A multi-center randomized controlled clinical trial of three-step acupuncture and cupping therapy for cervicogenic headache

Kai Zhang*, Ge-Li Jiang, Lei Xiao, Li-Tai Chen

1Department of Acupuncture and Moxibustion, Tianjin Public Security Hospital, Tianjin, China. 2Tianjin Ruhui Institute of Humanities and Holistic Medicine, Tianjin, China. 3The 254th Hospital of the Chinese People's Liberation Army,Tianjin, China. 4The 281th Hospital of the Chinese People's Liberation Army, Qinhuangdao, China.

Background

Cervicogenic headache (CEH) is one of the most common secondary headaches clinically, but current clinical recognition efficiency is low and misdiagnosis is simple [1, 2]. In 1983, Sjaastad [3] first proposed the concept of CEH where the pain is in the head but the pathology is in the cervical spine, at the World Headache Conference. CEH refers to a group of syndromes with ipsilateral headache caused by organic or functional damage of the cervical spine or soft tissue, often accompanied by neck tenderness, that is related to the stimulation of the cervical nerve [4, 5]. Its pathogenesis may be related to the convergence theory of pain afferents,mechanical stimulation caused by intervertebral disc degeneration, inflammatory edema, and muscle spasm [4,5]. Therefore, the treatment of CEH should take interventions for both pain relief and cervical spondylosis into account.

Modern medical treatments for CEH include oral medication, physical therapy, nerve block, and surgery,among others. However, there is no evidence supporting the effectiveness of oral medication for CEH [6]. In the case of treatment with minimally invasive nerve block injection, there is strong evidence supporting CEH treated only by greater/lesser occipital nerve block injection[7-9].

CEH falls in the category of Bizheng in the theory of traditional Chinese medicine (TCM). Early in Qin and Han Dynasties of China (the third century B.C.),Huangdi Neijingrecorded the principles and methods of acupuncture in the treatment of Bizheng. That is to say,according to the location of Bizheng, the corresponding viscera acupoints are taken for acupuncture.Suwen·Bilun(220–211 B.C., Han Dynasty of China) recorded that Bizheng is caused by a combination of wind, cold, and dampness. Li Shizhen described the application of cupping therapy for Bizheng in the bookBencaogangmu(1578 A.D., Ming Dynasty of China). In recent years, a large number of clinical reports have confirmed the efficacy of acupuncture and cupping in the treatment of cervical spondyloses, including CEH [10-12]. A number of meta-analyses have shown that [12-15] acupuncture is safe and effective in the treatment of cervical spondylosis,but there is a lack of high-quality clinical research evidence to support it. At present, there are some problems in the clinical research of acupuncture treatment for CEH, such as unclear diagnostic criteria, inconsistent criteria for the evaluation of curative effect, and non-standard randomized controlled studies. The results of the research are still controversial, which affects the promotion and application of acupuncture and moxibustion. Therefore, it is necessary to systematically evaluate acupuncture treatment for CEH in order to better guide clinical practice.

In long-term clinical practice, Professor Jiang Geli proposed a three-step acupuncture and cupping therapy regimen. The main points were the Zhengji, Zhongping,Houxi, and neck Jiaji points. The first step is to apply balanced needling to the main points. The second step is to acupuncture the neck Jiaji point using electro-acupuncture. The third step is blood-letting puncture and cupping. To further objectively evaluate the clinical efficacy of three-step acupuncture and cupping therapy, we conducted a multicenter, randomized,controlled clinical trial. This research protocol was approved by the Ethics Committee of Tianjin University of Traditional Chinese Medicine (Approval No.:TJUTCM-EC20130002), and has been registered with the China Clinical Trial Registration Center of the World Health Organization Level 1 Clinical Trial Registration Office, registration number is ChiCTR-TRC-13003606.The registration day is September 4, 2013, and the registration is titled Three-Step Acupuncture and Cupping Therapy for Multicenter Randomized Controlled Clinical Study of Cervical Headache.

Clinical data

Diagnostic criteria

The diagnostic criteria developed by the International Research Conference on Cervical Headaches [3] are as follows:

(A) Neck symptoms and signs:

1. Headache is aggravated with neck movement and/or the head is maintained in an abnormal posture. Headache is aggravated when pressing the upper neck or occipital region on the side of the headache.

