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Clonidine, an a2-adrenergic agonist (selective, central acting), has historically been used as an anti-hypertensive agent although studies demonstrating suppression of muscle activity in rats has led to its investigation as a possible antispastic agent in human SCI (Clark 2002).

Table 21 Summary of Clonidine Studies for Reducing Spasticity

Author Year

Country
Research Design

Score
Total Sample Size

MethodsOutcome
 

Stewart et al. 1991

Canada

RCT

PEDro=8

N=12

Population: Injury etiology: traumatic/non-traumatic SCI; Chronicity: chronic.

Intervention: 2 wk washout period between 4 wk of randomly assigned clonidine or Placebo treatment.

Medication was administered orally 2 or 3x/day. Initial dosage was 0.02 mg/day and systematically increased to an optimal level (0.05-0.25 mg/day).

Outcome Measures: BWS treadmill assisted walking with surface EMG, Footswitch and video recordings. Spasticity assessments: VAS subject self-report, daily spasticity diary, tonic stretch reflex (TSR) assessment at the ankle/knee and assessment of ankle clonus), Side Effects.

1.     1/3 paretic individuals had marked progression from non-ambulation to limited independent ambulation. The other 2 paretics who presented limited spasticity showed minimal changes while on clonidine.

2.     Spasticity-/+/0: VAS 6/1/2, Daily spasms 2/0/2, Daily clonus 4/0/1, Ankle TSR 5/2/2, Knee TSR 5/0/2, Evoked clonus 3/1/5.

3.     Side Effects in 8/9 individuals during dose titration included dryness of eyes and mouth, lethargy, mild hypotension and constipation. The majority were transient or negligible while 2 individuals experienced moderate to severe lethargy and constipation.

Malinovsky et al. 2003

France

Prospective Controlled Trial

N=36

Population: Age range: 21-73 yr.

Intervention: Individuals with urinary tract surgery under spinal anesthesia were divided into two groups: 1) those with SCI 2) normal matched individuals with no neurological disease. Individuals in each group were randomly assigned to receive: 10 mg of bupivacaine with 50 mcg of intrathecal clonidine, 150 mcg of intrathecal clonidine, 150 mcg of intramuscular clonidine.

Outcome Measures: Sedation, Bispectral Index (BIS).

1.     In the control group, complete sensory and motor block was seen with one individual becoming hypotensive from the 150-mcg group; while the SCI group was not affected by intrathecal bupivacaine and clonidine.

2.     50 mcg clonidine had no sedative effect on the SCI or control groups; while 150 mcg of intrathecal or intramuscular clonidine resulted in sedation of all individuals.

3.     A significant delay in sedation was seen in individuals with SCI in both the intrathecal and the intramuscular group; however, the duration of sedation was not different.

4.     Normal individuals showed a decrease in BIS earlier than the control individuals (p<0.001).

Remy-Neris et al. 2001

France

Prospective Controlled Trial

N=15

Population: Injury etiology: SCI=15; Level of severity: incomplete=15.

Intervention: Intrathecal clonidine injection (30/60/90 ug).

Outcome Measures: Amplitude and stimulation threshold of flexor reflex responses (FRR) in tibialis anterior after posterior tibial nerve stimulation; Ashworth Scale (AS)/pendulum test, EMG latency/amplitude of quadriceps stretch reflex.

1.     FRR amplitude change significant (p<0.02) between 30 and 90ug IT Clonidine but not significant between 30 and 50 ug between 30 and 90, NS for 30/60).

2.     FRR stimulation threshold significantly increased for each Clonidine dose compared to pre-injection. (p<0.05 for dose-dependent effect; no change in placebo effects showing no effect of lumbar puncture).

3.     Decrease in Ashworth score appeared a few min after injection, which lasted 4-6hr after a single 60ug dose.

4.     Latencies of the quadriceps stretch showed a significant increase in the latency after clonidine in all but 1 subject.

5.     Amplitudes of the quadriceps stretch showed a significant decrease in the latency after clonidine in all subjects.

6.     Parallel results seen in integrated rectified EMG observed with pendulum test.

7.     Reported AEs include hypotension, feelings of negativism and depression, sedation.

Remy-Neris et al. 1999

France

Prospective Controlled Trial

N=11

Population: Injury etiology: SCI=11; Level of injury: paraplegia=11; Level of severity: incomplete=11.

Intervention: Responders (walking capacity preserved) to a 60 μg intrathecal test dose were scheduled for 3, 15-90 μg doses of clonidine, and a placebo, by L2-3 puncture. Non-responders were given 30 and 15μg clonidine and a placebo when possible. A minimum interval of 3 days separated each injection.

Outcome Measures: Ashworth Scale (AS) (bilateral quadriceps), Walking parameters, H-reflex, Polysynaptic reflexes–recorded before and every hr for 4-6 hr after an intrathecal injection of clonidine or placebo.

1.     Significant decrease in AS (p<0.0001) at all dose levels (30, 60, 90 μg) with no consistent significant differences detected in reflexes.

2.     Statistically significant increase in the velocity at maximal overground speed (p=0.03) due to an increase in the stride amplitude (p=0.0009), without any significant decrease in the cycle duration (p=0.28).

3.     90 and 120 μg doses did not produce significant improvement in 3 subjects able to walk after 60 μg.

Nance et al. 1989

Canada

Prospective Controlled Trial N=6

Population: Injury etiology: SCI=6.

Intervention: Clonidine, clonidine and desipramine, diazepam, placebo.

