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Journal of Clinical Pharmacology, 2004; 44:1323-1327
© 2004 the American College of Clinical Pharmacology

HERBAL MEDICINE

Effects of Corydalis yanhusuo and Angelicae dahuricae on Cold Pressor-Induced Pain in Humans: A Controlled Trial

Chun-Su Yuan, MD, PhD, Sangeeta R. Mehendale, MD, PhD, Chong-Zhi Wang, PhD, Han H. Aung, MD, Tingliang Jiang, MD, PhD, Xiongfei Guan, MD and Yukihiro Shoyama, PhD

From the Tang Center for Herbal Medicine Research, Committee on Clinical Pharmacology, and Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, Illinois, and Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

Address for reprints: Chun-Su Yuan, MD, PhD, Department of Anesthesia & Critical Care, University of Chicago, 5841 S. Maryland Avenue, MC 4028, Chicago, IL 60637.


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pain is considered the most common complaint worldwide for which patients seek treatment. Conventional analgesic agents play an important role in modern pain therapy, but they cause several adverse effects. Therefore, newer and better analgesics continue to be investigated. In this controlled clinical trial, the authors evaluated the analgesic effects of 2 herbal medicines, Corydalis yanhusuo and Angelicae dahuricae. They used the cold-pressor test—a simple, reliable, and widely used model in humans—for induction of tonic pain. They demonstrated that after a single, oral administration of the extracts of C. yanhusuo and A. dahuricae, the pain intensity and pain bothersomeness scores significantly decreased (both P < .01). Dose-related analgesic effect was also observed. Results from this study suggest that C. yanhusuo and A. dahuricae may have a potential clinical value for treating mild to moderate pain.

Key Words: Corydalis yanhusuo • Angelicae dahuricae • herbal medicine • analgesics • Chinese traditional medicine

Pain is the most common clinical complaint that has caused considerable human suffering.1 In the United States alone, approximately 100 million people suffer from moderate to severe pain during any given year.2 Analgesic pharmacotherapy, with drugs such as acetic acid derivatives, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids, has made significant advances to date. These medications are, however, not devoid of side effects. In fact, some drugs have been associated with serious adverse events.3-5 Of the total number of patients who seek treatment for pain, 50% are reported to be dissatisfied with the available pharmacological options.6 Thus, research for newer analgesics, including those derived from herbal sources, is still ongoing.

In China, there is a widely used Chinese herbal pain-relieving formulation called the "Yuanhu analgesic capsule." This empirically used formula is listed in the Pharmacopoeia of Chinese Medicine.7,8 Yuanhu analgesic formula is one of the simplest herbal formulations in Chinese medicine, consisting of only 2 herbs, Corydalis yanhusuo and Angelicae dahuricae.9-11

Cold-induced tonic pain, which involves immersion of a limb in ice-cold water, is a widely used pain induction method in clinical trials.12,13 The advantage of the cold-pressor method is its simplicity and high validity.14 This method measures the pain intensity in a short, fixed time interval and has been considered safe for the subjects. The test is recognized as a sensitive and reliable technique for measurement of opioid-induced pain reduction in humans.15-17 We previously reported analgesic effects of acetaminophen, a non-opioid analgesic,18 and low-dose morphine16 on cold-induced pain in human subjects. In this controlled study, we investigated the effects of Yuanhu analgesic formula on cold pressor-induced pain in 15 healthy human subjects.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
With approval from the institutional review board, 10 males and 5 nonpregnant females were enrolled in the study. The mean age ±SD of the subjects was 24.9 ±5.7 years, with a range of 19 to 35 years.

Inclusion criteria for subjects in this study were 18- to 50-year-old male or nonpregnant female volunteers with no active disease states. Exclusion criteria were as follows: (1) history or current evidence of cardiovascular, respiratory, endocrine, renal, hepatic, hematologic, or psychiatric disorders; (2) history or current evidence of drug abuse; (3) abnormal physical examination or resting electrocardiogram; (4) current use of medications; or (5) presence of Raynaud's disease. Subjects also agreed to abstain from alcohol and caffeinated drinks during the study period. Signed consent forms were obtained at the end of the screening session. In addition, urine toxicology tests for use of other drugs were randomly performed during the study.

