Local Anaesthetics in the epidural space
In increasing order, the small postganglionic sympathetic fibres are blocked most readily, followed by sensory and finally motor fibres. The degree of block depends on the concentration and volume of local anaesthetic used. Bolus doses using bupivacaine 0.5%, 5-10 ml provide good analgesia after a range of operations from thoracotomy, laparotomy through to pelvic operations and procedures on the lower limbs. The duration of postoperative analgesia from local anaesthetics, even with long-acting agents after a single bolus injection, is usually no longer than 3-4 hours.
This is inadequate for postoperative pain relief, but indwelling catheters, which allow repeat dosing or infusions overcome this problem. Concentrations of 0.125-0.25% bupivacaine have been used as continuous infusions at rates of 6-10 ml per hour. Side effects and analgesia both increase as the dose of local anaesthetic is increased. Hypotension is the most common problem; it is caused by sympathetic blockade and its severity is related to the segmental height of the block and whether an adequate preload has been administered. Total spinal anaesthesia caused by excessively high spread of local anaesthetic may occur following a ‘dural tap’.
Opioids in the epidural space
Morphine, initially the most commonly used opioid in the epidural space, produces unpredictable late respiratory depression. This led researchers to use lipid-soluble opioids, partial agonist-antagonist opioids, opioid local anaesthetic combinations and, most recently, alpha agonists such as clonidine. The ideal opioid must cross the dura rapidly and enter the spinal cord, where it should bind with strong affinity to the opioid receptors in the substantia gelatinosa.
The lipid solubility and shape of the molecule are the most important factors that effect the passage of opioids across the dura. The CSF solubility should be poor, to allow rapid elimination from this compartment. Lipid-soluble drugs penetrate the spinal cord rapidly and are poorly soluble in the CSF, but may be extensively absorbed into the circulation. A potent lipid-soluble opioid with a strong affinity for the opioid receptor could provide effective analgesia at sufficiently low dosage to limit side effects.
Morphine is relatively lipid insoluble, which accounts for its slow penetration of the dura and hence its slow onset 45-60 minutes . However, its duration of action is long 8-24 hours because it persists in the CSF. Peak plasma concentrations are reached in 15 minutes, and the plasma concentration curve is similar to that following intramuscular injection.
Morphine appears in the CSF within 15 minutes and reaches peak concentration at 90-120 minutes . Analgesia results from spinal rather than systemic effects because lower doses (initial bolus dose is usually 2-6 mg) offer superior analgesia than intramuscular, intravenous and PCA techniques which attain higher plasma levels of morphine.
Infusions of morphine 0.1 mg/ml at a rate of 4-6 ml/h increase the duration of action. Complications of morphine even at these reduced doses still include nausea and vomiting (30-40%), sedation, respiratory depression (1%), as with parenteral routes, but to these can be added pruritus (10-50%) and urinary retention (5-40%), depending on which studies are reviewed. Pruritus is not due to histamine release but may respond to antihistamines; it will always respond to a small dose of naloxone without reducing analgesia.
Respiratory depression is often late in onset and is more likely in elderly patients or if there has been concomitant use of opioids by a different route. Its occurrence is still unpredictable and purely monitoring respiratory frequency is inadequate. Short periods of apnoea in patients who have had opioids are not uncommon; oximetry is helpful but measurement of end tidal carbon dioxide concentration would probably be the most useful, although this is impractical at present. Assessment of sedation is more useful and some clinicians believe an intensive care or high dependency type of care facility is the only safe place to nurse these patients. In reality the effective doses of morphine used have been reduced compared with the doses used in early studies and attitudes towards the use of epidural morphine have become more liberal.
Diamorphine is unavailable in many countries but is very popular by the epidural route in the UK. It is more lipid soluble than morphine and its onset of action is 20-40 minutes with a duration of action similar to that of morphine, to which it is converted once in the CSF. A bolus dose of 1.5-3 mg gives good analgesia and infusion concentrations of 0.1 mg/ml at a rate of only 2-6ml /h suggest a definite spinal effect from the drug.
The use of pethidine was first reported at the same time as morphine, but it has never been particularly popular. It is 40 times more lipid soluble than morphine and penetrates the dura quickly, onset of analgesia is 15-30 minutes, but duration of action is short 4-6 hours . A bolus dose of 50 mg is usually effective. It does have local anaesthetic actions and has been used intrathecally because of this. The local anaesthetic effect is difficult to detect epidurally as no sympathetic effects have been demonstrated . There is more scope for research into pethidine in the epidural space.
Fentanyl is 800 times more lipid soluble than morphine and rapidly is absorbed from the epidural space and CSF. Because of the reduced cephalic spread the side effects are theoretically less. It has a rapid onset of action 15-30 minutes, and its duration of action is 2-5 hours. The initial bolus dose is usually 50-100 ug. Case reports of respiratory depression at these doses are very rare and are usually associated with the use of other systemic opioids, or its accumulation from an infusion.
Pruritus is the most common side effect; nausea and vomiting are rare. The short duration of action has led to the widespread use of continuous epidural infusions at a dose of 0.5-1.0 ug/kg/h at a concentration of 10 ug/ml. If the catheter is not placed close to the appropriate dermatome level, then larger doses are needed, 1.5ug /kg/h which can lead to systemic levels of fentanyl of 1.0-2.0ng /ml, which is equivalent to the level required for systemically administered fentanyl (, ).
Alfentanil is seven times less soluble than fentanyl, with a lower pKa of 6.5. The drug is minimally ionised in CSF and it penetrates the dura rapidly. Onset of analgesia is rapid, about 15 minutes, and it has a duration of action of about 90 minutes. It is only of practical use in infusions and offers no real advantage over fentanyl. Sufentanil is unavailable in the UK; its lipid solubility is twice that of fentanyl, its onset of action is 15 minutes and its duration 4-6 hours. Early studies showed significant problems with early respiratory depression, but doses have since been reduced. A bolus dose of 15-30 ug is thought to be adequate.
Opioid and local anaesthetic combinations
Both local anaesthetics and opioids individually cause their own characteristic side effects. The two drugs act by different mechanisms and so a combination of both types of drugs should lead to synergism of effect, a reduced dose of each drug and therefore fewer side effects. Evidence from studies is controversial.
The addition of 0.125% bupivacaine to epidural morphine prolonged the duration of postoperative analgesia compared with morphine alone . Other studies showed no benefit when 0.1-0.125% bupivacaine was added to morphine (, , ) compared with morphine alone. Some (, ) involved bolus injections only and here the long duration of action of morphine compared with local anaesthetics make the comparisons difficult. Studies with fentanyl give similar confusing results, either no synergism (, pcc998) or some benefit (, ).
It is possible that the addition of bupivacaine 0.1% is inadequate to offer any extra advantage over epidural opioids alone. Studies where a higher concentration of local anaesthetic is used or infusion rates are high do show benefit from local anaesthetic (, ). In these studies a high sensory level block results and the dose and infusion rate of local anaesthetic would provide analgesia by themselves. The assessment of postoperative pain in the studies above is often by different techniques and these need to be standardised before valid comparisons are made. For example pain on movement or pain on coughing, etc.
The National Patient Safety Agency (NPSA) document Ensuring safer practice with high dose ampoules of diamorphine and morphine alerts the NHS in England and Wales to review and improve measures for safer practice in prescribing, storing, administering and identifying high dose morphine and diamorphine injections.
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