The Case for Local Needling in Successful Randomized Controlled Trials of Peripheral Neuropathy: A Follow-Up Systematic Review

Abstract

Objectives: This work follows-up on a systematic review, published in 2017, of acupuncture for the treatment of mono- and polyneuropathy and associated symptoms. Previously reviewed trials of acupuncture for neuropathy primarily used acupuncture points in close proximity to underlying nerves. Further exploration of point selection for the treatment of each neuropathic condition is needed to assess the anatomical relationships between acupuncture points and peripheral nerves with respect to the treatment of neuropathy.

Methods: The 13 randomized controlled trials included in the original review studied acupuncture for neuropathy caused by diabetes, Bell's palsy, carpal tunnel syndrome (CTS), human immunodeficiency virus (HIV), and idiopathic causes. The present review reexamines all acupuncture points used, focusing on specific neuropathic condition treated. Anatomical diagrams are presented to highlight acupuncture points underlying the nerves' anatomical relationships. Each selected acupuncture point is reviewed in detail, including its Traditional Chinese Medicine theory–based function, the point's indications for use, and the peripheral nerve most closely associated with it.

Results: In Bell's palsy, the majority of selected acupuncture points were associated with the ipsilateral facial nerve. In CTS, the majority of the selected acupuncture points were closely associated with the median nerve and its branches. In polyneuropathy caused by diabetes, HIV, or idiopathic causes, most selected acupuncture points were in close proximity to peripheral nerves.

Conclusions: All reviewed trials of acupuncture for neuropathy and neuropathic pain use acupuncture points that are closely associated with the peripheral nerves treated. Local needling is crucial for successful treatment of peripheral neuropathy.

Introduction

In the last few decades there has been a surge in acupuncture research, with multiple evidence-based reviews showing therapeutic benefits of acupuncture for chronic low-back pain,^1,2 migraine³ and tension headache,⁴ chemotherapy-induced nausea and vomiting⁵ and other conditions.⁶ The evidence for acupuncture in the treatment of peripheral neuropathy (PN) is emerging rapidly. PN is broadly defined as damage to the peripheral nervous system caused by a primary lesion or dysfunction.⁷ This includes polyneuropathy involving multiple nerves and mononeuropathy involving a single nerve. The most common causes of polyneuropathy are diabetes, thyroid disorders, vitamin B₁₂ deficiency, alcohol abuse, chemotherapy, and human immunodeficiency virus (HIV) infection.^7–9

This work is based on a 2017 summary of the evidence for acupuncture in the treatment of PN and associated symptoms, compared to sham acupuncture or conventional medical therapy.¹⁰ That article was the first systematic examination of the effectiveness of acupuncture for various types of neuropathy, including polyneuropathy and mononeuropathy. All successful randomized controlled trials (RCTs) that were selected and reviewed appeared to focus on points in close proximity to an underlying nerve. This prompted further investigation into acupuncture-point selection for the treatment of neuropathy.

For many decades, acupuncture practitioners and anatomists have attempted to correlate the location of acupuncture points to peripheral nerves, spinal segments, and spinal plexuses.^11–17 This neuroanatomical theory of acupuncture suggests that acupuncture's effect is mediated via afferent input through the peripheral nervous system, eliciting a reflex at the level of the spinal cord via the sympathetic plexuses and via efferent input to the visceral organs and skeletal muscle.^18,19 A closer examination of acupuncture-point selection in successful trials of PN could help explore further the connection between needle placement and effects on the underlying nerve.

Materials and Methods

The following databases were searched from their inceptions to July 2015: Medline,^® Cochrane Library, Scopus, Clintrials.gov, AMED [Allied and Complementary Medicine Database], and CINAHL [Cumulative Index to Nursing and Allied Health Literature]. The key search terms used were acupuncture OR acup* OR laser acupuncture OR moxibustion OR electroacupuncture AND neuropathy OR peripheral neuropathy OR neuropathic pain OR neuralgia OR carpal tunnel syndrome OR Bell's palsy. Review articles were used to identify additional references. Language restrictions were set to English and subject restrictions were set to humans. Gray literature in Clintrials.gov was reviewed for unpublished relevant data.