2. The range of neck movement is limited.

3. Non-root pain in the neck, shoulder, or upper limb of the ipsilateral side (unclear positioning), or occasional root pain.

(B) Diagnostic nerve block clearly abolishes headache.

(C) Unilateral headache, generally not transferred to the contralateral side.

In item (A), the diagnostic criteria are ranked from 1 to 3 according to their diagnostic importance, and one or more of them must be present to diagnose CEH. The presence of item 1 is sufficient for a diagnosis, while meeting item 2 or 3 is not sufficient for a diagnosis. If the three items are met at the same time, the diagnosis is unambiguous. The presence of (A) is diagnostic; (B) and(C) are additional criteria.

On the basis of this standard, diagnostic should be combined with cervical imaging (X-ray, compute tomography [CT], or magnetic resonance imaging [MRI]).If necessary, head CT or MRI is used to exclude intracranial organic lesions.

Inclusion criteria

Patients aged 18-65 years old diagnosed with CEH were included. There was no limitation based on sex. Subject voluntarily provided signed informed consent.

Exclusion criteria

The following patients were excluded: patients with cerebrovascular and bone destruction; patients with other organ tumors; patients with acute heart and brain disease in the past 1 month; uncooperative patients; patients with severe primary diseases such as heart, brain, liver, kidney and hematopoietic system disease; mentally ill patients;patients participating in other clinical trials; pregnant and lactating women; patients who are unable to provide visual analogue scale (VAS) scores due to visual problems or cognitive dysfunction; and patients who did not provide signed informed consent.

Patient elimination criteria

1. Those who did not meet the inclusion criteria.

2. Those who met the inclusion criteria but were included post-treatment.

3. Patients who were not interviewed after treatment.

Patient shedding criteria

1. During the test, the patient’s compliance was poor,affecting the validity and safety of the study findings.

2. Serious adverse events, complications, or special physiological changes occur, making it inappropriate to continue the test. Such cases are counted as adverse reactions.

3. Withdrawal of consent during the study process.

4. Due to various reasons, the treatment was not completed during the study and the patient was lost to follow-up.

5. The patient used a drug that had a greater impact on the test treatment, affecting the validity and safety of the study findings.

6. Incomplete data, affecting the validity and safety of the study findings.

7. The patient attended less than 80% or more than 120%of the predefined number of treatment sessions.

General information

From October 2013 to April 2016, a total of 64 patients with CEH in the 464th, 254th, and 281st hospitals of the Chinese People's Liberation Army were selected. Patients aged 18-65 years were randomized into a treatment or control group using a random number table, with 32 patients in each group. Among them, 32 were treated in the treatment group and none were shed; 31 patients were in the control group after one patient was shed. There were 20 males and 12 females in the treatment group,with an average age of 46 years. The longest history of CEH was 3 years and the shortest was 5 days. In the control group, there were 19 males and 12 females; the average age was 48 years, and the longest history of CEH was 3 years and the shortest was 7 days. There were no significant differences in sex, age, or duration of disease between the two groups.

Research methods

Random grouping

In this study, a randomized digital table method was used to randomly assign 64 patients with CEH who met the inclusion criteria into the treatment or control group.

Hidden assignment

A third person was assigned to handle the random number table and case allocation. The receiving and treating physicians did not know the group that the patient would enter before random allocation. The randomization process was performed independently by a physician who did not participate in the study using a random number table; the grouper and the patient were only informed that the study was to compare the therapeutic effects of two different acupuncture treatments. Patients assigned an odd random number were classified into group A, and those who were assigned an even random number were classified into group B. The specific treatment methods for the two groups were three-step canister therapy group for the treatment group and sham acupuncture for the control group.

Application of blinding method

All patients were only told that they would receive acupuncture treatment but were not aware of their specific grouping. Acupuncture treatment was performed by one to two acupuncturists in each center. The researchers arranged patients to be treated in an independent environment, such as a partitioned or separate room. They were not allowed to communicate with patients about the choice of acupuncture points.

Acupuncturist background

The acupuncturists participating in the study are practicing physicians, attending physicians, deputy directors, or chief physicians who have been engaged in the acupuncture industry for 5 or more years.

Treatment methods

The needle was a Huaying acupuncture needle produced by Suzhou Medical Products Co., Ltd. The model H specification is 0.3 mm × 30 mm and 0.3 mm × 40 mm needle.

