Quantitative Assessment Of Acupuncture
Analgesia Using A Human Experimental Pain Model:
A Randomized, Crossover Pilot Study
Farshad M. Ahadian, MD
Jennifer C. Braun, MPH
Gery Schulteis, PhD

ABSTRACT
Background Methodological deficiencies, the physical nature of acupuncture, and the multifactorial nature of pain have made it difficult to draw definitive conclusions from the vast body of acupuncture analgesia literature. These challenges may be addressed by development of a valid and reproducible experimental pain model.
Objective To evaluate the feasibility and validity of the subdermal capsaicin model in combination with heterotopic stimulation (acupuncture) and sham laser for acupuncture research.
Design, Setting, and Participants A randomized, crossover, placebo-controlled, blinded-observer study conducted at the University of California, San Diego Pain Medicine Research facilities. A total of 11 healthy volunteers were recruited through a research database and intrafacility advertisement.
Intervention Treatment consisted of stimulation of 4 pairs of acupoints along the inner BL line on 4 consecutive days using percutaneous electrical stimulation (acupuncture) or sham laser (placebo). Subsequent neurosensory testing was performed on the forearm.
Main Outcome Measures Spontaneous pain as measured on a visual analog scale (VAS). Secondary measures included acute neurosensory thresholds (warm sensation, cold sensation, warm pain, cold pain, touch, and mechanical pain) and central facilitation.
Results Following injection of capsaicin, VAS scores were significantly reduced in the acupuncture group vs the placebo group at 5, 10, and 15 minutes (P=.02). The normal neurosensory thresholds did not vary between groups.
Conclusions The proposed experimental model offers a reproducible alternative for quantitative assessment of acupuncture analgesia. Heterotopic stimulation and sham laser placebo provide improved blinding conditions.
KEY WORDS
Acupuncture, Pain, Capsaicin, Visual Analog Scale, Laser Acupuncture, Randomized Trial

INTRODUCTION
Methodological deficiencies have made it difficult to draw definitive conclusions from the vast body of acupuncture analgesia literature.^1-4 Acupuncture research is further complicated by the physical nature of this modality and the multifactorial nature of pain which do not conform well to traditional research design. These challenges may be addressed by development of 3 basic tools: (1) a valid and readily reproducible experimental pain model, (2) a valid heterotopic percutaneous electrical stimulation protocol (acupuncture) that does not interfere with subject blinding conditions, and (3) a valid placebo condition.

The Subdermal Capsaicin Model
Experimentally, the facilitated pain state can be evaluated beginning with the injection of subdermal capsaicin. This focal tissue injury induces a relatively transient (20-30 minutes) afferent barrage, but a potent state of allodynia and hyperalgesia surrounding the local injection site. These abnormal states of neural processing parallel the post-injury pain state in humans, and may be evaluated through quantitative neurosensory measurements. Experience with several classes of antinociceptive agents within the capsaicin model, as well as its parallel nature with clinical findings, make this model ideal for the study of acupuncture physiology. The subdermal capsaicin model has been used to study the pharmacology of experimental pain. Multiple pharmaceutical agents have been tested and the model appears to have predictive power for the efficacy of these agents.^5-10

Heterotopic Stimulation
The greatest challenge in research involving physical modalities such as acupuncture is the difficulty in blinding the subject or the observer to the treatment itself. For the subject, this is partly due to the ability to feel the needle insertion and distinguishing it from placebo. But even more importantly for both the subject and the observer, the difficulty in blinding is due to the ability to visually inspect and analyze the treatment as it is being performed.^4,11 For the observer, the issue is resolved by having an unblinded clinician perform the treatment and having a blinded observer perform the data collection. However, this is not possible for the subject, in distinct contrast to the use of pharmaceutical agents in which the active and placebo agents may be manufactured to look identical. Generally, for physical modalities, blinding tends to be easier to achieve when the site of treatment is not visible to the subject.

