Analgesics.pptx

CONTENTS
 INTRODUCTION
 HISTORY
 CLASSIFICATION
 NSAIDS
 OPIOIDS
 DRUGS FOR NEUROPATHIC PAIN
 RECENT ADVANCE
 REFERENCE

INTRODUCTION
 ALGESIA (pain) :- It is an ill-defined,
unpleasant bodily sensation, usually
evoked by an external or internal
noxious stimulus.
 ANALGESICS :- A drug that selectively
relieves pain by acting in CNS or on
peripheral pain mechanism, without
significantly altering consciousness.

History
Brune K., Hinz B. (2013) History of Analgesics. In: Gebhart G.F., Schmidt R.F. (eds)
Encyclopedia of Pain. Springer, Berlin, Heidelberg.
 Attempts to relieve pain are probably as
old as Mankind.
 A scientific approach to pain therapy
became possible in the nineteenth
century :- substances isolated from
plants including the willow tree (salicylic
acid esters).
 The first drug factory built (Salicylic Acid
Works founded by von Heyden in 1874.)

 Earlier (1806), a pharmacist in Einbeck, Sertburner, had isolated
morphine, the main analgesic ingredient of the opium resin.
 E. Fischer’s discovery of phenylhydrazine.
 L. Knorr, tried to synthesize quinine, but produced phenazone (Brune
1997), which proved to be active against fever.
 Two physicians, Cahn and Hepp led to the discovery of acetanilide.
 Bayer further investigated acetanilide and found that a by-product of
aniline dye production, namely, “acetophenetidin,” was equally
effective. It was marketed as Phenacetin.
 By the end of the nineteenth century, four prototype substances were
available for the treatment of pain: morphine, salicylic acid,
phenazone, and phenacetin.

 F. Hoffman attempted to improve the taste of
salicylic acid by adding acetyl group into salicyclic
acid (acetylsalicylic acid :- Aspirin).
 To further improve the tolerability of phenacetin,
Bayer investigated a metabolite of phenacetin,
acetaminophen (paracetamol).
 Roche substituted an amino group of phenazone
with isopropyl.
 In 1949, Geigy (Basel) produced an injection
containing the salt of the basic aminophenazone
with an acidic derivative – later named
phenylbutazone.

 Merck identified indols (including indomethacin and
sulindac,1984)
 Boots found propionic acid derivatives (ibuprofen and
flurbiprofen,1992 )
 Parke Davis developed fenamates (e.g., mefenamic
acid 1984)
 Geigy was successful with new aryl-acetic acids, e.g.,
diclofenac.
 Pfizer’s piroxicam (Otterness et al. 1982) was soon
followed by tenoxicam (Roche) and meloxicam
(Boehringer).

Classification
British National Formulary: Analgesics BNF online. Retrieved 8 June 2017.
 Analgesics are typically classified based on their mechanism of
action.
1. NSAIDs
2. Opioids
3. Alcohol
4. Cannabis
5. Combinations
6. Adjuvants
7. Other drugs
8. Other uses

1. NSAIDs
A. Nonselective COX inhibitors (traditional NSAIDs)
 1. Salicylates: Aspirin.
 2. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen,
Flurbiprofen.
 3. Fenamate: Mephenamic acid.
 4. Enolic acid derivatives: Piroxicam, Tenoxicam.
 5. Acetic acid derivatives: Ketorolac, Indomethacin,
Nabumetone.
 6. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone.

B. Preferential COX-2 inhibitors
 Nimesulide, Diclofenac, Aceclofenac, Meloxicam,
Etodolac.
C. Selective COX-2 inhibitors
 Celecoxib, Etoricoxib, Parecoxib.
D. Analgesic-antipyretics with poor
antiinflammatory action
 1. Paraaminophenol derivative: Paracetamol
(Acetaminophen).
 2. Pyrazolone derivatives: Metamizol (Dipyrone),
Propiphenazone.
 3. Benzoxazocine derivative: Nefopam.

2. Opioids
1. Natural opium alkaloids: Morphine, Codeine
2. Semisynthetic opiates: Diacetylmorphine (Heroin),
Pholcodeine, Ethylmorphine.
Many others like—Hydromorphone,Oxymorphone,
Hydrocodone,Oxycodone are not used in India.
3. Synthetic opioids: Pethidine (Meperidine),
 Fentanyl, Methadone, Dextropropoxyphene,
 Tramadol.
 Many others like—Levorphanol,
Dextromoramide,Dipipanone,Alfentanil, Sufentanil,
Remifentanil are not available in India.

3. Alcohol
 The majority of its analgesic effects come from
antagonizing NMDA receptors, similarly to
ketamine.
 Thus decreasing the activity of the primary
excitatory (signal boosting) neurotransmitter,
glutamate.
 It also functions as an analgesic to a lesser
degree by increasing the activity of the primary
inhibitory (signal reducing) neurotransmitter,
GABA.

4. Cannabis
 Medical cannabis, or medical marijuana,
refers to cannabis or
its cannabinoids used to treat disease or
improve symptoms.
 It is used to treat chronic
pain and muscle spasms, with some
trials indicating improved relief of
neuropathic pain over opioids.

5. Combinations
 Use of paracetamol,
aspirin, ibuprofen, naproxen, and
other NSAIDS concurrently with weak to
mid-range opiates has been said to
show beneficial synergistic effects by
combatting pain at multiple sites of
action.

