, Volume 6, Issue 6, pp 474-497
Date: 11 Nov 2012

Epidural Clonidine

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Abstract

Synopsis

Clonidine is an established α2 adrenoceptor agonist with antihypertensive properties which, when administered epidurally, has an analgesic action that is largely mediated by α2 adrenoceptors in the dorsal horn of the spinal cord. After epidural administration, the drug undergoes rapid systemic absorption and is able to pass through the placenta.

Datafrom clinical studies evaluating the efficacy of epidural clonidine indicate that it is a useful adjunct to opioid and/or local anaesthetic agents for postoperative analgesia after major abdominal or orthopaedic surgery or after caesarean section. Epidural clonidine has also proved to be an effective analgesic that enhances the duration of action of local anaesthetic agents during labour without neonatal adverse effects. Continuous infusions of epidural clonidine are effective in patients with cancer pain of neuropathic origin. Similarly, the utility of this agent appears to extend to patients with chronic non-cancer pain.

At doses producing the desired analgesic effects, sedation, bradycardia and hypotension are the most common adverse events associated with epidural clonidine. There has been a single report of rebound hypertension after abrupt cessation of epidural clonidine.

In conclusion, the available data suggest a role for epidural clonidine as an adjunctive agent for the control of pain (of postoperative, malignant or nonmalignant origin and during labour). In particular, it may be useful in patients unsatisfied with opioid or local anaesthetic agents or in those tolerant to opioids. However, the place of epidural clonidine as an alternative or adjunctive analgesic agent in any given patient group is likely to depend on the acceptability of the epidural route of administration and haemodynamic and sedative effects of the drug.

Pharmacodynamic Properties

The analgesic effects of spinally administered α2 adrenoceptor agonists are believed to be mediated by α2 adrenoceptors in the dorsal hom of the spinal cord. Amelioration of foot, but not hand, pain caused by immersion in iced water in healthy volunteers after epidural administration of clonidine indicated a spinal mechanism of action for the analgesic effect of the drug.

Decreases in mean arterial pressure and heart rate (HR) and ventilatory changes have been reported in healthy volunteers and surgical patients after epidural administration of clonidine. Such cardiovascular effects are generally evident within 15 to 30 minutes of epidural injection of clonidine and last for up to 3 hours. Changes in blood pressure (BP) appear to be dose-dependent.

Pharmacokinetic Properties

Clonidine is moderately lipid soluble, with a large apparent steady-state volume of distribution (approximately 2 L/kg) after intravenous administration. The drug is 20 to 40% bound to plasma proteins and is excreted predominantly via renal mechanisms.

Clonidine appears to be absorbed rapidly into the systemic circulation after epidural administration, with peak plasma drug concentrations being reached 8 to 15 minutes after administration. Peak concentrations in CSF were attained more slowly (after approximately 30 to 45 minutes) but were up to 362 times greater than those in plasma.

The pharmacokinetics of single dose epidural clonidine have been described by a first-order 2−compartment model, with short absorption half-lives in CSF and plasma followed by longer elimination phases in both fluids.

Placental transfer of clonidine has been demonstrated after epidural administration. At delivery, the mean maternal plasma concentration of clonidine was 0.62 ng/L, compared with 0.56 ng/L in umbilical cord plasma, after a cumulative dose of l50µg.

Therapeutic Efficacy

In patients with postoperative pain after major abdominal or orthopaedic surgery or caesarean section, epidural clonidine adjunctive to opioids or local anaesthetic agents provided effective and prolonged analgesia with a consequent decreased requirement for supplemental analgesia. The overall postoperative analgesic effect obtained with combinations involving clonidine was at least as good as that seen with opioids or local anaesthetic agents used alone or in combination.

Epidural clonidine administered as an adjunct to local anaesthetics during labour provided effective analgesia that was superior to and of longer duration than that seen with the latter agents alone. Limited data indicate that combinations of epidural clonidine and opioids have similar efficacy to combinations of local anaesthetics and opioids when a single dose is given. However, efficacy appears to be partially lost when subsequent doses of epidurally administered mixtures of clonidine and opioids are used. The use of epidural clonidine during labour did not worsen neonatal Apgar or adaptive capacity scores.

A continuous infusion of epidural clonidine provided effective analgesia in clinical studies in patients with intractable cancer pain, with a consequent decrease in supplemental opioid requirements. Efficacy was notably better in patients with neuropathic pain than in those with non-neuropathic pain. Likewise, limited data indicate that, in patients with chronic non-cancer pain, epidural clonidine provides analgesia at least as good as that seen with epidural morphine.

Tolerability

At clinically effective doses, sedation, hypotension and bradycardia are the main adverse effects of epidural clonidine. In general, clonidine did not intensify decreases in either BP or HR when combined with opioids and/or local anaesthetics. Rebound hypertension has been reported in a single patient after abrupt cessation of epidural clonidine.

Epidural clonidine, unlike local anaesthetic agents, did not interfere with proprioception or produce motor blockade. Unlike epidural opioid agents, clonidine did not produce respiratory depression or worsen the risk of urinary retention, nausea, vomiting or pruritus when administered concomitantly with these agents.

Dosage and Administration

In general, bolus doses of epidural clonidine 75 to 150µg administered concurrently with opioid or local anaesthetic agents have been shown to provide analgesia at least as good as that achieved with the opioids or local anaesthetic agents alone. Dosage regimens comprising a bolus dose followed by continuous infusion appear to be particularly well suited for analgesia during labour and postoperative analgesia.