KAMINENI INSTITUTE OF DENTAL SCIENCES

ANALGESICS
DOP : 21/03/2017

UNDER THE GUIDANCE OF: Dr.B.PAVAN KUMAR(Prof&HOD)

MODERATOR: Dr.G.SRINIVAS

PRESENTOR:DUSHYANT
First yr pg
 Contents
i. Introduction
ii. Goals of pain management
iii. Routes of analgesic administration
iv. Classification of analgesics
v. Aspirin
vi. Ibuprofen
vii. Mephenamic acid
viii. Diclofenac sodium
ix. Prefrential cox-2 inhibitor
x. Selective cox-2 inhibitor
xi. Paracetamol
XII Opioids
History of opioids
Classification of opioids
Individual drugs
Opioid receptors
Complex action opioids and opioid antagonists
XIII Opioids in dental pain
XIV Adjuvants
XV Pain management strategies
Post operative
Cancer pain
In elderly
XVI The future and related articles
XVII Conclusion
 Pain

“An unpleasant sensory and emotional experience associated

with actual or potential tissue damage, or described in
terms of such damage” ……..Beth Fahlberg

“Pain is an ill-defined, unpleasant sensation, usually evoked

by an external or internal noxious stimulus"

“Pain is whatever the experiencing person says it is and exists

whenever he says it does.”
It is a warning signal and primarily protective in nature

Causes discomfort and suffering (sometimes unbearable)

Pain is the most important symptom for which a patient

visits a doctor (especially dentist)

Post operative and dental pain is usually acute in nature

 Goals of pain management
To relieve suffering
Increase functional capacity
Improve quality of life
Pain Management Strategies
 What is Analgesia?
‘Analgesia simply means the absence of pain without
losing consciousness’

“The analgesia system is mediated by 3 major

components :
the periaquaductal grey matter (in the midbrain),
the nucleus raphe magnus (in the medulla), and
the pain inhibitory neurons within the dorsal horns
of the spinal cord . . . . . which act to inhibit pain-
transmitting neurons also located in the spinal
dorsal horn”
 Analgesics
“Analgesics are a class of drugs which obtunds the
perception of pain without producing unconsciousness”

“Analgesics are drugs that selectively relieve pain by acting

in the CNS or on the peripheral pain mechanisms,
without significantly altering consciousness”
Routes of analgesic administration
Oral
Intramuscular Injection
Intravenous Injection
PCA: patient controlled analgesia
Other routes
Transdermal
 Fentanyl patch
Sublingual
 Morphine
Epidural Administration
Spinal and Caudal Administration
 Classification of Analgesics

I. Non-narcotic
(non opioid / antipyretic / asprin like analgesics or
NSAID’s)

II. Narcotic
(opioid / morphine like analgesics)
 NSAIDs

1949: The NSAID Phenylbutazone introduced

 1963: Indomethacin introduced

 1971: Vane and Piper demonstrated NSAIDs

inhibit prostaglandin production
 1974: Ibuprofen introduced

 1976: Miyamoto et al purified the COX-1 enzyme

 1989: Simmons et al identified the COX-2
enzyme
 Classification of NSAIDs
I. 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
Preferential COX-2 inhibitors
Nimesulide, Meloxicam, Nabumetone

Selective COX-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
NSAID’s and prostaglandin (PG)
synthesis inhibition
In 1971, Vane and coworkers made the landmark
observation that asprin and some NSAID’s
blocked PG generation

Most NSAID’s inhibit COX-1 and COX-2 non

selectively

Some selective COX-2 inhibitors have now been

produced
 Cellular Arachidonic Acid
Metabolism
Cyclo oxygenase pathway
Beneficial actions due to PG synthesis inhibition

Analgesia: Prevention of pain nerve ending

sensitization

Anti pyresis

Anti inflammatory

Anti thrombotic

Closure of ductus arteriosus

 Shared toxicities due to PG synthesis inhibition

Gastric mucosa damage

Bleeding: inhibition of platelet function

Limitation of renal blood flow

Delay / prolongation of labour

Asthma and anaphylactoid 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)
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
 Salicylates :Asprin
Is acetylsalicylic acid

