Analgesics in Dentistry

2. ANALGESICS IN DENTISTRY
PRESENTED BY
DR RIPIKA SHARMA
1ST YEAR
POSTGRADUATE
DEPT OF PUBLIC
HEALTH DENTISTRY
MRADC

3. Contents
 Definition of analgesics
 Classification of analgesics
 Terminologies and concepts of pain
 CONCEPTS OF INFLAMMATION
 Pain Suppression (“Analgesia”) System in the Brain and Spinal
Cord
 NSAIDS
Classifications
Mechanism of action
INDICATIONS OF NSAIDS IN DENTISTRY
 Commonly used NSAID
 Uses
 Pharmacokinetics
 Pharmacodynamics
 Adverse effects
 Interactions

4. Contents
 Analgesics As Host Modulators
 Combination Analgesics
 Opiods
 Classification
 Mechanism Of Action
 Commonly Used Opoids
 Uses
 Pharmacokinetics
 Pharmacodynamics
 Adverse Effects
 Interactions
Conclusion
References

5. • Definition
Analgesics are medicines that selectively relieves pain by
acting in the central nervous system(CNS) or on the
peripheral pain mechanism, without significantly
altering consciousness.
• (Basic and Clinical Pharmacology- Lange 11th edition)

6. The term “Analgesic” is derived from two Greek words –
(1) an ("without") and
(2) algos ("pain").
Analgesic drugs produce analgesia by actions at several levels of the nervous
system, like
Inhibition of neurotransmitter release.
Inhibiting the COX1 and COX2 enzymes.
By acting on receptors located on neuronal cell membranes.

7. Classification of Analgesics
 Non-narcotic analgesics
Non-steroidal anti-inflammatory drugs (NSAIDs)
Narcotic analgesics
Opioids
(Essentials of medical pharmacology- KD Tripathi)

8. TERMINOLOGIES AND CONCEPTS
OF PAIN

9. Definition of Pain
“An unpleasant sensory and emotional experience
associated with actual or potential tissue damage, or
described in terms of such damage.”
International Association for the Study of Pain (IASP)

10. INCIDENCE OF PAIN
 According to Cohen – It was found that 21.8% of adult
experience orofacial pain symptoms within 6 months of
study.
 The most common pain was toothache, which was
estimated to have occurred in 12.3% of the population
10

11. Classification of Pain
Acute
Chronic
vs
Duration
Nociceptive
Neuropathic
vs
Pathophysiology

12. Acute Pain vs. Chronic Pain
Acute Chronic
 Usually accompanied by
obvious tissue damage
 Increased autonomic
nervous activity
 Pain resolves with healing of
the underlying injury
 Serves a protective function
 Pain that extends 3 or 6
months beyond onset or
beyond the expected
period of healing1
 Ceases to serve a
protective function
instead degrades health
and functional capability2
 Produces significant
psychiatric disturbancess3
vs.
1 Turk and Okifuji. Bonica’s Management of Pain.
2001.
2 Chapman and Stillman. Pain and Touch. 1996.
3 Fields. NNBN. 1991;4:83-92.

13. Definition of nociceptic and
neuropathic pain
The IASP defines
• nociception as being the pain initiated or caused by
activation of peripheral nociceptors (IASP, 1986). It serves as
an “alarm” and protective system against noxious stimuli
(Serra, 1999).
According to the IASP Task Force,
• neuropathic pain is defined as pain initiated or caused by a
primary lesion or dysfunction in the nervous system (Merskey
and Bogduk, 1994).

14. Nociceptive Neuropathic
• Pain that arises from a
stimulus that is outside
of the nervous system
• Proportionate to the
stimulation of the receptor
• When acute serves an
“alarm” and protective
function
• Musculoskeletal disorders
are a very common cause
of nociceptive pain
• Pain initiated or caused by a
primary lesion or
dysfunction in the nervous
system
• No nociceptive stimulation
required i.e pain in the
absence of trauma or
disesase
• Disproportionate to the
stimulation of receptor
vs

15. Mixed Type
(eg, Postoperative pain,
chronic back pain)
Classification of Pain by Pathophysiology
Nociceptive
Pain
Neuropathic
Pain
Visceral
Abdominal
Obstetrical
Head
Headache
Orofacial
Postherpetic
Neuralgia
Spinal cord injury
pain
Multiple
sclerosis
CRPS = complex regional pain syndrome.
Central
Poststroke Pain
Trigeminal
Neuralgia
Distal
Polyneuropathy
(eg, diabetic, HIV)
Musculoskeletal
Osteoarthritis
Rheumatoid Arthritis
Low Back Pain
Other
Postoperative
Cancer Pain

16. • Transduction
• Transmission
• Modulation
• Perception
• Interpretation
• Pain Behavior
Peripheral
Nerve
Ascending
Pathways
Injury
Descending
Pathway
Dorsal
Root
Ganglion
C-Fiber
A-beta Fiber
A-delta Fiber
Dorsal
Horn
Brain
Spinal Cord
Adapted with permission from WebMD Scientific American® Medicine.
Physiology of Pain Perception

17. CONCEPTS OF INFLAMMATION

19. INFLAMMATION
• Inflammation is a defense reaction caused by tissue damage
or injury
• Can be elicited by numerous stimuli including:
• infectious agents
• antigen-antibody interaction
• ischemia
• thermal and physical injury
• Noxious chemicals

20. The classic signs and symptoms of acute
inflammation
English Latin
Redness Rubor*
Swelling Tumor/
Heat Calor*
Pain Dolor*
Loss of function Functio laesa**

21. Inflammatory responses occur in three distinct
temporal phases, each apparently mediated by
different mechanisms:
 (1) AN ACUTE PHASE, characterized by transient
local vasodilation and increased capillary
permeability;
 (2) A DELAYED, SUBACUTE phase characterized by
infiltration of leukocytes and phagocytic cells; and
 (3)A CHRONIC PROLIFERATIVE PHASE, in which
tissue degeneration and fibrosis occur.

22. Pain Suppression (“Analgesia”) System in the Brain
and Spinal Cord
The degree to which a person reacts to pain varies tremendously. This results
partly from a capability of the brain itself to suppress input of pain signals to
the nervous system by activating a pain control system, called an analgesia
system.
Several transmitter substances are involved in the
analgesia system: they can block pain signals at the initial entry point to the
spinal cord.
They are:
1. Beta-endorphin (mu receptor affinity)
2. Enkephalins (delta receptor affinity)
3. Dynorphins A and B (k receptor affinity)
4. Nociceptin/Orphanin
5. Endomorphins 1 and 2
6. Milk and milk products contain opioid peptide β-casomorphins,
which are released from casein in intestine.

23. ROUTES OF ANALGESIC
ADMINISTRATION
 Oral
 Intramuscular Injection
 Intravenous Injection
 PCA: Patient Controlled Analgesia
 Other routes
Transdermal
Ketorolac (Khalid Al-Hezaimi et al.: J periodontol 2011;
Fentanyl patches. 82: 963-968)
Sublingual
Morphine
Epidural/ Intrathecal Administration

24. Among the most widely used therapeutic agents world
wide
They are frequently prescribed for ‘rheumatic’
musculo-skeletal complaints and are often taken
without prescription for minor aches and pains
NSAIDs

25. NSAIDs Cont..
Analgesic
Antipyretic
Anti-inflammatory actions
Compared to Morphine:
Weaker analgesics
Do not depress CNS
Do not produce physical dependence
No abuse liability

26. They are also called:
Non narcotic
Non opioid
Aspirin like analgesics
They act primarily on peripheral pain
mechanisms but also in CNS to raise pain
threshold
These drugs are chemically diverse, but most
are organic acids.
NSAIDs Cont..

27. MECHANISM OF ACTION -NSAIDS

28.  Prostaglandins and leukotrines (eicosanoid) are biologically
active derivatives of 20 Carbon atom polyunsaturated fatty
acids(aracidonic acid) that are released from phospholipid cell
membrane of Leucocytes, Platelets, Endothelial Cells.
 Eicosanoids are the universally most distributed autocoids in
the body.
 There are no preformed stores of PG’S and LT’S.
 They are synthesized locally at the rate governed by release of
arachidonic acid from membrane lipid in response to stimuli.
 Arachidonic acid gets metabolites by one of the following 2
pathways- cyclooxygenase
lipooxygenase

29.  Prostaglandins produce Hyperalgesia- they sensitize the nerve
endings to pain caused by other mediators of inflammation
like bradykinin and histamine.
• NSAIDS inhibits the PG synthesis by inhibiting the enzyme
CYCLO-OXYGENASE.

