Intra-Articular Botulinum Toxin Type A May Offer J

Newswise — Injections of intra-articular neurotoxins may offer relief from severe knee pain for osteoarthritis patients who are not candidates for joint reconstruction, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Washington, DC. For thousands of knee pain sufferers, arthroplasty is the solution of choice. This surgical replacement or reconstruction of the diseased joint restores function improves range of motion and decreases pain. However, for those who are too young, too old or too frail for such surgery, neurotoxins, which target the pain nerves within the joint, delivered to the knee joint cavity may provide sustained pain relief.

To determine the potential benefits of injecting a neurotoxin directly into the knee joint cavity, researchers embarked on a six-month study of Intra-articular Botulinum Toxin Type A (IA/BoNT/A) versus placebo in 37 patients with moderate to severe refractory knee pain due to osteoarthritis. IA/BoNT/A, otherwise known as Botox, disrupts pain nerve function and may reduce nerve-related inflammation.

The 36 men and one woman participating received either 100 units of IA/BoNT/A with lidocaine (a short-acting anesthetic) or a saline placebo with lidocaine. Double-blind assessments were scheduled for baseline, 1-month, 3-month and 6-month time points. Primary outcomes to be measured at each milestone include self-reported total pain score and a physical function score. A walking pain score, day pain severity, night pain severity and an observed timed-stands test were also measured.

At the 1-month interim analysis of this study, two placebo patients had dropped out from lack of benefit. Of the 18 patients in the severe pain group (half on IA/BoNT/A and half on placebo), there was a significant decrease in pain and improvement in physical function for those who received the botulinum toxin injection. Those injected with the placebo experienced minimal improvement. In the moderate pain group, neither injection produced significant changes in the primary outcome measures. Interestingly, in the moderate pain group, there was a 25% reduction in daytime pain severity after the placebo injections.

Three-month measurements will be completed by January of 2007, and the trial is scheduled for completion in August of 2007. To date, however, researchers point to clinically and statistically significant decreases in severe osteoarthritis knee pain and improvements in physical function.

"If this novel approach to local treatment for refractory join pain continues to prove beneficial, it offers a very welcome solution for fragile patients," explains Maren L. Mahowald, MD, Rheumatology Section Chief at the Minneapolis VA Medical Center, Professor of Medicine at the University of Minnesota, Minneapolis, Minnesota, and principal investigator in the study. "Local joint treatment with injection could replace oral medications that carry the risk of systemic side effects, and may negate or delay the need for joint surgery. Much more research will be needed to determine the most effective and safe dose of toxin for the joint injections and the most appropriate dosing intervals."

The American College of Rheumatology is the professional organization for rheumatologists and health professionals who share a dedication to healing, preventing disability and curing arthritis and related rheumatic and musculoskeletal diseases. For more information on the ACR's annual meeting, see http://www.rheumatology.org/annual.

Editor's Notes: Dr. Mahowald will present this research during a scientific poster session at the ACR Annual Scientific Meeting from 9:00 " 11:00 am EST on Monday, November 13, 2006 in Exhibit Hall A-B of The Washington Convention Center. She will be available for media questions and briefing at 8:30 am EST on Monday, November13, in the on-site Press Conference Room 209C. Presentation Number: L1

Interim Report of a Randomized Double Blind Controlled Trial of Intra-articular Botulinum Toxin Type A (IA-BoNT/A) vs Placebo for Moderate and Severe Refractory Knee Pain due to Osteoarthritis

Mahowald L. Mahowald1, Jasvinder A. Singh1, Anton Kushnaryov2, Hollis E. Krug1. 1Minneapolis VA Medical Center & University of Minnesota, Minneapolis, MN; 2University of Minnesota, Minneapolis, MN

Moderate and Severe OA knee pain refractory to oral and IA treatment in patients too young or too old and frail for arthroplasty represents a growing unmet need for new joint pain treatments. IA Neurotoxin injection for sustained analgesia is a promising new approach to persistent joint pain (J Neurotox Res 9:179-88,2006). BoNT/A inhibits vesicle release of neuropeptides such as Substance P and CGRP and disrupts nociceptor function to decrease pain and neurogenic inflammation.

Purpose: To describe the effects of IA-BoNT/A injections at 1 month (interim analysis).

Methods: 37 patients with moderate to severe, refractory knee pain due to OA have been randomized to 100 units IA-BoNT/A+lidocaine (B) or saline+lidocaine placebo (P). Double blind assessments are made at baseline, 1 mo, 3 mo and 6 mo/time of withdrawal. Primary outcome measures at 1 mo were Western Ontario McMaster OA index (WOMAC) Pain Score & Function Score. WOMAC Q1-walking pain, Day Pain and Night Pain on 0 to 10 numerical rating scale (NRS) & 10X Timed Stands Test (TST) were also compared. Patients in the Severe Pain group had 7 or greater on NRS & the Moderate Pain group had 4.5 to <7 NRS. Protocol was approved by IRB & participants gave signed informed consent.

Results: 37 patients (36M, 1F) were randomized and 1 patient in each group was unable to complete questionnaires because of cognitive impairments (MMSE<25). Two placebo patients dropped out due to lack of efficacy, last observation carried forward. One month data for 18 in the Severe Pain group (9 B, 9 P) & 17 in the Moderate Pain group (8 B, 9 P) were analyzed. In the Severe Knee Pain group there was a significant decrease in WOMAC Pain score- 12.4 (se 1.5) to 8.9 (se 3.1; p=.006) and improvement in WOMAC Physical Function score 42.4 (4.2) to 31.8 (10.3) (p=.033) 1 mo after IA-BoNT/A: Q1 Walking pain decreased 2.6 (0.7) to 1.7 (1) (p=.035); Daytime pain decreased 39%, 7.6 (1) to 4.6 (2.1) (p=.003), Nighttime pain decreased 24%, 5.4(2.7) to 4.1(2.1) (p=.015) and 10X TST improved 36.4 sec to 29.4 sec, p=0.046. There were no significant improvements in the Placebo injected Severe Pain group. In the Moderate Pain group, both B and P injections produced little change at 1 month. The only significant change was a decrease in Daytime pain 6.1 to 4.6 (25% ; p=0.02) in the Placebo Group. The Trial is ongoing for examinations at 3 and 6 month time points.

Conclusion: IA-BoNT/A produced clinically and statistically significant decreases in Severe OA knee pain and improvements in physical function. There were no significant adverse effects related to the neurotoxin injections. Maximal pain relief and duration of effects will be determined in the full 6 month study observation. These data provide further evidence supporting the efficacy of this novel approach to local treatment of refractory joint pain.

Disclosure Block: M.L. Mahowald, Unrestricted Educational grant and vial grant from Allergan Pharmaceuticals, 2; J.A. Singh, TAP pharmaceuticals, 2; A. Kushnaryov, None; H.E. Krug, None.