Parallel and crossover RCTs were selected, if their focus was acupuncture as an intervention for the treatment of PN, regardless of blinding. RCTs were selected if they included at least 1 group receiving acupuncture and 1 control group receiving sham acupuncture or another active treatment (e.g., medication).¹⁰ All of the selected studies involved adult subjects (older than age 18) who underwent acupuncture, with or without electric stimulation, with or without moxibustion (heating with the mugwort (Artemisia spp. herb). Controls had to be active and included sham acupuncture or relevant medical treatments such as drugs or injections. Included trials had outcome measures such as nerve-conduction studies (NCS), validated questionnaires, or clearly defined study-specific objective criteria distinguishing responders from nonresponders.

Trials were reviewed for inclusion by 2 neurologists with expertise in acupuncture, neuromuscular disorders, neurophysiology, and statistical methodology. RCT methodological quality was assessed using the Scale for Assessing Scientific Quality of Investigations–Complementary and Alternative Medicine (SAS-QI CAM) version, an instrument specifically designed to evaluate RCTs focused on integrative therapies.²⁰ It is used to assess methodological problems and sources of bias commonly encountered in integrative medicine research, such as allocation concealment, investigator- and subject-blinding, blinded outcome assessment, reproducibility of experimental procedures, and sound statistical analysis. The 2 reviewers assigned each article a SAS-QI CAM score independently and in a blinded fashion. As the 2 reviewers were in agreement, there was no need to use a third reviewer as a tiebreaker. Based on a recent study by D'Silva et al.,²¹ a SAS-QI CAM score of >9 (of 21) served as a cutoff for inclusion based on RCT overall scientific quality.

Results

After abstract reviews, 726 studies were excluded; 46 studies were reviewed in full; and 13 RCTs were included with a focus on acupuncture for the treatment of neuropathy caused by Bell's palsy,^22,23 carpal tunnel syndrome (CTS),^24–27 diabetes,^28–31 HIV,^32,33 and a combination of diabetes and idiopathic causes.³⁴ Of the included RCTs, researchers in 9 studied manual acupuncture with or without moxibustion, in 3 studied electroacupuncture (EA), and in 1 studied a combination of manual and EA. Other active interventions included per os medications, intramuscular/intravenous injections, or splinting. As planned, each selected study had an active control arm.

Polyneuropathy Results

The included studies on diabetic PN reported significant improvements in acupuncture groups, compared to controls in neurologic examination,^28,29,31 neuropathic symptoms, ^28,30,31 composite improvement scales,^28–31 NCS^28,29 and blood rheology.²⁸ One included study of acupuncture for HIV-related neuropathy³² showed significantly higher pain relief in an acupuncture group (P = 0.03); however, this was not true after adjustment for multiple comparisons. These data were reanalyzed by a different group of investigators,³⁵ who found that amitriptyline alone or acupuncture alone produced significant reductions in Gracely Pain Scale scores at 6 weeks; however, only acupuncture sustained this effect at 14 weeks. The second study on acupuncture for HIV neuropathy³³ also showed significant reductions in Gracely Pain Scale scores following a 6-week course of acupuncture/moxibustion, compared to a sham acupuncture/placebo moxibustion control. In addition, the acupuncture group had significant improvement on the Subjective Peripheral Neuropathy Screen, compared to the group's pretreatment baseline.

The 1 included study on idiopathic neuropathy³⁴ included 4 subjects with diabetic neuropathy and 12 subjects with idiopathic neuropathy, in a double-blinded crossover study comparing EA versus sham EA (8 subjects per group). There was no difference between acupuncture and control treatments in any of the outcome measures used. In addition, both groups showed no difference from baseline. The researchers did not perform a separate analysis on subjects with idiopathic neuropathy.

Mononeuropathy Results

All four RCTs focused on CTS^24–27 reported significant improvement with acupuncture, compared to baseline, in Global Symptom Score,^24,27 Boston Carpal Tunnel Score,²⁵ Carpal Tunnel Self-assessment Questionnaire,²⁶ and a visual analogue scale.²⁵ Three of the 4 RCTs included showed significantly greater effectiveness of acupuncture, compared to night splinting,²⁵ sham acupuncture,²⁴ oral vitamins B₁ and B₆,²⁴ and oral prednisolone.²⁷ In contrast, Yao et al.²⁶ revealed no difference in CTS symptoms between acupuncture + night splinting, and sham acupuncture + night splinting, with both groups improved from baseline. Most long-term follow-ups favored acupuncture at 4 weeks,^24,27 5 weeks,²⁵ and 7 and 13 months,³⁶ with only a single study showing no difference between acupuncture and control at 3 months.²⁶

One of the RCTs on Bell's palsy²² showed significant improvement in the House–Brackmann Scale and Facial Disability Index in acupuncture and in the acupuncture + medical therapy groups, compared to a medical therapy group. In contrast, the second included RCT²³ found no significant difference on the House–Brackmann Scale between an acupuncture group, compared to oral steroids and home exercise groups, as all 3 groups had high improvement rates.