30. Beneficial actions due to PG synthesis
inhibition
Analgesia
Antipyresis
Antiinflammatory
Antithrombotic
Closure of ductus arteriosus

31. Shared toxicities due to PG synthesis
inhibition
Gastric mucosal damage
Bleeding
Limitation of renal blood flow/Na+ & water
retention
Delay/prolongation of labour
Asthma and anaphylactoid reactions in
susceptible individuals

33. Two main forms of Cyclooxygenases (COX)
• Cyclooxygenase-1 (COX-1)
• Produces prostaglandins that
mediate homeostatic functions
• Constitutively expressed
• Homeostatic
Protection of gastric
mucosa
Platelet activation
Renal functions
Macrophage
differentiation
• Cyclooxygenase-2 (COX-2)
• Produces prostaglandins that
mediate inflammation, pain, and
fever.
• Induced mainly in sites of
inflammation by cytokines
• Pathologic
Inflammation
Pain
Fever
Dysregulated
proliferation
Selective Inhibition of COX-2 safe
anti-inflammatory therapy
Inhibition of COX-1  organ-specific
toxicity

34. Mechanism of action of NSAIDs

35. INDICATIONS OF NSAIDS IN DENTISTRY
 Irreversible pulpitis
 Apical periodontitis
 Acute alveolar abscess
 Infected cyst
 Sinusitis
 TMJ Arthritis
 MPDS
 After tooth extraction
 Dry socket
 Recurrent apthous ulcers
 Lichen planus
 Agranulocytosis
 Cyclic neutropenia

36. CLASSIFICATION OF
NSAIDS
• NSAIDS CAN BE CLASSIFIED
1. CHEMICALLY.
2. MECHANISM OF ACTION.
3. WHO CLASSIFICATION.

37. CHEMICAL CLASSIFICATION
• A: SALICYLATES
Acetyl salicylic acid (aspirin),
sodium salicylate, Mg salicylate,
choline salicylate,
Na thio salicylate.
• B: PROPIONIC ACID
DERIVATIVES
Ibuprofen, ketoprofen,
naproxen, oxaprozin, flurbiprofen
• C: INDOLE ACETIC ACID
Indomethacin, sulindac
• D: SUBSTITUTED
ANTHRANILIC ACIDS (Rarely
used)
Mefenamic acid,
meclofenamate Na
E: PYRROLE ALKANOIC
ACID (Rarely used)
Tolmetin
F: OXICAMS
Piroxicam, meloxicam
G: DIFLUOROPHENYL
DERIVATIVES
Diflunisal
H: PHENYLACETIC ACID
Diclofenac
I: ACETIC ACID
DERIVATIVES
Etodolac
J: NAPHTHYLACETIC ACID
PRODRUGS
Nabumetone
K: PARA-AMINO PHENOL
DERIVATIVES
Acetaminophen

38. CHEMICALLY NSAIDS CLASSIFIED AS

39. ACCORDING TO MECHANISM OF ACTION
NSAIDs
NON-SELECTIVE COX
INHIBITORS
PREFERENTIAL
COX-2
INHIBITORS
SELECTIVE COX-2
INHIBITORS
(Essentials of medical pharmacology- KD Tripathi )

40. WHO Classification
• A: DRUGS WITH WEAK ANTI-INFLAMMATORY
EFFECT
Acetaminophen
• B: DRUGS WITH MILD TO MODERATE ANTI-
INFLAMMATORY EFFECT
Propionic acid derivatives, anthranilic acid derivatives
• C: DRUGS WITH MARKED ANTI-INFLAMMATORY
EFFECTS
Salicylates, acetic acid derivatives, oxicams, diclofenac,
etodolac

41. HISTORY
• Derived from willow bark, salicin was used by MacIagan in
1874 to treat inflammation in rheumatic fever. Later, a
more efficacious and better tolerated synthetic derivative,
aspirin, was produced by Felix Hoffman of the Bayer
company
• In 1963, indomethacin was introduced to treat rheumatoid
arthritis, and this was followed by the development of
many other anti-inflammatory agents.
• The poor gastrointestinal (GI) tolerability of this class of
drugs, coupled with their widespread use, led to the
development of selective agents known as COX-2 inhibitors.

42. MECHANISM OF ACTION OF NSAIDS
1. Antiinflammatory effect:
– due to the inhibition of the enzymes cyclooxygenase, or
COX, which converts arachidonic acid to prostaglandins,
and to TXA2 and prostacyclin.
– Aspirin irreversibly inactivates COX-1 and COX-2 by
acetylation of a specific serine residue.
– This distinguishes it from other NSAIDs, which reversibly
inhibit COX-1 and COX-2.

43. 2. Analgesic effect:
A. The analgesic effect of NSAIDs is thought to be related to:
– the peripheral inhibition of prostaglandin production
– may also be due to the inhibition of pain stimuli at a
subcortical site.
B. NSAIDs inhibits bradykinin from stimulating pain receptors.
3. Antipyretic effect :
– The antipyretic effect of NSAIDs is believed to be related to:
• inhibition of production of prostaglandins induced by
cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-
6) in the hypothalamus
• the “resetting” of the thermoregulatory system, leading to
vasodilatation and increased heat loss.

44. 4.DYSMENORRHOEA -
 NSAIDS lower uterine PG levels and afford excellent relieve.
 Ancillary symptoms of headache muscle ache and nausea are also
relieved
5.ANTIPLATELET AGGREGATORY:
 Inhibits synthesis of both proaggregatory (TXA2)and antiaggregatory
PGI2 prostanoids, bleeding time is prolonged .
 Risk of postextraction bleeding is enhanced.
 Inhibition of platelet COX-1 (COX-2 is expressed only in megakaryocytes)
last for the lifetime of the platelet. Inhibition of platelet COX-1-
dependent TXA2 formation therefore is cumulative with repeated doses
of aspirin (at least as low as 30 mg/day) and takes roughly 8 to 12 days
-the platelet turnover time- to recover once therapy has been stopped
6.DUCTUS ARTERIOSUS CLOSURE:
 In late pregnancy it has been seen to found premature closure of ductus
in some cases.
 Hence, dentist should avoid prescribing NSAIDS near term.

45. 7.GASTRIC MUCOSAL DAMAGE :
 Gastric pain ,mucosal ulcerations and blood loss are produced
by all NSAIDS to varying extents.
 Paracetamol is a very weak inhibitor of COX is partially free of
gastric toxicity and selective COX2 inhibitors are safe.
 PPIs can also be used for the treatment of an NSAID-induced
ulcer and are especially appropriate if the patient will need to
continue NSAID treatment.
 H2-antihistamines (cimetidine, famotidine, nizatidine, and
ranitidine) relieve dyspepsia due to NSAIDS, but they may
mask serious GI complaints and may not be as effective as
PPIs for healing and preventing ulcer formation.

46. Risk of GI Complications & Death With Traditional NSAIDs
• Risk of GI complications and death is 3 to10 times
higher in users of traditional NSAIDs vs. non-
NSAID users
•  107,000 hospitalizations and
16,500 deaths annually related
to traditional NSAID use among people with arthritis
• Even 1 week of traditional NSAID use can cause
ulcers
1. Hawkey CJ. BMJ. 1990;300:278-84. 2. Gabriel SE, et al. Ann Intern Med.
1991;115:787-96. 3. Henry D, et al. BMJ. 1996;312:1563-66. 4. Griffin MR, et al. Ann
Intern Med. 1991;114:257-63. 5. Langman MJS, et al. Lancet. 1994;343:1075-78. 6.
Singh G. Am J Med. 1998;105 (suppl 1B):31S-38S. 7. Goldstein JL, et al. Am J
Gastroenterol. In press.

47. 8.RENAL EFFECTS:
 Na+ and water retention ,chronic renal failure, interstitial
nephritis, papillary necrosis
9. hepatic
 Raised transaminases ,hepatic failure (rare).
 Overt liver failure has been reported following use of many
NSAIDs, including diclofenac, flurbiprofen, and sulindac
 Sulindac has been associated with the highest incidence of
cholestasis
 All patients should be evaluated within 8-12 weeks treatment
of NSAIDs
 10.CNS:
 Headache ,behavioural disturbances,seizure precipitation.
11.HAEMATOLOGICAL:
 Bleeding,thrombocytopenia,haemolytic
anaemia,agranulocytosis.

48. 12. Effect on Respiration: triphasic
• The Salicylates - Aspirin
1. Low doses: uncoupling phosphorylation → ↑ CO2 →
stimulates respiration.
2. Direct stimulation of respiratory center → Hyperventilation
→ resp. alkalosis → renal compensation
3. Depression of respiratory center and cardiovascular center
→ ↓ BP, respiratory acidosis, no compensation + metabolic
acidosis also
13.OTHERS:
 Asthma,exacerbations,nasal polyposis,skin rashes,pruritus,
angiodema.