6. Alternative medicine
 Antidepressants :- amitriptyline,
duloxetine
 Atypical analgesics:-
orphenadrine, mexiletine, pregabalin,
baclofen,gabapentin, cyclobenzaprine,
hyoscine,
carbamazepine,Dextromethorphan

7. Other drugs
 Monoamine reuptake inhibitor :-
Nefopam
 K+ channel opener :- Flupirtine
 N‐type voltage‐gated calcium
channels blocker :- Ziconotide

8. Other uses
 Topical analgesia is recommended to
avoid systemic side-effects.
 E.g. Capsaicin, lidocaine, tetracaine,
benzocaine, and prilocaine

NSAIDs
 Main actions
 1.) Analgesic -effective against mild to moderate pain, do not cause
dependence
 2.) Anti-inflammatory
 3.) Anti-pyretic
 4.)Anti-platelet- prevent thromboxane production, derived from
prostaglandins and cause platelet aggregation
 Others
 5.) Useful in treatment of dysmenorrhea, associated with increased
prostaglandin synthesis and increased uterine contractility
 6.) Used to close the patent ductus arteriosus

NSAIDs Adverse effects
1.) Gastric or intestinal mucosal damage
2.) Disturbances of fluid and electrolyte balance
3.) Analgesic nephropathy

SALICYLATES
 Aspirin
 PHARMACOLOGICAL ACTIONS
1. Analgesic, antipyretic, antiinflammatory
Actions
2. Metabolic effects
3. Respiration
4. Acid-base and electrolyte balance
5. CVS
6. GIT
7. Blood

Aspirin
 ADVERSE EFFECTS
 Analgesic dose (0.3–1.5 g/day) are
nausea, vomiting, epigastric distress,
increased occult blood loss in stools.
 Antiinflammatory doses (3–5 g/day)
produce the syndrome called salicylism—
dizziness, tinnitus, vertigo, reversible
impairment of hearing and vision,
excitement and mental confusion,
hyperventilation and electrolyte imbalance.

Aspirin
 ‘Reye’s syndrome’, a rare form of
hepatic encephalopathy seen in children
having viral (varicella, influenza)
infection receiving Aspirin therapy.
 Acute salicylate poisoning It is more
common in children.
 Fatal dose in adults is estimated to be
15–30 g.

Precautions and
contraindications
 Contraindicated in patients who are sensitive to it and in peptic
ulcer, bleeding tendencies, in children suffering from chicken pox
or influenza.
 Cautious use in chronic liver disease
 Avoided in diabetics, with low cardiac reserve or frank CHF and
in juvenile rheumatoid arthritis.
 Aspirin should be stopped 1 week before elective surgery.
 It should be avoided by breastfeeding mothers.
 Avoid high doses in G-6PD deficient individuals—haemolysis can
occur.

Interactions
 Aspirin displaces warfarin, naproxen,
sulfonylureas, phenytoin and
methotrexate from binding sites on
plasma proteins.
 Aspirin blunts diuretic action of
furosemide and thiazides and reduces
K+ conserving action of spironolactone

USES
1. As analgesic
2. As antipyretic
3. Acute rheumatic fever
4. Rheumatoid arthritis
5. Osteoarthritis
6. Postmyocardial infarction and
poststroke patients

Trade name with dosage
 ASPIRIN 350 mg tab,
 COLSPRIN 100, 325 mg tabs,
 ECOSPRIN 75, 150, 325 mg tabs,
 DISPRIN 350 mg tab (with cal.
carbonate 105 mg + citric acid 35 mg),
 LOPRIN 75, 162.5 mg tabs.

PROPIONIC ACID
DERIVATIVES
 Ibuprofen was the first member of this
class to be introduced in 1969 as a
better tolerated alternative to aspirin.
 All have similar pharmacodynamic
properties but differ considerably in
potency and to some extent in duration
of action.

Uses
 simple analgesic and antipyretic in the same
way as low dose of aspirin.
 It is available as an ‘over-the-counter’ drug.
 In rheumatoid arthritis, osteoarthritis and other
musculoskeletal disorders, especially where
pain is more prominent than inflammation.
 soft tissue injuries, fractures, tooth extraction,
postpartum and postoperatively: suppress
swelling and inflammation.

Adverse effects
 Gastric discomfort, nausea and
vomiting.
 CNS side effects include headache,
dizziness, blurring of vision, tinnitus and
depression.
 They are not to be prescribed to
pregnant women and should be avoided
in peptic ulcer patient.

Ibuprofen
 It has been rated as the safest traditional
NSAID.
 Ibuprofen (400 mg) has been found
equally or more efficacious than a
combination of aspirin (650 mg) +
codeine (60 mg) in relieving dental
surgery pain.
 TRADE NAMES :- Tab BRUFEN,
EMFLAM,IBUSYNTH 200, 400, 600 mg.
 IBUGESIC 100 mg/5 ml susp.

Naproxen
 The antiinflammatory activity is stronger and it
is particularly potent in inhibiting leucocyte
migration.
 Recommended for rheumatoid arthritis and
ankylosing spondylitis.
 Dose should be reduced in the elderly.
 TRADE NAMES :- NAPROSYN, NAXID,
ARTAGEN, XENOBID TDS 250 mg tab.

Ketoprofen
 An additional action to stabilize
lysosomes and inhibit LOX has been
demonstrated with ketoprofen.
 TRADE NAME :- KETOFEN 50, 100 mg
tab, OSTOFEN 50 mg cap, RHOFENID
100 mg tab.

Flurbiprofen
 More effective than ibuprofen, but
gastric side effects are also more.
 It is used as an ocular antiinflammatory
as well.
 TRADE NAMES :- ARFLUR 50, 100,
200 mg tab , FLUROFEN 100 mg tab.
 OCUFLUR, FLUR, FLURBIN, 0.03%
eyedrops, 1 drop 6 hourly.

FENAMATE (Anthranilic acid
derivative)
 Mephenamic acid :- An analgesic, antipyretic
and weaker antiinflammatory drug.
 Mephenamic acid exerts peripheral as well as
central analgesic action.
 Plasma t½ is 2–4 hours.
 Adverse effects :- Diarrhoea, Epigastric
distress, Skin rashes, dizzines and other CNS
manifestations have occurred.

 Uses :- indicated primarily as analgesic in
muscle, joint and soft tissue pain where strong
antiinflammatory action is not needed.
 Effective in dysmenorrhoea.
 Dose: 250–500 mg TDS.
 TRADE NAMES :- MEDOL 250, 500 mg cap;
MEFTAL 250, 500 mg tab, 100 mg/5 ml susp.

