ANALGESICSANALGESICS

TYPES OF PAIN

symptomsymptom

PainPain

diseasedisease physphysologologicicalal

painpain

acutacutee patpathhologicologicalal

PainPain

cchhronicronic

PAIN CLASIFICATION

somaticsomatic

nociceptivnociceptivee

visceralvisceral

painpain

neuropaticneuropatic

nonnociceptivnonnociceptivee

pspsyyhogenhogenicic

R. Kannev, Pain Management Secrets, 1997R. Kannev, Pain Management Secrets, 1997

TREATMENT OF PAINLocal anesthetics

InfiltrationIntravenousEpiduralIntrarahidian

General anesthetics :InhalatoryIntravenousIntrarectalEpidural

TREATMENT OF PAINAnalgesics

Opioids Natural Semisynthetics synthetics

Non-opioids Inhibitors of COX1,2,3 Alfa 2 agonists 5HT agonists NMDA antagonists

TREATMENT OF PAIN

Class/ RepresentativesClass/ Representatives

CoanalgezicCoanalgezicss:: TricyclicTricyclic

antidepressantantidepressantss;; neurolepticneurolepticss;; anticonvulsantanticonvulsantantsants;; MMuscle ruscle rrelaxantrelaxantss;; calcitonincalcitoninee;; adenosineadenosineee;; metoclopramide;metoclopramide;

Calcium channel blockersCalcium channel blockers;; cannabinoidcannabinoiddsds;; GABA-agonistGABA-agonistss;; L-dopa;L-dopa; capsaicincapsaicinee;; antianti-ar-arrrhyhytthhmmiasias;; antiviralantiviralss..

ParaanalgeParaanalgessssicicss:: CorticoiCorticoids ds ((in inflammatory painin inflammatory pain);); nitritnitritee ( (in pectoris anginain pectoris angina);); antacidantacidss ( (ulcer diseaseulcer disease);); acetazolamidacetazolamidee ( (in glaucomasin glaucomas).).

CHRONOLOGICAL MARKERS

18031803 Morphin isolation from Morphin isolation from opiumopium

18741874 HeroinHeroinee – sem – semiissyyntnthesishesis

19391939 PetidinPetidinee – s – syyntnthesishesis

19521952 total sytotal syntnthheesissis of morphynof morphyn

1971-1971-19741974

Isolation of Isolation of opioiopioid d receptorsreceptors

1974 -1974 -19751975

IIsolation ofsolation of encephalin encephalinss

1976-1976-19861986

IIssolaolation oftion of endor endorphinesphines

↓↓ the list goes on….….

Non-opioid analgesicsNon-opioid analgesicsOpioid analgesicsOpioid analgesicsDrugs for neuropathic and Drugs for neuropathic and

functional painfunctional painAntimigraine drugsAntimigraine drugs

Acetaminophen (paracetamol)Acetaminophen (paracetamol)NSAIDs – non selectiveNSAIDs – non selective

- Selective Cox 2 inhibitors- Selective Cox 2 inhibitors

NONOPIOID ANALGESICSNONOPIOID ANALGESICS

ANALGESICS-ANTIPIRETICS-NONSTEROIDALANTIINFLAMMATORY AGENTS

Non selective inhibitors of COX•Organic acids

• Salicitats – acetic acid, sodium salicilate, diflunisal, sulfasalazine, olsalasine

• Heteroaril acetic acid deriv – indometacin, sulindac• Aril propionic deriv – tolmetin, diclofenac, ketorolac• Arilpropionic deriv – ibuprofen, naproxen, flurbiprofen• Antranilic deriv (fenamats) – mefenamic acid,

meclofenamic acid• Enolic acid deriv – piroxicam, meloxicam

•Non acidic compounds • Pirazolone deriv – metamizol (dipyrone)• Para-amino-fenol deriv – acetaminofem, fenacetine• Fenazone deriv – fenazone, propifenazone

ANALGESICS-ANTIPIRETICS-NONSTEROIDALANTIINFLAMMATORY AGENTS

Selective inhibitors of COX2•Sulfonanilide – nimesulide•Coxibi (furanone/pirazolone diaril-substitute) – rofecoxib, celecoxib•Indol-acetic acids - etodolac

NSAIDsNSAIDsClassificationsClassificationsMild to moderate anti-inflammatory actionMild to moderate anti-inflammatory action

-- propionic acid derivativespropionic acid derivatives ibuprofen, ibuprofen, naproxennaproxen

