prescibing analgesics

Prescribing Prescribing AnalgesicsAnalgesics

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Non-opioid analgesicsNon-opioid analgesics Opioid analgesicsOpioid analgesics Drugs for neuropathic and functional Drugs for neuropathic and functional

painpain Antimigraine drugsAntimigraine drugs

AnalgesicsAnalgesics


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

- Selective Cox 2 inhibitors- Selective Cox 2 inhibitors

Nonopioid analgesicsNonopioid analgesics


PARACETAMOLPARACETAMOL ((acetaminophen)acetaminophen)

equivalent analgesic efficacy to aspirinequivalent analgesic efficacy to aspirin no useful anti-inflammatory actionno useful anti-inflammatory action used for mild to moderate pain, but used for mild to moderate pain, but

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



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

and sulphateand sulphate a number of minor a number of minor oxidation productsoxidation products inc.inc.

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

inactivated by conjugation with SH (thiol) groups of inactivated by conjugation with SH (thiol) groups of glutathioneglutathione

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



Adverse effectsAdverse effects rare in therapeutic usagerare in therapeutic usage occasional skin rash and allergyoccasional skin rash and allergy Overdose can result in fulminant Overdose can result in fulminant

hepatic necrosis and liver failurehepatic necrosis and liver failure



Paracetamol overdoseParacetamol overdose Ingestion of >10g of paracetamol may be fatalIngestion of >10g of paracetamol may be fatal may 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 hoursup to 24 hours -- none or nausea and none or nausea and

vomitingvomiting > 24 hours> 24 hours -- nausea and vomiting, right nausea and vomiting, right

upper quadrant pain, upper quadrant pain, jaundice, jaundice, encephalopathyencephalopathy



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

( if in doubt of severe poisoning, don’t delay) ( if in doubt of severe poisoning, don’t delay) Check prothrombin time and plasma creatinineCheck prothrombin time and plasma creatinine, pH, pH acute 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 ingestion Indications 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 PTT >45 secs at 48 hours or >50 secs at 72 hourshours-- 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 action inhibits cyclo-oxygenase (prostaglandin inhibits cyclo-oxygenase (prostaglandin

synthase) that is responsible for conversion of synthase) that is responsible for conversion of arachidonic acid to cyclic endoperoxidesarachidonic acid to cyclic endoperoxides

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

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

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


NSAIDsNSAIDs

Main actionsMain actions

1.) Analgesic -effective against mild to moderate pain, 1.) Analgesic -effective against mild to moderate pain, do not cause do not cause dependencedependence

2.) Anti-inflammatory2.) Anti-inflammatory

3.) Anti-pyretic3.) Anti-pyretic

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

OthersOthers

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

6.) Used to close the patent ductus arteriosus6.) Used to close the patent ductus arteriosuswww.freelivedoctor.com

NSAIDsNSAIDs

Adverse effectsAdverse effects1.) Gastric or intestinal mucosal damage1.) Gastric or intestinal mucosal damage

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

submucosasubmucosa- Inhibition thus results in erosions, ulceration, bleeding, - Inhibition thus results in erosions, ulceration, bleeding, perforationperforation

2.) Disturbances of fluid and electrolyte balance2.) Disturbances of fluid and electrolyte balance- inhibition of renal prostaglandin production results in sodium - inhibition of renal prostaglandin production results in sodium retention and oedema, possible hyponatraemia, hyperkalaemia, retention and oedema, possible hyponatraemia, hyperkalaemia, antagonism of anti-hypertensive agentsantagonism of anti-hypertensive agents

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, renal papillary necrosis, acute renal - chronic interstitial nephritis, renal papillary necrosis, acute renal failurefailure


NSAIDsNSAIDs

Non selective Vs selective COX2 inhibitorsNon selective Vs selective COX2 inhibitors

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

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

strokestroke Mechanism _ ? Unopposed effect of Mechanism _ ? Unopposed effect of cox 1 cox 1

actionaction - ? Block protective effect of COX2 - ? Block protective effect of COX2

on on ishaemic myocardium or ishaemic myocardium or

atherogenesisatherogenesis


NSAIDsNSAIDs

ClassificationsClassifications Mild to moderate anti-inflammatory actionMild to moderate anti-inflammatory action