49. Aspirin and other salicylic acid derivatives
TRADE NAMES
• Colsprin 100,325,650 mg tabs,
• Ecosprin 75,150,325 mg tabs
• Dispirin 350mg tab..
• An injectable preparartion :biospirin recently available
• PHARMACOLOGIC PROPERTIES:
 Salicylates are weak organic acids;
 These agents are rapidly absorbed from the intestine as well
as from the stomach, where the low pH favors absorption.
 Mechanism of action:
 Aspirin is a weak organic acid that is unique among the
NSAIDs in that it irreversibly acetylates (and, thus, inactivates)
cyclooxygenase ..
SALICYLATES - ASPIRIN

50. • Pharmacokinetics: Absorbed in stomach and small
intestines. Excreted through kidneys and there is tubular
reabsorption.
• METABOLISM
• Salicylates are hydrolyzed rapidly by plasma and tissue
esterases to acetic acid and the active metabolite
salicylic acid.

51. Plasma t1/2
Salicylates have a t1/2
of 3—6 hours after
short-term
administration.
Long-term
administration of
high doses (to treat
arthritis) or
toxic overdose
•

52. Adverse effects:
1. Side effects in analgesic dose (0.3 -1.5g/day)
 Gastric mucosal damage – peptic ulcer.
(sheena Derry et al 2005)
 Nausea, vomiting, blood loss in stools (haemotochesia).
 Epigastric distress.
 Hypersentivity.
2. Side effects on anti-inflammatory doses (3-5g/day)
Salicylism: dizziness, tinnitus, vertigo. Reversible hearing,
vision loss, excitement, mental confusion, hyperventilation.
Reye’s syndrome: in children – hepatic encephalopathy
(children suffering form chicken pox or influenza).

53. Acute salicylate poisoning: 15 – 30gm – vomiting, dehydration,
delirium, hallucination, hyperpyrexia, convulsion, coma,
respiratory failure finally leading to death.

54. TREATMENT OF SALICYLATE POISONING
• Decrease absorption - activated charcoal,
emetics, gastric lavage
• Enhance excretion – ion trapping (alkalinize
urine), forced diuresis, hemodialysis
• Supportive measures - fluids, decrease
temperature, bicarbonate, electrolytes,
glucose, etc

55. Medical drug Potential effects
Vitamin C
NIZATIDINE
STERIODS
ANTACIDS
INCREASES SALICYLATE LEVELS
DECRESASES SALICYLATE LEVELS
Ethyl alcohol Increases ASA induced gastric damage
and bleeding time.
ORAL ANTICOANGULANT-WARFARIN
(COUMADIN)
BLEEDING/HEMORRHAGE
METHOTREXATE (MTX) Increases The Level Of MTX;
Increases Toxicity
VALPORIC ACID (VA) Increases risk of VA Toxicity ;bleeding
/hemorrhage
Sulfonlyureaas (eg chlorpropamide),
insulin
Enhances hypoglycemic response.
DRUG INTERACTIONS OF ASPIRIN
ALTERS SALICYLATE LEVELS
INCREASES EFFECT OF MEDICAL DRUG

56. ACE INHIBITORS
β –BLOCKERS
LOOP DIURETCS
REDUCES ANTIHYPERTENSIVE EFFECT
PROBENECID(BENEMID) DECREASES URICOSURIC EFFECT
REDUCES EFFECT OF MEDICAL DRUG

57. THERAPEUTIC USES
Antipyresis:
 The antipyretic dose of salicylate for adults is 325 mg to 650
mg orally every 4 hours.
 Salicylates are contraindicated for fever associated with viral
infection in children;, 50 to 75 mg/kg per day has been given
in four to six divided doses, not to exceed a total daily dose of
3.6 g.

58.  Analgesia.
 Salicylates are valuable for the nonspecific relief of minor
aches and pain (e.g., headache, arthritis, dysmenorrhea,
neuralgia, and myalgia).
 For this purpose, they are prescribed in the same doses and
manner as for antipyresis.
 Rheumatoid Arthritis :
 aspirin is regarded as the standard against which other drugs
should be compared for the treatment.
 Therapy with salicylates produces analgesia adequate to allow
more effective movement and physical therapy in
osteoarthritis and rheumatoid arthritis.
 Cancer Chemoprevention:
 Epidemiological studies suggested that frequent use of aspirin
is associated with as much as a 50% decrease in the risk of
colon cancer .

59. • Local Irritant Effects.
 Salicylic acid is irritating to skin and mucosa and destroys
epithelial cells.
 The keratolytic action of the free acid is employed for the
local treatment of warts, corns, fungal infections, and certain
types of eczematous dermatitis.

60. PRECAUTIONS AND CONTRAINDICATIONS
• Peptic ulcer
• Sensitive pts
• Children suffering from influenza, chickenpox
• Chronic liver diseases
• vitamin K deficiency
• CHF, lower cardiac reserve
• Pregnancy
Delayed labor, more postpartum bleed,
premature In pregnancy:
 Aspirin is classified as FDA pregnancy category C risk during
Trimesters 1 and 2 and category D during Trimester 3.
 Because salicylates are excreted in breast milk, aspirin should
be avoided during pregnancy and while breast-feeding
 closure of ductus arteiosus.
• G6PD deficiency
• Aspirin can cause a mild degree of hemolysis in individuals with a
deficiency of glucose-6-phosphate dehydrogenase.
• STOPPED 1 WEEK BEFORE ELECTIVE SURGERY.

61. Indole Derivatives
• INDOMETHACIN -a methylated indole derivative.
• PHARMACOLOGICAL PROPERTIES:
 Indomethacin has prominent antiinflammatory and analgesic-
antipyretic properties.
 More potent inhibitor of cox than aspirin .
 It inhibits the motility of polymorphonuclear leukocytes and
depresses the biosynthesis of mucopolysaccharides.
 Indomethacin may increase the risk of myocardial infarction
and stroke

62. PHARMACOKINETICS AND METABOLISM
 Oral indomethacin has excellent bioavailability.
 Peak concentrations occur 1 to 2 hours.
 90% bound to plasma proteins and tissues.
 The concentration of the drug in the CSF is low.
 Metabolites, includes those formed by O-demethylation (50%);
unchanged (20%),conjugation with glucuronic acid (about 10%), and
N-deacylation. Free and conjugated metabolites are eliminated in
the urine, bile, and feces.
 half-life in plasma averages about 2.5 hours.
INDOMETHACIN … cont..

63. Drug Interactions
 Indomethacin does not interfere with the uricosuric effect of
probenecid.
 Indomethacin does not directly modify the effect of warfarin,
but platelet inhibition and gastric irritation increase the risk of
bleeding.
 It antagonizes the natriuretic and antihypertensive effects of
furosemide and thiazide diuretics
 It blunts the antihypertensive effect of β receptor
antagonists, AT1 receptor and ACE inhibitors.
INDOMETHACIN … cont..

64. THERAPEUTIC USES
 A high rate of intolerance limits the long-term analgesic use of
indomethacin (INDOCIN).
 Indomethacin is effective for relieving joint pain, swelling, and
tenderness.
 20 times more potent than aspirin,more effective than aspirin
in the treatment of ankylosing spondylitis and osteoarthritis.
INDOMETHACIN … cont..

65.  It also is very effective in the treatment of acute gout,
although it is not uricosuric.
 Indomethacin is FDA approved for closure of persistent
patent ductus arteriosus.
 . Gingival inflammation is reduced after administration of
indometacin oral rinse.
INDOMETHACIN … cont..

66. COMMON ADVERSE EFFECTS
 Most adverse effects are dose-related.
 Gastrointestinal complaints are common .
 Diarrhea with ulcerative lesions of the bowel.
 Acute pancreatitis .
 The most frequent CNS effect is severe frontal headache in patients
who take the drug for long periods.
 Dizziness, vertigo, light-headedness, and mental confusion may
occur.
 Seizures have been reported, as have severe depression, psychosis,
hallucinations, and suicide.
INDOMETHACIN … cont..

67.  Caution when administering to elderly patients or to those with
underlying epilepsy, psychiatric disorders, or Parkinson's disease, because
they are at greater risk for the development of serious CNS adverse
effects.
 Hematopoietic reactions include neutropenia, thrombocytopenia, and
rarely aplastic anemia.
 As is common with other tNSAIDs, platelet function is impaired
transiently during the dosing interval.
 Contraindicated in pregnant women and children.
 DOSE: 25-50mg BD-QID .
INDICIN ,INDOCAP 25mg, 75mg SR CAP, ARTICID 25MG,50 mg
cap,1 % eye drop. RECTIN 50 mg suppository
INDOMETHACIN … cont..