Pharmacological actions
Analgesic, antipyretic, anti inflammatory actions
 Asprin 600mg = codeine 60mg
 Analgesic action due to obtunding of peripheral pain
receptors and prevention of PG mediated sensitization of
nerve endings
 Resets the hypothalamic thermostat
 Anti inflammatory at high doses (100mg/kg/day)

Metabolic effects
 Chronic use can increase cellular metabolism
 Increased utilisation of glucose
Respiration
 Anti inflammatory doses – stimulated
 Hyperventilation in salicylate poisoning, in doses higher
than this causes respiratory depression

Acid-base electrolyte balance

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

CVS
 No direct effect in therapeutic doses
GIT
 Asprin and released salicylic acid irritate gastric mucosa
causes epigastric pain, nausea and vomitting
 ‘Ion trapping’ in gastric mucosa increases gastric toxicity
 Acute ulcers, erosive gastritis, congestion and microscopic
haemorrhages

Blood
 Irreversibly inhibits TXA2 synthesis by platelets, thus
interferes with platelet aggregation and BT is prolonged
 Long term use of large doses decrease synthesis of clotting
factors in liver
Pharmacokinetics
Absorbed from stomach and small intestine

Precautions and contraindications

C/I 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 1week before elective
surgery, dental extraction
Pregnancy and lactating mothers
Adverse effects
Most important – gastric mucosal damage and
peptic ulceration
Assosiated with Reye’s syndrome

Uses
As analgesic
As antipyretic
Acute rheumatic fever
Rheumatoid arthritis
Osteoarthritis
Post myocardial and post stroke patients
 Propionic acid derivatives
Ibuprofen - first introduced member of this class
Anti inflammatory efficacy is lower than asprin
Inhibit PG synthesis
Naproxen – most potent

Adverse effects
Milder and better tolerated than asprin
GI disturbances are present
Precipitate asprin-induced asthma
Pharmacokinetics
Well absorbed orally

Uses
Simple analgesic and antipyretic
Rheumatoid arthritis, osteoarthritis and
musculoskeletal disorders… where pain is more
prominent than inflammation
Soft tissue injuries, tooth extraction, fractures,
vasectomy, post partum and post operatively

Very popular in dentistry

 Anthranilic acid dervative
Mephenamic acid
Inhibits COX also 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
Analgesic in 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
 Rheumatoid arthritis and osteoarthritis
 Toothache
 Post operative and post traumatic inflammatory
conditions
 Oxicam derivatives
Piroxicam
Long acting NSAID
Reversible inhibitor of COX

Pyrrolo-pyrrole derivative
Ketorolac
Potent analgesic and modest anti inflammatory
activity
Used in post operative and dental pain
Also used for pain due to bony metastasis
 Indole derivative
Indomethacin
Potent antiinflammatory and prompt antipyretic
action
High incidence of GI and CNS side effects

Pyrazolones
Metamizol and propiphenazone are used as analgesic
and antipyretics (marketed in India)
Metamizol banned in USA and some European
countries- found to cause agranulocytosis
 Preferential COX-2 inhibitors
Nimesulide
Newer NSAID
Completely absorbed orally
Used for short-lasting painful inflammatory
conditions like - sports injuries,
- sinusitis and other ENT disorders
- dental surgery
- fever and low back pain

 Recently instances of fulminant hepatic failure have been

reported
 Withdrawn in Spain, Finland and Turkey
 Banned in Portugal and Isreal
 Selective COX-2 inhibitors

