper
somniforum)

 Undisputed reference to opium found in writings from

the third century BC
 Use of Opium was first recorded in China over 2000
years ago

 Greeks dedicated the Opium poppy to the Gods of Death

(Thanatos), Sleep (Hypnos), and Dreams (Morpheus)

 Sixteenth Century is the first reported use of Opium for

its Analgesic qualities
 Contnd…
 1949: The NSAID Phenylbutazone was introduced
 1963: Indomethacin was introduced

 1971: Vane and Piper demonstrated that NSAIDs inhibit

prostaglandin production
 1974: Ibuprofen was introduced

 1976: Miyamoto et al identified the COX-1 enzyme

 1989: Simmons et al identified the COX-2 enzyme

 1999: The COXIBs celecoxib and rofecoxib were introduced

 2004: Rofecoxib was banned in india due to its cardiotoxic effect .
 Classification of NSAIDs
 Non selective COX inhibitors (conventional NSAID’s)
– Salicylates: Asprin
– Propionic acid derivatives: Ibuprofen, Naproxen,
Ketoprofen, Flurbiprofen
– Anthranilic acid derivative: Mephenamic acid
– Aryl-acetic acid derivatives: Diclofenac
– Oxicam derivatives: Piroxicam, Tenoxicam
– Pyrrolo-pyrrole derivative: Ketorolac
– Indole derivative: Indomethacin
– Pyrazolone derivatives: Phenylbutazone,
Oxyphenbutazone
 Classification of NSAID’s contd…
 Preferential
COX-2 inhibitors
– Nimesulide, Meloxicam, Nabumetone

 SelectiveCOX-2 inhibitors
– Celecoxib, Rofecoxib, Valdecoxib, Etoricoxib

 Analgesics-antipyretics with poor anti inflammatory

action
– Para aminophenol derivative: Parcetamol
(Acetaminophen)
– Pyrazolone derivatives: Metamizol (Dipyrone),
Propiphenazone
– Benzoxazocine derivative: Nefopam
 NSAIDs and prostaglandin (PG)
synthesis inhibition
 Prostaglandins,
prostacyclin (PGI2) and thromboxane
A2(TXA2) are produced from arachidonic acid by the
enzyme cyclo oxygenase which exists in 2 forms

– (COX-1) - Cyclo oxygenase -1

– (COX-2) - Cyclo oxygenase -2

• Most NSAID’s inhibit COX-1 and COX-2

non selectively
• Some selective COX-2 inhibitors have now been
produced
 Cellular Arachidonic Acid Metabolism
Inflammatory
Stimulus

Phospholiapase A2

Lipoxygenases

Leukotrienes
Cyclo oxygenase pathway
 Beneficial actions due to PG
synthesis inhibition

 Analgesia
 Anti pyresis
 Anti inflammatory
 Anti thrombotic
 Toxicities due to PG synthesis
inhibition

 Gastric mucosal damage

 Bleeding: inhibition of platelet function
 Limitation of renal blood flow: sodium and water
retention
 Delay / prolongation of labour
 Asthma and anaphylactic reactions in susceptible
individuals
 Adverse effects of NSAID’s

 Gastrointestinal
– Gastric irritation, erosions, peptic ulceration,
gastric bleeding / perforation, esophagitis

 Renal
– Sodium and water retention, chronic renal
failure, interstitial nephritis, papillary necrosis
(rare)

 Hepatic
– Raised transaminases, hepatic failure (rare)
 Adverse effects of NSAID’s
 CNS
– Headache, mental confusion, behavioural
disturbances, seizure precipitation

 Haematological
– Bleeding, thrombocytopenia, hemolytic
anaemia, agranulocytosis

 Others
– Asthma exacerbation, nasal polyposis, skin
rashes, pruritis, angioedema
NSAID - GI toxicity
Routes of analgesic administration
 Oral
 Intramuscular Injection
 Intravenous Injection
 Other routes
– Transdermal
• Fentanyl patch
– Sublingual
• Morphine
 Salicylates -Asprin
 Is acetylsalicylic acid

 Pharmacological actions
– Analgesic, antipyretic, anti inflammatory actions
• Analgesic action is due to prevention of PG mediated
sensitization of nerve endings
• Resets the hypothalamic thermoregulatory centre
• Anti inflammatory at high doses

– Blood
• Irreversibly inhibits TXA2 synthesis thus interferes
with platelet aggregation and BT is prolonged
• Long term use of large doses decreases synthesis of
clotting factors in liver
 Aspirin
– Respiration
• Anti inflammatory doses – stimulates respiration
• Hyperventilation in salicylate poisoning, in doses
higher than this there is respiratory depression

– Acid-base electrolyte balance

• Adults treated with aspirin 4-6g/day stay in a state of
compensated respiratory alkalosis
• Still higher doses can cause respiratory acidosis
• Dehydration occurs in poisoning due to increased
urine output, sweating and hyperventilation