68. Indole Derivatives Cont..
Sulindac:
• Fluorinated derivative of indomethacin
• It is a prodrug and has a longer duration of action
• Given orally in the dose of 100-200mg twice a day

69. Pyrollo pyrollo Derivatives
 A novel NSAID with potent analgesic and modest anti-
inflammatory activity.
 In post operative pain has equal efficacy of morphine and is
free of morphine side effects.
 Parenteral NSAID: Ketorolac (Toradol).The Only Non-Opioid
Parenteral Analgesic
KETOROLAC

70. PHARMACOKINETICS AND METABOLISM
 . Ketorolac has a rapid onset of action, extensive protein
binding, and a short duration of action
 Oral bioavailability is about 80%. .
 Achieving peak plasma concentration in 30-50 minute
 Elimination half life of 4-6 hours. The rate of elimination is
reduced in elderly & in renal failure.
 Inhibit platelet aggregation & promote gastric ulceration
KETOROLAC… cont..

71. SIDE EFFECTS
 at usual oral doses include somnolence, dizziness,
headache, gastrointestinal pain, dyspepsia, nausea, and pain
at the site of injection.
CONTRA-INDICATIONS:
 Patients on anticoagulants.(safely used in patient with peptic
ulcer, cardiac and renal problems)
 Like other NSAIDs, aspirin sensitivity is a contraindication to
the use of ketorolac.
KETOROLAC… cont..

72. THERAPEUTIC USES
 Ketorolac (administered as the tromethamine salt TORADOL,
ULTRAM) has been used as a short-term alternative (less than 5
days) to opioids for the treatment of moderate to severe pain and is
administered intramuscularly, intravenously, or orally.
 Typical doses are 30 to 60 mg (intramuscular); 15 to 30 mg
(intravenous); and 5 to 30 mg (oral). KETOROL ,TOROLAC 10 mg tab
 Ketorolac is used widely in postoperative dental and
musculoskeletal pain.
 Topical (ophthalmic) ketorolac is FDA approved for the treatment of
seasonal allergic conjunctivitis and postoperative ocular
inflammation after cataract extraction.
 In dental pain ketorolac has been rated superior to aspirin 650mg
,pcm 600mg,and equivalent to ibuprofen 400mg.
KETOROLAC… cont..

73.  Infiltration injection of ketorolac at on oral site produced significant
analgesic effects, particularly in treating pain of mandibular origin
 KT effectively reduces severe odontogenic pain within 40 min after
administration in human subjects, with minimal side effects
 0.1% ketorolac tromethamine oral rinse for the prevention of
periodontal disease progression in adults has recently been
demonstrated.
 Ketorolac tromethamine (KT) gel, an antiinflammatory drug,
significantly reduces the amount of alveolar bone loss from
gingivitis, KT is a particularly suitable NSAID for treating alveolar
bone loss because it is not bitter, irritating, and is soluble in water
(Dionne and Berthold, 2001).
KETOROLAC… cont..

74. PROPIONIC ACID DERIVATIVE-Ibuprofen
• IBUPROFEN is a derivative of phenylpropionic acid introduced
in 1969.
• In doses of 2.4 g daily it is is equivalent to 4 g of Aspirin in
anti-inflammatory effect.
• Oral ibuprofen is often prescribed in lower doses (< 2.4 g/d),
at which it has analgesic but not antiinflammatory efficacy.

75. PHARMACOKINETICS AND INTERACTIONS
 Well absorbed orally ,highly bound to plasma proteins 90-
99%.
 Displacement interactions are not clinically significant –dose
of oral anticoagulants and oral hypoglycemic need not to be
altered.
 They decrease diuretic and antihypertensive action of
thiazides, furosemide and β blockers.
 Largely metabolized in liver by hydroxylation and glucuronide
conjugation and excreted in urine as well as bile.
IBUPROFEN.. CONT..

76. ADVERSE EFFECTS
 Side effects are milder than aspirin.
 Gastric discomfort ,nausea ,vomiting most common side effects.
 CNS side effects include head ache , dizziness, blurring of vision ,tinnitus
and depression.
 Contraindicated in pregnant women and avoided in peptic ulcer patient.
 51% increase in the rate of renal cell carcinoma, the most common form
of kidney cancer, in nurses who regularly took ibuprofen and other
NSAIDs, such as naproxen.
 ibuprofen has been associated with the onset of bullous pemphigoid or
pemphigoid-like blistering.
IBUPROFEN.. CONT..

77. USES
 Widely used in rheumatoid arthritis, osteoarthritis, and other
musculoskeletal disorders.
 Ibuprofen (400mg) has been found equally or more efficacious than a
combination of aspirin650mg +codeine 60mg in relieving dental surgery
pain.
 Indicated in soft tissue injuries ,tooth extraction ,fractures, vasectomy,
postpartum and postoperatively.
 A topical cream preparation is absorbed into fascia and muscle.
 A liquid gel preparation of ibuprofen provides prompt relief in postsurgical
dental pain.
IBUPROFEN.. CONT..

78.  A single dose of ibuprofen 600 mg administered preoperatively, decreases
tooth sensitivity associated with in-office bleaching.
 Ibuprofen arginine, because of its rapid onset of action and long duration,
its favourable safety profile and the possibility of easy oral administration
shortly before a dental procedure, is a promising agent to achieve pain
control during and after periodontal scaling and root planing (SRP).
 Less pain is experienced with orthodontic appliances if 400 mg of
ibuprofen is taken 1 hour before, 3 hours after, and 7 hours after
placement.
IBUPROFEN.. CONT..

79.  Ibuprofen used as a postoperative analgesic (1-week course of 600
mg of ibuprofen taken four times daily) may not have a significant
negative impact on marginal bone level around dental implants,
after implant placement.
 It is effective in closing ductus arteriosus in preterm infants, with
much the same efficacy as indometacin
 DOSE:400-600mgTDS,
 BRUFEN, EMFLAM, IBUSYNTH 200,400,600mg tab, ibugesic also
100mg/5ml susp.
IBUPROFEN.. CONT..

80. PHENYLACETIC ACID DERIVATIVE-DICLOFENAC
• PHARMACOLOGICAL PROPERTIES.
• Diclofenac has analgesic, antipyretic, and antiinflammatory
activities.
• Its potency against COX-2 is substantially greater than that of
indomethacin, naproxen, or several other tNSAIDs.
• It appears to reduce intracellular concentrations of free AA in
leukocytes, perhaps by altering its release or uptake.
• The selectivity of diclofenac for COX-2 resembles that of
celecoxib.
• There are possibility of a cardiovascular hazard from chronic
therapy with diclofenac.

81.  Diclofenac is available in two enteral formulations:
1)diclofenac sodium and 2)diclofenac potassium.
 Diclofenac potassium is formulated to be released and
absorbed in the stomach.
 Diclofenac sodium is usually distributed in enteric coated tab,
resist dissolution in low pH gastric environments, releasing
instead in the duodenum
 They are available in topical gels (voltaren gel),and
transdermal patches (flector patch).additionally available in
parenteral formulation for infusion (voltarol ampules)and
more recently diclofenac sodium iv bolus have been
developed (dico75V ,Dylojet).
DICLOFENAC…CONT..

82. • Pharmacokinetics.
 Diclofenac has rapid absorption, extensive protein binding, and a short
half-life
 Well absorbed orally 99% protein bound,
 plasma t1/2 is 2 hours
 There is a substantial first-pass effect, such that only about 50% of
diclofenac is available systemically.
 Diclofenac is metabolized in the liver by a member of the CYP2C
subfamily to 4-hydroxydiclofenac, the principal metabolite, and other
hydroxylated forms; after glucuronidation and sulfation the metabolites
are excreted in the urine (65%) and bile (35%).
DICLOFENAC…CONT..

83. Therapeutic Uses.
 Diclofenac is used for the long-term symptomatic treatment
of rheumatoid arthritis, osteoarthritis, and ankylosing
spondylitis, toothache, brusitis, dysmenorrhoea and post
operative inflammatory conditions
 Three formulations are available: an intermediate-release
potassium salt (CATAFLAM), a delayed-release form
(VOLTARIN, VOLTAROL [UK]), and an extended-release form
(VOLTARIN-XR).
 The usual daily dosage for the above indications is 100 to 200
mg, given in several divided doses.
DICLOFENAC…CONT..