ENOLIC ACID DERIVATIVES
(Oxicams)
 Piroxicam :- It is a nonselective, reversible inhibitor
of COX.
 long-acting potent NSAID with antiinflammatory
potency and good analgesic-antipyretic action.
 Plasma t½ is long— nearly 2 days. Single daily
administration is sufficient.
 Adverse effects :- The g.i. side effects are more
than ibuprofen.
 Rashes and pruritus are seen in < 1% patients, but
serious skin reactions are possible.

 Uses :- rheumatoid and osteo-arthritis, acute
gout, musculoskeletal injuries and in dentistry.
 Dose: 20 mg BD for two days followed by 20
mg OD
 TRADE NAMES :- DOLONEX, PIROX 10, 20
mg cap, 20 mg dispersible tab, PIRICAM 10, 20
mg cap.

ACETIC ACID
DERIVATIVES
 Ketorolac :- This arylacetic acid NSAID
has potent analgesic but modest
antiinflammatory activity.
 In postoperative pain :- equalled efficacy
of morphine, but does not interact with
opioid receptors and is free of opioid side
effects.
 plasma t½ is 5–7 hours.

 Adverse effects :-
 Nausea,
 Abdominal pain,
 Dyspepsia,
 Ulceration,
 Loose stools,
 Drowsiness,
 Headache,
 Dizziness,
 Nervousness,
 Pruritus,
 Pain at injection site.

 Use :- Ketorolac is frequently used In
postoperative, dental and acute musculoskeletal
pain: 15–30 mg i.m. or i.v. every 4–6 hours (max.
90 mg/day)
 Orally it is used in a dose of 10–20 mg 6 hourly for
short-term management of moderate pain.
 Topical ketorolac is quite popular for noninfective
ocular conditions.
 TRADE NAMES :- KETOROL, ZOROVON,
KETANOV, TOROLAC 10 mg tab.
 KETLUR, ACULAR 0.5% eye drops; 1–2 drops 2–4
times a day

Indomethacin
 This indole acetic acid derivative is a
potent antiinflammatory drug with
prompt antipyretic action.
 It is a highly potent inhibitor of PG
synthesis and suppresses neutrophill
motility.

 Adverse effects :-Gastric irritation, nausea, anorexia,
gastric bleeding and diarrhoea are prominent.
 Frontal headache (very common), dizziness, ataxia,
mental confusion, hallucination, depression and
psychosis can occur.
 Increased risk of bleeding due to decreased platelet
aggregability.
 It is contraindicated in machinery operators, drivers,
psychiatric patients, epileptics, kidney disease,
pregnant women and in children.

 Uses :- ankylosing spondylitis, acute exacerbations of
destructive arthropathies, psoriatic arthritis and acute
gout or rheumatoid arthritis.
 most common drug used for medical closure of patent
ductus arteriosus: three 12 hourly i.v. injections of 0.1–
0.2 mg/kg achieve closure in majority of cases.
 Dose: 25–50 mg BD-QID.
 TRADE NAMES :- IDICIN, INDOCAP, INDOFLAM 25,
75 mg caps

Nabumetone
 Inhibits both COX-1 and COX-2.
 It possesses analgesic, antipyretic and
antiinflammatory activities.
 lower incidence of gastric erosions, ulcers and
bleeding.
 No data on its relative side effect prevalence
compared to other NSAIDs.
 The plasma t½ is 24 hours.
 TRADE NAME :- NABUFLAM 500 mg tab; 1
tab OD

PYRAZOLONES
 Metamizol (Dipyrone) :- this derivative of amidopyrine is a
potent and promptly acting analgesic and antipyretic but poor
antiinflammatory.
 Few cases of agranulocytosis were reported and metamizol is
banned in the USA and some European countries.
 Its fixed dose combination with antispasmodics is banned in
India.
 Dose: 0.5–1.5 g oral/i.m./i.v
 TRADE NAMES :- ANALGIN, NOVALGIN, BARALGAN 0.5 g
tab, BARALGAN 0.5 g/ml in 2 ml and 5 ml amps

Propiphenazone
 Similar in properties to metamizol; claimed to be
better tolerated.
 Agranulocytosis has not been reported.
 Dose: 300–600 mg TDS.
 TRADE NAMES :- ANAFEBRIN: propiphenazone
150 mg + paracetamol 250 mg tab.
 DART: propiphenazone 150 mg + paracetamol300
mg + caffeine 50 mg tab.

PREFERENTIAL COX-2
INHIBITORS
 Nimesulide :- relatively weak inhibitor of PG synthesis and
moderately COX-2 selective.
 Uses:- for short-lasting painful inflammatory conditions like sports
injuries,
 sinusitis
 ear-nose-throat disorders,
 dental surgery,
 bursitis,
 low backache,
 dysmenorrhoea,
 postoperative pain,
 osteoarthritis and for fever.
 t½ of 2–5 hours.

 Adverse effects :- gastrointestinal (epigastralgia, heart burn,
nausea, loose motions),
 dermatological (rash, pruritus),
 central (somnolence, dizziness).
 Instances of fulminant hepatic failure have been associated
with nimesulide it has been withdrawn in Spain, Ireland,
Singapore and Turkey.
 use in children is banned in Portugal, Israel and now in India as
well.
 Dose: 100 mg BD
 TRADE NAMES :- NIMULID, NIMEGESIC, NIMODOL 100 mg
tab, 50 mg/5 ml susp.

Diclofenac sodium
 It inhibits PG synthesis and is somewhat
COX-2 selective.
 The antiplatelet action is not appreciable
due to sparing of COX-1.
 The plasma t½ is ~2 hours.
 Adverse effects :- mild epigastric pain,
nausea, headache, dizziness, rashes.
 elevation of serum amino-transferases has
been reported more commonly.