Various methodological concerns were encountered and discussed as part of a critical appraisal of the evidence. These included problems with standardization of acupuncture regimens (points used, number of sessions, and follow-up periods), problems with control-treatment selection, problems with sample-size calculations, problems with subject and investigator blinding, problems involving the placebo effect and subject expectancy, and problems with outcome measures.

Adverse Events

Critical review of acupuncture safety and adverse events across trials led to the conclusion that acupuncture in the treatment of neuropathy was safe overall, without serious adverse events, except in the early study on HIV-related neuropathy,³² in which both groups experienced significant morbidity that was unrelated to acupuncture.

Acupuncture Point Selection

Only one of the 13 reviewed trials justified point selections.³⁰ The reviewed RCTs used various acupuncture treatment courses in terms or number of sessions per week, session durations, total numbers of sessions, and the use of modalities such as EA and moxibustion (Table 1). While there were a wide variety of acupuncture points used across the trials, most acupuncture regimens included needling of local points, which have close anatomical associations with underlying nerves (Table 1).

Table 1.

Acupuncture Point Selection and Treatment Course

CTS, carpal tunnel syndrome: DPN, diabetic peripheral neuropathy; HIV, human immunodeficiency virus; IPN, idiopathic peripheral neuropathy; EA, electroacupuncture; IM, intramuscular; IV, intravenous; min, minutes

Discussion

For many decades, acupuncture practitioners and anatomists have attempted to correlate the location of acupuncture points to peripheral nerves, spinal segments, and spinal plexuses.^11–17 This neuroanatomical theory of acupuncture suggests that acupuncture's effect is mediated via afferent input through the peripheral nervous system, eliciting a reflex at the level of the spinal cord via the sympathetic plexuses and via efferent input to the visceral organs and skeletal muscle.^18,19 In the case of local needling in close proximity to a nerve, acupuncture's likely mechanism of action is direct mechanical stimulation, such as pressure on the perineural tissues by the needle in manual acupuncture or electrical current stimulation of the nerve with EA.

The neurophysiologic testing to support these theories is lacking so far, and further study on the local effects of acupuncture on the peripheral nervous system is needed. There is a consensus, however, that the nervous system is vital in processing the effects of acupuncture.

More so than polyneuropathy trials, the trials focused on Bell's palsy and CTS used local points that are closely associated with the facial nerve and the median nerve, respectively (Table 2). All included CTS trials involved points on the ipsilateral Pericardium meridian—PC 6,^24,26,27 PC 7,^{24– 27} and PC 8.²⁵ Pericardium meridian points are commonly used in CTS treatment due to their close association with the median nerve, which is affected in CTS (Fig. 1). The anatomical correlation between the acupuncture point PC 6 and the median nerve has been well-established, both in cadavers³⁷ and in live subjects by using ultrasound,^38,39 most strikingly with a documented case of the acupuncture needle piercing through the median nerve sheath, with absence of any symptoms in the subject.³⁹

Table 2.

Acupuncture Point Summary by Neuropathic Condition

HIV, human immunodeficiency virus; IV, intravenous.

^*Bold indicates neurological conditions.

FIG. 1.

Carpal tunnel syndrome points. Color images available online at www.liebertpub.com/acu

Similarly, both included Bell's palsy trials used ipsilateral points on the Stomach meridian—ST 2,²³ ST 4^22,23 ST 6,^22,23 and ST 7,²² as well as GB 14,^22,23 which are in close proximity to branches of the facial nerve (Fig. 2). Both trials also included needling of bilateral LI 4, which is one of the most commonly used points for addressing headache and facial pain. The anatomical correlations between acupuncture points and the cranial nerves (facial nerve in particular) have been well-established.^11,40 The local points used on the Stomach and Gall Bladder meridians are traditionally used for addressing facial pain and weakness (Table 2) and are closely related to various branches of the facial nerve (Fig. 2). These points are commonly used in acupuncture trials on Bell's palsy.¹⁸

FIG. 2.

