AnalgesicsAnalgesics

Dr. Amit T. SuryawanshiOral and Maxillofacial Surgeon

Pune, India

Contact details :Email ID - amitsuryawanshi999@gmail.com

Mobile No - 9405622455

Contents Contents Introduction

– Pain– Analgesia

Analgesics Classification of analgesics NSAID’s

– History– Classification of NSAID’s– Mechanism of action– Adverse effects– Individual drugs

ContentsContents Opioids

– Classification of opioids– Individual drugs– Opioid receptors– Complex action opioids and opioid antagonists

- Opioids in dental pain Analgesics and Medical conditions Adjuvant drugs Future of Analgesics References

Pain -Pain - “ An unpleasant emotional experience usually

initiated by a noxious stimulus and transmitted over a specialized neural network to the central nervous system where it is interpreted as such ”

- Monheim’s

“Pain is whatever the experiencing person says it is and exists whenever he says it does.”

Introduction Introduction

Goals of pain managementGoals of pain management

To relieve sufferingTo increase functional capacityTo improve quality of life

Methods of pain controlMethods of pain control

1. Removing the cause

2. Blocking the pathway of painful impulses

3. Raising the pain threshold

4. Preventing pain reaction by cortical depression

5. Using psychosomatic methods

What is Analgesia?What is Analgesia? The word analgesia is derived from Greek word

analgetos (an – without ; algesia – pain )

‘Analgesia simply means the absence of pain without losing consciousness’

“The analgesia system is mediated by 3 major components :

1. Periaquaductal grey matter

2. Nucleus raphe magnus

3. Pain inhibitory neurons

Analgesics

“Analgesics are drugs that selectively relieve pain by acting in the CNS or on the peripheral pain mechanisms, without altering consciousness”

Definition -

History of AnalgesicsHistory of Analgesics BC:BC: Ancient Greeks and Romans used salicylate

extracts derived from willow leaves as analgesics and antipyretics

Middle Ages: Medicinal herb gardens featured salicylate containing wintergreen and meadowsweet plants

1763: Edward Stone reported on use of willow bark powder as an anti-inflammatory agent.

1853: Von Gerhardt synthesized a crude form of aspirin (acetylsalicylic acid)

1860: Felix Hoffman synthesized pure aspirin

continued Opiates are one of the oldest types of drugs in history Opium is extracted from poppy seeds (Paper

somniforum)

Undisputed reference to opium found in writings from the third century BC

Use of Opium was first recorded in China over 2000 years ago

Greeks dedicated the Opium poppy to the Gods of Death (Thanatos), Sleep (Hypnos), and Dreams (Morpheus)

Sixteenth Century is the first reported use of Opium for its Analgesic qualities

Contnd…

1949: The NSAID Phenylbutazone was introduced 1963: Indomethacin was introduced

1971: Vane and Piper demonstrated that NSAIDs inhibit prostaglandin production

1974: Ibuprofen was introduced

1976: Miyamoto et al identified the COX-1 enzyme 1989: Simmons et al identified the COX-2 enzyme

1999: The COXIBs celecoxib and rofecoxib were introduced 2004: Rofecoxib was banned in india due to its cardiotoxic effect .

Classification of NSAIDsClassification of NSAIDs

Non selective COX inhibitors (conventional NSAID’s)– Salicylates: Asprin– Propionic acid derivatives: Ibuprofen, Naproxen,

Ketoprofen, Flurbiprofen

– Anthranilic acid derivative: Mephenamic acid– Aryl-acetic acid derivatives: Diclofenac– Oxicam derivatives: Piroxicam, Tenoxicam

– Pyrrolo-pyrrole derivative: Ketorolac– Indole derivative: Indomethacin– Pyrazolone derivatives: Phenylbutazone,

Oxyphenbutazone

Classification of NSAIDClassification of NSAID’’s s contdcontd……

Preferential COX-2 inhibitors– Nimesulide, Meloxicam, Nabumetone

Selective COX-2 inhibitors– Celecoxib, Rofecoxib, Valdecoxib, Etoricoxib

Analgesics-antipyretics with poor anti inflammatory action– Para aminophenol derivative: Parcetamol