-- propionic acid derivativespropionic acid derivatives ibuprofen, naproxenibuprofen, naproxen -- 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, indomethacindiclofenac, indomethacin-- oxicam derivativesoxicam derivatives piroxicampiroxicam

Selective COX2 inhibitorsSelective COX2 inhibitors celecoxib, rofecoxibcelecoxib, rofecoxib


Aspirin (acetyl salicylate)Aspirin (acetyl salicylate)

ActionsActions Analgesic - central and peripheral actionAnalgesic - central and peripheral action Antipyretic - act in hypothalamus to lower the Antipyretic - act in hypothalamus to lower the

set point set point of temperature control of temperature control elevated by fever,elevated by fever,

also causes sweatingalso causes sweating anti-inflammatory - inhibition of peripheral anti-inflammatory - inhibition of peripheral

prostaglandin synthesis prostaglandin synthesis respiratory stimulation -respiratory stimulation - direct action on direct action on

respiratory respiratory centre, centre, indirectly by ↑ CO2 indirectly by ↑ CO2 productionproduction



Metabolic effectsMetabolic effects

i.) i.) ↑ peripheral O↑ peripheral O22 consumption (uncoupled consumption (uncoupled oxidative oxidative phosphorylation) hence ↑CO2 phosphorylation) hence ↑CO2 production with ↑ production with ↑ respiration, and direct respiration, and direct analeptic action - respiratory analeptic action - respiratory alkalosis alkalosis

ii) ii) renal loss of bicarbonate with sodium, renal loss of bicarbonate with sodium, potassium and potassium and waterwater

iii) iii) dehydration dehydration

iv) iv) metabolic acidosis - effects on Krebs cycle, ↑ metabolic acidosis - 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

v) v) hypoglycaemia or even hyperglycaemia can hypoglycaemia or even hyperglycaemia can occuroccur



Uricosuric effectsUricosuric effects

reduces renal tubular reabsorption of urate but reduces renal tubular reabsorption of urate but treatment of gout requires 5-8g/d, < 2g/d may cause treatment of gout requires 5-8g/d, < 2g/d may cause retention of urate.retention of urate.

antagonises the uricosuric action of other drugsantagonises the uricosuric action of other drugs

Reduced platelet adhesion-Reduced platelet adhesion- irreversible inhibition of irreversible inhibition of COX by acetylation, prolongs bleeding time, useful in COX by acetylation, prolongs bleeding time, useful in arterial diseasearterial 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



OVERDOSAGEOVERDOSAGE Ingestion of > 10 g can cause Ingestion of > 10 g can cause

moderate/severe poisoning in an moderate/severe poisoning in an adultadult

Clinical features - Clinical features - ‘salicylism’‘salicylism’

tremor, tinnitus, hyperventilation, tremor, tinnitus, hyperventilation, nausea, vomiting, sweatingnausea, vomiting, sweating

Management- mainly supportiveManagement- mainly supportive


OPIATE ANALGESICSOPIATE ANALGESICS

ClassificationClassification Low efficacyLow efficacy CodeineCodeine

DihydrocodeineDihydrocodeineDextropropoxyphene Dextropropoxyphene

(coproxamol- (coproxamol- withdrawn withdrawn from market)from market)

Medium efficacy Medium efficacy BupranorphineBupranorphinemeptazinolmeptazinol

High efficacyHigh efficacy MorphineMorphineDiamorphineDiamorphinepethidinepethidine



Routes of administrationRoutes of administration OralOral ParenteralParenteral SuppositoriesSuppositories Transdermal- PatchTransdermal- Patch s/c Syringe drivers/c Syringe driver



Mechanism of actionMechanism of action

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



ActionsActions CNSCNS

DepressionDepression StimulationStimulationAnalgesiaAnalgesia vomitingvomitingRespiratory depressionRespiratory depression miosismiosisDepression of cough reflexDepression of cough reflex↑ spinal reflexes ↑ spinal reflexes sleepsleep (convulsions)(convulsions)

mood changes-mood changes- Euphoria Euphoria

Dependence –Dependence – also affects other systems also affects other systems



Smooth muscle stimulationSmooth muscle stimulationGI muscle spasm causing delayed transit and GI muscle spasm causing delayed transit and constipationconstipationBiliary spasmBiliary spasmBronchospasmBronchospasm

CardiovascularCardiovascularDilation of resistance vessels (arterioles) and Dilation of resistance vessels (arterioles) and capacitance vessels (veins)capacitance vessels (veins)



