This broad group of drugs have anti-infl ammatory, anti-pyrexial, and analgesic actions. They act by inhibiting the enzyme cyclo-oxygenase (COX). COX is responsible for the production of thromboxanes and prostaglandins from arachidonic acid. Inhibition of prostaglandin produc- tion accounts for their anti-infl ammatory effects peripherally and their anti-pyretic effects centrally. Inhibition of thromboxanes leads to reduced platelet aggregation. Many subtypes of prostaglandins have been identi- fi ed, accounting for the variation in side effect profi les of different groups of NSAIDs. There are two subtypes of cyclo-oxygenase inhibited by NSAIDs, COX-1 and COX-2. Broadly speaking, inhibition of COX-1 is responsible for the side effects. Inhibition of COX-2 accounts for the anti-infl ammatory, anti-pyretic, and analgesic effects. As such NSAIDs can be classed as either non-specifi c COX inhibitors (e.g. aspirin, ibuprofen, diclofenac, ketorolac) or COX-2 selective inhibitors (e.g. meloxicam, celecoxib, parecoxib).
The use of NSAIDs is limited by their side effect profi le:
Gastrointestinal effects
• – inhibition of gastro-protective prostaglandins leads to gastric irritation, ulceration, and bleeding (acute haemorrhage iron defi ciency anaemia). Bleeding is further compounded by the anti-platelet effects of NSAIDs. Preferential COX-2 selection can reduce the incidence of GI effects.
Asthma
• – inhibition of the COX enzyme leads to a build-up of arachidonic acid and an increase in leukotriene production. This can lead to acute severe bronchospasm in up to 20% of susceptible asthmatic patients. Selective COX-2 inhibition appears not to induce bronchospasm in aspirin-sensitive asthmatics.
Renal impairment
• – prostaglandins are involved in regulation of renal blood fl ow, hence reducing their production can reduce renal blood fl ow leading to acute renal impairment/failure. This can be compounded in the post-operative patient by factors such as hypovolaemia, hypotension, and sepsis. Selective COX-2 inhibition displays the same renal toxicity.
Fluid retention
• – NSAIDs cause fl uid retention, which can lead to heart failure in susceptible patients.
Anti-platelet effects
• – the anti-platelet effect of NSAIDs, via inhibition of thromboxane production, can lead to increased bleeding post- operatively. COX-2 inhibitors do not display the same anti-platelet effect.
Drug interactions
• – NSAIDs are highly protein bound in the plasma and as such can displace other highly protein bound drugs, potentiating their effects (e.g. warfarin). Lithium levels can increase with NSAID use.
Hepatotoxicity
• – NSAIDs have been associated with impaired hepatic function.
COX-2 inhibitors and cardiovascular risk
• – rofecoxib was withdrawn
from the market in 2004 after several studies demonstrated an increased risk of myocardial infarction and cerebrovascular accidents. Similar concerns over the safety of other drugs in this class have been raised.
11
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)
Cautions: Contraindications:
post-op bleeding
• • renal failure avoid in hypotensive/septic patients
• • history of upper GI bleed anticoagulation
• • patients on warfarin non-NSAID-sensitive asthmatics.
• • asthmatics with history of
NSAID-induced
bronchospasm.
Common NSAIDs Ibuprofen
non-selective COX inhibitor, only available orally •
adult dose: 400mg 8 hourly with food •
paediatric dose: 5–10mg/kg 8 hourly. •
Diclofenac
non-selective COX inhibitor, available in oral, rectal, and intravenous •
preparations
adult oral dose: 50mg 8 hourly. •
COX-2 selective inhibitors
fewer GI side effects, appear safe in aspirin-sensitive asthmatics, no •
anti-platelet effect
similar renal toxicity to regular NSAIDs •
questions over cardiovascular safety •
adult dose celecoxib: 100–200mg orally 12 hourly •
adult dose valdecoxib: 10–20mg orally once daily •
adult dose
• parecoxib: 20–40mg IV 6–12 hourly (max. 80mg/24hrs)
valdecoxib/parecoxib contraindicated after cardiac surgery due to •
12
CHAPTER 1Post-operative pain
Opioids
Opioids are naturally occurring or synthetic compounds that are agonists at the opioid receptor. Opioid receptors are found throughout the CNS, spinal cord, and peripheral nervous system. Stimulation of the receptors modulates transmission of pain and other signals. There are three classes of opioid receptor: mu, delta, and kappa (the sigma subclass has been shown not to be blocked by naloxone and has therefore been removed from the opioid receptor classifi cation).