 Uses :-rheumatoid and osteoarthritis,
 bursitis,
 ankylosing spondylitis,
 toothache,
 dysmenorrhoea,
 renal colic,
 posttraumatic and postoperative inflammatory conditions.
 Dose: 50 mg TDS, then BD oral, 75 mg deep i.m.
 TRADE NAMES :- VOVERAN, DICLONAC, MOVONAC 50
mg enteric coated tab,

Aceclofenac
 A moderately COX-2 selective congener
of diclofenac having similar properties.
 Dose: 100 mg BD.
 TRADE NAMES :- ACECLO,
DOLOKIND 100 mg tab, 200 mg SR tab.

Meloxicam
 This newer congener of piroxicam &
‘preferential COX-2 inhibitor’.
 Plasma t½ is 15–20 hours permitting single
daily dose.
 Gastric side effects of meloxicam are milder
but Gastric bleeding is reported in long-term
use.
 Dose: 7.5–15 mg OD.
 TRADE NAMES :- MELFLAM, MEL-OD,
WELLCAM, MCAM 7.5 mg, 15 mg tabs.

Etodolac
 This newer indole-acetic acid NSAID is moderately COX-2
selective with properties similar to diclofenac.
 Gastric tolerance is better than older NSAIDs.
 t½ of 7 hours.
 Side effects :- abdominal pain, rashes and dizziness.
 Use in osteo- and rheumatoid arthritis as well as in
acute musculoskeletal pain.
 Dose: 200–400 mg BD–TDS.
 TRADE NAMES :- ETOVA 200, 300, 400 mg tabs

SELECTIVE COX-2
INHIBITORS (Coxibs)
 Currently, 3 selective COX-2 inhibitors (also
called coxibs) Celecoxib, Etoricoxib and
Parecoxib are available in India.
 It should be used only in patients at high risk
of peptic ulcer, perforation or bleeds.
 should be avoided in patients with history of
ischaemic heart disease/hypertension/cardiac
failure/cerebrovascular disease, who are
predisposed to CV events.

Celecoxib
 It exerts antiinflammatory, analgesic and antipyretic
actions with low ulcerogenic potential.
 Side effects :- abdominal pain, dyspepsia and mild
diarrhoea.
 t½ of ~10 hours.
 use :- osteo- and rheumatoid arthritis in a dose of
100–200 mg BD.
 TRADE NAMES :- COBIX,CELACT, REVIBRA,
COLCIBRA 100, 200 mg caps.

Etoricoxib
 This newer COX-2 inhibitor has the highest COX-2
selectivity.
 The t½ is ~ 24 hours.
 Uses :- osteo/rheumatoid/acute gouty arthritis, ankylosing
spondylitis, dysmenorrhoea, acute dental surgery pain.
 Side effects:- dyspepsia, abdominal pain, pedal edema,
rise in BP, dry mouth, aphthous ulcers, taste disturbance
and paresthesias.
 Dose: 60–120 mg OD.
 TRADE NAMES :- ETOSHINE, TOROCOXIA, ETOXIB,
NUCOXIA 60, 90, 120 mg tabs.

Parecoxib
 It is a prodrug of valdecoxib suitable for
injection.
 Caution is needed in its use; it should be
stopped at the first appearance of a rash.
 Dose: 40 mg oral/i.m./i.v., repeated after 6–
12 hours.
 TRADE NAMES :- REVALDO, DYNASTAT
40 mg/vial inj, PAROXIB 40 mg tab.

PARA-AMINO PHENOL
DERIVATIVES
 Phenacetin introduced in 1887 was
extensively used as analgesic-
antipyretic, but is now banned because
it was implicated in analgesic abuse
nephropathy.
 Paracetamol (acetaminophen) the
deethylated active metabolite of
phenacetin commonly use since 1950.

Paracetamol (acetaminophen)
 Paracetamol has negligible
antiinflammatory action.
 Good antipyretic and analgesic effect
 Effects after an oral dose last for 3–5
hours.
 At Antipyretic doses paracetamol is safe
and well tolerated.
 Nausea and rashes occur occasionally.

Acute paracetamol
poisoning
 It 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.
 Fatality is common with > 250 mg/kg.
 Early manifestations are just nausea, vomiting,
abdominal pain and liver tenderness with no
impairment of consciousness.

 After 12–18 hours centrilobular hepatic necrosis
occurs which may be accompanied by renal
tubular necrosis and hypoglycaemia that may
progress to coma.
 Jaundice starts after 2 days.
 Hepatic failure and death are likely if the
plasma levels are above the line joining 200
μg/ml at 4 hours and 30 μg/ml at 15 hours.

Mechanism of toxicity
 N-acetyl-p-benzoquinoneimine (NAPQI) .
 Detoxified by conjugation with glutathione.
large dose
 Glucuronidation capacity is saturated
 Hepatic glutathione is depleted
 NAPQI binds covalently to proteins in liver
cells (and renal tubules) causing necrosis.

Treatment
 If the patient is brought early, vomiting should be
induced or gastric lavage done.
 Specific: N-acetylcysteine (MUCOMIX, ANTIFEN
200 mg/ml inj in 2, 5 ml amps) 150 mg/kg should be
infused i.v. over 15 min, followed by the same dose
i.v. over the next 20 hours.
 Alternatively, 75 mg/kg may be given orally every 4–
6 hours for 2–3 days.
 It is practically ineffective if started 16 hours or more
after paracetamol ingestion.

Uses
 Paracetamol is one of the most commonly
used ‘over-the-counter’ analgesic for
headache, mild migraine, musculoskeletal
pain, dysmenorrhoea, etc.
 Best drug to be used as antipyretic,
especially in children.
 all age groups (infants to elderly)
pregnant/lactating women.
 In presence of other disease states and in
patients in whom aspirin is contraindicated.