-- fenamic acidsfenamic acids mefanamic acidmefanamic acid

Marked anti-inflammatory actionMarked anti-inflammatory action-- salicylic acidssalicylic acids aspirinaspirin-- pyrazolone derivativespyrazolone derivatives azapropazone, azapropazone,

phenylbutazonephenylbutazone-- acetic acid derivativesacetic acid derivatives diclofenac, diclofenac, indomethacinindomethacin-- oxicam derivativesoxicam derivatives piroxicampiroxicam

Selective COX2 inhibitorsSelective COX2 inhibitors celecoxib, celecoxib, rofecoxibrofecoxib

Aspirin (acetyl salicylate)Aspirin (acetyl salicylate)

ActionsActionsAnalgesicAnalgesic - central and peripheral action - central and peripheral actionAntipyreticAntipyretic - act in - act in hypothalamushypothalamus to to

lower the set point of temperaturelower the set point of temperature control elevated by fever, also causes control elevated by fever, also causes sweatingsweating

anti-inflammatoryanti-inflammatory - inhibition of - inhibition of peripheral prostaglandin synthesisperipheral prostaglandin synthesis

respiratory stimulationrespiratory stimulation - direct action on - direct action on respiratory centre, indirectly by ↑ CO2 respiratory centre, indirectly by ↑ CO2 productionproduction

Aspirin (acetyl salicylate)Aspirin (acetyl salicylate)Metabolic effectsMetabolic effects

↑↑peripheral Operipheral O22 consumption consumption (uncoupled oxidative (uncoupled oxidative phosphorylation) hence ↑CO2 production phosphorylation) hence ↑CO2 production

with ↑ with ↑ respiration, and direct analeptic action respiration, and direct analeptic action - - respiratory respiratory alkalosisalkalosis

renal loss ofrenal loss of bicarbonate with sodium, potassium bicarbonate with sodium, potassium and waterand water

DehydrationDehydrationmetabolic acidosismetabolic acidosis - effects on Krebs cycle, ↑ - effects on Krebs cycle, ↑

ketone ketone body, salicylic acid in blood, renal body, salicylic acid in blood, renal insufficiency due to insufficiency due to vascular collapse, vascular collapse, dehydrationdehydration

hypoglycaemia or even hyperglycaemia can occurhypoglycaemia or even hyperglycaemia can occur

Aspirin (acetyl salicylate)Aspirin (acetyl salicylate)Uricosuric effectsUricosuric effects

reduces renal tubular reabsorption of uratereduces renal tubular reabsorption of urate but but treatment of gout requires 5-8g/d, treatment of gout requires 5-8g/d,

< 2g/d may cause retention of urate< 2g/d may cause retention of urateantagonises the uricosuric action of other drugsantagonises the uricosuric action of other drugs

Reduced platelet adhesion Reduced platelet adhesion –– irreversible inhibition of COX by acetylation, irreversible inhibition of COX by acetylation,

prolongs bleeding time, useful in arterial diseaseprolongs bleeding time, useful in arterial disease

Note: Note: low doses are adequate for this purpose since low doses are adequate for this purpose since the platelet has no biosynthetic capacity and can not the platelet has no biosynthetic capacity and can not regenerate the enzymeregenerate the enzyme

HypothrombinaemiaHypothrombinaemia : occurs with large doses ie : occurs with large doses ie >5g/day>5g/day

Aspirin (acetyl salicylate)Aspirin (acetyl salicylate)

OVERDOSAGEOVERDOSAGEIngestion of > 10 g can cause moderate/severe Ingestion of > 10 g can cause moderate/severe

poisoning in an adultpoisoning in an adultClinical features - Clinical features - ‘salicylism’‘salicylism’

TremorTremorTinnitusTinnitusHyperventilationHyperventilationNauseaNauseaVomitingVomitingsweatingsweating

Management- mainly supportiveManagement- mainly supportive

PARACETAMOLPARACETAMOL ((acetaminophen)acetaminophen)

equivalent analgesicequivalent analgesic efficacy to efficacy to aspirinaspirin

no useful anti-inflammatory actionno useful anti-inflammatory actionused for used for mild to moderate painmild to moderate pain, ,

but aspirin is preferred if due to but aspirin is preferred if due to inflammatory processinflammatory process

PARACETAMOLPARACETAMOL ((acetaminophen)acetaminophen)

MetabolismMetabolismis is conjugatedconjugated in the liver in the liver as the inactive glucuronide as the inactive glucuronide

and sulphateand sulphatea number of minor a number of minor oxidation productsoxidation products