Smooth muscle stimulationSmooth muscle stimulationGI muscle spasm causing delayed transit and GI muscle spasm causing delayed transit and constipationconstipationBiliary spasmBiliary spasmBronchospasmBronchospasm

CardiovascularCardiovascularDilation of resistance vessels (arterioles) and Dilation of resistance vessels (arterioles) and capacitance vessels (veins)capacitance vessels (veins)

Hazards of Clinical UseHazards of Clinical UseRespiratory depressionRespiratory depressionRetention in hepatic and renal impairmentRetention in hepatic and renal impairmentDependenceDependence


OPIATE ANALGESICSOPIATE ANALGESICSDependenceDependence Up to 8 h- Mild psychological withdrawal stressUp to 8 h- Mild psychological withdrawal stress 8-12 h - increasing nervousness, restlessness and anxiety8-12 h - increasing nervousness, restlessness and anxiety 12-24h - yawning, sweating, runny eyes and nose12-24h - yawning, sweating, runny eyes and nose 24 h24 h - pupils dilate, waves of goose flesh - pupils dilate, waves of goose flesh 36 h - twitching of muscles, leg & abdominal cramps36 h - twitching of muscles, leg & abdominal cramps

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

48-72 h - peak withdrawal symptoms48-72 h - peak withdrawal symptoms up to 10 d- symptoms gradually subsideup to 10 d- symptoms gradually subside Complete recovery requires 3-6 monthsComplete recovery requires 3-6 months Note : Withdrawal syndrome can be in part alleviated by Note : Withdrawal syndrome can be in part alleviated by

long long acting opioid such as methadone acting opioid such as methadone Reduction of rebound sympathetic activity with Reduction of rebound sympathetic activity with

clonidine clonidine may be neededmay be needed



Opioid overdoseOpioid overdose Death usually due to respiratory depressionDeath usually due to respiratory depression Cardiovascular function usually well Cardiovascular function usually well

preserved unless severe anoxiapreserved unless severe anoxia Treatment with iv naloxone Treatment with iv naloxone May need infusion - naloxone has shorter May need infusion - naloxone has shorter

tt1/2 1/2 (1h), particularly for opioids with long (1h), particularly for opioids with long tt1/2 – 1/2 – (methadone) and tight binding (methadone) and tight binding (bupranorphine)(bupranorphine)


Mild painMild painNon-opioid analgesics Non-opioid analgesics paracetamolparacetamolNSAIDsNSAIDs aspirin, ibuprofenaspirin, ibuprofen

Moderate painModerate pain1. Low efficacy opioid1. Low efficacy opioid dihydrocodeinedihydrocodeine2. low efficacy opioid 2. low efficacy opioid ++ NSAID NSAID dihydrocodeine dihydrocodeine ++ ibuprofen ibuprofen3. Moderate efficacy opioid 3. Moderate efficacy opioid ++ NSAID NSAID meptazinol meptazinol ++ ibuprofenibuprofen

Severe painSevere pain1. High efficacy opioids 1. High efficacy opioids morphinemorphine2. High efficacy opioids + NSAIDS2. High efficacy opioids + NSAIDS morphine + ibuprofenmorphine + ibuprofen

Overwhelming painOverwhelming pain1. High efficacy opioid + anxiolytic 1. High efficacy opioid + anxiolytic morphine + diazepammorphine + diazepam and/or major tranquilliserand/or major tranquilliser morphine + morphine + chlorpromazinechlorpromazine

Overall Management of PainOverall Management of Pain


Keep it simpleKeep it simple Become familiar with a couple of Become familiar with a couple of

agents from each class. If in doubt, agents from each class. If in doubt, check in BNFcheck in BNF

Familiarise with used of control drug Familiarise with used of control drug (opioid)(opioid)

Identify and treat the underlying Identify and treat the underlying pathology wherever possible pathology wherever possible

Be careful with potential overdoses Be careful with potential overdoses and dependencyand dependency

Explanation and reassurance Explanation and reassurance contribute greatly to analgesiacontribute greatly to analgesia

Messages Messages


prescibing analgesics

Documents

opiate analgesics dependence

moderate efficacy opioid

prescribing analgesics

longacting opioid

g of paracetamol

ibuprofen severe pain

ibuprofen moderate pain

high efficacy opioidsmorphine