Treatment group: three-step canister therapy was used.In the first step, a balanced needle method was used. The patient sat on the bed. After routine disinfection, filiform needles were used to acupuncture at the main points including the Zhengji points (the center point of the Shenting and Yintang lines), Houxi points, and Zhongping points. The needle was inserted perpendicularly 20-30 mm at the Zhengji point; reducing manipulation by lifting and thrusting was applied until a feeling of numbness radiated to the base of the nose. The reducing method was performed on the Houxi and Zhongping points (singular points, the outer point of the outer knee and the outer sac line) by both lifting and thrusting, as well as twirling and rotating the needle. On both sides of the Houxi point, acupuncture was applied obliquely for 10-20mm towards the wrist and until the needling sensation radiated to the forearm. Bilateral Zhongping points were punctured perpendicularly for 20-30 mm until the needling sensation radiated to the foot.The patient was required to move the affected part for 2 minutes without removing the needles. In the second step,an electric needle punctured both sides of the neck Jiaji points and a neutral reinforcing-reducing method was applied. The needle was inserted 20-30 mm inch at the Jiaji until a needling sensation radiated to the shoulder after the arrival of Qi. The Jiaji points were then stimulated with a bilateral symmetrical dense wave for 20 minutes using the KWD2-808 electro-acupuncture instrument. In the third step, after removing the needle,Dazhui and one or two Ashi points were chosen for the release of blood and cupping. The points were sterilized with 75% ethanol, and the points were penetrated with a three-edged needle to a depth of 2-4 mm, after which the needle was withdrawn immediately. The cupping method was then applied to the points, leading to the discharge of 3-5 ml of blood. The cup was left in situ for 10-15 minutes. Acupuncture of the Zhengji, Houxi, and Zhongping points was performed five times a week.Pricking bloodletting was performed 1-2 times a week,and cupping once every other day. Treatment for 10 days was considered a course of treatment. Patients underwent a total of two courses of treatment with a 2-day interval between each treatment course.

In the control group, a sham needle was used. The eight selected acupoints were as follows: the two sides of the midpoint of the connection of the Jiaosun and Suaigu points, the two sides of the midpoint of the connection of the Fengchi and Anmian points, the two sides of the midpoint of the connection of the Qiuxu and Jiexi points,the middle of the Shanjiao channel and small intestine channel on the same horizontal line as the Waiguan point,and the middle of the gallbladder channel and bladder channel on the same horizontal line as the Yanglingquan points. Using a shallow needling method, a shallow puncture of 1-4 mm located at the above points was performed without manipulation. After removing the needle, cupping was applied at the Dazhui points and one or two areas located at 45 degree below and 30-40 mm from the Dazhui points. The cups were left in situ for 10-15 minutes, once every other day. Treatment for 10 days was considered a course of treatment. Patients underwent a total of two courses of treatment, with a 2-day interval between each treatment course.

Combined administration during the study: As far as possible, no other therapeutic drugs, such as analgesics,sedatives, calcium ion antagonists, and ergotamine preparations, were used. The basic medications must be the same for both groups of patients.

Therapeutic observations

The simplified McGill Pain Questionnaire (SF-MPQ) [16]consisting of three parts, pain rating index (PRI), visual analogue scale (VAS), and present pain intensity (PPI),was performed pre-treatment, immediately after the first treatment, 10 days after treatment, 20 days after treatment,and 3 months follow-up at the end of the treatment. The first 11 items in the PRI are the patient's pain perception scores, the last four items are the patient's emotional scores, and the sum of the 15 items gives the total PRI score. The VAS score was obtained using a 10cm long straight line with the ends of the line representing either pain-free or severe pain, with patient's selecting a location to indicate their current degree of pain. The PPI scores are divided into six levels of “no pain,” “mild,”“discomforting,” “distressing,” “horrible,” and“excruciating,” with each category scoring 0, 1, 2, 3, 4, or 5 points, respectively.

Neck stiffness and range of motion (ROM) in the neck scoring criteria [17] were as follows: 1 point, no impact on daily life, free movement; 2 points, there is a certain influence, the degree and scope of activity is limited; 3 points, the impact is great, the activity is stiff and laborious; and 4 points, basically cannot be active.