84. • Diclofenac is also available in combination with misoprostol, a PGE1 analog
(ARTHROTEC) .
• This combination, which retains the efficacy of diclofenac while reducing
the frequency of gastrointestinal ulcers and erosions, is cost-effective
relative to the selective COX-2 inhibitors despite the cost of the added
misoprostol.
• In addition, an ophthalmic solution of diclofenac is available for treatment
of postoperative inflammation following cataract extraction.
• Oral preparation have been shown to provide significant analgesia in the
postoperative periods for adults experiencing moderate or severe pain
following a surgical procedure.
• Dose:
• 50 mg TDS, Then BD oral, 75mg deep im, voveran, Diclonac,Diclomax
25,50,75mg/3ml inj
DICLOFENAC…CONT..

85. DICLOFENAC MOUTHWASH
 DICLOFENAC EPOLAMINE
[diclofenacN-(2-hydroxyethyl) pyrrolidine; DHEP] is a
diclofenac salt with greater water solubility and better
cutaneous absorption properties than other commonly used
forms of the drug.
 MOUTHWASH FORMULATION of DHEP is used for the topical
treatment of inflammatory conditions of the oral cavity.
 (FARMAKA DICLOFENAC MOUTHWASH 0.074%) 0.074%
diclofenac mouthwash at a dose of 15 ml twice daily is
endowed with significant local analgesic effects. The
mouthwash is efficacious and tolerable in the treatment of
inflammatory condition of the buccal cavity following
oral/periodontal surgery.

86. DICLOFENAC MOUTHWASH..cont…
 INDICATIONS
 Symptomatic treatment of irritation-inflammatory states of
the oro-pharyngeal cavity, also associated with pain (e.G.
Gingivitis, stomatitis, pharyngitis), also as a consequence of
conservative dental treatment or dental extraction
 Diclofenac mouthwash is also used in treating mucositis of the
oral cavity by radiotherapy. Diclofenac-based formulations
also had been evaluated for treatment of recurrent apthous
stomatitis. Three percent diclofenac in 2.5% hyaluronan gel
was found to have anti-inflammatory and pain-relieving
effects.

87. TRANSDERMAL DICLOFENAC PATCH
 The transdermal diclofenac patch provides potent analgesia
as the oral .
 Diclofenac tablets with the added advantage of better patient
compliance and may be used for routine post extraction
analgesia.
 Studies revealed patients were more comfortable using the
transdermal patch than oral tablets particularly due to the
once-a-day application and lesser frequency of systemic
adverse effects.
 100 mg transdermal diclofenac patch (nu patch - zydus-cadilla
labs) are available.

88.  The matrix controlled diclofenac transdermal patch is a flat
and transparent transdermal delivery system (TDS) that
provides continuous and systemic release of diclofenac and is
designed to remain at the site of application for 24 hours.
 Each 50 sq. cm patch contains 100 mg of diclofenac
diethylamine as its active ingredient.
TRANSDERMAL DICLOFENAC PATCH..cont..

89. • COMMON ADVERSE EFFECTS.
 Diclofenac produces side effects (particularly gastrointestinal)
in about 20% of patients, and approximately 2% of patients
discontinue therapy as a result.
 Modest elevation of hepatic transaminases in plasma occurs
in 5% to 15% of patients..The elevations usually are reversible.
 Therefore, transaminases should be measured during the
first 8 weeks of therapy with diclofenac, and the drug should
be discontinued if abnormal values persist or if other signs or
symptoms develop.
DICLOFENAC…CONT..

90.  Other effects include CNS effects, rashes, allergic reactions,
fluid retention, and edema, and rarely impairment of renal
function.
 The drug is not recommended for children, nursing mothers,
or pregnant women.
 Consistent with its preference for COX-2, and unlike
ibuprofen, diclofenac does not interfere with the antiplatelet
effect of aspirin
DICLOFENAC…CONT..

91. Para aminophenol Derivatives
 INTRODUCTION:
 Acetaminophen (paracetamol; N-acetyl-p-aminophenol;
TYLENOL, others) is the active metabolite of phenacetin, a so-
called coal tar analgesic.
 Used as a first line analgesics.
 It is an effective alternative to aspirin as an analgesic-
antipyretic agent; however, its anti inflammatory effects are
much weaker.
 Increased pain threshold, poor inhibition of prostaglandins
 . Acetaminophen is well tolerated and has a low incidence of
gastrointestinal side effects.
 . It is available without a prescription and is used as a
common household analgesic.

92. 94
Actions of non-steroidal anti inflammatory
drugs (NSAIDs) and acetaminophen
History.
Acetaminophen was first used in medicine by von Mering in 1893

93. Para aminophenol Derivatives..cont..
• Pharmacological Properties.
• Acetaminophen inhibits prostaglandin synthesis in the CNS.
This explains its antipyretic and analgesic properties.
• Acetaminophen has less effect on cyclooxygenase in
peripheral tissues, which accounts for its weak anti-
inflammatory activity.
• Therapeutic doses of acetaminophen have no effect on the
cardiovascular and respiratory systems, on platelets, or on
coagulation.
• Does not produce gastric irritation, erosion, or bleeding that
may occur after salicylate administration.

94. • Pharmacokinetics and Metabolism.
 Oral acetaminophen has excellent bioavailability.
 Peak plasma concentrations occur within 30 to 60 minutes
 the half-life in plasma is about 2 hours after therapeutic
doses.
 Metabolites: Glucuronide conjugates (60%); sulfuric acid
conjugates (35%).metabolites excreted through urine
Para aminophenol Derivatives..cont..

95. DOSAGE
• Available in many combinations and elixirs.
• The usual adult dose is 325-500mg not more than 4gms in 24
hours should be ingested by adults.
• The concentration of elixir is 120mg/5ml (1 tea spoon);the
drop contains 60mg/0.6ml.
• TRADE NAMES:
• Crocin 0.5,1.0 gTab, Paracin 500mg Tab, Calpol 500mg
Tab,125mg/5ml Syrup, Febrinil 300mg/2ml Inj. Crocin Pain
Relief: Paracetamol 650mg+caffeine 50mg Tab
Para aminophenol Derivatives..cont..

96. • DOSAGE AND PREPARATION
Age (mo) Dose (mg)
0-3
4-11
40
80
Age (yr)
1
2-3
4-5
6-8
9-10
Dose (mg)
120
160
240
320
400
ACETAMINOPHEN DOSING IN CHILDREN
Para aminophenol Derivatives..cont..

97. Therapeutic Uses:
 Acetaminophen is a suitable substitute for aspirin, valuable for patients in
whom aspirin is contraindicated (e.g., those with peptic ulcer, aspirin
hypersensitivity, children with a febrile illness).
 It can be used in all age groups,lactating/pregnant women ,in presence of
other disease states and in patients in whom aspirin is contraindicated.
 Used for headache, musculoskeletal pain, and all most all acute dental
pains(eg.pulpitis)and post operative analgesia, any chronic pain
undergoing an acute flare up.
 Commonly prescribed for cancer pain mamagement.
 The conventional oral dose of acetaminophen is 325 to 1000 mg (650 mg
rectally); total daily doses should not exceed 4000 mg (2000 mg/day for
chronic alcoholics).
Para aminophenol Derivatives..cont..

98. • Toxicity and Common Adverse Effects
• usually well tolerated at recommended therapeutic doses.
• Contraindicated in patients with preexisting liver disease .
• Long-term use of acetaminophen has been associated with:
– a 3-fold increase in kidney disease
– women taking more than 500 mg/day had a doubling in
the incidence of hypertension.
• DRUG INTERACTIONS
• Free of drug interactions at therapeutic doses.
• Chronic large doses of alcohol can increase the toxicity of
acetaminophen.
• The hepatoxicity can be potentiated by drugs llike
barbiturates,carbamazepine,phenytoin,and rifampin.
Para aminophenol Derivatives..cont..

99. Acute paracetamol poisoning occurs especially in small children who
have low hepatic glucuronide conjugating ability.
If a large dose (> 150 mg/kg or > 10 g in adult) is taken, serious toxicity
can occur. The letal dose is 250 mg/kg.
N-acetyl-p-benzoquinoneimine (NABQI) is a highly reactive arylating
metabolite of paracetamol which is detoxicated by conjugation with
glutathione. When a very large doses of paracetamol are taken, the
glucuroconjugation capacity is saturated, more NABQI is formed, hepatic
glutathione is depleted and it binds covalently to proteins in liver cells
(and renal tubules) causing necrosis.
Treatment needs activated charcoal, given orally or through the tube to
prevent GI absorption, and acetylcysteine (150 mg/g by i.v. infusion).
Para aminophenol Derivatives..cont..