Outcome Measures: Vibratory inhibition index (VII) of the H-reflex, Achilles reflex, Duration of clonus.

1.     VII significantly reduced by clonidine (p<0.001) but not the other interventions.

2.     Achilles reflex not affected by any intervention.

3.     Duration of clonus not affected by any intervention.

Nance 1994

Canada

Pre-Post

N=25

Population: Injury etiology: SCI=25; Level of severity: complete, incomplete; Chronicity: chronic.

Intervention: 1 wk up-titration, 1 wk target dose (0.05 mg bid clonidine; 4 mg qid cyproheptadine; 20 mg qid baclofen), 1 wk down-titration.

Outcome Measures: Ashworth Scale (AS), Pendulum, Vibratory Inhibition Index (VII).

1.     AS and Pendulum correlated well (r=0.88) in no-drug condition.

2.     Ashworth significantly reduced, significantly increased first swing amplitude, and increased VII in all three drug conditions (p<0.0001, all 3 outcome measures) with baclofen showing the most improvement (p=0.06).

3.     No difference between treatments (p=0.2618) for Ashworth and Pendulum.

4.     Cyproheptadine and baclofen produced a greater reduction in the VII than Clonidine (p=0.01).

Yablon & Sipski 1993

USA

Case Series

N=3

 

Population: Injury etiology: traumatic SCI=3; Level of injury: cervical=3; Chronicity: sub-acute.

Intervention: 0.1-0.3 mg/wk Transdermal clonidine patch (Constant/continuous systemic delivery).

Outcome Measures: Change in spasticity (no specific measure noted).

1.     Case 1: Marked improvement noted in relief of flexor spasms;

2.     Case 2: Excellent improvement noted in both spastic hypertonia and flexor spasms.

3.     Case 3: Moderate improvement in spastic hypertonia and flexor spasms.

Weingarden & Belen 1992

USA

Case Series

N=17

Population: Injury etiology: traumatic SCI=17.

Intervention: Transdermal clonidine.

Outcome Measures: Clinically significant relief of spasticity,
Continuation of study drug after trial, Discontinuation of other anti-spasticity medications.

1.     5/17 had clinically significant relief.

2.     12/15 continued to use the medication.

3.     10/15 were able to decrease or discontinue their current antispasticity medications.

Donovan et al. 1988

USA

Case Series

N=55

Population: Injury etiology: SCI=55; Level of injury: paraplegia, tetraplegia; Level of severity: complete, incomplete.

Intervention: Oral clonidine–0.05 mg bid and increased to 0.4 mg bid if tolerated by the subject.

Outcome Measures: Success of medication was defined as a decrease in hypertonicity, Adverse Events (AE).

1.     Results indicate that quadriplegics responded to the medication better than the paraplegics. (p<0.033).

2.     No significant difference based on complete versus incomplete lesions.

3.     31/55 subjects responded to clonidine.

4.     Many non-responders withdrew due to AEs.

Discussion

There have been two placebo-controlled trials (Stewart et al. 1991; Remy-Neris et al. 1999) providing evidence for clonidine’s effectiveness in reducing SCI spasticity. Stewart et al. (1991) used oral clonidine in a randomized trial but the spasticity outcome measures are not validated or well-known clinically compared to the Ashworth measure used by Remy-Neris et al. 1999). However, the latter study was not randomized; therefore, it was less rigorous in design. Both studies had small sample sizes. In another non-randomized, placebo controlled study by Nance et al. (1989) with a small sample size (N=6), the results concurred with clonidine’s antispasmodic properties through the use of a non-validated Vibratory Inhibition Index (VII) which is not commonly known clinically. A subsequent pre-post study by the same author (Nance 1994) using the Ashworth and Pendulum measures as well as the VII compared clonidine with cyproheptadine and baclofen for their anti-spastic properties. Although all three treatments were significantly beneficial in reducing spasticity as measured by the Ashworth and Pendulum tests, clonidine was significantly inferior to baclofen and cyproheptadine as measured by the VII. The remaining reports of antispastic effects of clonidine in various formulations (oral, transdermal and additional intrathecal studies) were derived from case series studies (Donovan et al. 1988; Weingarden & Belen 1992; Yablon & Sipski 1993; Remy-Neris et al. 2001). All presented results in favour of using clonidine as an anti-spasmodic but the outcome measures chosen for each study were not specified and there were reports of several adverse events (Donovan et al. 1988). A 2003 study by Malinovsky presented evidence of the systemic and sedating effect of clonidine (150 ug intramuscularly or intrathecally) in patients with traumatic SCI, regardless of the mode of administration. He concluded that patients receiving treatment for spasticity may be susceptible to this sedating effect because of an altered susceptibility rather than a delayed cephalad spread of medication. Although most of studies presented results in favour of clonidine for the treatment of spasticity, the evidence is not entirely convincing given the use of small sample size, predominantly non-validated outcome measures, reports of adverse events and less robust study designs. Furthermore, when directly compared to baclofen, clonidine was significantly inferior to baclofen in its anti-spastic properties.

Conclusions

There is level 1b evidence (from one RCT, two prospective controlled trials; Stewart et al. 1991; Malinovsky et al. 2003; Remy-Neris et al. 1999) supported by several non-controlled studies in favour of using clonidine as a SCI anti-spasmodic although this must be interpreted cautiously given small study sample sizes, inadequate outcome measure selection, occurrence of adverse events and less than robust study designs.

Clonidine may be effective in treating SCI spasticity but more evidence is required to support its routine use.