 Dose: 325–650 mg (children 10–15
mg/kg) 3–5 times a day.
 TRADE NAMES :- CROCIN 0.5, 1.0 g
tabs, METACIN, PARACIN, CALPOL
500 mg tab, 125 mg/5 ml syrup,

BENZOXAZOCINE
DERIVATIVE
 Nefopam :- does not inhibit PG synthesis but relieves
traumatic, postoperative and short lasting musculoskeletal
pain.
 It may be used if pain is persistent and is not adequately
relieved by other analgesics.
 side effects :- dry mouth, urinary retention, blurred vision
 Dose: 30–60 mg TDS oral, 20 mg i.m. 6 hourly.
 TRADE NAMES :- ACUPAN,NEFOMAX 30 mg tab, 20 mg in
1 ml amp.

Topical NSAIDs
 Diclofenac 1% gel : VOLINI GEL, RELAXYL
GEL, DICLONAC GEL
 Ibuprofen 10% gel : RIBUFEN GEL
 Naproxen 10% gel : NAPROSYN GEL
 Ketoprofen 2.5% gel : RHOFENID GEL
 Flurbiprofen 5% gel : FROBEN GEL
 Nimesulide 1% gel : NIMULID TRANS GEL,
ZOLANDIN GEL, NIMEGESIC-T-GEL
 Piroxicam 0.5% gel : DOLONEX GEL, MOVON
GEL, PIROX GEL, MINICAM GEL

Choice of NSAIDS
 Efficacy differences among different
NSAIDs are minor, but they have their
own spectrum of adverse effects.
 No single drug is superior to all others
for every patient.
 The cause and nature of pain along with
consideration of risk factors in the given
patient govern selection of the
analgesic.

Opioids
 Opium :- A dark brown, resinous material
obtained from poppy (Papaver somniferum)
capsule.
 It contains two types of alkaloids.
 Phenanthrene derivatives
1. Morphine (10% in opium)
2. Codeine (0.5% in opium)
3. Thebaine (0.2% in opium), (Nonanalgesic)
 Benzoisoquinoline derivatives
1. Papaverine (1%) (Nonanalgesic)
2. Noscapine (6%) (Nonanalgesic)

OPIOID RECEPTORS
 Radioligand binding studies divided the
opioid receptors into three types (μ, κ, δ)
 Each has a specific pharmacological
profile and pattern of anatomical
distribution in the brain, spinal cord and
peripheral tissues.
 Opioid ligands can interact with different
opioid receptors as agonists, partial
agonists or competitive antagonists.

MORPHINE
 PHARMACOLOGICAL ACTIONS
1. CNS
(a) Analgesia :- Nociceptive pain arising from
stimulation of peripheral pain receptors is
relieved better than neuretic pain.
 Perception of pain and the emotional
component (anxiety, fear, suffering,
distress) induced by it are both altered so
that pain is no longer as unpleasant or
distressing.

(b) Sedation :- is different from that
produced by hypnotics is seen.
 Drowsiness and indifference to
surroundings as well as to own body
occurs without motor incoordination,
ataxia or apparent excitement.
 Higher doses progressively induce sleep
and then coma.

(c) Mood and subjective effects :- Morphine has
a calming effect,
 loss of apprehension,
 feeling of detachment,
 lack of initiative,
 limbs feel heavy and body warm,
 mental clouding and inability to concentrate
occurs.
 Perceive it as pleasurable floating sensation:
refer it as ‘high’.

(d) Respiratory centre :- Morphine depresses
respiratory centre in a dose dependent manner.
 Respiratory rate and tidal volume are both
decreased.
 Doesn’t effect at analgesic dose but it may be
marked in the presence of other sedatives,
cardiopulmonary/liver/kidney disease, etc.
 Death in morphine poisoning is due to respiratory
failure.

(e) Cough centre :- It is depressed by morphine,
and is more sensitive than respiratory centre.
(f) Temperature regulating centre It is depressed;
hypothermia occurs in cold surroundings.
(g) Vasomotor centre It is depressed at higher
doses and contributes to the fall in BP.

2. Neuro-endocrine :- Hypothalamic influence on
pituitary is reduced.
 As a result FSH, LH, ACTH levels are lowered.
 Prolactin and GH levels are raised
 The sex hormone and cortisol levels are
lowered.

3. CVS :- Morphine causes vasodilatation due
to:
 (a) histamine release.
 (b) depression of vasomotor centre.
 (c) direct action decreasing tone of blood
vessels.
 Therapeutic doses cause little change in
the BP.
 Postural hypotension and fainting do occur
due to vesodilatation and impairment of
vascular reflexes.

4. GIT :- Morphine exerts marked effect on g.i.
motility as well as on fluid dynamics across g.i.
mucosa.
 Constipation is a prominent feature of
morphine action.
 Decrease in all gastrointestinal secretions due
to reduction in movement of water and
electrolytes from mucosa to the lumen.

5. Other smooth muscles :-
 (a) Biliary tract :- spasm of sphincter of Oddi →
intrabiliary pressure is increased several fold →
may cause biliary colic.
 (b) Urinary bladder :- Tone of both detrusor and
sphincter muscle is increased → urinary urgency
and difficulty in micturition.
 (c) Bronchi :-releases histamine which can cause
bronchoconstriction.

ADVERSE EFFECTS
1. Side effects :- Sedation, mental clouding, Lethargy,
constipation, Respiratory depression, blurring of
vision, urinary retention.
2. Idiosyncrasy and allergy :- urticaria, swelling of lip,
local reaction at injection site and generalized itching
may occur due to histamine release.
3. Apnoea of the newborn :- occurs when morphine is
given to the mother during labour.
 Blood-brain barrier of the foetus is undeveloped,
morphine attains higher concentration in foetal brain
than in that of mother.

4. Acute morphine poisoning :- It may be
accidental, suicidal or seen in drug abusers.
 In the nontolerant adult, 50 mg of morphine
i.m. produces serious toxicity.
 The human lethal dose is estimated to be
about 250 mg.
 coma, flaccidity, shallow and occasional
breathing, cyanosis, pinpoint pupil, fall in BP
and shock.
 pulmonary edema occurs at terminal stages,
death is due to respiratory failure.