Altering the location of the selected acupoints, nonetheless, must not sacrifice efficacy. Therefore, the treatment protocol for this study was selected to satisfy 2 important criteria: (1) lack of visibility from the subject, and (2) analgesic efficacy. Heterotopic stimulation refers to treating the subject at a site away from the site of pain or site of testing; in this case, the application of subdermal capsaicin to the forearm and subsequent testing. Heterotopic stimulation provides the additional benefit of eliminating other confounding factors such as the role of local effects of the treatment. With regards to analgesic efficacy, the Wei Qi tonification protocol was selected.¹² Extensive clinical experience has demonstrated the analgesic efficacy of this treatment protocol for a variety of acute and chronic painful conditions, making the study results of further clinical relevance.

Sham Laser
Low-energy laser is an accepted therapy for symptomatic treatment of a variety of painful conditions and as a means of stimulating acupoints.^11,13-15 Sham low-energy laser was thus selected for the placebo condition because it does not cause any physiologic consequences and logistically, it is easily applied in the clinical setting. The heterotopic nature of the target sites away from the subject's field of vision makes application of the sham laser simple.

The aim of this pilot study was to determine the feasibility and validity of use of the subdermal capsaicin human experimental pain model, in combination with a predetermined heterotopic acupuncture treatment protocol and sham laser placebo condition for quantitative assessment of acupuncture analgesia.

METHODS
Design
We conducted a randomized, crossover, placebo-controlled, blinded-observer design. All participants received both active and placebo treatments. Half were randomized to receive active treatment followed by the placebo treatment, and the other half were administered treatments in the reverse order. Participants were informed that they would receive needle acupuncture during 1 treatment phase and low-energy laser acupuncture during the alternate phase of treatment. Three sets of measurements were conducted. Baseline measurements were performed on all participants at the time of enrollment. Subsequent measurements were performed immediately after the 4th session of each treatment (active or placebo).

The treatment protocols began as early as the following day after baseline measurements were taken. Patients crossed over into the 2nd treatment phase following a washout period of 2 weeks from the end of the 1st treatment. The primary reason for performing baseline measurements prior to entering each treatment arm was to familiarize participants with the testing paradigm and eliminate the between-group bias.

Participants
Men and women aged 18 years or older were included in the study if the following exclusion factors were ruled out: pain condition, hepatic or renal insufficiency, heart disease, psychiatric illness that could interfere with the interpretation of results, concurrent use of anticonvulsants or any local anesthetic derivative, pregnancy, or acupuncture treatment within 6 weeks of starting the study. Healthy volunteers were recruited from a research database and through intrafacility advertisement. Eleven individuals participated in the study and informed consent was obtained from each, indicating their awareness of the investigational nature of the study. The institutional review board of the University of California, San Diego, approved this study prior to initiation.

Treatment Protocol
The acupuncture treatment consisted of the Wei Qi Tonification protocol.¹² The participant was made comfortable in the prone position. Four pairs of needles (Serin Laser LC, 0.3 mm diameter, 4 cm length, Seirin Kasei Co., Shizuoka, Japan) were inserted bilaterally into the acupoints BL 18, BL 23, BL 25, and BL 27. The points were identified in the following manner. In the thoracic region, the spinous process of T1 was identified as the 1st immobile spinous process at the junction of the cervical and thoracic vertebrae in response to neck rotation, flexion, and extension. Then the spinous processes were counted in the caudad direction until T9 was identified. In the lumbosacral region, a line passing through the iliac crests was drawn. This line passes through the L3-4 interspace, which is identified by palpation. From that point, the lumbar and sacral spinous processes were identified by palpation in the cephalad and caudad directions. Two electroacupuncture stimulation devices (IC-1107, Ito Co) were used to stimulate these points. Acupoints BL 18 and BL 23 were connected together on each side, and BL 25 and BL 27 were connected together in the same manner. All points were then stimulated at 4 Hz frequency for 30 minutes. The intensity of treatment was adjusted so the participant felt the treatment well, but did not experience pain. The stimulation was then discontinued and the needles removed. This treatment was repeated daily for 4 consecutive days. Immediately after the last treatment, the participant was tested.