N-acetylbenzoquinoneimine (N-acetylbenzoquinoneimine (NABQI)NABQI) are also formed are also formedNABQI is highly chemically reactiveNABQI is highly chemically reactive and is usually and is usually

inactivated by conjugation with SH (thiol)inactivated by conjugation with SH (thiol) groups groups of glutathioneof glutathione

Supply of glutathione is limited and exhausted in Supply of glutathione is limited and exhausted in overdoseoverdose

NABQI then reacts with cellular macromolecules and NABQI then reacts with cellular macromolecules and causes cell deathcauses cell death

PARACETAMOLPARACETAMOL ((acetaminophen)acetaminophen)

Adverse effectsAdverse effectsrare in therapeutic usagerare in therapeutic usageoccasional skin rash and allergyoccasional skin rash and allergyoverdose can result in overdose can result in fulminant hepatic fulminant hepatic

necrosisnecrosis and liver failure and liver failure

PARACETAMOLPARACETAMOL ((acetaminophen)acetaminophen)

Paracetamol overdoseParacetamol overdoseIngestion of Ingestion of >10g of paracetamol>10g of paracetamol may be fatal may be fatalmay be lower in chronic alcoholics or subjects may be lower in chronic alcoholics or subjects

with underlying liver disease. with underlying liver disease.

Clinical featuresClinical features

In severe poisoning In severe poisoning up to 24 hours – none/nausea and vomitingup to 24 hours – none/nausea and vomiting> 24 hours> 24 hours

nausea and vomiting nausea and vomiting Right upper quadrant painRight upper quadrant pain jaundicejaundiceencephalopathyencephalopathy

PARACETAMOLPARACETAMOL ((acetaminophen)acetaminophen)

Management Management Blood for paracetamol at 4 hours post ingestionBlood for paracetamol at 4 hours post ingestion Check treatment curve for Check treatment curve for N-acetylcysteine infusionN-acetylcysteine infusion ( (

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

failure and occur at 36-72 hours after ingestionfailure and occur at 36-72 hours after ingestionIndications for referral to liver unit areIndications for referral to liver unit are

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

NSAIDsNSAIDs

Mechanism of actionMechanism of actioninhibits cyclo-oxygenaseinhibits cyclo-oxygenase (prostaglandin synthase) (prostaglandin synthase)

that is responsible for conversion of arachidonic that is responsible for conversion of arachidonic acid to cyclic endoperoxidesacid to cyclic endoperoxides

2 isoforms of enzyme2 isoforms of enzyme-- COX-1COX-1 constitutiveconstitutive, present in platelets, , present in platelets,

stomach and kidneystomach and kidney -- COX-2COX-2 inducibleinducible by cytokines & by cytokines &

endotoxins at endotoxins at sites of sites of inflammation e.g., jointsinflammation e.g., joints

NSAIDsNSAIDsMain actionsMain actions

11.) .) AnalgesiAnalgesicc -effective against -effective against mild to moderate mild to moderate painpain, do not cause dependence, do not cause dependence

2.) 2.) Anti-inflammatoryAnti-inflammatory

3.) 3.) Anti-pyreticAnti-pyretic

4.)4.)Anti-plateletAnti-platelet- prevent thromboxane production, - prevent thromboxane production, derived from prostaglandins and cause platelet derived from prostaglandins and cause platelet aggregationaggregation

OthersOthers

5.) Useful in treatment of 5.) Useful in treatment of dysmenorrheadysmenorrhea, associated , associated with increased prostaglandin synthesis and increased with increased prostaglandin synthesis and increased uterine contractilityuterine contractility

6.) Used to close the 6.) Used to close the patent ductus arteriosuspatent ductus arteriosus

NSAIDsNSAIDs

Adverse effectsAdverse effects1.) 1.) Gastric or intestinal mucosal damageGastric or intestinal mucosal damage

- mucosal prostaglandins inhibit acid secretion, - mucosal prostaglandins inhibit acid secretion, promote mucus promote mucus

secretion, prevent back diffusion of acid into the secretion, prevent back diffusion of acid into the gastric submucosagastric submucosa- Inhibition thus results in - Inhibition thus results in erosions, ulceration, erosions, ulceration, bleeding, perforationbleeding, perforation

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

NSAIDsNSAIDs

Adverse effectsAdverse effects

3.) Analgesic nephropathy3.) Analgesic nephropathy- due to long term ingestion of mixtures of agents - due to long term ingestion of mixtures of agents - chronic interstitial nephritis, - chronic interstitial nephritis, renal papillary renal papillary necrosis,necrosis, acute renal failure acute renal failure

