Elsevier

Phytomedicine

Volume 12, Issue 10, 15 November 2005, Pages 707-714
Phytomedicine

Efficacy of a Comfrey root extract ointment in comparison to a Diclo-fenac gel in the treatment of ankle distortions: Results of an observer-blind, randomized, multicenter study

https://doi.org/10.1016/j.phymed.2005.06.001Get rights and content

Abstract

In the treatment of minor blunt injuries several topical drugs are known to have anti-inflammatory and analgesic properties. They represent, however, two fundamentally different major pharmacological therapy approaches: the “chemical-synthetical” and the “phytotherapeutical” approach. The main objective of this trial (CODEC_2004) was to compare the efficacy and tolerability of an ointment of Comfrey extract (Extr. Rad. Symphyti) with that of a Diclofenac gel in the treatment of acute unilateral ankle sprain (distortion). In a single-blind, controlled, randomized, parallel-group, multicenter and confirmatory clinical trial outpatients with acute unilateral ankle sprains (n=164, mean age 29.0 years, 47.6% female) received either a 6 cm long ointment layer of Kytta-Salbe® f (Comfrey extract) (n=82) or of Diclofenac gel containing 1.16 g of diclofenac diethylamine salt (n=82) for 7±1 days, four times a day.

Primary variable was the area-under-the-curve (AUC) of the pain reaction to pressure on the injured area measured by a calibrated caliper (tonometer). Secondary variables were the circumference of the joint (swelling, figure-of-eight method), the individual spontaneous pain sensation at rest and at movement according to a Visual Analogue Scale (VAS), the judgment of impaired movements of the injured joint by the method of “neutral-zero”, consumption of rescue medication (paracetamol), as well as the global efficacy evaluation and the global assessment of tolerability (both by physician and patient, 4 ranks). In this study the primary variable was also to be validated prospectively.

It was confirmatorily shown that Comfrey extract is non-inferior to diclofenac. The 95% confidence interval for the AUC (Comfrey extract minus Diclofenac gel) was 19.01–103.09 h*N/cm2 and was completely above the margin of non-inferiority. Moreover, the results of the primary and secondary variables indicate that Comfrey extract may be superior to Diclofenac gel.

Introduction

Both topical drugs tested in this clinical trial are well known as state-of-the-art pharmacological treatments of minor blunt injuries. The therapeutic properties of comfrey are based on its anti-inflammatory and analgesic effects as well as its activity in stimulating granulation and tissue regeneration (Andres et al., 1989; Koehler and Franz, 1987). Comfrey (Symphytum officinale L.) is a medicinal plant with a long heritage and tradition in the treatment of painful muscular and joint complaints (Englert et al., 2005; Kothmann, 2003; Prinzing, 1960), proven in numerous studies (Hess, 1991; Koll and Klingenburg, 2002; Kucera et al., 2000; Mayer, 1991, Mayer, 1992, Mayer, 1993; Pabst and Ottersbach, 2004; Petersen et al., 1993; Schmidtke-Schrezenmeier et al., 1992; Tschaikin, 2004). For the pharmacological effect and clinical efficacy of comfrey preparation at topical application three major constituents of comfrey might be responsible: the purin derivative allantoine, rosmarinic acid and the mucilages (polysaccharides) (Wagner and Wiesenauer, 2003). Recent clinical trials again prove the efficacy in bruises, strains, contusion, and sprains.

In 1999, a preparation of Comfrey root extract (1:2, ethanol 60% V/V, 35%, Kytta Salbe® f) was compared to placebo in a multicenter, randomized, double-blind, parallel group study in 142 patients suffering from a unilateral ankle sprain. Treatment was started at the latest 6 h after occurrence of the injury. The duration of treatment was 8 days and assessments were made on days 0, 4 and 7. The affected ankle joint was locally treated with about 2 g of ointment four times a day. The primary variable was tenderness of the ankle joint, measured by tonometry (pressure difference between the injured and healthy foot). During the course of treatment, pain regressed significantly more in the group with Comfrey extract than in the placebo group. At the final measurement, the reduction compared to initial tenderness was 2.44 kp/cm2 in the active treatment group whilst it was only 0.95 kp/cm2 under placebo. Compared to placebo, verum was clearly superior regarding the reduction of pain (tonometric measurement, p<0.0001) and ankle edema (figure-of-eight method, p=0.0001). Significant differences between active treatment and placebo could also be revealed for ankle mobility (neutral-zero method), and global efficacy (Koll et al., 2004).

In a controlled, double-blind, randomized multicenter study, the efficacy and safety of a topical Comfrey extract product (10% active ingredient of a 2.5:1 aqueous ethanolic Comfrey extract (Symphytum×uplandicum NYMAN), corresponding to 25 g of fresh herb per 100 g of cream; n=104) was tested against a 1% product (corresponding to 2.5 g of fresh comfrey herb in 100 g of cream; n=99) in 203 patients with acute ankle sprains. With the high concentration, decrease of the scores for pain during active motion, pain at rest and functional impairment was highly significant and clinically relevant on days 3–4 as well as on day 7 (p<0.001). Amelioration of swellings as compared to reference was also significant on days 3–4 (p<0.01). Efficacy was judged good to excellent in 85.6% of cases with verum and in 65.7% of cases with reference on days 3–4 (Kucera et al., 2004).

Diclofenac acts as a potent cyclooxigenase inhibitor. Its pharmacological properties are well documented and generally known (Hardman and Limbird, 1996; Sweetman, 2004). Pharmacokinetic trials have shown that diclofenamic acid, when applied topically, penetrates the skin barrier to reach joints, muscles and synovial fluid, in sufficiently high concentration to exert local therapeutic activity (Assandri et al., 1993; Radermacher et al., 1991; Riess et al., 1986). Several clinical trials on diclofenac have been published and prove the efficacy not only on blunt injuries but further muscle and joint complaints like activated osteoarthritis of the finger joints (Bahamonde and Saavedra, 1990; Bouchier-Hayes et al., 1990; Kyuki et al., 1983; Predel et al., 2004; Zacher et al., 2001).

Section snippets

Methods and substances

This clinical study (CODEC_2004) was planned and carried out as a multicenter, controlled trial (two parallel groups) with patients suffering from unilateral ankle sprains. The two groups were treated either with commercially available Kytta-Salbe® f or Voltaren® Schmerzgel (Voltaren, 1999, Kytta, 2001).

A double-blind design was not possible due to the differences between the two products (cream vs. gel, color, odour). Therefore, the study was carried out as an “investigator-blind” trial: at no

General data

A total of 164 male and female outpatients were randomized and took the study medications after having given written informed consent. All randomized patients were assessed for efficacy in the intention-to-treat and per protocol population. There were 82 patients (50.0%), aged on average 29.6 years, randomized to Comfrey extract and 82 patients (50.0%), aged on average 28.4 years, randomized to Diclofenac gel. All of the patients were Caucasians. A history of allergy was reported in 48 cases

Discussion

The two topical drugs tested in this clinical trial are well known as state-of-the-art pharmacological treatments of minor blunt injuries (De Lange de Klerk, 2005). They represent, however, two fundamentally different major pharmacological therapy approaches: the “chemical-synthetical” and the “phytotherapeutical” approach, the one being a pure synthetic product and the other being a plant extract. A direct comparison of these two therapies has not been described before and is of quite some

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