Safety evaluation

During the test, the adverse reactions of subjects, such as hysteresis, fainting, subcutaneous hematoma,pneumothorax, and neuralgia, were observed and recorded.

Statistical analysis

The clinical data were analyzed using SPSS version 24.0.The significance level wasP＜ 0.05. The t-test was used to compare the two groups of numerical variables. If the overall distribution was skewed, the rank sum test was used. Count data were analyzed using the χ2test.

Results

The PRI, VAS, and PPI of the SF-MPQ were used to compare scores between the two groups before and after treatment. Neck stiffness and ROM between the two groups before and after treatment were also compared.

Comparison of PRI scores before and after treatment between the two groups of patients

Table 1 and Table 2 show that there was no significant difference in total PRI scores, PRI sensory, or PRI emotional scores between the two groups before treatment. Total PRI scores after treatment in both groups were lower than those before treatment. Compared with those of the control group, total PRI scores after 10 days of treatment, 20 days of treatment, and 3 months after the end of treatment were all significantly lower in the treatment group (P= 0.001,P< 0.001,P< 0.001).Compared with those of the control group, the PRI feeling item scores and emotional item scores after 10 days of treatment, 20 days of treatment, and 3 months after the end of the treatment were all significantly lower in the treatment group (feeling item scores:P= 0.001,P< 0.001,P< 0.001; emotional item scores:P= 0.032,P= 0.035,P= 0.013.). The results indicate that both the short-term and long-term effects in the treatment group were significantly better than those in the control group.There was no significant difference in total PRI scores between 3 months after the end of the treatment and after 20 days of treatment in the treatment group.

Comparison of VAS between the two groups before and after treatment

Table 3 suggests that there was no significant difference in VAS score between the two groups before treatment.After treatment, the VAS scores of the treatment and control group were lower than prior to treatment. The VAS scores of the two groups were significantly different at different time points. Compared with those of the control group, VAS scores after the first treatment, 10 days of treatment, 20 days of treatment, and 3 months after the end of the treatment in the treatment group were all significantly lower (P= 0.024,P= 0.001,P< 0.001,P< 0.001.). It shows that the treatment group received superior pain relief to the control group, and experienced better long-term effects and a low recurrence rate.

Comparison of existing pain intensity between the two groups before and after treatment

Table 4 suggests that the PPI scores of the treatment and control groups after treatment were lower than after the last treatment, showing a downward trend. After the first treatment, the PPI score of the treatment group was significantly lower than that of the control group (P=0.043). It indicates that the treatment group received excellent immediate pain relief. Compared with those of control group, the PPI scores 3 months after the end of the treatment in the treatment group were significantly lower (P= 0.015). It shows that the long-term analgesic effect of the treatment is good.

Comparison of cervical vertebrae activity ROM before and after treatment in both groups

Table 5 suggests that the ROM scores of the treatment and control groups were lower than those before treatment, showing a decreasing trend. After the first treatment, the ROM score of the treatment group was significantly lower than that of the control group (P=0.033). This indicates that the treatment group experienced an improvement in cervical ROM immediately. Compared with those of the control group,ROM scores after the first treatment, 10 days of treatment,20 days of treatment, and 3 months after the end of treatment in the treatment group were significantly lower(P= 0.033,P= 0.020,P= 0.015,P= 0.002). There was no significant difference in ROM scores between 3 months after the end of the treatment and after 20 days of treatment in the treatment group. However, 3 months after the end of the treatment in control group, the ROM score was significantly higher than that of after 20 days of treatment (P= 0.037). This shows that the long-term analgesic effect in the treatment group is good.

Safety evaluation

Table 1 Comparison of the total PRI scores before and after treatment between the two groups

Table 1 Comparison of the total PRI scores before and after treatment between the two groups

Comparison with before treatment: a, P < 0.001; d, P < 0.001. Comparison with last treatment: b, P < 0.001; c, P =0.006; e, P = 0.001; f, P < 0.001; g, P = 0.031. Comparison with control group: h, P = 0.001; i, P < 0.001; j, P < 0.001.

