ANALGESICS

RAJESH SARDANAPG 1ST YR.

CONTENTS

• PHASES OF PAIN• METHODS IN PAIN CONTROL• WHO LADDER ANALGESICS REGIME• CLASSIFICATION OF ANALGESICS• APPLICATION OF ANALGESICS IN OMFS• RECENT ADVANCES IN PAIN CONTROL• REFERENCES

PainDerived from Greek ”Poin”; meaning penalty.

• Derived from Latin “Poena”; meaning

punishment from God

PHASES OF PAIN 

• A) Phases I (Acute nociceptive pain ) : • brief noxious stimuli--fairly simple & direct route-- centrally towards the

thalamus & cortex --- conscious perception of pain-- possibility for modulation -- synaptic relays along the way

• Close correlation the discharges in peripheral nociceptors & subjective expression pain

B) Phase 2 ( Inflammatory pain )

• Noxious stimulus very intense or prolonged tissue damage & inflammation .• Increased activity and responsiveness of sensitized nociceptors.

• Increased afferent inflow to CNS from injured area

• Nociceptive neurons in spinal cord modify their responsiveness.

C) Phase 3(NEUROPATHIC PAIN)

• Symptom of neurological disease •Lesions of peripheral nerves or damage to any portion of somatosensory system within the CNS.• Spontaneous pain ,triggered by innocuous stimuli or are exaggerated responses to minor noxious stimuli.•Probable reason1)      Pathological changes in damaged neurons2)      Reactive changes in response to nociceptive afferent input and to loss of portions of the normal afferent inputs

Pain is perfect misery, the worst of evils, and excessive,

overturns all patience”.

John Milton (1608- 1674) Paradise Lost.

One of the greatest services doctors can do their patients

is to acquire skill in the management of pain.

THEORIES OF PAIN

1.THEORY OF SPECIFICITY2.PATTERN THEORY3 GATE CONTROL THEORY

Methods of pain control

• Removing the cause. • Blocking the pathway of painful impulses.• Raising the pain threshold.• Preventing pain reaction by cortical depression.• Using psychosomatic methods.

Removing the cause

• It is the desirable method of controlling pain.• If it is accomplished, the environmental change in tissue would

be eliminated.• Free nerve endings would not be excited and no impulses

would be initiated.• This method clearly affects pain perception.

Blocking the pathway of painful impulses

• It is the most widely used method in dentistry for controlling pain.

• A suitable drug, possessing local anesthetic properties is injected into the tissues in proximity to the nerves involved.

• It prevents depolarization of the nerve fibers at the area of absorption, thus preventing those fibers from conducting any impulses beyond that point.

• This method of pain control is possible by interfering with pain perception.

Raising the pain threshold

• It depends on the pharmacologic actions of the drugs possessing analgesic properties.

• These drugs raise the pain threshold centrally and therefore interfere with pain reaction.

• The cause of the organic stimulus may still be present.• Pain perception is unaffected, but pain reaction is decreased

and thus pain reaction threshold is raised, but it is impossible to eliminate all pain of the most severe nature.

Preventing pain reaction by cortical depression

• Eliminating pain by this method by general anesthesia and general anesthetic agents.

• The agent, by increasing depression of the CNS, prevents any conscious action to a painful stimulus.

• Using psychosomatic methods

• Relaxation Training Relaxation involves concentration and slow, deep breathing to release tension

from muscles and relieve pain. Learning to relax takes practice, but relaxation training can focus attention away from pain and release tension from all muscles. Relaxation tapes are widely available to help you learn these skills.

• Biofeedback Biofeedback is taught by a professional who uses special machines to help you

learn to control bodily functions, such as heart rate and muscle tension. As you learn to release muscle tension, the machine immediately indicates success. Biofeedback can be used to reinforce relaxation training. Once the technique is mastered, it can be practiced without the use of the machine.

• Visual Imagery and Distraction

The WHO advocates “This stepped approach of administering the right drug in the right dose at the right time is inexpensive and generally effective in managing acute pain.

Simplicity, Flexibility to a large variety of pain situations and also to prescribers globally.Emphasis on multimodal analgesia.

Its disadvantages include:

It may be too simplistic for management of certain types of pain, especially neuropathic pain or for those who are opioid dependant.