(Acetaminophen)– Pyrazolone derivatives: Metamizol (Dipyrone),

Propiphenazone– Benzoxazocine derivative: Nefopam

NSAIDs and prostaglandin (PG) NSAIDs and prostaglandin (PG) synthesis inhibitionsynthesis inhibition

Prostaglandins, prostacyclin (PGI2) and thromboxane A2(TXA2) are produced from arachidonic acid by the enzyme cyclo oxygenase which exists in 2 forms

– (COX-1) - Cyclo oxygenase -1– (COX-2) - Cyclo oxygenase -2

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

• Some selective COX-2 inhibitors have now been produced

Cellular Arachidonic Acid MetabolismCellular Arachidonic Acid Metabolism

Stimulus

Phospholiapase A2

Lipoxygenases

Inflammatory

Leukotrienes

Cyclo oxygenase pathwayCyclo oxygenase pathway

Beneficial actions due to PG Beneficial actions due to PG synthesis inhibitionsynthesis inhibition

AnalgesiaAnti pyresisAnti inflammatoryAnti thrombotic

Toxicities due to PG synthesis Toxicities due to PG synthesis inhibitioninhibition

Gastric mucosal damage Bleeding: inhibition of platelet function Limitation of renal blood flow: sodium and water

retention Delay / prolongation of labour Asthma and anaphylactic reactions in susceptible

individuals

Adverse effects of NSAIDAdverse effects of NSAID’’ss

Gastrointestinal– Gastric irritation, erosions, peptic ulceration,

gastric bleeding / perforation, esophagitis

Renal– Sodium and water retention, chronic renal

failure, interstitial nephritis, papillary necrosis (rare)

Hepatic – Raised transaminases, hepatic failure (rare)

Adverse effects of NSAIDAdverse effects of NSAID’’ss CNS

– Headache, mental confusion, behavioural disturbances, seizure precipitation

Haematological– Bleeding, thrombocytopenia, hemolytic

anaemia, agranulocytosis

Others– Asthma exacerbation, nasal polyposis, skin

rashes, pruritis, angioedema

NSAID - GI toxicityNSAID - GI toxicity

Routes of analgesic administrationRoutes of analgesic administration

OralIntramuscular InjectionIntravenous InjectionOther routes

– Transdermal• Fentanyl patch

– Sublingual • Morphine

Salicylates -Asprin Salicylates -Asprin Is acetylsalicylic acid

Pharmacological actions– Analgesic, antipyretic, anti inflammatory actions

• Analgesic action is due to prevention of PG mediated sensitization of nerve endings

• Resets the hypothalamic thermoregulatory centre• Anti inflammatory at high doses

– Blood• Irreversibly inhibits TXA2 synthesis thus interferes

with platelet aggregation and BT is prolonged• Long term use of large doses decreases synthesis of

clotting factors in liver

AspirinAspirin– Respiration

• Anti inflammatory doses – stimulates respiration• Hyperventilation in salicylate poisoning, in doses

higher than this there is respiratory depression

– Acid-base electrolyte balance• Adults treated with aspirin 4-6g/day stay in a state of

compensated respiratory alkalosis • Still higher doses can cause respiratory acidosis• Dehydration occurs in poisoning due to increased

urine output, sweating and hyperventilation

– CVS• No direct effect in therapeutic doses

AspirinAspirin

– GIT• Aspirin irritates gastric mucosa & causes epigastric

pain, nausea and vomiting• ‘Ion trapping’ in gastric mucosa increases gastric

toxicity• Acute ulcers, erosive gastritis, congestion and

microscopic hemorrhages

– Metabolic effects• Chronic use can cause negative nitrogen balance by

increased conversion of protein to carbohydrate.