– CVS
• No direct effect in therapeutic doses
 Aspirin
– GIT
• Aspirin irritates gastric mucosa & causes epigastric
pain, nausea and vomiting
• ‘Ion trapping’ in gastric mucosa increases gastric
toxicity
• Acute ulcers, erosive gastritis, congestion and
microscopic hemorrhages

– Metabolic effects
• Chronic use can cause negative nitrogen balance by
increased conversion of protein to carbohydrate.
 Aspirin
 Pharmacokinetics
– Absorbed from stomach and small intestine

 Precautions and contraindications

– Contraindicated in patients sensitive to it and in
peptic ulcer, bleeding tendencies, & in children
suffering from chicken pox or influenza. (due to
risk of Reye’s syndrome)
– In chronic liver disease
– Asprin should be stopped 5 days before elective
surgery, dental extraction
– Pregnancy and lactating mothers
 Asprin
 Adverse effects
– Most important – gastric mucosal damage and
peptic ulceration
– Acute salicylate poisoning
– Assosiated with Reye’s syndrome

 Uses
– As analgesic
– As antipyretic
– Acute rheumatic fever
– Rheumatoid arthritis
– Osteoarthritis
 Propionic acid derivatives
Ibuprofen –
 first introduced member of this class
 Anti inflammatory efficacy is lower than asprin
 Inhibit Prostaglandin synthesis

 Adverse effects
– Milder and better tolerated than asprin
– GI disturbances are present
– Precipitate asprin-induced asthma
 Propionic acid derivatives
 Pharmacokinetics
– Well absorbed orally

 Uses
– Analgesic and Antipyretic and anti-inflammatory
– Soft tissue injuries, tooth extraction, fractures, post
operative pain.
– Rheumatoid arthritis, osteoarthritis and
musculoskeletal disorders… where pain is more
prominent than inflammation
 Anthranilic acid dervative
 Mephenamic acid-
– Inhibits COX & antagonises certain actions of PG’s
– Exerts peripheral as well as central analgesic action

 Pharmacokinetics
– Oral absorption is slow but complete

 Adverse effects - Diarrhoea

 Uses
– Muscle, joint and soft tissue pain
– Effective in dysmenorrhoea
 Aryl-acetic acid derivative
 Diclofenac sodium
– Inhibits PG synthesis
– Has short lasting anti platelet action
– Adverse effects are mild

 Pharmacokinetics
– Well absorbed orally
– Excreted both in urine and bile

 Uses
– Toothache
– Post operative and post traumatic inflammatory conditions
– Rheumatoid arthritis and osteoarthritis
 Oxicam derivatives
Piroxicam -
– Long acting NSAID
– Reversible inhibitor of COX

Pyrrolo-pyrrole derivative
Ketorolac
– Potent analgesic and moderate anti inflammatory
activity
– Used in post operative pain after surgery and acute
dental pain
 Indole derivative
 Indomethacin
– Potent antiinflammatory and antipyretic action
– High incidence of GI and CNS side effects.

Pyrazolones derivative
 Metamizol and propiphenazone are used as analgesic
and antipyretics
 Preferential COX-2 inhibitors
 Nimesulide
– Newer NSAID
– Completely absorbed orally
– Used in patient with history of asthma and
anaphylactic reactions to other NSAIDs.
– Used for short-lasting painful inflammatory
conditions like -
- sports injuries,
- sinusitis and other ENT disorders
- fever and low back pain

Adverse effect – Hepatotoxic in pediatric patients .

 Para-amino phenol derivatives
 Paracetamol (Acetaminophen) -

– Central analgesic action similar to asprin, i.e it raises

pain threshold
– Has weak peripheral anti inflammatory component
– Promptly acting antipyretic

 Pharmacokinetics
– Well absorbed orally
– Effects after oral dose last for 3-5 hours
 Adverse effects
– Acute paracetamol poisoning – children
 Paracetamol (Acetaminophen)
 Uses –

– Most commonly used drug & One of the best

antipyretic drugs
– Can be used in all age groups, also in pregnant
and lactating women

Clinical studies have found paracetamol and

asprin to be equally effective in relieving pain
after 3rd molar extraction

And it is more safer than asprin – lesser GI

disturbances and bleeding tendencies
Opioid analgesics
 Classification of opioids
 Naturalopium alkaloids
– Morphine, codeine

 Semi synthetic opiates

– Diacetylmorphine (heroin), pholcodeine

 Synthetic opioids
– Pethidine (meperidine), fentanyl, methadone,
dextropropoxyphene, tramadol
 Morphine
– Alkaloid of opium
– Widely used