ReferencesOrganisation W. Analgesic Ladder. World Health Organization; 1986.

NSAIDS

PGI2 (prostacyclin) is located predominantly in vascular endothelium. Main effects:•vasodilatation•inhibition of platelet aggregation

TxA2 is found in the platelets.Main effects:•platelet aggregation•vasoconstriction

PROSTANOIDS (PGs & Txs)PROSTANOIDS (PGs & Txs)

PGE2 causes:• inhibition of gastric acid secretion•contraction of pregnant uterus•contraction of GI smooth muscles

PGF2α – main effects:•contraction of bronchi•contraction of miometrium

Cyclooxygenase (COX) is found bound to the endoplasmaticreticulum. It exists in 3 isoforms:• COX-1 (constitutive) acts in physiological conditions.• COX-2 (inducible) is induced in inflammatory cells by pathological stimulus.• COX-3 (in brain).

(+)

Phospholipase A2Phospholipids

Arachidonic acid

5-lipoxygenase

Leucotrienes

Cyclooxy genase (COX)

Endoperoxides

PGs TxA2

15-lipoxygenase

Lipoxins

Inflammatory stimulus

Ex

In

Essential of Medical Pharmacology – 5st Ed. (2003)Essential of Medical Pharmacology – 5st Ed. (2003)

COX-2inhibitors

• Selective (coxibs)• Preferential

COX-3inhibitors• Antipyretic

analgesics

NonselectiveCOX-1/COX-2

inhibitorsNSAIDsNSAIDs

COX inhibitors

COX-2inhibitors (1) Selective COX-2inhibitors (Coxibs)• Celecoxib• Etoricoxib• Parecoxib (2) PreferentialCOX-2 inhibitors• Meloxicam• Nimesulide• Nabumetone

NSAIDs

NSAIDs

Classifications• Mild to moderate anti-inflammatory action

- propionic acid derivatives ibuprofen, naproxen - fenamic acids mefanamic acid

• Marked anti-inflammatory action- salicylic acids aspirin- pyrazolone derivatives azapropazone,

phenylbutazone- acetic acid derivatives diclofenac, indomethacin- oxicam derivatives piroxicam

• Selective COX2 inhibitors celecoxib, rofecoxib

NSAIDsMain actions1.) Analgesic -effective against mild to moderate pain, do not

cause dependence2.) Anti-inflammatory3.) Anti-pyretic4.)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 effects1.) Gastric or intestinal mucosal damage

- mucosal prostaglandins inhibit acid secretion, promote mucus secretion, prevent back diffusion of acid into the gastric submucosa

- Inhibition thus results in erosions, ulceration, bleeding, perforation

2.) Disturbances of fluid and electrolyte balance- inhibition of renal prostaglandin production results in sodium retention and oedema, possible hyponatraemia, hyperkalaemia, antagonism of anti-hypertensive agents

3.) Analgesic nephropathy- due to long term ingestion of mixtures of agents - chronic interstitial nephritis, renal papillary necrosis, acute renal failure

Acetaminophen• equivalent analgesic efficacy to aspirin• no useful anti-inflammatory actionused for mild to moderate pain, but aspirin is preferred if due to inflammatory

process Metabolism• is conjugated in the liver as the inactive glucuronide and sulphate• a number of minor oxidation products inc.

N-acetylbenzoquinoneimine (NABQI) are also formed• NABQI is highly chemically reactive and is usually inactivated by conjugation

with SH (thiol) groups of glutathione• Supply of glutathione is limited and exhausted in overdoseNABQI then reacts with cellular macromolecules and causes cell death Adverse

effects• rare in therapeutic usage• occasional skin rash and allergy• Overdose can result in fulminant hepatic necrosis and liver failure

NSAIDs

Paracetamol overdose• Ingestion of >4g of paracetamol may be fatal• may be lower in chronic alcoholics or subjects with

underlying liver disease. Clinical featuresIn severe poisoning • up to 24 hours - none or nausea and vomiting• > 24 hours - nausea and vomiting, right

upper quadrant pain, jaundice, encephalopathy

Rang et al. Pharmacology – 6th Ed. (2007)Rang et al. Pharmacology – 6th Ed. (2007)

Metabolism ofparacetamol to hepatotoxicmetabolites (NABQI etc.)(GSH – glutathione; SG – glutathione moiety)

Daily dose > 4gm

hepatotoxicityand

nephrotoxicity

NABQI

NB: Acetylcysteine and GSHcontain –SH groups.