Group N Before treatment First treatment After 10 days of treatment After 20 days of treatment Follow-up 3 months after the end of treatment Treatment 32 23.34 ± 2.88 18.63 ± 4.22a 14.09 ± 5.22b, h 11.78 ± 5.90c, i 12.63 ± 6.14j Control 31 22.71 ± 4.01 20.87 ± 4.43d 18.42 ± 4.19e 16.81 ± 4.46f 18.90 ± 6.02g

Table 2 Comparison of PRI sensory and emotional scores before and after treatment between the two groups

Table 2 Comparison of PRI sensory and emotional scores before and after treatment between the two groups

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Table 3 Comparison of VAS before and after treatment between the two groups

Table 3 Comparison of VAS before and after treatment between the two groups

Comparison with before treatment: a, P < 0.001; d, P < 0.001. Comparison with last treatment: b, P < 0.001; c, P =0.005; e, P < 0.001; f, P = 0.037. Comparison with control group: g, P = 0.024; h, P = 0.001; i, P < 0.001; j, P <0.001.

Group Before treatment Immediately after first treatment After 10 days of treatment After 20 days of treatment Follow-up 3 months after the end of treatment Treatment 7.30 ± 1.14 5.58 ± 1.48a, g 4.14 ± 1.67b, h 3.48 ± 1.62c, i 3.74 ± 1.69j Control 7.17 ± 0.96 6.35 ± 1.12d 5.45 ± 1.17e 5.13 ± 1.29 5.58 ± 1.46f

Table 4 Comparison of PPI between the two groups before and after treatment

Table 4 Comparison of PPI between the two groups before and after treatment

Comparison with before treatment: a, P < 0.001; d, P < 0.001. Comparison with last treatment: b, P = 0.001; c, P =0.048; e, P = 0.001; f, P = 0.012. Comparison with control group: g, P = 0.043; h, P = 0.008; i, P = 0.011; j, P =0.015.

Group Before treatment Immediately after first treatment After 10 days of treatment After 20 days of treatment Follow-up 3 months after the end of treatment Treatment group 3.66 ± 0.65 2.63 ± 0.91a, g 2.00 ± 0.98b, h 1.75 ± 1.02c, i 2.03 ± 1.06j Control group 3.45 ± 0.72 3.06 ± 0.77d 2.58 ± 0.67e 2.35 ± 0.80 2.65 ± 0.88f

Table 5 Comparison of ROM before and after treatment in both groups

Table 5 Comparison of ROM before and after treatment in both groups

Comparison with before treatment: a, P < 0.001. Comparison with last treatment: b, P = 0.010; c, P = 0.037.Comparison between groups: d, P = 0.033; e, P = 0.020; f, P = 0.015; g, P = 0.002.

Group Before treatment Immediately after first treatment After 10 days of treatment After 20 days of treatment Follow-up 3 months after the end of treatment Treatment group 2.47 ± 0.76 1.75 ± 0.67a, d 1.44 ± 0.76b,e 1.34 ± 0.70f 1.56 ± 0.56g Control group 2.29 ± 0.69 2.16 ± 0.82 1.87 ± 0.67 1.84 ± 0.86 2.16 ± 0.90c

Adverse events. In the treatment group, there were 11 patients with acupuncture pain, four patients with subcutaneous hematoma, one patient with stagnation, and one patient with itching after acupuncture. In the control group, there were nine patients with acupuncture pain and three patients with subcutaneous hematoma. The acupuncture pain was within a range that the patients could tolerate. After acupuncture, the hematoma disappeared after applying pressure for 1-5 minutes. The patient with stagnation may have been related to the movement of the body after acupuncture. The needle was removed and itching of the skin was relieved half an hour after the needle was taken. In the control group, one 34-year-old man fainted, and had dizziness, palpitations,and sweating after the first treatment. Immediately after the needle was removed, the symptoms were relieved after 10 minutes of rest. The patient had no past history of acupuncture, but he was on an empty stomach before treatment. The patient was asked to have breakfast before treatment next time and no fainting appeared after the treatment.