AspirinAspirin

Pharmacokinetics– Absorbed from stomach and small intestine

Precautions and contraindications– Contraindicated in patients sensitive to it and in

peptic ulcer, bleeding tendencies, & in children suffering from chicken pox or influenza. (due to risk of Reye’s syndrome)

– In chronic liver disease– Asprin should be stopped 5 days before elective

surgery, dental extraction– Pregnancy and lactating mothers

AsprinAsprin

Adverse effects– Most important – gastric mucosal damage and

peptic ulceration– Acute salicylate poisoning– Assosiated with Reye’s syndrome

Uses– As analgesic– As antipyretic– Acute rheumatic fever– Rheumatoid arthritis– Osteoarthritis

Propionic acid derivativesPropionic acid derivatives

Ibuprofen – first introduced member of this class Anti inflammatory efficacy is lower than asprin Inhibit Prostaglandin synthesis

Adverse effects– Milder and better tolerated than asprin– GI disturbances are present– Precipitate asprin-induced asthma

Propionic acid derivativesPropionic acid derivatives

Pharmacokinetics– Well absorbed orally

Uses– Analgesic and Antipyretic and anti-inflammatory– Soft tissue injuries, tooth extraction, fractures, post

operative pain.– Rheumatoid arthritis, osteoarthritis and

musculoskeletal disorders… where pain is more prominent than inflammation

Anthranilic acid dervativeAnthranilic acid dervative Mephenamic acid-

– Inhibits COX & antagonises certain actions of PG’s– Exerts peripheral as well as central analgesic action

Pharmacokinetics– Oral absorption is slow but complete

Adverse effects - Diarrhoea

Uses– Muscle, joint and soft tissue pain– Effective in dysmenorrhoea

Aryl-acetic acid derivativeAryl-acetic acid derivative Diclofenac sodium

– Inhibits PG synthesis– Has short lasting anti platelet action– Adverse effects are mild

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

Uses– Toothache– Post operative and post traumatic inflammatory conditions– Rheumatoid arthritis and osteoarthritis

Oxicam derivativesOxicam derivatives

Piroxicam -– Long acting NSAID– Reversible inhibitor of COX

Pyrrolo-pyrrole derivativeKetorolac

– Potent analgesic and moderate anti inflammatory activity

– Used in post operative pain after surgery and acute dental pain

Indole derivativeIndole derivativeIndomethacin

– Potent antiinflammatory and antipyretic action– High incidence of GI and CNS side effects.

Pyrazolones derivative Metamizol and propiphenazone are used as analgesic

and antipyretics

Preferential COX-2 inhibitorsPreferential COX-2 inhibitorsNimesulide

– Newer NSAID– Completely absorbed orally– Used in patient with history of asthma and

anaphylactic reactions to other NSAIDs.– Used for short-lasting painful inflammatory

conditions like - - sports injuries, - sinusitis and other ENT disorders - fever and low back pain

Adverse effect – Hepatotoxic in pediatric patients .

• Recently instances of hepatic failure have been reported

Para-amino phenol derivativesPara-amino phenol derivativesParacetamol (Acetaminophen) -

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

– Has weak peripheral anti inflammatory component– Promptly acting antipyretic

Pharmacokinetics– Well absorbed orally– Effects after oral dose last for 3-5 hours

Adverse effects– Acute paracetamol poisoning – children

Paracetamol (Acetaminophen)Paracetamol (Acetaminophen)

Uses –

– Most commonly used drug & One of the best antipyretic drugs

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

Clinical studies have found paracetamol and asprin to be equally effective in relieving pain after 3rd molar extraction

And it is more safer than asprin – lesser GI disturbances and bleeding tendencies

Opioid analgesicsOpioid analgesics

Classification of opioidsClassification of opioids

Natural opium alkaloids– Morphine, codeine

Semi synthetic opiates– Diacetylmorphine (heroin), pholcodeine

Synthetic opioids– Pethidine (meperidine), fentanyl, methadone,

dextropropoxyphene, tramadol

Morphine Morphine

– Alkaloid of opium– Widely used

Pharmacological actions CNS

– Analgesia• Strong analgesic• Nociceptive pain arising from peripheral pain

receptors is better relieved than neuritic pain• Reactions associated with intense pain –

apprehension, fear are also depressed

MorphineMorphine

– CNS– Sedation

• Drowsiness and indifference to surroundings as well as to own body , ataxia and apparent excitement also occur