Basic & Clinical Pharmacology – 10th Ed. (2007) Basic & Clinical Pharmacology – 10th Ed. (2007)

Management • Blood for paracetamol at 4 hours post ingestion • Check treatment curve for N-acetylcysteine infusion ( if in

doubt of severe poisoning, don’t delay) • Check prothrombin time and plasma creatinine, pH• acute renal (due to acute tubular necrosis) and hepatic

failure and occur at 36-72 hours after ingestion• Indications for referral to liver unit are

- rapid development of Grade 2 encephalopathy- PTT >45 secs at 48 hours or >50 secs at 72 hours- rising plasma creatinine- Arterial pH <7.3 more than 24 hours after ingestion

Bark of willow tree was used in folk medicine for years for mild pain and fever. Salicylic acid was obtained by hydrolysis of the bitter glycoside obtained from this plant.

Acetylsalicylic acid was synthesized in 1853

1875 sodium salicylate was used in fever and pain.

1899 it was found to be effective in arthritis and was well tolerated.

Aspirin (acetyl salicylate)

Actions• Analgesic - central and peripheral action• Antipyretic - act in hypothalamus to lower the set

point of temperature control elevated by fever, also causes sweating

• anti-inflammatory - inhibition of peripheral prostaglandin synthesis

• respiratory stimulation - direct action on respiratory centre, indirectly by ↑ CO2 production

Effects of NSAIDs1. Analgesic and antipyretic actionAspirin is a weaker analgesic than morphine-type drugs

Aspirin 600 mg < Codeine 60 mg < 6 mg Morphine

Aspirin relieves inflammatory, tissue injury related, connective tissue and integumental pain but is rela-tively ineffective in severe visceral and ischemic pain. The analgesic action is mainly due to obtunding perip-heral pain receptors and prevention of PG mediatedsensitization of nerve endings. A central subcortical action, raising threshold to pain perception also contri-

butes. No sedation, tolerance, and dependence are produced.

Aspirin (acetyl salicylate)

• Metabolic effects i.) ↑ peripheral O2 consumption (uncoupled oxidative phosphorylation) hence ↑CO2 production with ↑ respiration, and direct analeptic action - respiratory alkalosis ii) renal loss of bicarbonate with sodium, potassium wateriii) dehydration iv) metabolic acidosis - effects on Krebs cycle, ↑ ketone body, salicylic acid in blood, renal insufficiency due to vascular collapse, dehydrationv) hypoglycaemia or even hyperglycaemia can occur

Aspirin (acetyl salicylate)

• Uricosuric effectsreduces renal tubular reabsorption of urate but treatment of gout requires 5-8g/d, < 2g/d may cause retention of urate.antagonises the uricosuric action of other drugs

• Reduced platelet adhesion- irreversible inhibition of COX by acetylation, prolongs bleeding time, useful in arterial diseaseNote: low doses are adequate for this purpose since the platelet has no biosynthetic capacity and can not regenerate the enzyme

• Hypothrombinaemia : occurs with large doses ie >5g/day

Alcohol increases GI toxicity of NSAIDs.

. Urate excretion. Aspirin in high dose reduces renaltubular excretion of urate (both substances are trans-ported by the same mechanism).

.

GIT. Aspirin and its metabolite salicylic acid irritate gastric mucosa and cause epigastralgia, nausea, andvomiting. In higher doses it also stimulates CTZ.Aspirin (pKa 3.5) remains unionized and diffusible inthe acid gastric juice, but on entering the mucosal cell(pH 7.1) it ionizes and becomes indiffusible. This“ion trapping” in the gastric mucosal cell enhances gastric toxicity.