Treatment
 Consists of respiratory support and
maintenance of BP.
 Gastric lavage should be done with pot.
permanganate to remove unabsorbed
drug.
 Specific antidote: Naloxone 0.4–0.8 mg i.v.
repeated every 2–3 min till respiration picks
up.
 Due to short duration of action, naloxone
should be repeated every 1–4 hours,
according to the response.

5. Tolerance and dependence :- High degree of
tolerance can be developed to morphine and
related opioids if the drug is used repeatedly.
 Morphine produces pronounced
psychological and physical dependence, its
abuse liability is very high.
 Abuse is higher among medical and
paramedical personnel.

Withdrawal Symptoms
 Lacrimation,
 Sweating,
 Yawning,
 Anxiety &fear,
 Restlessness,
 Mydriasis,
 Tremor,
 Insomnia,
 Abdominal colic,
 Diarrhoea,
 Dehydration,
 Rise in BP,
 Palpitation and rapid weight loss.

Treatment
 Consists of withdrawal of morphine and
substitution with oral methadone
followed by gradual withdrawal of
methadone.

PRECAUTIONS AND
CONTRAINDICATIONS
 Infants and the elderly more susceptible to the respiratory
depressant action of morphine.
 Dangerous in patients with respiratory insufficiency
(emphysema, pulmonary fibrosis, cor pulmonale).
 Contraindicated in Bronchial asthma.
 Contraindicated in patients with head injury.
 Contraindicated in Undiagnosed acute abdominal pain.
 Contraindicated in Elderly male: chances of urinary
retention are high.
 Hypothyroidism, liver and kidney disease pt. are more
sensitive.
 Unstable personalities : are liable to continue with its use
and become addicted.

Dose: 10–50 mg oral, 10–15 mg i.m. or s.c.
 2–6 mg i.v.,
 2–3 mg epidural/intrathecal,
 children 0.1–0.2 mg/kg. i.m. or s.c.
TRADE NAME :- MORPHINE SULPHATE 10
mg/ml inj,
 MORCONTIN 10, 30, 60,100 mg
continuous release tabs 30–100 mg BD,
 RILIMORF 10, 20 mg tabs, 60 mg SR tab.

Codeine
 less potent than morphine (1/10th as analgesic), also less
efficacious.
 It is a partial agonist at μ opioid receptor with a low ceiling effect.
 Codeine has good activity by the oral route, A single oral dose acts
for 4–6 hours.
 Codeine is regarded as the standard antitussive, suppresses
cough for about 6 hours.
 Constipation is a prominent side effect.
 Abuse liability is low.
 Dose: 10–30 mg; children 2–6 years 2.5–5 mg, 6–12 years 5–10
mg,

Ethylmorphine
 It is closely related to codeine and has
antitussive, respiratory depressant
properties like it,
 but is believed to be less constipating.
 Dose: 10–30 mg TDS.
 TRADE NAMES :- DIONINDON 16 mg
tab.

Pholcodeine
 It has practically no analgesic or
addicting property, but is similar in
efficacy as antitussive to codeine and is
longer acting acts for 12 hours.
 Dose: 10–15 mg.

Heroin
 It is about 3 times more potent than
morphine.
 It is considered to be more euphorient
(especially on i.v. injection) and highly
addicting.
 it has no outstanding therapeutic
advantage over morphine and has been
banned in most countries except U.K.

Pethidine (Meperidine)
 Chemically unrelated to morphine, it
interacts with μ opioid receptors and its
actions are blocked by naloxone.
 Side effects :- dry mouth, blurred vision,
tachycardia.
 Overdose of pethidine produces many
excitatory effects—tremors, mydriasis,
hyperreflexia, delirium, myoclonus and
convulsions.

 Use :- primarily used as an analgesic
(substitute of morphine) and in
preanaesthetic medication.
 To control shivering during recovery from
anaesthesia or while receiving i.v.
infusions.
 Preferred opioid analgesic during labour.
 Dose: 50–100 mg i.m., s.c.
 TRADE NAME :- PETHIDINE HCL 100
mg/2 ml inj; 50, 100 mg tab.

Fentanyl
 80–100 times more potent than morphine, both in
analgesia and respiratory depression.
 Because of high lipid solubility, it enters brain rapidly and
produces peak analgesia in 5 min after i.v. injection.
 t½ is ~4 hr.
 In the injectable form it is almost exclusively used in
anaesthesia.
 Transdermal fentanyl has become available for use in
cancer/ terminal illness or other types of chronic pain for
patients requiring opioid analgesia.
 TRADE NAMES :- DUROGESIC transdermal patch
delivering 12 μg/hr, 25 μg/hr, 50 μg/hr, 75 μg/hr or 100 μg
per hour; the patch is changed every 3 days.

Methadone
 A synthetic opioid, chemically dissimilar but
pharmacologically very similar to morphine.
 The most important feature of methadone
is high oral: parenteral activity ratio (1 : 2)
and its firm binding to tissue proteins.
 t½ on chronic use is 24–36 hours.
 It is probably incapable of giving a ‘kick’.
 The abuse potential is rated lower than
morphine. Tolerance develops more slowly.

 used primarily as substitution therapy for opioid dependence: 1
mg of oral methadone can be substituted for 4 mg of morphine,
2 mg of heroin and 20 mg of pethidine.
 Methadone maintenance therapy in opioid addicts— sufficient
dose of methadone (10–40 mg/day) is given orally over long
term so that pleasurable effects of i.v. doses of morphine or
heroin are not perceived and the subject gives up the habit.
 Analgesic dose 2.5–10 mg oral or i.m.
 TRADE NAMES :- METHADONE 5mg/ml and 10mg/ml syr; 5,
10, 20, 40 mg tabs.
 PHYSEPTONE 10 mg inj,

Dextropropoxyphene
 It is chemically related to methadone but is quite similar in
analgesic action and in side effects to codeine.
 t½ is variable (4–12 hours).
 (60–120 mg) is used as a mild oral analgesic.
 It is marketed only in combination with paracetamol ±
other drugs
 Demethylated metabolite of propoxyphene has a longer
t½ (>24 hours), accumulates on repeated dosing and is
cardiotoxic.
 TRADE NAMES :- PARVODEX 60 mg cap,
 PARVON, PROXYVON, WALAGESIC:
dextropropoxyphene 65 mg + paracetamol 400 mg cap;
 WYGESIC, SUDHINOL 65 mg + paracetamol 650 mg
cap.

