Abstract ID: A18

Abstract Title: An Open-Label, Dose-Escalation Study of Dextromethorphan and Quinidine in Painful Diabetic Neuropathy

Poster Type: Either


ABSTRACT BODY

Introduction: An open-label dose escalation study was conducted to evaluate the safety and tolerability of dextromethorphan and quinidine (DM/Q) in the treatment of pain associated with diabetic neuropathy and to obtain a preliminary assessment of efficacy in the condition. DM is a CNS active agent that may control pain. Clinical studies have suggested efficacy of DM; however, results are inconsistent, possibly due to variations in DM plasma levels resulting from phenotypic differences in patients' metabolism. By inclusion of the CYP2D6 inhibitor Q, consistently elevated DM levels are maintained that may relieve the pain of polyneuropathies.

Materials and Methods: Adult patients with distal symmetrical diabetic neuropathy and daily pain in the lower extremities for the previous 3 months were recruited. Following a 1-2 week discontinuation period from analgesics, patients scoring moderate or greater pain (≥2) on a Likert rating scale received escalating oral doses of capsules of 30 mg DM and 30 mg Q to a maximum tolerated dose (MTD) not to exceed 120 mg DM and 120 mg Q per day starting with one capsule per day. Safety was assessed with adverse events, laboratory values, vital signs, physical examinations, electrocardiography, and nerve conduction. The Pain Intensity Rating and the Pain Relief Rating Scales (PIRS, PRRS) were administered weekly and the Peripheral Neuropathy Quality of Life Instrument (QOL) was administered on Day 1 and at the final visit (Day 29). Inferential analysis and summary statistics for safety and efficacy variables were calculated on all subjects and subjects categorized by MTD.

Results: Thirty-six patients enrolled at 5 U.S. centers; 33 patients completed the study (Fig. 1). The majority (N = 23; 69.7%) tolerated 120 mg DM; 2-, 6-, and 5 patients, respectively, had MTDs of 90-, 60-, and 30 mg. The most common AEs were nausea (28% subjects), dizziness (25%), and headache (25%). Two patients discontinued due to adverse events (AEs), possibly related (chest pain NEC) or not related (colonic polyp). There were no clinically significant findings for any other safety variable. Improvements from baseline were seen in >82% of patients on the PIRS (Fig. 2), PRRS, QOL, Diary Sleep Rating Scale, Diary Activity Rating Scale, and Diary Pain Rating Scale (all p-values ≤0.0002) and in 68% of patients on the Diary Present Pain Intensity Rating Scale (p=0.04) (Fig 3). The changes from baseline in all parameters improved with study duration; mean changes from baseline for the PIRS were -1.0, -1.3, -1.5, and -1.7 on Days 8, 15, 22, and 29, respectively (all p-values <0.0001). By the end of the study only 20% of patients had moderate or greater pain (the entry criteria), and 40% of patients reported no pain.

Discussion: DM/Q was safe and well-tolerated up to 120 mg DM and 120 mg Q per day in patients with painful diabetic neuropathy. Changes from baseline in pain assessments that improved with study duration suggest the value of a larger, placebo-controlled study.




ATTACHED FILES

A18_Fig1andlegend.doc

A18_Figure 2and legend.doc

A18_Figure 3andlegend.doc

Reg Anesth Pain Med 2004; 29(2):A18