Uses of Aspirin® (Bayer, 1899)As analgesic (300 to 600 mg during 6 to 8 h) for head-ache, backache, pulled muscle, toothache, neuralgias.As antipyretic in fever of any origin in the same doses as for analglesia..Acute rheumatic fever. Aspirin is the first drug ofchoice. Other drugs substitute aspirin only when itfails or in severe cases. Antirheumatic doses are 75 to100 mg/kg/24 h (resp. 4–6 g daily) in the first weeks.Rheumatoid arthritis. Aspirin a dose of 3 to 5 g/24 h after meal is effective in most cases. Since largedoses of aspirin are poorly tolerated for a long time, thenew NSAIDs (diclofenac, ibuprofen, etc.)

Aspirin (acetyl salicylate)

OVERDOSAGE• Ingestion of > 10 g can cause moderate/severe

poisoning in an adult• Clinical features - ‘salicylism’

tremor, tinnitus, hyperventilation, nausea, vomiting, sweating

• Management- mainly supportive

Aspirin therapy in children with rheumatoid arthritishas been found to raise serum concentration trans-aminases, indicating liver damage. Most cases are asymptomatic but it is potentially dangerous. An association between salicylate therapy and “Reye’s syndrome”, a rare form of hepatic encephalopathy seen in children, having viral infection(varicella, influenza), has been noted.Aspirin should not be given to children under 15years unless specifically indicated, e.g. for juvenilearthritis (paracetamol is preferred).

Postmyocardial infarction and poststroke patients.By inhibiting platelet aggregation in low doses (100 mgdaily) aspirin decreases the incidence of reinfarction.

Arachidonic acid

Cyclooxygenase (COX)

Endoperoxides

PGs TxA2

(-)

Aspirin

Thromboxane A2 synthase (-) 100 mg/24 h

>1 g/24 h

Drugs ResultDiuretics Decrease diuresis

Beta-blockers Decrease antihypertensive effectACE inhibitors Decrease antihypertensive effect

Anticoagulants Increase of GI bleedingSulfonylurea Increase hypoglycemic riskCyclosporine Increase nephrotoxicity

Alcohol Increase of GI bleeding

Drug interactions with NSAIDs

Ibuprofen is a derivative of phenylpropionic acid. In doses of 2.4 g daily it is is equivalent to 4 g of aspirin in anti-inflammatory effect. Oral ibuprofen isoften prescribed in lower doses (< 2.4 g/d), at whichit has analgesic but not antiinflammatory efficacy.

A topical cream preparation is absorbed into fascia and muscle.A liquid gel preparation of ibuprofen providesprompt relief in postsurgical dental pain.

It is effective in closing ductus arteriosus in preterm infants,with much the same efficacy as indometacin.

Ketoprofen is a propionic acid derivative thatinhibits both COX (nonselectively) and lipoxygenase.Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life.The effectiveness of ketoprofen at dosages of 100–300 mg/d is equivalent to that of other NSAIDsin the treatment of rheumatoid arthritis, osteoarthritis,gout, dysmenorrhea, and other painful conditions. In spite of its dual effect on prostaglandins and leukotrienes, ketoprofen is not superior to other NSAIDs. Its major adverse effects are on the GITand the CNS.

Phenylbutazone is a derivative of pyrazolidinedionewith a high GI toxicity. It is rarely used now.

Indomethacin is a potent nonselective COX inhibitorand may also inhibit phospholipase A and C, reduceneutrophil migration, and decrease T cell and B cellproliferation. Probenecid prolongs indometacin's half-life by inhibiting both renal and biliary clearance.Indometacin is indicated for use in juvenile rheumatoidarthritis, gout and ankylosing spondylitis, etc. It has been used to treat patent ductusarteriosus.

An ophthalmic preparation seems to be efficacious for conjunctival inflammation and to reducepain after traumatic corneal abrasion. Gingival inflammation is reduced after administration of indometacin oral rinse.

A high incidence (up to 50%) of GI and CNS side effects is produced: GI bleeding,diarrhoea, frontal headache, mental confusion, etc.

Diclofenac is a phenylacetic acid derivative. A 0.1% ophthalmic preparation is recommended forprevention of postoperative ophthalmic inflammationand can be used after intraocular lens implantationand strabismus surgery. A topical gel containing 3% diclofenac is effective for solar keratoses.

Diclofenac in rectal suppository form can be considered a drug of choice foranalgesia and postoperative nausea. It is alsoavailable for intramuscular and oral administration(Voltaren® and Feloran® – SR tablet: 100 mg/24 h).