Routes of administration
Oral – dependent on ability to ingest and absorb, limited by nausea and •
vomiting.
Intramuscular/subcutaneous – fast and effective, limited by lipid •
solubility and changes in regional perfusion.
Intravenous – rapid onset, titrate small boluses up to adequate pain •
relief, vigilance to ensure early detection of side effects.
Trans-mucosal – sublingual/buccal/intranasal – fast and effective, limited •
by lipid solubility.
Transdermal – limited to lipophilic opioids (e.g. fentanyl). •
Epidural/caudal/intrathecal – possible delayed onset of side effects. •
Effects
All opioids display a similar side effect pattern, but to varying degrees: analgesia
•
nausea and vomiting •
sedation, euphoria, dysphoria •
respiratory depression •
bradycardia, hypotension secondary to histamine release •
reduced bowel mobility, constipation • urinary retention • itching. • Common opioids Morphine
Naturally occurring opiate, reference opioid to which all others are •
compared.
Given IV, IM, SC, orally (as short acting or slow release preparations), •
intrathecal/epidural (associated with delayed respiratory depression). Adult oral dose 10–30mg 4 hourly, IM/SC dose 5–10mg, titrate •
intravenous dose in small boluses (1–2mg every 75 minutes) until adequate pain relief (close monitoring for signs of side effects). Paediatric oral doses 0.3–0.5mg/kg 4 hourly, titrate IV doses in boluses •
(50–100μg/kg every 75 minutes). Peak effects IV/SC/IM
• 710–30 minutes, duration of action 3–4 hours. Metabolized via active metabolites to varying degrees. This may explain •
inter-patient differences in effect. Metabolites are renally excreted and can accumulate in renal failure.
More pronounced effect in extremes of age. •
13
OPIOIDS
Diamorphine
Naturally occurring pro-drug converted to morphine
• in vivo.
More lipid soluble than morphine, therefore reaches the effector site •
in higher concentration, therefore potency is up to two times that of morphine.
Marked euphoria, hence it has become drug of abuse. •
Used IV, IM, SC, epidural, and intrathecal. High fi rst pass metabolism •
therefore not used orally. Adult dose 2.5–5mg 4 hourly. •
Other uses include respiratory distress associated with acute LVF. •
Pethidine
Synthetic opioid, given IM, SC, or IV. •
Adult dose IM/SC 25–100mg, IV 22–50mg 3 hourly. •
No better than morphine for renal/biliary colic. •
Active metabolites renally excreted and accumulate in renal failure. •
Not reversed by naloxone. •
High doses associated with hallucinations and seizures. •
Interacts with monoamine oxidase inhibitors (MAOIs). •
Side effects and interactions make pethidine less suitable than •
morphine.
Codeine
Natural opioid, acts directly as a weak opioid agonist and indirectly •
710% metabolized to morphine.
Given orally, IM, PR in children. Not given intravenously as associated •
with histamine release, profound hypotension, and death. Adult dose 30–60mg 4–6 hourly.
•
Paediatric dose 0.1mg/kg 6 hourly (max. 3mg/kg per 24 hours). •
Genetic variability in the proportion of conversion to morphine; this •
explains the marked effects in some patients and lack of in others. Particular problems with constipation; patients may need laxatives. •
Other uses: cough suppressant, anti-diarrhoeal agent. •
Tramadol
Non-selective synthetic opioid agonist, inhibits noradrenaline re-uptake •
and enhances serotonin release. Used IV, IM, and orally. •
Adult dose 50–100mg 4–6 hourly (max 400mg/24 hours). •
Paediatric dose 1–2mg/kg 6 hourly (not licensed for children under •
12 years, max 400mg /24 hours).
