Stage 1 Seminar: Prescribing Analgesics

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Stage 1 SeminarPrescribing Analgesics

• Dr. Swe Myint
• Specialist Registrar
• Clinical Pharmacology Unit

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Analgesics

• Non-opioid analgesics
• Opioid analgesics
• Drugs for neuropathic and functional pain
• Antimigraine drugs

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Nonopioid analgesics

• Acetaminophen (paracetamol)
• NSAIDs non selective
• - Selective Cox 2 inhibitors

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PARACETAMOL (acetaminophen)

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

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PARACETAMOL (acetaminophen)

• 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
  overdose
• NABQI then reacts with cellular macromolecules
  and causes cell death

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PARACETAMOL (acetaminophen)

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

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PARACETAMOL (acetaminophen)

• Paracetamol overdose
• Ingestion of gt10g of paracetamol may be fatal
• may be lower in chronic alcoholics or subjects
  with underlying liver disease.
• Clinical features
• In severe poisoning
• up to 24 hours - none or nausea and vomiting
• gt 24 hours - nausea and vomiting, right upper
  quadrant pain, jaundice, encephalopathy

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PARACETAMOL (acetaminophen)

• Management
• Blood for paracetamol at 4 hours post ingestion
• Check treatment curve for N-acetylcysteine
  infusion ( if in doubt of severe poisoning, dont
  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 gt45 secs at 48 hours or gt50 secs at 72
  hours
• - rising plasma creatinine
• - Arterial pH lt7.3 more than 24 hours after
  ingestion

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NSAIDs

• Mechanism of action
• inhibits cyclo-oxygenase (prostaglandin synthase)
  that is responsible for conversion of arachidonic
  acid to cyclic endoperoxides
• 2 isoforms of enzyme
• - COX-1 constitutive, present in platelets,
• stomach and kidney
• - COX-2 inducible by cytokines endotoxins at
  sites of inflammation e.g., joints

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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

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NSAIDs

• Adverse effects
• 1.) 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

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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

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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

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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

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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 and water
• iii) dehydration
• iv) metabolic acidosis - effects on Krebs
  cycle, ? ketone body, salicylic acid in blood,
  renal insufficiency due to vascular collapse,
  dehydration
• v) hypoglycaemia or even hyperglycaemia can
  occur

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Aspirin (acetyl salicylate)

• Uricosuric effects
• reduces renal tubular reabsorption of urate but
  treatment of gout requires 5-8g/d, lt 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 disease
• Note 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
  gt5g/day

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Aspirin (acetyl salicylate)

• OVERDOSAGE
• Ingestion of gt 10 g can cause moderate/severe
  poisoning in an adult
• Clinical features - salicylism
• tremor, tinnitus, hyperventilation, nausea,
  vomiting, sweating
• Management- mainly supportive

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OPIATE ANALGESICS

• Classification
• Low efficacy Codeine
• Dihydrocodeine
• Dextropropoxyphene (coproxamol- withdrawn
  from market)
• Medium efficacy Bupranorphine
• meptazinol
• High efficacy Morphine
• Diamorphine
• pethidine

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OPIATE ANALGESICS

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

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OPIATE ANALGESICS

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

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OPIATE ANALGESICS

• Actions
• CNS
• Depression Stimulation
• Analgesia vomiting
• Respiratory depression miosis
• Depression of cough reflex ? spinal reflexes
• sleep (convulsions)
• mood changes- Euphoria
• Dependence also affects other systems

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OPIATE ANALGESICS

• Smooth muscle stimulation
• GI muscle spasm causing delayed transit and
  constipation
• Biliary spasm
• Bronchospasm
• Cardiovascular
• Dilation of resistance vessels (arterioles) and
  capacitance vessels (veins)

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OPIATE ANALGESICS

• Smooth muscle stimulation
• GI muscle spasm causing delayed transit and
  constipation
• Biliary spasm
• Bronchospasm
• Cardiovascular
• Dilation of resistance vessels (arterioles) and
  capacitance vessels (veins)
• Hazards of Clinical Use
• Respiratory depression
• Retention in hepatic and renal impairment
• Dependence

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OPIATE ANALGESICS

• Dependence
• 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
• Reduction of rebound sympathetic activity with
  clonidine may be needed

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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)

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Overall Management of Pain

• Mild pain
• Non-opioid analgesics paracetamol
• NSAIDs aspirin, ibuprofen
• Moderate pain
• 1. Low efficacy opioid dihydrocodeine
• 2. low efficacy opioid NSAID dihydrocodeine
  ibuprofen
• 3. Moderate efficacy opioid NSAID meptazinol
  ibuprofen
• Severe pain
• 1. High efficacy opioids morphine
• 2. High efficacy opioids NSAIDS morphine
  ibuprofen
• Overwhelming pain
• 1. High efficacy opioid anxiolytic morphine
  diazepam
• and/or major tranquilliser morphine
  chlorpromazine

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Messages

• Keep it simple
• Become familiar with a couple of agents from each
  class. If in doubt, check in BNF
• Familiarise with used of control drug (opioid)
• Identify and treat the underlying pathology
  wherever possible
• Be careful with potential overdoses and
  dependency
• Explanation and reassurance contribute greatly to
  analgesia