100. Benzoxazocine Derivatives
Nefopam:
Different from other NSAIDs since it has atropin like
actions
Effective in traumatic and post operative pain, and in
musculoskeletal pain not responding to other NSAIDs
Atropine like adverse effects
Contraindicated in epilepsy

101. NIMESULIDE
• Preferential COX-2 inhibitors
• Relative weak PGs inhibitor with COX-2 selective action
• Other mechanisms implicated are reduced superoxide
generation by neutrophils, inhibition of PAF synthesis and free
radical scavenging action
• Used for short lasting painful inflammatory conditions like
sports injuries, sinusitis, ear nose throat disorders, dental
surgery, bursitis, low backache, dysmenorrhoea, post
operative pain, osteoarthritis & for fever.
• Useful in asthmatics, bronchospasm or intolerance to aspirin
& other NSAIDs
• Completely absorbed orally, excreted in urine, t ½ of 2-5 hrs
Pref COX-2 inhibitors
These are: Nimesulide, Meloxicam, Nabumatone

102. • ADVERSE EFFECTS:
 Epigastralgia, heart burn, nausea, loose motions, rash pruritus.
 Hematuria & fulminant hepatic failure in few cases
 Gastric and other adverse effects are similar to other NSAIDs.
 Has been reported to cause nephrotoxicity and hepatotoxicity
 Not licensed in some developed countries
 And it has been withdrawn from others
 Use should be avoided especially in children and old persons
• Dose: 100 mg BD
• Commercially available as-
Nimulid, Nimegesic, Nise, Nobel, Nimodol : 100mg tab.

103. These are:
Aminopyrine and antipyrine
Phenylbutazone and oxyphenbutazone
Analgin (dipyrone)
Phenylbutazone:
Potent anti - inflammatory drug
Poorly tolerated by many patients
Causes GI, hepatic, renal and fatal hematologic,
agranulocytosis toxic effects
Gives rise to various drug interactions
Hence now it is rarely used.
Pyrazolone Derivatives

104. Pyrazolone Derivatives Cont…
Oxyphenbutazone:
Metabolic degradation product of phenylbutazone
Less gastric irritation than phenylbutazone
It shares all toxic effects of phenylbutazone
Analgin (Dipyrone, Novalgin):
Has potent analgesic antipyretic but no antiinflammatory actions
Has no advantage over aspirin
Toxic effects are similar to phenylbutazone

105. Anthranilic acid Derivatives (Fenamates)
Mefenamic acid:
Useful in chronic and dull aching pains
No advantages over other NSAIDs
Weaker analgesic than aspirin
Adverse reactions include gastric upset, diarrhoea,
dizziness, headache, skin rashes, hemolytic anemia
Dose is 500mg 2-3 times a day
Used in Dysmenorrhoea

106. Selective COX-2 Inhibitors
Selectively block COX-2 activity more than COX-1 activity
Less action on stomach, blood vessels and kidneys
This group includes:
Celecoxib, Rofecoxib and Valdecoxib
Given orally, absorption is complete
Established analgesic- antiinflammatory NSAIDs
They have to be shown effective in treatment of
osteoarthritis and rheumatoid arthritis
Their major advantage is that they cause fewer gastric
ulcers and do not inhibit platelet aggregation
Stomach friendly

107. Selective COX-2 Inhibitors Cont..
Adverse effects:
The most common adverse effects are nausea, vomiting,
dyspepsia, abdominal pain, diarrhoea and edema of the
lower extremities
Share some of the renal adverse effects of non selective
COX inhibitors and renal toxicity
Hence their use should be restricted to patients who do not
tolerate other NSAIDs

108. Analgesics as host modulators
• In late 20th century the concept of host modulation was introduced as a
medical approach to periodontal therapy.
• In 1979, Nyman, Schroeder and Lindhe showed how it was possible to
block periodontal bone loss in animals with the drug Indomethacin.
• Evidence presented that flurbiprofen and ibuprofen can slow down the
development of experimental gingivitis, as well as loss of alvolear bone in
periodontitis.
• Eli E Machtei et al. reported that flurbiprofen significantly inhibited
radiographic alvolear bone loss.
(J Clin Periodontol 2011; 38: 1037-1043)

109. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) currently under
investigation for host modulatory therapy are:
Flurbiprufen,
Naproxen and
Ketorolac.

110. Combination analgesics
• Combining analgesics with different mechanisms of action enables
lower doses of the component analgesics to be prescribed, thus
analgesia can be enhanced without increasing the risk of adverse
events.
(Mehlisch. 2002).
• Macleod et al. (2002) found that the combination of
Paracetamol (lOOOmg) + Codeine (30mg)
resulted in significantly better analgesia than lOOOmg of
paracetamol alone.
• Synergistic action of the two analgesics extend the duration of
analgesia by one hour compared to paracetamol alone.
(Toms, et al. 2011).

111. 1. Tramadol + Paracetamol
• More rapid onset of action compared to either of the analgesics
alone, with onset of analgesia occurring within 17 minutes
(compared to 51 min for tramadol and 18 min for paracetamol)
• Additionally it displays a longer duration of analgesia of 5 hours,
compared to 2 hrs for tramadol and 3.1hrs for paracetamol.
(Mehlisch. 2002).
2. Oxycodone + Acetaminophen
3. Hydrocodone + Acetaminophen

112. – Benzydamine (also known as Tantum Verde and branded in
some countries as Difflam), available as the hydrochloride, is a
locally acting nonsteroidal anti-inflammatory drug with
local anaesthetic and analgesic properties for pain relief and
anti-inflammatory treatment of inflammatory conditions of
the mouth and throat.
– Inflammatory conditions: Pharyngitis, aphthous ulcers and oral
ulceration due to radiation therapy.
Difflam Oral Rinse
As gel

113. Analgesic/NSAIDS in dentistry
There is no single drug superior to all others for every patient..
Some guidelines for NSAIDS are..
1.MILD TO MODERATE PAIN WITH LITTLE INFLAMMATION:
PARACETAMOL OR LOW DOSE IBUPROFEN.
2.POSTEXTRACTION OR SIMILAR ACUTE BUT SHORT LASTING PAIN:
KETOROLAC,IBUPROFEN,DICLOFENAC, NIMESULIDE, OR ASPIRIN.
3.GASTRIC INTOLERANCE TO CONVENTIONAL NSAIDS: SELECTIVE COX 2 INHIBITOR OR
PARACETAMOL
4.PATIENT WITH HISTORY OF ASTHMA OR ANAPHYLACTOID REACTION TO ASPIRIN/OTHER
NSAIDS: Analgesic of choice for these patients is ACETAMINOPHEN /NIMESULIDE.
5.PAEDIATRIC PATIENTS: PARACETAMOL, IBUPROFEN, NAPROXEN.
6.PREGNANCY: PARACETAMOL IS THE SAFEST;LOW-DOSE APIRIN IS PROBABLY THE SECOND BEST.
7.HYPERTENSIVE,DIABETIC,ISCHAEMIC HEART DISEASE,EPILEPTIC AND OTHER PATIENTS RECEIVING
LONG TERM REGULAR MEDICATION:POSSIBLITY OF DRUG INTERACTION WITH NSAIDS SHOULD BE
CONSIDERED AND THE PHYSICIAN CONSULTED .

115. Selective COX-2 Inhibitors Cont..
Recently, the use of rofecoxib and valdecoxib has been
reported to be associated with increased incidence of MI
and stroke
Hence, they have been withdrawn by the original
manufacturers
Currently all the selective COX -2 inhibitors are under
suspicion regarding their long term toxicity
They have been described as drugs with “marginal
efficacy, heighted risk and excessive cost compared with
traditional NSAIDs”

116. OPIOID
ANALGESICS

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

118. History cont’d
• Used medicinally and recreationally
from early Greek and Roman times
• Opium and laudanum (opium
combined with alcohol) were used to
treat almost all known diseases

119. Friedrich Wilhelm Adam
Sertürner, a German
pharmacist, isolated
Morphine from opium,
in 1805.
Morpheus
is the Greek god of
dreams and sleep.

120. History and Background
• 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

121. Definitions
1. Opioids are drugs with morphine-like activity that produce
analgesia (i.e., reduce pain) without the loss of consciousness
and can induce tolerance and physical dependence. Opioids
are also referred to as narcotic analgesics

122. Classification
Chemically
Phenanthrene group
Eg:
Morphine,codiene
Benzylisoquinoline
group
Eg: Papaverine
Based on receptor
occupation
Agonists
Eg: Morphine
Antagonists
Eg:
Naloxone,naltrexo
ne
Mixed agonist-
antagonist
Eg:
Nalorphine,pentazoc
ine
According to
source
Natural opium
alkaloids
Eg:
Morphine,codeine
Semisynthetic
derivatives
Eg:
Heroine,oxymorpho
ne
Synthetic opioids
Eg:
Pethidine,fentanyl
,tramadol

123. MORPHINE
• Morphine is the most important alkalloid of opium.
• Many new opioids have been synthesized but none of them
are superior to morphine as an analgesic.
• It is the protype of this group.