NSAIDsNSAIDs

Non selective Vs selective COX2 inhibitorsNon selective Vs selective COX2 inhibitors

↑ ↑ risk of cardiovascular adverse eventsrisk of cardiovascular adverse events with COX with COX 2 inhibitors2 inhibitors

Rofecoxib was withdrawn from the marketRofecoxib was withdrawn from the marketHigher BP, incidence of myocardial infarction, Higher BP, incidence of myocardial infarction,

strokestrokeMechanism _ ? Unopposed effect of cox 1 actionMechanism _ ? Unopposed effect of cox 1 action

- ? Block protective effect of COX2 on - ? Block protective effect of COX2 on ishaemic myocardium or ishaemic myocardium or

atherogenesisatherogenesis

SOURCE Opium is obtained from the opium

poppy by incision of the seed pod after the petals of the flower have dropped. The white latex that oozes out turns brown and hardens on standing.

This sticky brown gum is opium. It contains about 20 alkaloids, including morphine, codeine etc. The principal alkaloid in opium is morphine, present in a concentration of about 10%.

OPIOID ANALGESICS

OPIOID AGONISTS

Morphine (strong mu receptor agonist)CodeineHeroinMeperidine (pethidine)FentanylLoperamide (over the counter for diarrhea)DiphenoxylateDextromethorphan

OPIOID AGONIST-ANTAGONIST/PARTIAL AGONIST

NalbuphinePentazocine

OPIOID ANTAGONISTS

NalorphineNaloxoneNaltrexone

Routes of administrationRoutes of administrationOralOralParenteralParenteralSuppositoriesSuppositoriesTransdermal- PatchTransdermal- Patchs/c Syringe drivers/c Syringe driver

OPIATE ANALGESICSOPIATE ANALGESICS

Pethidine/meperidine and fentanyl are the most widely used agents in this family of synthetic opioids

The principal effects of pethidine with affinity for mu receptors are on the central nervous system.

Opioid Analgesics-Pethidine

Pharmacological Effects

• the pharmacological effects of Pethidine is similar to morphine, primarily at the mu receptor

•it has less potent analgesics than morphine and has a shorter duration of action

•Pethidine dosn`t delay delivery

The Opioid Antagonists

The opioid antagonist drugs naloxone and naltrexone are morphine derivatives.

When given in the absence of an agonist drug these antagonists are almost inert at doses that produce marked antagonism of agonist effects.

When given intravenously to a morphine-treated subject, the antagonist will completely and dramatically reverse the opioid effects within 1-3 min.

Mechanism of action

Opioid agonists produce analgesia by binding to specific receptors, located primarily in brain and spinal brain and spinal cord regionscord regions involved in the transmission and modulation of transmission and modulation of pain.pain.

Mechanism of actionReceptor types: The major classes of receptors areµ (mu for morphine)delta (δ)Kappa (κ)All are members of the G-protein-coupled family of receptors.

Mechanism of action

Analgesia, as well as the euphoriant, respiratory depressant, and physiologic dependence properties of morphine result principally from actions at mu receptors.

Most of the currently available opioid analgesics act primarily at the mu receptor.

OPIOID RECEPTORS Certain opioid receptors are located:

on primary afferent and spinal cord pain transmission neurons (ascending pathways)

in the midbrain and medulla (descending pathways) that function in pain modulation

All 3 receptors appear to be involved in anti nociceptive and analgesics mechanisms

OPIOID RECEPTORSPresynaptically:

Opioid receptor activation can close voltage –gated calcium ion channels to inhibit neurotransmitter release (serotonin, glutamate and substance P)

OPIOID RECEPTORS

Postsynaptically:Activation of these receptors can open potassium

ion channels to cause membrane hyperpolarization (inhibitory post synaptic potential).

Direct inhibition of neurons in ascending pathways

PHARMACOLOGICAL EFFECTS

CNS: Analgesia: most powerful drug available for relief of

painEuphoria: addict experiences a pleasant floating

sensation and freedom from anxiety and distress.SedationRespiratory depression: main cause of death

from opioid overdose due to reduced responsiveness of respiratory centre in brainstem to blood levels of CO2

PHARMACOLOGICAL EFFECTSIncrease arterial CO2 retention causes cerebral

vasodilation resulting in increase intracranial pressureCough suppression: suppression of cough centre in

nucleus of tractus solitariusMiosis: results from stimulation of Edinger-

Westphal nucleus causing pin-point pupils except meperidine.