Herbal Medications
Yuanhu Pain-Relieving Capsule from 1 lot was obtained from the Beijing Chinese Herbal Medicine Company. The capsule consists of extracts of 2 herbs: the rhizome of Corydalis yanhusuo W. T. Wang and the root of Angelica dahuricae (Fisch. ex Hoffm.) Benth. et Hook. f. var. formosana (Boiss) Shan et Yuan. Each capsule contains 67% of C. yanhusuo and 33% of A. dahuricae (w/w).8 Using international protocols from the Association of Official Agricultural Chemistry (AOAC), an independent laboratory tested both herbs and found them to be free of detectable levels of lead, mercury, cadmium, pesticide residues, and 20 other contaminants.

Based on previous chemical analysis, several major constituents of C. yanhusuo and A. dahuricae have been identified.19 Figure 1 shows the chemical structures of 2 major constituents isolated from each herb. These major constituents have been used to characterize and standardize the extracts.9,11,20



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  		Figure 1. Chemical structures of major constituents isolated from Corydalis yanhusuo (tetrahydropalmatine and corydaline) and from Angelicae dahuricae (imperatorin and isoimperatorin).

 

Protocol
This was a double-blinded, placebo-controlled crossover study. Subjects were asked to participate in 3 sessions or treatments. Each session lasted approximately 60 min, and sessions were separated by at least 48 h. Individual subjects' sessions began at the same time of the day.

At the onset of each session, subjects were given a single oral dose (in 5 capsules) of (1) placebo, (2) low herbal dose (containing 3.25 g raw herbs), and (3) high herbal dose (containing 6.5 g raw herbs) with 100 mL tap water. No food intake was allowed 2 h prior to capsule ingestion. The identical-appearing placebo-containing capsules were prepared with cornstarch powder. Drug preparation and administration was done by staff members who did not participate in subject observation or data acquisition. The order of the drug assignments for each subject was prepared by a biostatistician using a table of random numbers. Drug administrations were blinded to both subjects and investigators.

In each session, a cold-pressor test (see below) was performed 40 min after study drug administration. After completion of all 3 sessions, subjects were asked to identify the session in which they received either the placebo or the high herbal dose. All study data were then entered into a computer, and thereafter, drug assignments were unblinded for statistical analysis.

Cold-Pressor Test
The cold-pressor apparatus consisted of a standard ice chest divided into 2 compartments by a wire screen. The tank was filled with water, and ice was added to one side of the screen. A cradle for the subject's non-dominant forearm was positioned on the side of the chest with no ice, allowing the subject to rest the forearm while immersing it into the cold water. The water in the ice chest was constantly circulated by a pump and was maintained at 1.5 ±0.5°C during the test.

The study was conducted in a quiet room with medium-intensity room light. There was no visual or audio stimulus during the sessions. Subjects were asked to sit back comfortably in a chair during tests. Before the first immersion, subjects were instructed to rest their arm on the cradle, not to make a fist, and not to hold their breath during the immersion. The depth of the water (measured from the surface to the top of the cradle) was consistently kept at 16 cm.

Each immersion trial lasted approximately 180 sec. During each arm immersion in the ice-cold water, the subject was instructed to verbally rate the pain intensity on a scale of 0 to 10 (0 = not painful at all to 10 = extreme pain). The questions—"How painful is it?" and "How much does it bother you?"—were asked at 30, 70, 110, and 170 sec after the immersion to elicit the responses. These scores were collected during all 3 cold-pressor trials.

Statistics
Data were analyzed using repeated-measures analysis of variance (ANOVA) using StatView (Abacus Concepts, Inc, Berkeley, Calif, 1994). In addition, we employed the generalized estimating equations (GEE) approach for repeated measurements developed to estimate dose-response effects. The 2 methods yielded similar results; P < .05 was considered statistically significant.


   RESULTS
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
All 15 subjects completed all 3 sessions. Figure 2 shows pain intensity and pain bothersomeness scores after placebo, low herbal dose, or high herbal dose during the 170-sec cold-water immersion in these subjects.






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  		Figure 2. Dose-related analgesic effects of single oral administration of Corydalis yanhusuo and Angelicae dahuricae extracts on pain intensity and pain bothersomeness ratings as a function of immersion time (A) 30 sec, (B) 70 sec, (C) 110 sec, and (D) 170 sec in ice-cold water. After high herbal dose, the pain scores significantly decreased (P < .01 compared to placebo). A significant dose-related analgesic effect was also reported (P < .05). Each bar represents the average rating of 15 subjects, and brackets indicate SEM. Low dose, extracts of C. yanhusuo and A. dahuricae containing 3.25 g raw herbs. High dose, extracts of C. yanhusuo and A. dahuricae containing 6.5 g raw herbs.