Tramadol
 Tramadol causes less respiratory depression, sedation,
constipation, urinary retention and rise in intrabiliary pressure
than morphine.
 side effects :- dizziness, nausea, sleepiness, dry mouth,
sweating and lowering of seizure threshold.
 Indicated :- mild-to-moderate short-lasting pain. not effective in
severe pain.
 t½ is 5–6 hours
 Dose: 50–100 mg oral/i.m./slow i.v. infusion (children 1–2
mg/kg) 4–6 hourly.
 TRADE NAMES :- CONTRAMAL, DOMADOL, TRAMAZAC 50
mg cap, 100 mg SR tab; 50 mg/ml inj in 1 and 2 ml amps.

Pentazocine
 It has weak μ antagonistic and more marked κ agonistic
actions.
 Analgesia caused by pentazocine is primarily spinal (κ1)
and has a different character than that caused by
morphine.
 Sedation, respiratory depression, Tachycardia, rise in BP,
Biliary spasm, constipation, Vomiting are less frequent
compared to Morphine.
 indicated for postoperative and moderately severe pain in
burns, trauma, fracture, cancer, etc.

 Oral dose: 50–100 mg.
 Parenteral dose: 30–60 mg i.m., s.c.
 TRADE NAMES :- FORTWIN 25 mg
tab., 30 mg/ml inj., FORTSTAR,
SUSEVIN 30 mg/ml inj; FORTAGESIC
pentazocine 15 mg+paracetamol 500
mg tab.

Butorphanol
 It is a κ analgesic, similar to but more
potent than pentazocine (butorphanol 2 mg
= pentazocine 30 mg).
 Abuse potential of butorphanol is low.
 used in a dose of 1–4 mg i.m. or i.v. for
postoperative and other short-lasting (e.g.
renal colic) painful conditions.
 Should be avoided in patients with cardiac
ischaemia.
 TRADE NAME :- BUTRUM 1 mg/ml, 2
mg/ml inj.

Buprenorphine
 Highly lipid-soluble μ analgesic that is 25 times more
potent than morphine.
 Sedation, vomiting, miosis, subjective and cardiovascular
effects are similar to morphine, but constipation is less
marked.
 Lower degree of tolerance and physical as well as
psychological dependence develops with buprenorphine
on chronic use.
 Buprenorphine has good efficacy by sublingual route.
 Uses :- indicated for long-lasting painful conditions
requiring an opioid analgesic, e.g. cancer pain.
 In premedication, postoperative pain, in myocardial
infarction and in the treatment of morphine dependence.

 Dose: 0.3–0.6 mg i.m., s.c. or slow i.v.,
also sublingual 0.2–0.4 mg 6–8 hourly.
 TRADE NAMES :- NORPHIN,
TIDIGESIC 0.3 mg/ml inj. 1 and 2 ml
amps. 0.2 mg sublingual tab;
BUPRIGESIC, PENTOREL 0.3 mg/ml inj
in 1, 2 ml amp.

DRUGS FOR NEUROPATHIC
PAIN
 Carbamazepine :- gold standard for the
management of trigeminal neuralgia.
 also used to treat other neuropathic pain
conditions and headache.
 plasma t½ is 20–40 hours but, decreases
to 10–20 hr on chronic medication due to
autoinduction of metabolism.
 Adverse effects :- dose-related
neurotoxicity—sedation, dizziness, vertigo,
diplopia, ataxia & foetal malformation .

 Dose: 200–400 mg TDS; Children 15–
30 mg/kg/day.
 TRADE NAMES :- TEGRETOL,
MAZETOL 100, 200, 400 mg tab, 100
mg/5 ml syr; CARBATOL 100, 200, 400
mg tab.

Gabapentin
 It is newer congener pregabalin &
exerts a specific analgesic effect in
neuropathic pain.
 t½ of 6 hrs.
 Side effects are mild sedation,
tiredness, dizziness and unsteadiness.
 Dose: Start with 300 mg OD, increase
to 300–600 mg TDS as required.
 TRADE NAMES :- NEURONTIN 300
mg, 400 mg cap, GABANTIN,
GABAPIN 100, 300, 400 mg cap.

American Journal of Orthopedics (Belle Mead, N.J.), 01 Oct
2014, 43(10 Suppl):S2-5
PMID: 25303456
 EXPAREL® (bupivacaine liposome
injectable suspension) is an extended-
release anesthetic that is approved by
the US Food and Drug Administration
for single-dose injection into the surgical
site to produace postsurgical analgesia.
 EXPAREL was used in Total knee and
hip replacement surgeries.

Central Sensitization
 Central sensitization is a condition of the
nervous system that is associated with the
development and maintenance of chronic
pain.
 Central sensitization has two main
characteristics. Both involve a heightened
sensitivity to pain and the sensation of
touch.
 They are called allodynia and hyperalgesia.
 Central sensitization has long been
recognized as a possible consequence of
stroke and spinal cord injury.

 Treatments for chronic pain syndromes that
involve central sensitization typically target
the central nervous system or the
inflammation that corresponds with central
sensitization.
 These are antidepressants and
anticonvulsant medications and cognitive
behavioral therapy.
 Non-steroidal anti-inflammatories are used
for the inflammation associated with central
sensitization.