Emesis: due to stimulation of brainstem chemoreceptor trigger zone results in nause and vomiting

MIOSIS

PHARMACOLOGICAL EFFECTSCVS: No significant direct effect on CVSHypotension may occur if CVS is already stressed.

Due to the peripheral arterial and venous dilation resulting from histamine release.

GIT: Decrease intestinal propulsive peristalsis and stomach motility leads to constipation

Biliary tract: Constriction of biliary smooth muscles leads to biliary colic except meperidine

Constriction of sphincter of oddi leads to increase biliary pressure, reflux of biliary and pancreatic secretions and elevated plasma and lipase levels

PHARMACOLOGICAL EFFECTSRenal functions: depressed due to decrease renal

plasma flow.Also has antidiuretic effect. Mechanism involve both

CNS and peripheral siteUreteral and bladder tone is increasedIncreased sphincter tone….urinary retentionOccasionally, ureteral colic caused by renal calculus

is made worse by opioid induced increase in ureteral tone

PHARMACOLOGICAL EFFECTS

Uterus: decrease uterine tone lead to prolong laborSkin: flushing and warming, sweating, itching due to

histamine release

CLINICAL USES

Analgesia forMIterminal illnesssurgeryobstetrical procedurescancer

CoughDiarrhea

CLINICAL USESAcute pulmonary edema: decrease dyspneaProposed mechanism:

Reduced anxiety (perception of shortness of breath)Reduced cardiac preload (reduced venous tone)Reduced afterload (decreased peripheral resistance)

If respiratory depression is there then use furosemide

Clincal UseThe major application of naloxone is in the

treatment of acute opioid overdoseIn individuals who are acutely depressed by

an overdose of an opioid, the antagonist will effectively normalize respiration, level of consciousness, pupil size

More recently, considerable interest has been aroused by reports that naltrexone decreases craving for alcohol in chronic alcoholics, and it has been approved by the FDA for this purpose.

ADVERSE EFFECTS

OPIOID ANALGESICSMorphineMorphin 6 glucuronid3.7 s.c.

45 i.c.v. Foley 1993Dosage form with slow release

Bashford 2001Roxanol SR (8 ore)MS Contin (12 ore)MST

Heroine – metabolit: - Morphine im 2 - - 6 acetil morphine - (link to opioid receptors)

OPIOID ANALGESICS Hydromorphon 5 - benefits the elderly (t1/2 1.5-2 ore)

- excellent analgesia - minimal side effects (Brose 1991)

Levorphanol 2 - in chronic pain who can not tolerate morphyne

- affinity for receptor Codeine – for stage II– in combinations DH codeina Oxycodone 10 codeine – moderate and severe pain - present in combination

OPIOID ANALGESICS Meperidine – 75 mg = 10 mg morphine i.m. - normepteridine: activ metabolit – convulsant 2

- analgezic ½ Metadone - 10mg = 10mg morphine

- analges stage II - addiction therapy

Propoxifen – moderate pain 1/2 – 1/3 from codeine -metabolit: norpropoxifen (convulsant)

Fentanyl – 1:20, 1:30 from morphine- intra and post operative pain- various routes of administration- inactive metabolites

AGONISTS /ANTAGONISTS Pentazocine 35 mg = 10 mg morphine. Receptors ,

BP – disphoria, psyhotic effects Nalbufina – equivalent to morphine

- for postoperative pain- substitute for morphine (fewer side

effects)- lower potential for abuse as morphine

- Potential low psyhotic edffect Butorfanol – 2 mg i.m. = 10 mg morphine

- low physical dependence potential- useful for acute pain in patients who have

not received opioids

TOLERANCE

TOLERANCETolerance occur due to receptor uncoupling.Physical dependence:It results in withdrawal (abstinence) syndrome

if there is failure to continue administer drug. Sudden withdrawal (abstinence syndrome) has following signs/symptoms: lacrimation yawning chills hyperventilation hyperthermia diarrhea,vomiting anxiety

SYMPTOMS OF WITHDRAWAL

TOLERANCE

Psychological dependence:euphoriaindifference to stimulisedation

Morphine poisoning….antidote is naloxone

Acute morphine poisoning:ComaSevere respiratory depressionMiosiswith blood pressure decreasedUrinary retention.

Respiratory paralysis often is the mainly lethal reason.

Treatment: respiratory support intravenous injection of naloxone.

Toxicity