• Higher doses produce sleep and coma

– Mood and subjective changes• Calming effect• Loss of apprehension, feeling of detachment,mental

clouding and inability to concentrate

MorphineMorphine

– Respiratory and cough centres• Depresses Repiration and Cough centre

– Temperature regulating and vasomotor centre• Depressed

– CTZ, vagal centre & certain cortical areas are stimulated

– GIT• Constipation is a prominent feature

MorphineMorphine

Neuro-endocrine– Enhances ADH release and so urine volume is reduced– Causes sympathetic stimulation – mild hypoglycemia

CVS– Causes vasodilation– Cardiac work is consistently reduced due to decrease in

peripheral resistance

MorphineMorphine Pharmacokinetics

– Oral absorption is unreliable – high and variable first pass metabolism

– Freely crosses placenta, affects foetus more than the mother

Adverse effects– Mental clouding, sedation and lethargy– constipation– Acute morphine poisoning

• Human lethal dose is 250mg .• Death is due to respiratory failure

MorphineMorphine Tolerance and dependence

– Partly pharmacokinetic (enhanced rate of metabolism) but mainly pharmacodynamic (cellular tolerance)

– Treated by substitution with oral methadone

Precautions and contraindications– Infants and elderly– Bronchial asthma– Head injury

Codeine Codeine

Is methyl morphine Less potent than morphine (1/10th as analgesic) Is more selective cough suppressant

Pethidine Pethidine

Synthesized as an atropine substitute Interacts with opioid receptors (mu) Similar to morphine in most of its properties

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

Methadone Methadone

Chemically dissimilar but pharmacologically similar to morphine

Used– primarily as substitution therapy for opioid

dependence– Also in methadone maintenance therapy

Tramadol Tramadol

Centrally acting analgesic It is believed to work through modulation of serotonin

and norepinephrine in addition to its relatively-weak μ-opioid receptor agonism

100mg tramadol IV is equally analgesic to 10mg morphine IM

Uses– Mild to moderate intensity short lasting pain due to

surgery, dental procedures, injury etc

Opioid receptorsOpioid receptors

Opioids interact with specific receptors present on neurons in the CNS and peripheral tissues

Radioligand binding studies divide receptors into– mu, kappa and delta

Pattern of effect of particular agent depends on the nature of its interaction with different opioid receptors and also its relative affinity to these receptors

Complex action opioids and opioid Complex action opioids and opioid antagonistsantagonists

Agonist- antagonist – Nalorphine– Pentazocaine– Butorphanol

Partial /weak agonist– Buprenorphine

Pure antagonist– Naloxone, naltrexone

Pentazocaine Pentazocaine Indicated in post operative and moderately severe

pain in trauma, cancer and burns,

Naloxone

Competitive antagonist for all opioid receptors Injected i.v (0.4- 0.8mg) it antagonizes all actions

of morphine Drug of choice in morphine poisoning

Opioids in dental pain Opioids in dental pain Opioids are less effective and suitable than NSAID’s for

dental pain

Mostly used as additional drugs with NSAID’s to boost their analgesic effect

Among opioids oral codeine is most suitable

Oral tramadol and pentazocine are alternatives

Injectable opioids like morphine, pethidine are limited to intra-operative use to supplement anaesthesia and to allay apprehension

Analgesics & Medical conditionsAnalgesics & Medical conditions

NSAIDs should be given in 2nd triemister of pregnancy and opioids should be avoided .

Paracetamol is the safest drug to use in pregnancyAspirin & Ibuprofen should not be given in

asthmatic patientsAspirin & Paracetamol should not be given in

nephropathy.Codein should not be used in renal dysfunction

while fentanyl & methadone are safe .

Adjuvant drugs Adjuvant drugs To supplement the action of analgesics To limit the side effects of analgesics

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

Adjuvant medications are mostly used for chronic pain

FUTUREFUTURE

Fentanyl patches Tramadol patches Diclofenac patches

Patient controlled transdermal system

ReferencesReferences

GOODMAN & GILLMAN PHARMACOLOGY

Lippincott's Pharmacology

Rang & Dale's Pharmacology Essentials of Medical pharmacology – KD Tripathi

Essentials of Dental pharmacology – KD Tripathi Oral and Maxillofacial surgery –Vol. 1 - Danial Laskin

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