Side effects occur in approximately 20%: GI distressand occult bleeding, gastric ulceration. A preparationcombining diclofenac and misoprostol (PGE1) decrea-ses upper GI ulceration but may result in diarrhoea.

British Journal of Oral and Maxillofacial SurgeryVolume 49, Issue 2, March 2011,

• Postoperative analgesia in orthognathic surgery patients: diclofenac sodium or paracetamol?

• Ayşegül Mine Tüzüner Öncül, Emre Çimen, , Zuhal Küçükyavuz, Mine Cambazoğlu• Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Ankara University, Besevler, Pe

• . Thirty patients were randomly allocated into two groups (n = 15 in each) using sealed envelopes. The first group was given paracetamol 1 g intravenously and the second diclofenac sodium 75 mg intramuscularly. The analgesics were given during the last 15 min of the operation while the mucosa was being sutured. The number of requests for further analgesia, and the amount of analgesia given postoperatively (as diclofenac sodium) were recorded. The intensity of postoperative pain was recorded on a visual analogue scale (VAS), and postoperative requests for analgesia, haemodynamic variables (systolic blood pressure and heart rate), and complications were compared. The groups were comparable. A single dose of diclofenac or paracetamol effectively decreases the intensity of postoperative pain after bimaxillary osteotomy.

PYRROLO-PYRROLE DERIVATIVE (Ketorolac)

Ketorolac A novel NSAID with potent analgesic and modest anti-inflammatory activity. In postoperative pain it has equaled the efficacy of morphine no interaction with opioid receptors and is free of respiratory depressant, dependence producing, hypotensive and constipating side effects.

Pharmacokinetics -

Ketorolac is rapidly absorbed after oral and i.m.

administration. It is highly plasma protein bound and

60% excreted unchanged in urine. Major metabolic

pathway is glucuronidation; plasma t1/2 is 5-7 hours.

Adverse effects Nausea, abdominal pain, dyspepsia, ulceration, loose stools, drowsiness, headache, dizziness, nervousness, pruritus, pain at injection site, rise in serumtransaminase and fluid retention have been noted..No significant drug interactions have been reported and it has been used concurrently with morphine. However, it should not be given to patients on anticoagulants..

Piroxicam, an oxicam (enolate derivative), is a nonselective COX-1/COX-2 inhibitor that at high concentrations also inhibits polymorphonuclearleukocyte migration, decreases oxygen radicalproduction, and inhibits lymphocyte function. Its long half-life permits once-daily dosing. Toxicity includes GI symptoms (20% of patients), dizziness, tinnitus, headache, rash.When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcerand bleeding is encountered. This risk is as much as10 times higher with piroxicam than with other NSAIDs.

Inhibiting activity rate (COX-2/COX-1)

•Aspirin•Indometacin•Meloxicam

155 60 0,8

(Preferential COX-2 inhibitor)

ClassicalNSAIDs

• Coxibs are selective COX-2 inhibitors. They exert• antiinflammatory, analgesic, and antipyretic action• with low ulcerogenic potential. Coxibs can cause• infertility. They have prothrombotic cardiovascular• risk. The ulcerogenic potential of preferential • COX-2 inhibitors Meloxicam, Nabumetone, and• Nimesulide (Aulin®) is significant

SULFONANILIDE DERIVATIVE (Nimesulide )

Nimesulide- this newer NSAID is a relatively weak

inhibitor of PG synthesis (may be somewhat selective for

COX-2); appears to exert its effects by other mechanisms like

reduced generation of superoxide by neutrophils, inhibition

of PAF synthesis and TNF release, free radical scavanging,

inhibition of metalloproteinase activity in cartilage.

HEPATOTOXICITY

Celecoxib is as effective as other NSAIDs in thetreatment of rheumatoid arthritis and osteoarthritis,and in trials it has caused fewer endoscopic ulcersthan most other NSAIDs. Probably because it isa sulfonamide, celecoxib may cause rashes. It does not affect platelet aggregation at usual doses.