For the sham laser treatment (placebo), the participant was prepared and made comfortable in the prone position (as in the acupuncture group). A laser generator was modified to mimic normal functioning, including presence of the guiding beam and the sound of the machine. However, no laser energy was emitted. The device was suspended above the participant's back using the balanced mechanical arm of the laser machine approximately 20 cm from the skin. The operator then altered the position of the laser beam once every 3.75 minutes for a total treatment time of 30 minutes.

Testing Paradigm
At baseline and following completion of each treatment phase, neurosensory testing was performed on the volar aspect of the forearm in the prehyperalgesic state. Fifteen minutes following the induction of the hyeralgesic state with capsaicin, allodynia and dysesthesia were
mapped out on the subject's arm. Neurosensory testing was performed at the center of the hyperalgesic distribution. Pain scores were measured using a 10-cm visual analog scale (VAS) with pain severity in scores from 0-100 (100 being the most severe).

Four neurosensory tests were performed: (1) warm and cold sensation, (2) warm and cold pain, (3) touch, and (4) mechanical pain.

Warm and cold sensation and pain were measured using a Thermal Sensory Analyzer (Medoc Advanced Medical Systems, Minnesota), which consisted of a thermode measuring 46 x 29 mm that rises and falls in temperature (at a rate of 1.0°C/second). The subject pushed a switch to indicate warm/cold sensation and pain. Touch was measured using von Frey hairs, which are calibrated filaments of varying size. The filaments were selected at random, and 3 successive stimuli were applied for 1.5 seconds at 5-second intervals per filament in an ascending pattern. The participant was instructed to report if the stimulus was felt and when pain was experienced. Sensation and pain thresholds were established with a modification of the widely used method of Dixon in animal and human psychophysical testing.¹⁶

To induce secondary hyperalgesia, a volume of 10 µL of capsaicin was delivered intradermally, followed by VAS measurements at 5-minute intervals beginning at time 0. The region of secondary hyperalgesia was established from a participant's report of pain in response to stimulation with a 5.18 von Frey hair, foam brush gently stroked on the skin, and a 2 x 2 cm probe heated to 40°C. The regions of secondary hyperalgesia and flare response were measured in squared centimeters, and neurosensory threshold testing was repeated in this area.

Two central facilitation tests were performed: (1) train of 3 heat pulses and (2) intradermal capsaicin. Heat pulses were delivered by means of the thermal sensory analyzer (TSA). The TSA delivered 3 rising heat pulses with peak intensity of 52°C and at a frequency of 1 pulse/2.8 seconds. Participants were asked to rate the 1st and 2nd pain on a VAS.

Statistical Analysis
Data for all VAS scores (spontaneous pain, mechanical allodynia, mechanical dysesthesia) were subjected to 2-factor repeated measures ANOVA with crossover treatment condition (placebo, acupuncture), as well as time post-capsaicin as the factors. Significant main effects of treatment condition, or treatment x time interactions, were followed by individual means comparisons of placebo and acupuncture conditions at specific time points, with P<.05 taken as significant for all comparisons. Areas of mechanical dysesthesia and mechanical allodynia were subjected to 1-factor repeated measures ANOVA (treatment condition).

Figure 1. Spontaneous Pain Figure 2. Hyperalgesia Figure 3. Allodynia

RESULTS
All 11 participants completed both treatments. The intradermal injection of capsaicin resulted in a reliable report of pain, flair response, and secondary hyperalgesia.

Primary Outcome Measures
Following the injection of capsaicin, spontaneous pain VAS scores demonstrated a significant reduction in the acupuncture group as compared with the laser. This statistical significance was observed at 5, 10, and 15 minutes after capsaicin injection (P=.02) (Figure 1).