 

In every treatment group, pain intensity and pain bothersomeness scores gradually increased from 30 to 170 sec. After the high herbal dose administration, the pain intensity and pain bothersomeness scores reported by subjects significantly decreased (both P <.01 compared to placebo). We also observed a significant dose-related analgesic effect of the Yuanhu analgesic formula using the cold pressor-induced pain model in these subjects (P < .05). For both pain intensity and pain bothersomeness scores, there was no significant dose-time interaction (ie, the effect of the herb was similar at each time point). Pain and bothersomeness ratings increased over time and decreased with increasing herbal dose.

After completion of the study, the subjects were asked to identify the session during which they received either placebo or the high herbal dose. Nine of 15 subjects were able to correctly identify the placebo session. If the subjects were merely guessing, the probability that 9 (or more) would have been correct is only approximately 1 in 500 (P < .05 using the binomial distribution). Similarly, 8 of 15 subjects were able to correctly identify the session during which they received the high herbal dose (P < .05).

No adverse effects of clinical importance were observed during the study.


   DISCUSSION
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
As the major component of traditional Chinese medicine (TCM), Chinese herbal medicine has been playing an important role in the promotion of health, prevention of disease, and treatment of illnesses for several thousand years in China. There are more than 5000 documented Chinese herbs.21 In contrast to Western prescription drugs that constitute well-defined pharmacological compounds, Chinese medicinal formulas are usually composed of a number of herbs (often more than 4 different botanicals). It is believed that several herbs in a formula are combined to enhance efficacy and reduce side effects.20 In the past several decades, efforts have been made by the TCM practitioners and researchers to simplify the complexity of formulations without violating the general principles of TCM. Introduced in China approximately 40 years ago, the Yuanhu pain-relieving formulation is a successful example with recognized efficacy.7,11

C. yanhusuo and A. dahuricae have been used in TCM for hundreds of years for several indications.22,23 Several reports investigating these 2 herbs have been found in Chinese literature.20,24,25 Attempts have also been made to identify single constituents from the herbs, and a few studies in English literature have evaluated the pharmacological effects of these 2 herbs.26,27 However, understanding the pharmacological effects of these herbs is complicated by the inconsistencies due to differing methods of preparation/extraction, dose regimens and routes of administration, experimental conditions, and varied effects among species. In this study, we adhered to standard herbal sources and extraction procedures to minimize these potential confounding effects.

The mechanisms of the analgesic action of C. yanhusuo and A. dahuricae are unclear. Some previous studies from China showed that C. yanhusuo and/or A. dahuricae might act on opioid, {gamma}-aminobutyric acid (GABA), or dopamine receptors.20,24,25 Further investigations are needed to elucidate the precise mechanisms of action of these herbs.

Data from this study demonstrate and confirm the pain-relieving efficacy of C. yanhusuo and A. dahuricae. It is possible that the combination of the 2 herbs could potentiate mutual analgesic effects while helping to reduce side effects. For example, the extract from C. yanhusuo is known to reduce gastric ulcers.9 Herbs with anti-inflammatory activities, such as A. dahuricae,10 could have potential side effects on the gastric mucosa (if mediated by inhibition of prostaglandin synthesis), as seen with other anti-inflammatory agents.3 Thus, the combination of C. yanhusuo and A. dahuricae could prevent or reduce the adverse gastric events, which is a beneficial effect. In addition, because C. yanhusuo appears to alleviate visceral pain,9 the herbal combination will broaden the spectrum of antinociceptive activity.28 Furthermore, C. yanhusuo and A. dahuricae are postulated to work via opioid, GABAergic, and dopaminergic mechanisms with each neurotransmitter known to act synergistically to improve analgesia.1,29,30 Because opioid-like activity would represent only part of the synergistic analgesic activity of the herbal combination, opioid-related adverse effects may also be reduced.

Results from this controlled clinical trial demonstrated that extracts of C. yanhusuo and A. dahuricae induced significant analgesia against cold-induced pain. Although several NSAIDs did not produce consistent analgesic effects on the cold-induced pain model,18,31-34 dose-related analgesic effects of C. yanhusuo and A. dahuricae were observed in this study. It is possible that C. yanhusuo and A. dahuricae may be particularly effective for the treatment of certain kinds of pain. Results from our study suggest that C. yanhusuo and A. dahuricae may have a clinical value as an herbal analgesic for treating mild to moderate pain.


   FOOTNOTES
 
DOI: 10.1177/0091270004267809

Submitted for publication April 1, 2004; Revised version accepted May 31, 2004.


   REFERENCES
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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