Meloxicam is an enolcarboxamide related to piroxicam that has been shown to preferentially inhibit COX-2 over COX-1, particularly at its lowesttherapeutic dose of 7.5 mg/d. It is not as selective as the other coxibs and may be considered “preferentially" selective rather than “highly” selective.The drug has been approved for the treatmentof osteoarthritis and rheumatoid arthritis. It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen. Other toxicities aresimilar to those of other NSAIDs.

NSAIDs

Non selective Vs selective COX2 inhibitors

↑ risk of cardiovascular adverse events with COX 2 inhibitors

• Rofecoxib was withdrawn from the market• Higher BP, incidence of myocardial infarction, stroke• Mechanism _ ? Unopposed effect of cox 1 action

- ? Block protective effect of COX2 on ishaemic myocardium or

atherogenesis

Comparative action betweenCOX inhibitors

COX-1/COX-2inhibitors

COX-2inhibitors

1. Analgesic action (+) (+) (+)

2. Antipyretic action (+) (+)

3. Antiinflammatory action (+) (+) (+)

4. Antiplatelet aggregatory (+) (-)

5. Gastric mucosal damage (+) (+) (+) (+)

6. Renal salt / water retention (+) (+)

7. Delay/prolongation of labor8. Infertility

(+) (+)(-)

(+)(+) (+)

9. Ductus arteriosus closure (+) ?

10. Aspirin-like asthma 11. Cardiotoxicity

(+)(-)

?(+) (+)

OUT OF DATE

Many severe side effects•Infertility (> PGF2α)•Thrombosis (< PGI2; > TxA2)

Bextra® (Valdecoxib): Pfizer (penalty!)

OUT OF DATE

DERIVATIVES OF ACIDSSalicylates

Acetylsalicylic acid (Aspirin®, 1899), DiflunisalMethyl salicylate (revulsive drug)

Phenylacetates: Acelcofenac, DiclofenacIndolacetates: Indometacin, SulindacEnolates (oxicams)

Piroxicam, Piroxicam beta-cyclodextrin (prodrug), Lornoxicam, Tenoxicam

Propionates Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen

OTHERS (with less application)Pyrazolones: Phenazone, Propyphenazone, etc.Pyrazolidinediones: Oxyphenbutazone, Phenylbutazone

Nonselective COX-1/COX-2 inhibitors

Beneficial actions of NSAIDs dueto prostanoid synthesis inhibition1. Analgesia

prevention of pain nerve ending sensitization2. Antipyresis

connected with influence of thermoregulatorycentre in the hypothalamus

3. Antiinflammatory actionmainly antiexudative effect

4. Antithrombotic actionin very low daily doses

5. Closure of ductus arteriosus

Shared toxicities of NSAIDs dueto prostanoid synthesis inhibition1. Gastric mucosal damage

connected with PGE inhibition 2. Bleeding: inhibition of platelet

function (TxA2 synthesis)3. Limitation of renal blood flow

Na+ and water retention4. Delay / prolongation of labour

connected with PGF2α inhibition5. Asthma and anaphylactoid reactions

connected with PGF2α inhibition

Mechanisms by which NSAIDs may induce mucosal injury Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

Brain’s opiate systemEndorphin & Enkephalin

• multiple areas of brain show opiate receptors • Enkephalin and Leu-Enkephalin---Brain stem

and spinal cord• -Endorphine—Hypothalamus and spinal

cord• Dynorphin-- Brain stem and spinal cord

Endorphins

• Behave like morphine & bind to opiate receptors to obtund pain Like morphine

• B – endorphin closely related to pituitary function• May act like hormone. • The Enkephalin & endorphins have antinociceptive

effects, • Underlying mechanism not fully analyzed

Brain’s Opiate system• 3 major components • 1. Periaqueductal gray and periventricular nucleus—

Enkephalinergic fibers

• 2. Raphe Magnus nucleus,—Serotonergic fibers

• 3. A pain inhibitory complex located in dorsal horns of spinal cord—Enkephalinergic fibers

• At this point, the analgesia signals can block the pain before it is relayed to the brain.

NSAIDS

Opioids

OPIATE ANALGESICS

Classification• Low efficacy Codeine

DihydrocodeineDextropropoxyphene

• Medium efficacy Bupranorphine

• High efficacy MorphineDiamorphinepethidine

OPIATE ANALGESICS

Routes of administration• Oral• Parenteral• Suppositories• Transdermal- Patch• s/c Syringe driver

OPIATE ANALGESICS

Mechanism of action

• Bind to CNS opioid receptors whose natural ligands are endorphins and encephalins.