 Pharmacological actions
 CNS
– Analgesia
• Strong analgesic
• Nociceptive pain arising from peripheral pain
receptors is better relieved than neuritic pain
• Reactions associated with intense pain –
apprehension, fear are also depressed
 Morphine
– CNS
– Sedation
• Drowsiness and indifference to surroundings as well
as to own body , ataxia and apparent excitement also
occur
• Higher doses produce sleep and coma

– Mood and subjective changes

• Calming effect
• Loss of apprehension, feeling of detachment,mental
clouding and inability to concentrate
 Morphine
– Respiratory and cough centres
• Depresses Repiration and Cough centre

– Temperature regulating and vasomotor centre

• Depressed

– CTZ, vagal centre & certain cortical areas are

stimulated

– GIT
• Constipation is a prominent feature
 Morphine
 Neuro-endocrine
– Enhances ADH release and so urine volume is reduced
– Causes sympathetic stimulation – mild hypoglycemia

 CVS
– Causes vasodilation
– Cardiac work is consistently reduced due to decrease in
peripheral resistance
 Morphine
 Pharmacokinetics
– Oral absorption is unreliable – high and variable first
pass metabolism
– Freely crosses placenta, affects foetus more than the
mother

 Adverse effects
– Mental clouding, sedation and lethargy
– constipation
– Acute morphine poisoning
• Human lethal dose is 250mg .
• Death is due to respiratory failure
 Morphine
 Tolerance and dependence
– Partly pharmacokinetic (enhanced rate of metabolism)
but mainly pharmacodynamic (cellular tolerance)
– Treated by substitution with oral methadone

Precautions and contraindications

– Infants and elderly
– Bronchial asthma
– Head injury

 Codeine

 Is methyl morphine
 Less potent than morphine (1/10th as analgesic)
 Is more selective cough suppressant
 Pethidine
 Synthesized as an atropine substitute
 Interacts with opioid receptors (mu)
 Similar to morphine in most of its properties

– Uses
• As analgesic (substitute to morphine)
• In pre anaesthetic medication
 Methadone

 Chemically dissimilar but pharmacologically

similar to morphine

 Used
– primarily as substitution therapy for opioid
dependence
– Also in methadone maintenance therapy
 Tramadol

 Centrally acting analgesic

 It is believed to work through modulation of serotonin
and norepinephrine in addition to its relatively-weak μ-
opioid receptor agonism
 100mg tramadol IV is equally analgesic to 10mg
morphine IM

 Uses
– Mild to moderate intensity short lasting pain due to
surgery, dental procedures, injury etc
 Opioid receptors
 Opioids interact with specific receptors present on neurons
in the CNS and peripheral tissues

 Radioligand binding studies divide receptors into

– mu, kappa and delta

 Pattern of effect of particular agent depends on the nature

of its interaction with different opioid receptors and also
its relative affinity to these receptors
Complex action opioids and opioid
antagonists

 Agonist- antagonist
– Nalorphine
– Pentazocaine
– Butorphanol

 Partial/weak agonist
– Buprenorphine

 Pure antagonist
– Naloxone, naltrexone
 Pentazocaine
 Indicated in post operative and moderately severe
pain in trauma, cancer and burns,

Naloxone

 Competitive antagonist for all opioid receptors

 Injected i.v (0.4- 0.8mg) it antagonizes all actions
of morphine
 Drug of choice in morphine poisoning
 Opioids in dental pain
 Opioids are less effective and suitable than NSAID’s for
dental pain

 Mostly used as additional drugs with NSAID’s to boost

their analgesic effect

 Among opioids oral codeine is most suitable

 Oral tramadol and pentazocine are alternatives

 Injectable opioids like morphine, pethidine are limited

to intra-operative use to supplement anaesthesia and to
allay apprehension
 Analgesics & Medical conditions
 NSAIDs should be given in 2nd triemister of
pregnancy and opioids should be avoided .
 Paracetamol is the safest drug to use in pregnancy
 Aspirin & Ibuprofen should not be given in
asthmatic patients
 Aspirin & Paracetamol should not be given in
nephropathy.
 Codein should not be used in renal dysfunction
while fentanyl & methadone are safe .
 Adjuvant drugs
 To supplement the action of analgesics
 To limit the side effects of analgesics

Adjuvants
– Steroids
– Anti arrythmics
– Anti depressants
– Anti epileptics
– Serotonin reuptake inhibitors
– Muscle relaxants

Adjuvant medications are mostly used for chronic pain

 FUTURE
Patient controlled transdermal system
 Fentanyl patches
 Tramadol patches
 Diclofenac patches
 References

 GOODMAN & GILLMAN PHARMACOLOGY

 Lippincott's Pharmacology
 Rang & Dale's Pharmacology
 Essentials of Medical pharmacology – KD Tripathi
 Essentials of Dental pharmacology – KD Tripathi
 Oral and Maxillofacial surgery –Vol. 1 - Danial Laskin
Thank you....