Ionotrophic delivery of
morphine
 Iontophoresis is a method of
transdermal administration of ionized
drugs in which electrically charged
molecules are propelled through the skin
by an external electrical field.
 In the past, drug delivery has been
limited to 15-30 min due to technical
reasons, but recent improvements in
electrode technology now permit longer
drug delivery.

 Iontophoretic delivery of morphine to
healthy human volunteers can lead to
analgesic plasma concentrations after
only 20 min of treatment.
 The rate of morphine delivery is
proportional to the intensity of current
used.

 Ginseng is a widespread herbal
medicine that has been used in China,
Korea and Japan for thousands of
years.
 Ginsenosides or ginseng saponins are
the active principles of Panax ginseng.
 like opioid analgesics, the Rf
ginsenoside inhibited calcium channels
resulting an analgesic effect.

MULTIMODAL ANALGESIA
 multimodal or ‘‘balanced’’ analgesia
suggests that combinations of several
analgesics of different classes and
different sites of analgesic
administration rather than single
analgesic or single technique provide
superior pain relief with reduced
analgesic related side effects.

Analgesia options for multimodal
techniques
 Opioids
 Local anesthetics
 NSAIDs
 N-methyl-d-aspartate (NMDA) receptor
antagonists (ketamine and
dextromethorphan)
 a2 agonists (clonidine and
dexmedetomidine)
 Anticonvulsants ( gabapentin and
pregabalin)
 Corticosteroids

 Although the concept of multimodal
analgesia has been well accepted and
included in our current pain management
plan, it has not resulted in improved
postoperative outcome.
 Because of an inappropriate combination
of analgesic techniques or inadequate
duration of analgesia.
 Future postoperative multimodal strategies
will need to be patient-specific and
procedure-specific.

PAIN MANAGEMENT APPROACHES
TARGETED AT
THE PREOPERATIVE PERIOD
 Preemptive analgesia :- involves the
preoperative administration of an
analgesic so that it is active during
surgery.
 NSAIDs ,Anticonvulsants & Anxiolytics
can be used as Preemptive analgesia.

TARGETED AT
THE INTRAOPERATIVE PERIOD
 1. Neuraxial Analgesia :- local
administration of an anesthetic
and/or opioids into the
neuraxial space of the spinal
cord.
 Aims to reduce the afferent
transmission of nociceptive
signaling and to block the
development of central
sensitization.

 2. Continuous Local Anesthetic
Wound Infusion :- produce analgesic
effects by direct inhibition of afferent
nociceptive signaling and direct
inhibition of the local inflammatory
response to surgical trauma.

 3. TAP Block (transversus abdominis
plane) :- Involves the injection of LA into
the neurovascular plane of the
abdominal wall.
 This will result in less postoperative
morphine consumption.

 4. EREM (Extended-release epidural
morphine) :- single-dose analgesic
administered by epidural injection at the
lumbar level for the treatment of pain
following major surgery.

 5. Intravenous Acetaminophen :- I.V.
acetaminophen for the management of
postoperative pain found that patients
receiving perioperative I.V.
acetaminophen had lower pain scores in
12 of 14 trials and less postoperative
opioid use in 10 of 14 trials.

 6. Intravenous Ketamine :- acts by
antagonizing the N-methyl-D-aspartate
receptor.
 Decrease in postoperative pain scores
in 37.5% of studies at early time points
(30 minutes to 4 hours) and 25% of
studies at later time points (24 to 72
hours).

TARGETED AT
THE POSTOPERATIVE PERIOD
 1. Intravenous Ibuprofen :- 800 mg of
intravenous ibuprofen every 6 hours
after surgery is efficacious as an adjunct
to morphine and as a morphine-sparing
agent.

 2. New Opioids and Opioid Formulations
 Tapentadol :- is a novel, centrally
acting, l-opioid agonist, and
norepinephrine reuptake inhibitor that is
approved for the treatment of moderate
to severe pain.
 Two oral formulations are available:
tapentadol hydrochloride for acute pain,
and extended-release tapentadol for
chronic pain.

 Morphine–Oxycodone :- ratio (3:2)
 Analgesic effects of morphine–
oxycodone are greater than those
achieved with equivalent doses of
morphine or oxycodone alone.
 Incidence of nausea and vomiting is
higher.

 3. PCA (Patient-controlled analgesia) :-
Intravenous PCA with opioids and patient-
controlled epidural analgesia (PCEA) with
opioids and/or local anesthetics are the
most common methods of PCA.
 Less common approaches for PCA include
 patient-controlled regional anesthesia
(PCRA),
 patient-controlled intranasal analgesia
(PCINA),
 Patient controlled transdermal analgesia
(PCTA),
 Patient controlled sublingual analgesia
(PCSA).

PCRA
 Patient-controlled regional anesthesia
(PCRA) typically involves the
administration of a local anesthetic
(ropivacaine) into the surgical incision,
intra-articular tissue, or perineural site.

PCINA
 A patient-controlled intranasal
formulation of ketorolac tromethamine
can be use as a short-term (up to 5
days) management of moderate to
moderately severe pain in adults
requiring opioids.
 nasal irritation is sideeffect.

PCTA
 Fentanyl ITS (iontophoretic transdermal
system) was developed as an
alternative to intravenous PCA, with a
lower risk of intravenous PCA–related
complications.
 such as operating errors, mechanical
pump errors, and intravenous catheter
infections.

PCSA
 A new, patient-controlled, sublingual,
sufentanil system is underdevelopment
and designed to overcome the key
disadvantages of intravenous PCA.

REFRENCES
 Essentials of Medical Pharmacology,
Seventh Edition, KD TRIPATHI.
 Textbook of Pharmacology for Dental
and Allied Health Sciences 7th Edition,
Padmaja Udaykumar.
 Pharmacology for Dentistry, 2nd Edition,
Tara V Shanbhag.

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