OPIATE ANALGESICS

Actions• CNS

Depression StimulationAnalgesia vomitingRespiratory depression miosisDepression of cough reflex ↑ spinal reflexes sleep (convulsions)

mood changes- Euphoria

Dependence – also affects other systems

OPIATE ANALGESICS

• Smooth muscle stimulationGI muscle spasm causing delayed transit and constipationBiliary spasmBronchospasm

• CardiovascularDilation of resistance vessels (arterioles) and capacitance vessels (veins)

OPIATE ANALGESICSDependence• Up to 8 h- Mild psychological withdrawal stress• 8-12 h - increasing nervousness, restlessness and anxiety• 12-24h - yawning, sweating, runny eyes and nose• 24 h - pupils dilate, waves of goose flesh• 36 h - twitching of muscles, leg & abdominal cramps

vomiting and diarrhoea and anorexia, insomnia tachypnoea, ↑ BMR and mild pyrexia

• 48-72 h - peak withdrawal symptoms• up to 10 d- symptoms gradually subside• Complete recovery requires 3-6 months• Note : Withdrawal syndrome can be in part alleviated by long

acting opioid such as methadone

OPIATE ANALGESICS

Opioid overdose• Death usually due to respiratory depression• Cardiovascular function usually well preserved

unless severe anoxia• Treatment with iv naloxone • May need infusion - naloxone has shorter t1/2

(1h), particularly for opioids with long t1/2 –

(methadone) and tight binding (bupranorphine)

Morphine is naturally occurringsubstance of the juice in the

unripe seedpods of the opium poppy.

It is a potent narcotic analgesic, and its primary clinicaluse is for moderately severe and severe pain.

After heroin, morphine has the greatest dependence liabilityof the narcotic analgesics in common use.

It is legally available only in the

form of water-soluble salts, such as

Morphine sulfate and

Morphine hydrochloride. Morphine is

taken orally, injected or inhaled, or taken

through rectal suppositories.

Morphine is so effective because it acts directly atpain-modulating receptors in the nervous system, termed

opioid receptors. The receptors respond to naturalcompounds built by our bodies to control the level

of pain experienced at different times.

Although morphine remains the most effective drug for pain relief, it is far from perfect. Morphine’s pharmacological effect is on the nervous system and the gastrointestinal tract. Morphine is highly addictive and tolerance and physical and psychological dependence develop quickly.

TRAMADOL

Acute Pain

• Many small studies vs. opioids– Likley = morphine in equi-analgesic doses (T:M =

~10:1) up to 400 – 600mg/day maximum• Many small studies vs. non-opioids

– Similar analgesia compared to NSAIDs post-operatively in a variety of doses

Grond S, et al. Clin Pharmacokin 2004;43:879-923.

How does it work?

• Weak -opioid receptor effects– Structurally related to morphine and codeine

• ~10-fold less affinity for receptor than codeine and up to 6000-fold less than morphine

• Metabolized to highly active M1 300-fold greater affinity than parent compound

– Analgesia only partially blocked by naloxone (~33%)

• Serotonin and norepinephrine reuptake inhibition

Grond S, et al. Clin Pharmacokin 2004;43:879-923.Raffa RB. J Clin Pharm Therap 2008;33:101-8.

• Analgesic and adjuvant anesthetic effect of submucosal tramadol• after mandibular third molar surgery• Marcelo Minharro Ceccheti• University of Sao Paulo, São Paulo, Brazil( ORAL SURG ORAL PATHOL.ORAL RADIO 2012)• The aim of this study was to assess analgesic and adjuvant anesthetic effects of

submucosal tramadol after third• molar extraction.• . Submucosal tramadol injection after oral surgery improved postoperative analgesia, but

did not extend duration of anaesthesia

Pre-Emptive Analgesic Effectiveness ofMeloxicam Versus Tramadol AfterMandibular Third Molar Surgery:A Pilot StudyMario A. Isiordia-Espinoza, DDS, MS,*Martín Sánchez-Prieto, DDS,† Francisco Tobías-Azúa, DDS,‡and Juan G. Reyes-García, PhD§© 2012 American Association of Oral and Maxillofacial Surgeons 70;31-36.2012

To compare the pre-emptive analgesic effectiveness of 15 mg of meloxicam and 50 mg oftramadol after mandibular third molar surgery.