124. Mechanism of Action
 Opioids exert their major effects by interacting with opioid receptors
in the CNS
 Opioids activate 7- transmembrane GPCRs located pre-synaptically
and post-synaptically along pain transmission pathways.
 High densities of opioid receptors known as mu, delta and kappa are
found in the dorsal horn of the spinal cord and higher CNS centers.
 Most currently used opioid analgesics act mainly at mu- opioid
receptors
 Morphine acts at kappa receptors in lamina 1 and 11 of the
substantia Granulose of the spinal cord and decreases the release
of substance p, which modulates pain perception in the spinal cord.

125. Mechanism of Action….cont..
 Opioids have an onset of action that depends on the route of
administration .
 Opioids causes hyper polarization of nerve cells , inhibition of
nerve firing and presynaptic inhibition of transmitter relea
 Cellular effects of these drugs involve enhancement of
neuronal potassium efflux ( hyperpolarizes neurons and
makes them less likely to respond to a pain stimulus ) and
inhibition of calcium influx ( decreases neuro- transmitter
release from neurons located along the pain transmission
pathway )
 Opioids relieve pain both by raising the pain threshold at the
spinal cord level and more importantly by altering the brains
perception of pain

127. Pharmacological actions
 Analgesia
 Respiratory depression
 Cough suppression
 Vagal stimulation (bradycardia)
 Sedation & hypnosis
 Hypothermia
 Itching
 Physical & pshycological dependence
 Euphoria
 Histamine release , hypotension….etc

128. Adverse effects
• Morphine can produce a wide range of adverse effects like
nausea, vomiting, dizziness, mental clouding, respiratory
depression, constipation, dysphoria, urinary retention, &
hypotension, allergic reactions.
• Tolerance- Repeated administration of morphine results in the
development of tolerance to some of its effects including
respiratory depression, analgesia, sedation, etc .
• Dependence- Opium has been a drug of addiction for many
centuries. Its ability to produce euphoria makes it a drug of
addiction. Opioids produce both physiological & pshycological
dependence. Manifestations are lacrimination, sweating,
yawning, anxiety, restlessness..etc.

129. Morphine can be used as an analgesic to
relieve:
pain in myocardial infarction
pain associated with surgical conditions, pre- and postoperatively (pre-
anesthetic medication, balanced anesthesia, surgical analgesia)
pain associated with trauma, burns
severe chronic pain, e.g., cancer
pain from kidney stones, renal colic, uretero lithiasis.
traumas of thorax accompanied by cough (morphine depresses
central links of coughing reflexes)

130. Acute left-ventricular cardiac failure
(cardiac asthma)
 Reduce preload on heard due to vasodilatation
 Tending to shift blood from pulmonary to systemic circuit;
relieves pulmonary congestion and edema
 Allays air hunger by depressing respiratory centre
 Cuts down sympathetic stimulation by calming the patient

131. Applications in Dentistry
• Narcotic (opioid) analgesics are extremely
effective in reducing acute dental and
postoperative pain.
• The narcotic analgesics have established a
niche for the treatment of pain in those
situations where the NSAIDs are less effective.
• Hydrocodone, oxycodone, codeine, and
occasionally meperidine are the narcotics used
to treat dental pain.

132. CONTRAINDICATIONS FOR ADMINISTRATION
OF MORPHINE
 acute respiratory depression
 renal failure (due to accumulation of the metabolites morphine-3-
glucuronide and morphine-6-glucuronide)
 chemical toxicity (potentially lethal in low tolerance subjects)
 raised intracranial pressure, including head injury (risk of worsening
respiratory depression)
 Biliary colic
Precautation
 pain that accompanies chronic inflammatory pain
 children before the age of 2 years

133. Side effects of morphine
 Respiratory depression
 Vomiting (excitation of starting zone of vomiting
center)
 bradycardia (increasing of tone of n. vagus
nuclei)
 spasm of sphincters of gastro-intestinal tract
accompanied by constipations
 increasing of tone of smooth musculature of
urinary and bile-excreting tracts (retentions of
urination, bile stasis)
 Decreasing of BP

134. Tolerance
• Tolerance is a diminished responsiveness to the drug’s
action that is seen with many compounds
• Tolerance can be demonstrated by a decreased effect
from a constant dose of drug or by an increase in the
minimum drug dose required to produce a given level of
effect
• Physiological tolerance involves changes in the binding
of a drug to receptors or changes in receptor
transductional processes related to the drug of action
• This type of tolerance occurs in opioids

135. Addiction
• Physical dependence
• Physiological dependence
• Withdrawal reactions

136. Tolerance and Dependence

137. Withdrawl Reactions
Acute Action
• Analgesia
• Respiratory Depression
• Euphoria
• Relaxation and sleep
• Tranquilization
• Decreased blood pressure
• Constipation
• Pupillary constriction
• Hypothermia
• Drying of secretions
• Reduced sex drive
• Flushed and warm skin
Withdrawl Sign
• Pain and irritability
• Hyperventilation
• Dysphoria and depression
• Restlessness and insomnia
• Fearfulness and hostility
• Increased blood pressure
• Diarrhea
• Pupillary dilation
• Hyperthermia
• Lacrimation, runny nose
• Spontaneous ejaculation
• Chilliness and “gooseflesh”

138. Pethidine
• Is a phenyl piperidine derivative of morphine.
• COMPARE AND CONTRAST MORPHINE AND
PETHIDINE
Features Morphine Pethidine
source Natural opium alkaloid synthetic
potency More potent Less potent (1/10th)
Corneal anaesthesia No effect Corneal anaesthetic
Higher doses Profound CNS depression CNS stimulation
Antitussive property good Poor or nil
Constipation effect marked less
Analgesic dose 10mg 100mg
Anticholinergic effect absent present
Use during labour Significant respiratory
depression in neonates
Less neonatal respiratory
depression

139. Pethidine ..cont..
It causes less histamine release hence safer in asthamatics.
After im injection onset of action is more rapid but duration is
shorter (3-4 hours)
Well absorbed ,completely metabolized in liver.
Plasma t ½ is 2-3 hours.
SIDE EFFECTS :
Similar to morphine..
Some atrophic effects may be noted in addition.

140. Pethidine – contd.
• Pharmacokinetics
– Well absorbed orally, bioavailability 50%
– Effects appear in 10-15 min. after oral absorption
– On parenteral administration action lasts for 2-3 Hrs
– Metabolized in liver – mepiridinic acid and norpethidine
– Norpethidine accumulates on chronic use
– Excreted in urine

141. Pethidine ..cont..
• Uses
• Primarily used as an analgesic and preanaesthetic medication.
• As analgesic during labor – less fetal respiratory depression
• Dose: 50-100mg i.m /s.c .. Occasionally given
orally or i.v.

142. FENTANYL
• Fentanyl is a pethidine congener.
• Commonly used opioid analgesic.
• synthetic opioid analgesic of short action: starts wearing
of after 30-40 mins due to redistribution,while elimination
t ½ is 4 hours.
• analgesic activity is 100 times higher than of morphine.
• Fast acting maximum effect within 5 minutes.
• Fentanyl is used to supplement the analgesia and sedative–
hypnotic effects of nitrous oxide and halothane in a ‘‘balanced
anesthesia’’ approach. Morphine also is used for this
indication

143. FENTANYL….CONT..
• Fentanyl has mild effects on the cvs. It slightly reduces the HR
and BP,safer than other opoids in cardiovascular surgery.
• Fentanyl is administered as a preanesthetic and intraoperative
medication for its analgesic, anxiolytic, and sedative
properties
• Unlike morphine does not increase the intra cranial pressure.
• used with neuroleptic droperidol (complex drug –
“talamonal”) for neuroleptanalgesia . 0.05mg fentanyl +2.5mg
droperidol per ml. patient is drowsy but responds to
command.

144. FENTANYL TRANSDERMAL SYSTEM
• should be used for long-term
(chronic) pain eg cancer
,requiring continuous narcotic
pain
• Is designed to release the drug
into the skin at a constant rate
ranging from 25 to 100
micrograms/h.
• It acts for 48 hours.
Dose: durogesic transdermal patch 25,50,75 mcg/hour

145. Fentanyl….cont..
 Adverse effects:
 Nausea
 Vomiting
 Respiratory depression
 Bolus doses causes muscle rigidity, can be reduced by
avoiding bolus dose.

146. METHADONE
 (also levomethadyl acetate)
 Methadone, like morphine, has good analgesic activity. It
is administered orally and has a longer duration of action
than morphine .
 Methadone is associated with a less severe withdrawal
syndrome than morphine; it is often substituted for other
opioids as a treatment for physical dependence because
it allows a smoother withdrawal with tapered dose
reduction.
 It is also used for maintenance therapy of the heroin-
dependent addict.

