Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy

Abstract

A length-dependent neuropathy with pain in the feet is a common complication of diabetes (painful diabetic neuropathy). It was hypothesized that pain may arise from sensitized-hyperactive cutaneous nociceptors, and that this abnormal signaling may be reduced by topical administration of the α(2)-adrenergic agonist, clonidine, to the painful area. This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Nociceptor function was measured by determining the painfulness of 0.1% topical capsaicin applied to the pretibial area of each subject for 30minutes during screening. Subjects were then randomized to receive 0.1% topical clonidine gel (n=89) or placebo gel (n=90) applied 3 times a day to their feet for 12weeks. The difference in foot pain at week 12 in relation to baseline, rated on a 0-10 numerical pain rating scale (NPRS), was compared between groups. Baseline NPRS was imputed for missing data for subjects who terminated the study early. The subjects treated with clonidine showed a trend toward decreased foot pain compared to the placebo-treated group (the primary endpoint; P=0.07). In subjects who felt any level of pain to capsaicin, clonidine was superior to placebo (P<0.05). In subjects with a capsaicin pain rating ⩾2 (0-10, NPRS), the mean decrease in foot pain was 2.6 for active compared to 1.4 for placebo (P=0.01). Topical clonidine gel significantly reduces the level of foot pain in painful diabetic neuropathy subjects with functional (and possibly sensitized) nociceptors in the affected skin as revealed by testing with topical capsaicin. Screening for cutaneous nociceptor function may help distinguish candidates for topical therapy for neuropathic pain.

Figure 1

Timeline

Figure 2

CONSORT (Consolidated Standards of Reporting Trials) diagram

Figure 3

Change in pain by capsaicin response level [(Mean ± SEM) Y-axis = ΔNPRS; X-axis = Week]. Effects of Clonidine over Placebo varied with capsaicin response determined during screening. Weekly means of “average pain over the last 24 hours” rated on 0-10 numerical pain rating scale (NPRS).

Figure 4

Cumulative proportion of responder's analysis (CPRA) graph displaying proportion of patients who had a given percentage decrease in pain compared to baseline at week 12 with Clonidine or Placebo. Effects of Clonidine over Placebo varied with capsaicin response determined during screening. Ratings of pain were obtained through 0-10 NPRS.

Figure 5

Clinician and patient global impression of change (CGIC; PGIC) at point of study termination (12 weeks) for capsaicin responders [(≥2); Y-axis = percent of patients]. CGIC and PGIC were assessed by having the investigator and patient independently rate overall global impression of change in the subject's pain status at the final treatment visit using a 7 point verbal rating scale. The investigator and subject were asked: “Relative to Baseline, please rate from among the following choices the subject's total improvement whether or not, in your judgment, it is due entirely to study drug treatment: ‘very much improved,’ ‘much improved,’ ‘minimally improved,’ ‘no change,’ ‘minimally worse,’ ‘much worse,’ or ‘very much worse’.” Percentages are displayed by treatment group on the y-axis, the n for each group is included within each bar.

Figure 6

Nerve fiber count by capsaicin response. Participating subjects (n=97) received a 3 mm punch skin biopsy on the lower extremity six cm above the ankle. Intra-epidermal nerve fiber density (IENFD) was determined using the pan-axonal marker PGP 9.5 by a central laboratory (Therapath: www.therapath.com). Sites were selected for participation based on willingness to do skin biopsy and a prespecified intent to do the biopsy in about one half of the subjects.