Introduced over the past decade

Celecoxib
As effective as diclofenac or naproxen
Rofecoxib
Has been withdrawn in Sept 2004 because of higher
incidence of MI and stroke compared to placebo
Valdecoxib
Few cases of severe skin reactions such as Stevens-
Johnson Syndrome have been reported
Etoricoxib
 Para-amino phenol derivatives
Paracetamol (acetaminophen)
Deethylated active metabolite of phenacetin
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 lasts for 3-5 hours
Adverse effects
Acute paracetamol poisoning – children
Uses
Most commonly used ‘over the counter’ 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

equieffective in relieving pain after 3rd molar extraction
 And it is more safer than asprin – lesser GI disturbances and
bleeding tendencies
 Analgesic combinations
No convincing evidence that combinations are superior
to single agents

Combination of asprin and paracetamol is additive

Combination of codeine with asprin or paracetamol is

additive and also provides analgesia beyond the ceiling
effect of asprin or paracetamol
This combination used for pain refractory to single
agent
 History Of Opium

 Opiates are one of the oldest types of drugs in history

 Opium is extracted from poppy seeds (Paper
somniforum)

 Undisputed reference to opium found in writings

(Theophrastus) from the third century BC
 Use of Opium recorded in China and Mesopotamia
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
Preparations of opium in the form of elixirs became
increasingly popular in the 17th, 18th, and 19th centuries
By the 19th century Opium in various forms was
considered “as legitimate as tobacco or tea”

Invention of the hypodermic needle in 1856 produced

drug abusers who self administered opioids by
injection
Controlling the widespread use of opioids has been
unsuccessful because of the euphoria, tolerance and
physiological dependence that opioids produce
 Classification of opioids

Natural opium alkaloids

Morphine, codeine

Semi synthetic opiates

Diacetylmorphine (heroin), pholcodeine

Synthetic opioids
Pethidine (meperidine), fentanyl, methadone,
dextropropoxyphene, tramadol
 Opiod analgesics
Opium contains two types of alkaloids

Phenanthrene derivatives
 Morphine (10% in opium)
 Codeine (0.5% in opium)

 Thebaine (0.2% in opium), (non analgesic)

Benzoisoquinoline derivatives (non analgesic)

 Papaverine(1%)
 Noscapine (6%)
 Morphine
 Principal alkaloid of opium
 Still widely used

 Pharmacological actions
 CNS
 Analgesia
 Strong analgesic
 Nociceptive pain arising from peripheral pain receptors
is better relieved than neuretic pain
 Reactions associated with intense pain – apprehension,
fear, autonomic effects … are also depressed
 Analgesic action of morphine has spinal and supraspinal
components
Sedation
 Drowsiness and indifference to surroundings as well as to
own body without motor incoordination occur, ataxia
and apparent excitement also occur
 Higher doses produce sleep and coma

Mood and subjective changes

 Calming effect
 Loss of apprehension, feeling of detachment, lack of
initiative, mental clouding and inability to concentrate
Respiratory and cough centres
 Depressed

Temperature regulating and vasomotor centre

 Depressed

CTZ, Edinger Westphal nucleus, vagal centre,

certain cortical areas and hippocampal areas are
stimulated

GIT
 Constipation is a prominent feature
Neuro-endocrine
Acting on hypothalamus reduces FSH, LH and
ACTH release
Increases prolactin and GH release

CVS
Causes vasodilation
Cardiac work is consistently reduced due to
decrease in peripheral resistance

It affects other smooth muscles of: urinary bladder,

uterus , bronchi
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
 50mg of morphine produces serious toxicity
 Death is due to respiratory failure
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
Unstable personalities
 Codeine
Is methyl morphine
Occurs naturally in opium
Less potent than morphine (1/10th as analgesic)
Is more selective cough suppressant

Heroin
3 times more potent than morphine
Euphorient and highly addicting
No outstanding therapeutic advantage over morphine
Banned in most countries except UK
 Pethidine
Synthesized as an atropine substitute in 1939
Interacts with opioid receptors (mu)
Similar to morphine in most of its properties