147. DEXTROPROPOXYPHENE
• Is a congener of methadone
• Marketed in combination with paracetamol;for relief of mild
to moderate pain.
• Its overdose can produce rapid onset respiratory
depression,delirium and convulsions.
• Also has abuse potential
• Dose: proxyvon :65mg dextropropoxyphene +400mg
paracetamol cap; sudhinol 65mg + 650mg paracetamol cap.
The regulatory authorities in india have announced a ban on dextropropoxyphene
Ministry of Health and Family Welfare has notified their withdrawal from market

148. CODEINE
 opium alkaloid
 analgesic action is not strong, but anticough effect is
considerable
 administered as an anticough drug of central action
 combination with non opiod analgesics
(eg. Paracetamol) is supra-additive

149. Pentazocine
• Is the agonist-antagonist of opioid receptors
• Weak μ-receptor antagonist, but agonist of κ-receptor
• One of the commonly used agents, given orally and IM
• Low abuse liability
• Pharmacokinetics:
– High 1st pass metabolism but effective orally
– Half life = 3-4 Hrs
– Metabolized in liver by glucoronide conjugation
– Dose: orally 50-100 mg and parenterally 30-60 mg IM
• Uses: Moderately severe pain in Injury, Burns, Fracture
Trauma, Cancer and Orthopaedic manuevers
(Fortwin, Fortagesic)

150. Pentazocine Vs Morphine
• Spinal analgesia via kappa receptor
• Dose is 30 mg Vs 10 mg and low ceiling effect
• Sedation and Respiratory depression at lower doses
• Tachycardia and rise in BP – dangerous in MI
• Lesser smooth muscle spasms
• Vomiting and other side effects are less
• Subjective effects – lower ceiling (psycomimetic effects)
• Tolerance develops on repeated use, but lesser than Morphine
• Withdrawal symptoms – both Morphine and Nalorphine like
• Good analgesic in subjects not exposed to Morphine
• Precipitate withdrawal – in Morphine addicts

151. Pentazocin ..cont
Contraindications
 it can cause increasing of blood pressure and tachycardia
that’s why it’s not advised to use in case of acute
myocardium infarction
 if it is administered for people with narcotic addiction
manifestations of abstinence develop

152. Buprenorphine
• Partly agonist of mu-opioid receptors
• Acts longer than morphine (approximately 6 hours)
• Analgesic activity is higher than of morphine
• In case of breathing depression, which it causes,
naloxon is less effective since buprenorphine is slowly
released from the connection with mu-receptors
• Indicated for pain decreasing in the same situations as
other narcotic analgesics
• May be used for detoxication and supporting treatment
of individuals who is addicted to heroine

153. Buprenorphine – contd.
• Adverse Effects:
– Hypotension (Postural)
– Respiratory depression (fatal in neonates) and cannot be reversed by
Naloxone
• Uses:
– Long lasting painful conditions – cancer
– Postoperative pain
– Myocardial infarction
• Preparations: Norphine, Tidigesic
• 0.3 mg/ml injections and 0.2 mg sublingual tablets

154. TRAMADOL
Analgesic activity is similar to the activity
of morphine
Abuse potential is low
Less respiratory depression
Hemodynamic effects are minimal
In case of intravenous administration effect
develops after 5-10 min, if administered
orally – after 30-40 min, action lasts for
3-5 hours.
Tramadol possesses agonist actions at the μ-opioid receptor

155. ADMINISTRATION OF TRAMADOL
For all kinds of acute and chronic pain of moderate and
considerable intensity, including neuralgias, postoperative,
traumatic pain
diagnostic and therapeutic interventions
oncologic pathology

156. Acute poisoning with opioid
analgesics
• Respiratory Depression
• Euphoria
• Relaxation and sleep
• Tranquilization
• Decreased blood pressure
• Constipation
• Pupillary constriction
• Hypothermia
• Drying of secretions
• Flushed and warm skin

157. Triad in case
poisoning with
morphine
Acute miosis
(Pinpoint
pupils)
Cheyne Stokes
respiration
deep tendon
reflexes
increased

158. Treatment of acute poisoning
 Naloxon (antagonist of opioid receptors)
intravenously - 0,4-1,2 mg
general dose of naloxon should not overcome 10 mg
 stomach lavage (for morphine enterohepatic
circulation is typical) with 0,05-0,1% solution of
potassium permanganate and 0,5 % tannin solution
 suspension of 20-30 g of activated charcoal
 salt laxative agents (sodium sulfate)
 forced diuresis
 atropine sulfate
 inhalation of carbogen (5-7 % СО2 and 93-95 % O2)

159. PATIENT CONTROLLED ANALGESIA
• Patient Controlled Analgesia (PCA) is an interactive method of pain
management that permits patients to manage their pain by self-
administering doses of analgesics, usually opioids.
• PCA is a unique way of administering pain medications.
• The medication is administered with the help of a pump.
• Patient has the freedom to control the amount and dose of the pain
medication.
• The response time is minimal compared to intermittent administration by
a nurse.
• Pain relief is achieved faster and satisfaction rates are higher.
• Any patient with basic understanding skills can benefit from the use of
PCA.

160. PATIENT CONTROLLED ANALGESIA.. Cont..
• It has been used successfully in pediatric as well as geriatric
populations. It has been used for hospital inpatients as well as
ambulatory and home/ hospice use.
• Common indications for PCA:
• Post-operative pain
• Severe acute pain
• Acute exacerbations of chronic pain
• Cancer pain
• Patients unable to take oral medications
• Contra-indications:
• Poor understanding of the PCA
• Poor health care support for PCA

161. PATIENT CONTROLLED ANALGESIA.. Cont..
• Routes: I.V. PCA and epidural . Other routes are intrathecal /
transdermal (E-Trans) / surgical incisional (On-Q pumps) /
intra-articular (On-Q pumps) etc.
• Drugs commonly used:
• Opioids: Morphine, Fentanyl and Hydromorphone
• Local anesthetics: Bupivacaine and Ropivacaine.
• Other drugs: Clonidine, Baclofen etc.
• Various combinations of the above drugs to achieve
synergistic effect and to minimize side effects.

162. Conclusion
• Before prescription of any analgesic, the dental practitioner should
have a clear idea on its advantages and disadvantages, mechanism of
action, pharmacokinetics and dynamics, adverse effects in general
and in relation to that individual patient, whilst reducing the risks
and providing a streamlined treatment.
A clinicians goal should be, to avoid chronic use of any
analgesic whenever possible and use these drugs optimally to treat
dental pain most effectively.

163. REFRENCES
165

164. REFRENCES
1.Portenoy RK, Kanner RM. Definition and Assessment of Pain. In: Portenoy
RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia,
Pa: FA Davis Company; 1996:4
2.Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis,
Minn: The McGraw-Hill Companies Inc; 2000:8-9
3. Goodman & Gilman's The Pharmacological Basis Of Therapeutics - 11th Ed.
(2006)
4. Susan G. Penniston, DDS, MS1, Kenneth M. Hargreaves, DDS, PhD
Evaluation of periapical injection of ketorolac for management of
endodontic pain
,. Journal of endodontics 1996vol2
5. Agarwal S, Mathur S, Kothiwale S, Benjamin A.Efficacy and acceptability of
0.074% diclofenac-containing mouthwash after periodontal surgery: a
clinical study.

165. REFRENCES
6. Hemant Bhaskar, Pranav Kapoor,1 and Ragini1 Comparison of transdermal diclofenac
patch with oral diclofenac as an analgesic modality following multiple premolar
extractions in orthodontic patients: A cross over efficacy trial.Contemp Clin
Dent. 2010 Jul-Sep; 1(3): 158–163.
7. P. F. Cavanaugh ,The use of ketorolac tromethamine oral rinse for the treatment of
periodontitis in adults Inflammo Pharmacology 1995, Volume 3, Issue 4, pp 313-
320
8. Carin E. Dugowson, MD, MPH*,Priya Gnanashanmugam, MD Nonsteroidal Anti-
Inflammatory Drugs .. Phys Med Rehabil Clin N Am 17 (2006) 347–354.
9. P.N bennet,M.J.Brown clinical pharmacologgy 10th edition
11.Barbara .S etal. Applied Pharmacology For The Dental Hygenist .3rd edition.
12.Katzung, B. Basic and Clinical Pharmacology. 11th ed. McGraw Hill Medical, 2009
13.The use of opioids for chronic pain @ The APS
14. Pain management for dentists: the role of ibuprofen Alessandro Pozzi, DDS, PhD
Luca Gallelli, MD, PhD
15. Tb of pharmacology KD TRIPATHI

166. 168