Conclusion: The patients receiving 15 mg of preoperative meloxicam had less pain intensity and totalanalgesic consumption than those receiving 50 mg of preoperative tramadol.

RECENT TRENDS OF ANALGESIA

Acupuncture and Electroacupuncutre 

1. Needle acupuncture2. Electroacupuncutre.release of B- endorphin intoPeripheral circulation.current applied at specific site

whereDeeper nociceptors available to

bestimulated .profound analgesic effect for 1

hr

Pain – Gene THERAPY

• Gene transfer technology to manipulate specific, localized biochemicalpathways involved in pain generation.

• useful in ch.pain• viral mediated transfer of

genes encoding opiate peptides to peripheral and central neurons

ELECTRONIC ANALGESIA

• History in 46 AD, Scribonius Largus, physician to

emperor Claudius, used the torpedo fish to relieve the pain of gout.

Mechanism of action (TENS )• At the low frequency of 2Hz ,which is most often used in management of

pain, TENS produces measurable changes in the blood levels of 1-tryptophan, serotonin, and beta endorphins.

• Serotonin possess analgesic actions, elevating the pain reaction threshold

• Simultaneously levels of beta endorphins and encephalin increases in the cerebral circulation

Pharmacological behaviour managment

102

CONSCIOUS SEDATION

• Conscious sedation is a minimally depressed level of consciousness that retains the patient’s ability to maintain an airway independently and respond appropriately to physical stimulation and / or verbal command, such as “open your eyes”.

Nitrous oxide

• Non- irritant, sweet smelling and colorless gas, not inflammable, not explosive but support combustion.

• Concentrations of 35% to 40% enhance the sedative effects and have the degree of analgesia equivalent of 15mg of morphine.

• It attains its peak effect in 3-5 min, first symptom appearing in less than 1 min.

• It does not combine with any body tissue and is eliminated unchanged through the lungs in less than 5 min.

Pharmacological behaviour managment

104

DRUG ROUTE OF ADMINSTRATION

DOSAGE

MIDAZOLAM ORAL INTRAMUSCULARINTRAVENOUSINTRANASAL

Oral Dosage in children under 25 kg of weight--0.3-0.5 mg/kg Maximum dose 12 mg.Children over 25kg of weight--12mg1 to 0.15 mg/kg to a maximum dose of 10 mgSlow IV titrationIt produces sedative effect within 5 mins of administration.

FLUMAZENIL(ROMAZICON)

INTRAVENOUS 0.01mg/kg upto 0.2mg maximum dose of 1mg

CHORAL HYDRATE(Noctec, Aquachloral Supprettes)

ORALRECTAL

25 to 50 mg/kg to a maximum of 1 gm325, 500 and 650 mg.

NSAIDS IN PREGNANCY

• ANALGESICS: - Codeine causes fetal toxicity (FDA-C)in 1st trimester can use

in 2nd or 3rd trimester. - Morphine & Meperidine is safe for short period, chronic use

causes fetal toxicity (FDA-B).

- NSAID: Inhibition of prostaglandin synthesis can cause premature closure of fetal ductus arteriosus constricture which will induce primary pulmonary hypertension and fetal bleeding tendencies.

Aspirin—not used (FDA-C/D). Acetaminophen (FDA-B).-safe in all trimesters Ibuprofen (FDA-B)- avoid in third trimester can close the

pda. Cox-2 inhibitors (FDA-C) avoid in third trimester can close

the pda.

• BEST ANALGESICS EVER DISCOVERED OR INVENTED TILL DATE !!!!!!

HEALTHY SMILES NURTURING OUR NEURONS

REFERENCES

• KD TRIPATI, ESSENTIALS OF MEDICAL PHARMACOLOGY

• LIPPINCOTT • WWW. SCIENCE DIRECT.COM• Selzer—Pain control and diagnosis in dentistry• Guyton—Textbook of physiology