Comparatively favourable side effect profi le. •
Side effects include nausea, sedation, dizziness, and dry mouth. •
Caution in epilepsy and concurrent with monoamine oxidase inhibitors •
(MAOI).
Not antagonized by naloxone; will precipitate withdrawal in opioid- •
dependent patients if used alone.
Metabolized in the liver to active metabolites that are predominantly •
14
CHAPTER 1Post-operative pain
FentanylSynthetic opioid often used in anaesthesia. •
Used IV, epidural, intrathecal, transdermal, and buccal (due to high lipid •
solubility).
Transdermal patches take up to 12 hours to reach equilibrium with •
plasma levels.
Post-operatively can be used in a PCA pump intravenously. •
New patient-controlled active transdermal systems are available, •
though not yet widely used.
Inactive metabolites excreted in the urine, therefore does not •
accumulate in renal failure.
Dosages given are intended as a guide only, and for the initial management of acute pain in an average, opioid-naıïve patient. Reduce dose for elderly/ frail patients; increase dose appropriately for opioid-tolerant patients. Adult doses
Drug Dose – IV Dose – IM/SC Dose – oral
Morphine titrate 1–2mg bolus up to 0.1–0.2mg/kg 3–4 hourly 5–10mg/kg 3–4 hourly 10–30mg 4 hourly, increase dose as required
Diamorphine 2.5–5mg 4 hourly 2.5–5mg 4 hourly –
Pethidine 25–50mg 4 hourly 25–100mg 4 hourly –
Codeine – 30–60mg 4–6 hourly 30–60mg 4–6 hourly
Tramadol 50–100mg 4–6 hourly (max 400mg/ 24 hours) 50–100mg 4–6 hourly (max 400mg/ 24 hours) 50–100mg 4–8 hourly (max 400mg/ 24 hours) Paediatric doses
Drug Dose – IV Dose – IM/SC Dose – oral
Morphine Titrate IV doses in boluses of 50–100μg/kg
0.1–0.2mg/kg 3–4 hourly
0.3–0.5mg/kg 4 hourly
Pethidine 0.5–1mg/kg 4 hourly 0.5–1mg/kg 4 hourly –
Codeine – 0.1mg/kg 6 hourly 0.1mg/kg 6 hourly
16
CHAPTER 1Post-operative pain
Narcosis
Treatment of opioid overdose is initially supportive. Ensure the following: Patent airway (give 100% oxygen via high-fl ow device,
•
e.g. non re-breathe mask).
Adequate respiration (may need to assist with bag-valve-mask •
ventilation – if so call arrest team). Call for help early.
•
If respiratory arrest, begin bag-valve-mask ventilation and call arrest •
team (2222).
If cardiac arrest/cardiovascular collapse, begin CPR/resuscitation and •
call arrest team (2222).
Secure intravenous access; treat bradycardia and hypotension. •
Give naloxone intravenously in small bolus doses. If carefully titrated •
naloxone can reverse the sedative and respiratory depressive effects without reversing the analgesic effects.
Naloxone
Opioid antagonist used in the treatment of the over-opiated patient. •
Competitive antagonist predominantly at the mu receptor. •
Adult dose 200–400μg, paediatric dose 5–10μg/kg. Use small •
intravenous boluses and titrate to effect. Duration of action of
• 720 minutes so care must be taken as the effects of the opioid can outlive the effects of naloxone; repeated doses or an infusion may be required.
Side effects include hypertension, pulmonary oedema, and arrhythmias, •
and it can be antianalgesic or cause withdrawal symptoms in opioid users.
Other uses include treating pruritus, nausea, and respiratory •
17
PATIENT CONTROLLED ANALGESIA (PCA)