The normal neurosensory thresholds did not vary between the groups. These included warm sensation, cold sensation, warm pain, cold pain, touch, and mechanical pain (data not shown). This is an expected finding and confirms that neither the acupuncture treatment itself nor the control condition caused an alteration or impairment of the normal somatosensory pathways.

There was a trend toward reduction of hyperalgesia and allodynia in the acupuncture group compared with placebo, with respect to both VAS pain scores and surface area measured, although statistical significance was not reached. The VAS pain scores to stimulate with the von Frey filament (Figure 2) as well as brush stroke (Figure 3) were reduced at all time points (0, 5, 10, and 15 minutes) following capsaicin injection in the acupuncture group, as compared with laser, with an average P value of .08 and .06, respectively. The surface areas of hyperalgesia and allodynia around the injection site were smaller for the acupuncture group vs placebo. For hyperalgesia, the surface area for acupuncture was 17.34 cm2 vs 26.5 cm2 for placebo (P=.11). For allodynia, the surface area for acupuncture was 9.69 cm2 vs 20.99 cm2 in placebo (P=.23).

DISCUSSION
The proposed paradigm, combining subdermal capsaicin with heterotopic application of either an active or placebo acupuncture condition, offers a reproducible experimental pain model ideal for quantitative study of acupuncture analgesia.

The limited number of participants was a disadvantage in this preliminary pilot study. This notwithstanding, the study did reach statistical significance with respect to spontaneous pain, and consistently demonstrated a trend toward reduction of hyperalgesia and allodynia. This is promising, considering the limited nature of the acupuncture treatment protocol used, and underscores the validity of the model.

There were no statistically significant differences in the normal neurosensory thresholds, either between the 2 treatment groups or between either treatment group and baseline measurements. This is an expected finding consistent with the currently understood mechanisms of acupuncture analgesia. This underscores the role of central processing as the key underlying mechanism of this analgesia. Persistence of normal thresholds also validates the persistence of a normal afferent circuit, an indication that neither the treatment protocol nor the subdermal capsaicin interfered with the normal functioning of the afferent circuit.

This model has key advantages. The subdermal capsaicin model causes a transient state of somatic pain and central facilitation parallel to the post-injury state in humans, which may be evaluated using quantitative neurosensory measurements. The model has been used extensively, yielding substantial existing data on the pharmacology of human experimental pain, making this paradigm ideal for research on the physiologic basis of acupuncture analgesia in humans. In addition, acupuncture treatment protocols using heterotopic stimulation eliminate the subject's ability to visually inspect and analyze the treatment administered, in turn eliminating the difficulties with subject blinding, traditionally the greatest challenge in acupuncture research. The model also allows significant flexibility in choosing acupuncture points for a variety of treatment protocols with the only limitation being avoidance of the upper extremities, such that all selected points are outside of the subject's visual field. Finally, the model is easily adaptable to the use of a variety of control conditions.

Conclusions
The current pilot study emphasized a number of questions deserving of further consideration for future studies: (1) What is the optimal number of treatments necessary to induce physiologic changes? (2) What is the optimal duration of each treatment? (3) What is the optimal frequency of treatment to avoid the possibility of tolerance or tachphylaxis? (4) Do tolerance and tachyphylaxis to acupuncture exist in clinical practice? (5) What are the optimal frequencies for electrical stimulation and how do they correspond to the underlying physiology of acupuncture analgesia?

These questions present not only academic but also clinical relevance for patients, clinicians, and 3rd-party payers. Currently, clinicians rely on traditional teaching and experience to determine these parameters. Yet these are important issues for medical acupuncture to address if it is to continue to mature from a scientific and clinical standpoint. The proposed experimental pain model appears to be well suited to address those questions.