Discussion

CEH has been widely accepted by medical workers after years of research and development. CEH can be classified into neurogenic pain and myogenic pain depending on which part of the nerve root is involved. The sensory root fibers of the nerve root are stimulated to cause neuropathic pain, while the ventral motor nerve roots are stimulated to cause myogenic pain. The medial branch of the second cervical nerve and fibers from the third cervical nerve together form the occipital nerve. The occipital nerve and auricular nerve are the main nerves that conduct an otogenic headache. In addition, the first,second, and third cervical nerves mostly pass through the soft muscle tissue after leaving the spinal canal. When the soft tissue is inflamed, ischemic, damaged, or stressed, it will affect the function of the nerve and cause CEH.Cervical intervertebral disc degeneration, protrusion, and intervertebral disc material release can directly cause aseptic inflammation and edema, produce immunoreactive inflammation, and cause discogenic radiculitis. In addition to direct root pain, the distal release of inflammatory mediators, causing the inflammation of the inner soft tissue, can also produce pain. This is the mechanism by which some patients develop refractory CEH [18, 19].

A number of studies [18-25] have confirmed that acupuncture is safe and effective in treating CEH.According to the pathogenesis of CEH, the possible mechanisms of action of acupuncture treatment in CEH may include improving local blood circulation, relieving edema, loosening adhesions, and thus providing relief to some extent from disc herniation, spinal stenosis, and muscle spasm, among other pathologies. The pressure on the vascular nerves makes the symptoms disappear. This may be because it promotes the metabolism of pain-causing substances. Acupuncture can reduce the expression of FOS protein in the thalamic pain-sensing area and cyclooxygenase-2 in the spinal dorsal horn and can significantly inhibit the expression of pain-related information. Acupuncture may also act via effects on pain and protecting the nerve roots [26]. Treatment may promote the production of biologically active substances in the body, slowing the degeneration of cervical intervertebral disc tissue, regulating the microenvironmental changes in the cervical intervertebral disc tissue, and thereby stimulating vascular endothelial growth factor (VEGF) and the expression of delta-like ligand 4 (D114), both of which can promote angiogenesis.Acupuncture may lead to the upregulation of VEGF and D114 protein and mRNA expression in the cervical intervertebral disc tissue, and promote the production of cervical intervertebral disc blood vessels, thus delaying the degree of degeneration of the cervical disc and restoring degenerated cervical intervertebral disc tissue[27].

CEH belongs to the "Bizheng" category of TCM.Chinese medicine believes that the pathogenesis of this disease is Qi and blood blockage, and meridian obstruction. The treatment principle of “promoting blood circulation to remove meridian obstruction” was established, and “three-step acupuncture and cupping therapy” was invented [28]. The Zhengji points on the Du meridian are the places where meridian-Qi of Taiyang is concentrated [29]. The Du Meridian, the governor's Yang,can smooth Taiyang meridian and Du meridian as well as activate blood and relieve pain. The Houxi point, one of Eight Confluent Points that is connected with the Du Meridian, can arouse the brain, calm the nerves and smooth pain. Zhongping acupoints, one of the Extra Points, is located on the route of stomach meridian. The stomach meridian is a multi-Qi and multi-blood meridian;its branches intersect with the Du meridian at Dazhui acupoint, so acupuncture at this point affects the Qi and blood, smooth blood, and nourishes the brain, eliminating headache. The cervical Jiaji points are located between the Du meridian and the Taiyang bladder meridian, and the internal organs are closely related to them. Then stimulating the neck Jiaji points can directly clear the local meridians, Qi, and blood. Local puncture cupping at the Dazhui or Ashi points have the effect of promoting blood circulation and relieving pain.

Zhang Kai,et al. [12] conducted a meta-analysis of the efficacy of acupuncture and non-steroidal antiinflammatory drugs in the treatment of CEH,demonstrating that acupuncture has better curative effect than oral non-steroidal anti-inflammatory drugs, and,furthermore, needle sting therapy does not increase the incidence of adverse reactions [30, 31]. However, most of the studies included had problems concerning factors such as blinding, allocation concealment, and adverse reaction analysis. This study confirmed the safety and effectiveness of acupuncture treatment for CEH from the perspective of evidence-based medicine. It shows that three-step therapy is more effective than the sham acupuncture, with good immediate analgesic effect, low recurrence rate, and good long-term curative effect. The shortcoming of this study is the small sample size, which limits the strength of the evidence.

Conclusion

In summary, in the treatment of CEH, the three-step canister therapy group is significantly better than the control treatment in improving PRI, VAS, PPI, and ROM scores. The three-step canister therapy has an immediate analgesic effect. It can also quickly improve cervical vertebra ROM and has good short-term and long-term effects.

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