Mechanism of Action

Epidurally administered clonidine produces dose-dependent analgesia not antagonized by opiate antagonists. The analgesia is limited to the body regions innervated by the spinal segments where analgesic concentrations of clonidine are present. Clonidine is thought to produce analgesia at presynaptic and postjunctional alpha-2-adrenoceptors in the spinal cord by preventing pain signal transmission to the brain.

Pharmacokinetics

Following a 10 minute intravenous infusion of 300 mcg clonidine HCl to five male volunteers, plasma clonidine levels showed an initial rapid distribution phase (mean ± SD t1/2= 11 ± 9 minutes) followed by a slower elimination phase (t1/2= 9 ± 2 hours) over 24 hours. Clonidine’s total body clearance (CL) was 219 ± 92 mL/min.

Following a 700 mcg clonidine HCl epidural dose given over five minutes to four male and five female volunteers, peak clonidine plasma levels (4.4 ± 1.4 ng/mL) were obtained in 19 ± 27 minutes. The plasma elimination half-life was determined to be 22 ± 15 hours following sample collection for 24 hours. CL was 190 ± 70 mL/min. In cerebral spinal fluid (CSF), peak clonidine levels (418 ± 255 ng/mL) were achieved in 26 ± 11 minutes. The clonidine CSF elimination half-life was 1.3 ± 0.5 hours when samples were collected for 6 hours. Compared to men, women had a lower mean plasma clearance, longer mean plasma half-life, and higher mean peak level of clonidine in both plasma and CSF.

In cancer patients who received 14 days of clonidine HCl epidural infusion (rate = 30 mcg/hr) plus morphine by patient-controlled analgesia (PCA), steady state clonidine plasma concentrations of 2.2 ± 1.1 and 2.4 ± 1.4 ng/mL were obtained on dosing days 7 and 14, respectively. CL was 279 ± 184 and 272 ± 163 mL/min on these days. CSF concentrations were not determined in these patients.

Distribution

Clonidine is highly lipid soluble and readily distributes into extravascular sites including the central nervous system. Clonidine’s volume of distribution is 2.1 ± 0.4 L/kg. The binding of clonidine to plasma protein is primarily to albumin and varies between 20 and 40% in vitro. Epidurally administered clonidine readily partitions into plasma via the epidural veins and attains systemic concentrations (0.5 – 2.0 ng/mL) that are associated with a hypotensive effect mediated by the central nervous system.

Excretion

Following an intravenous dose of 14C-clonidine, 72% of the administered dose was excreted in urine in 96 hours of which 40 - 50% was unchanged clonidine. Renal clearance for clonidine was determined to be 133 ± 66 mL/min. In a study where 14C-clonidine was given to subjects with varying degrees of kidney function, elimination half-lives varied (17.5 to 41 hours) as a function of creatinine clearance. In subjects undergoing hemodialysis only 5% of body clonidine stores were removed.

Metabolism

In humans, clonidine metabolism follows minor pathways with the major metabolite, p-hydroxy-clonidine, being present at less than 10% of the concentration of uncharged drug in urine.

Special Populations

The pharmacokinetics of epidurally administered clonidine has not been studied in the pediatric population or in patients with renal or hepatic disease.

Clinical Trials

In a double-blind, randomized study of cancer patients with severe intractable pain below the C4 dermatome not controlled by morphine, 38 patients were randomized to an epidural infusion of clonidine hydrochloride injection plus epidural morphine, whereas 47 subjects received epidural placebo plus epidural morphine. Both groups were allowed rescue doses of epidural morphine. Successful analgesia, defined as a decrease in either morphine use or Visual Analog Score (VAS) pain, was significantly more common with epidural clonidine than placebo (45% vs 21%, p=0.016). Only the subgroup of 36 patients with “neuropathic” pain, characterized by the investigator was well-localized, burning, shooting, or electric-like pain in a dermatomal or peripheral nerve distribution had significant analgesic effects relative to placebo in this study.

The most frequent adverse events with clonidine were hypotension (45% vs 11% for placebo, p<0.001), postural hypotension (32% vs 0%, p<0.001), dizziness (13% vs 4%, p=0.234), anxiety (11% vs 2%, p=0.168) and dry mouth (13% vs 9%, p=0.505). Both mean blood pressure and heart rate were reduced in the clonidine group. At the conclusion of the two-week study period in the clinical trial, all patients were abruptly withdrawn from study drug or placebo. Four patients of the clonidine group suffered rebound hypertension upon withdrawal of clonidine; one of these patients suffered a cerebrovascular accident. Asymptomatic bradycardia was noted in one clonidine patient.