REFERENCES

1. NIH Consensus Conference. Acupuncture. JAMA. 1998;280:1518-1524.
2. NIH Acupuncture Consensus Statement. 1997:1-34.
3. Berman BM. Seminal studies in acupuncture research. J Altern Complement Med. 2001;7:S129-S137.
4. .Fink M, Gutenbrunner C, Rollnik J, Karst M. Credibility of a newly designed placebo needle for clinical trials in acupuncture research. Forsch Komplementarmed Klass Naturheilkd. 2001;8:368-372.
5. Ando K, Wallace MS, Braun J, Schulteis G. Effect of oral mexiletine on capsaicin-induced allodynia and hyperalgesia: a double-blind, placebo-controlled, crossover study. Reg Anesth Pain Med. 2000;25:468-474.
6. Wallace MS, Barger D, Schulteis G. The effect of chronic oral desipramine on capsaicin-induced allodynia and hyperalgesia: a double-blinded, placebo-controlled, crossover study. Anesth Analg. 2002;95:973-978.
7. Wallace MS, Braun J, Schulteis G. Postdelivery of alfentanil and ketamine has no effect on intradermal capsaicin-induced pain and hyperalgesia. Clin J Pain. 2002;18:373-379.
8. Wallace MS, Laitin S, Licht D, Yaksh TL. Concentration-effect relations for intravenous lidocaine infusions in human volunteers: effects on acute sensory thresholds and capsaicin-evoked hyperpathia. Anesthesiology. 1997; 86:1262-1272.
9. Wallace MS, Quessy S, Schulteis G. Lack of effect of two oral sodium channel antagonists, lamotrigine and 4030W92, on intradermal capsaicin-induced hyperalgesia model. Pharmacol Biochem Behav. 2004;78:349-355.
10. Wallace MS, Ridgeway B III, Leung A, Schulteis G, Yaksh TL. Concentration-effect relationships for intravenous alfentanil and ketamine infusions in human volunteers: effects on acute thresholds and capsaicin-evoked hyperpathia.  J Clin Pharmacol. 2002;42:70-80.
11. Dincer F, Linde K. Sham interventions in randomized clinical trials of acupuncture – a review. Complement Ther Med. 2003;11:235-242.
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AUTHORS INFORMATION
Dr Farshad M. Ahadian is Associate Clinical Professor of Anesthesiology and Medical Director, Center For Pain and Palliative Medicine

(CPPM), at the University of California, San Diego, CA. CPPM provides medical education for fellows, residents, and students at all levels of training, as well as clinical services for chronic benign and cancer pain in a multi-disciplinary and integrative setting. Dr. Ahadian pursues innovative clinical research in acupuncture.

Farshad M. Ahadian, MD*
Associate Clinical Professor of Anesthesiology
Medical Director, Center for Pain
     & Palliative Medicine
University of California, San Diego
9500 Gilman Dr, Mail Code 0924
La Jolla, CA 92093
Phone: 858-657-7030 • Fax: 858-657-7035
E-mail: fahadian@ucsd.edu

Jennifer C. Braun, MPH, is a Clinical Research Consultant in multiple therapeutic areas including bioelectric devices for tissue repair and pain management.
Jennifer C. Braun, MPH, CCRA
ProTrials Research
5925 Mildred St
San Diego, CA 92110
Phone: 858-657-7030 • Fax: 858-657-7035
E-mail: jennifer.braun@gmail.com

Gery Schulteis, PhD, is Associate Professor of Anesthesiology at the University of California, San Diego, and Principal Investigator within the Research Service of the VA San Diego Healthcare System. Dr Schulteis' preclinical research included neurobiological mechanisms mediating the onset of opioid and alcohol tolerance and dependence. He collaborates with colleagues within the Department of Anesthesiology and the Moores Cancer Center at UC San Diego on a variety of clinical studies.
Gery Schulteis, PhD
Associate Professor of Anesthesiology
UCSD School of Medicine
and
VA San Diego Healthcare System
3350 La Jolla Village Dr MC125A
San Diego, CA 92161-5008
Phone: 858-642-3209 • Fax: 858-822-5009
E-mail: gschulteis@vapop.ucsd.edu

*Correspondence and reprint requests

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