Uses
 As analgesic (substitute to morphine) and
 In pre anaesthetic medication
 Fentanyl
Is a pethidine congener
80-100 times more potent than morphine (both in
analgesia and respiratory depression)
Enters brain rapidly and produces peak analgesia 5min
after i.v inj.
Short acting- 30 to 40mins

Used exclusively in anaesthesia

Transdermal fentanyl available for cancer pain and

other chronic pain
 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

100mg tramadol equianalgesic to 10mg morphine

Uses
Mild to moderate intensity short lasting pain due to
diagnostic procedures, injury, surgery, dentistry etc
 Opioid receptors
Opioids interact with specific receptors present on
neurones in the CNS and peripheral tissues

Radioligand binding studies divide receptors into

 mu, kappa and delta

Each has specific pharmacological profile and pattern

of anatomical distribution

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
 Opioid receptors
mu kappa delta
Analgesia Analgesia Analgesia
Resp. depression Resp. depression Resp. depression
Sedation Dysphoria, Affective behavior
Euphoria hallucinations Reinforcing
Miosis Miosis actions
Reduced GI motility Sedation Reduced GI
Physical motility
Physical dependence
dependence
Complex action opioids and opioid
antagonists

Agonist- antagonist (kappa analgesics)

Nalorphine
Pentazocaine
Butorphanol

Partial /weak agonist

Buprenorphine

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

Naloxone
It is N-alylnor oxymorphone
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 suited

Oral tramadol and pentazocine are alternatives

Injected opioids like morphine, pethdine and fentanyl

are limited to intra-operative or peri-operative use to
supplement anaesthesia and to allay apprehension
 Adjuvants
 To supplement the action of analgesics
 To limit the side effects of analgesics

 Co - analgesics
 Steroids
 Anti arrythmics
 Anti depressants
 Anti epileptics
 Serotonin reuptake inhibitors
 Muscle relaxants

Adjunct medications are mostly used for chronic pain

 Pain Management Strategies
Preoperative preparation
Pain history

Postoperative pain
Regular & frequent dosing intervals in early post op
period
 PCA, Epidural, IV
 Opioid + NSAID
 Switch to oral dosing

Medicate prior to anticipated pain

 Ambulation & physical therapy
 Dressing changes
Pain Management Strategies
Benefits of effective post operative pain management
Early mobilization
Shorter hospital stay and reduced cost

Pre emptive analgesia (PEA)

Is administration of effective analgesia prior to
surgical trauma
PEA reduces acute pain scores and analgesic
requirements
Timing of initiation and prevention of sensitization
are central to use of PEA
 Cancer Pain
 Causes:
 Tumor progression
 Operations and other invasive procedures
 Toxicity of chemotherapy and radiation
 Infection
 Limited physical activity

 Pain-related pathology
 Bone Metastasis
 Spinal cord or nerve compression
 Peripheral neuropathy
 Abdominal tumors
 Mucositis
The WHO three-step analgesic ladder
Pain Management in the Elderly
More sensitive to pain medications
Longer duration of pain relief
More sensitive to sedation &
respiratory depression
 THE FUTURE

Fentanyl PCTS
Iontophoretic patient controlled transdermal system
 THE FUTURE

ACRUX

Analgesics, anxiolytics, antiemetics

 Guidelines for use of NSAID’s

Mild – moderate pain with little inflammation:

paracetamol or low dose ibuprofen
Post extraction: ketorolac, diclofenac, nimesulide or
asprin
Gastric intolerence to conventional NSAID’s: selective
COX-2 inhibitor or paracetamol
Patients with history of asthma: nimesulide
Peadiatric patients: paracetamol, asprin, ibuprofen,
naproxen –preferred
Pregnancy: paracetamol- safest, low dose asprin- 2nd best

Hypertensive, diabetic, IHD, epileptic patients on long

term medications- possibility of drug interactions
 Refrences
Essentials of medical pharmacology :
KD Tripathi
Pharmacology and pharmacotherapeutics :
R.S Satoskar
THANK YOU