Bell's palsy points. Color images available online at www.liebertpub.com/acu

With respect to reviewed trials of polyneuropathy, the RCTs on acupuncture for diabetic, HIV-related, and idiopathic neuropathy used a greater variety of acupuncture points; however there were some underlying themes (Table 2). Points used were on the Large Intestine, Triple Energizer, Gall Bladder, Stomach, Bladder, Spleen, Kidney, and Liver channels, as well as the accessory points BaFeng (EX-LE 10) and BaXie (EX-UE 9). The points used in multiple trials of polyneuropathy were SP 6, SP 9, KI 3, BaFeng (EX-LE 10), and ST 36.

The majority of the used acupuncture points are in close anatomical correlation with distal nerves in the arm and leg (Figs. 3, 4, and 5) and each used point could be correlated to a large peripheral nerve or its branch. These correlations are known and have been explored before.^13–16,40

FIG. 3.

Polyneuropathy points in the arm. Color images available online at www.liebertpub.com/acu

FIG. 4.

Polyneuropathy points in the anterior leg. Color images available online at www.liebertpub.com/acu

FIG. 5.

Polyneuropathy points in the posterior leg. Color images available online at www.liebertpub.com/acu

Clinical Implications

The awareness that local needling is effective for addressing neuropathic conditions could guide point selection for points that are in close proximity with affected nerves in cases of mononeuropathy or for multiple points that allow needle proximity to large peripheral nerves in cases of polyneuropathy. This structural approach has led to the development of a standardized protocol for the treatment of PN, regardless of its etiology.⁴¹ While this approach is somewhat reductionist, it is well-suited for use by medical acupuncturists because of its neuroanatomical basis.

Conclusions

Much has been written about the anatomical correlations among acupuncture points, cranial nerves, and peripheral nerves. Close examination of acupuncture points used in trials of mono- and polyneuropathy confirms that the majority of selected acupuncture points overlie the pathways of the nerves implicated in the specific neuropathic conditions addressed. Future studies should explore the functional aspect of acupuncture point–nerve correlations, such as electrophysiologic measurements of changes in nerve function as direct result of needling.

Acknowledgments

This study was funded by the following grants: NIH K23 AT008405 (principal investigator: Dr. Dimitrova), NIH 5T32 AT002688 (principal investigator: Dr. Oken).

Author Disclosure Statement

No competing financial interests exist.

CME Quiz Questions

Article learning objectives:

After studying this article, participants should be able to identify some of the important research questions about acupuncture point use in treating neuropathic conditions and summarize some of the research on anatomical relationships of acupuncture points and peripheral nerves in the treatment of neuropathy.

Publication date: August 20, 2018

Expiration date: August 31, 2019

Disclosure Information:

Authors have nothing to disclose.

Richard C. Niemtzow, MD, PhD, MPH, Editor‐in‐Chief, has nothing to disclose.

Questions:

• 1.Identify the incorrect statement
  • a.The authors in this paper have conducted a multicenter trial evaluating the anatomical relationships of acupuncture points and peripheral nerves in the treatment of diabetic neuropathy.
  • b.The method utilized in this paper is that of a systematic review of randomized controlled trials of acupuncture treatment for neuropathy.
  • c.The RCTs in this review included neuropathies categorized as diabetic, Bell's Palsy, HIV, carpal tunnel, and idiopathic type.
  • d.The authors emphasize acupuncture point and their anatomical relationship to underlying nerves rather than Traditional Chinese Medical theory.
  • e.This paper includes RCTs for mono‐ and polyneuropathies.

• 2. Identify the incorrect statement

  • a.Neuroanatomical theory of acupuncture suggests that acupuncture's effect is mediated via afferent input through the peripheral nervous system, eliciting a reflex at the level of the spinal cord via the sympathetic plexuses and via efferent nerve fibers to the visceral organs and skeletal muscle.
  • b.Peripheral neuropathy is generally defined as damage to the peripheral nervous system caused by a primary lesion or dysfunction of the nerve itself.
  • c.The authors rely upon Traditional Chinese Medicine theory of channels and collaterals to explain acupuncture's use in the treatment of neuropathy.
  • d.The most common causes of polyneuropathy are diabetes, thyroid disorders, Vitamin B 12 deficiency, alcohol abuse, chemotherapy, and HIV induced.
  • e.Signs and symptoms of peripheral neuropathy may include gradual onset of numbness or tingling in the hands or feet, freezing or burning pain, extreme sensitivity to touch, lack of coordination and falling, and muscle weakness.

• 3. Identify the incorrect statement

  • a.The RCTs included on diabetic peripheral neuropathy reported significant improvement in acupuncture groups compared to control in neurologic exam, neuropathic symptoms, composite improvement scores, and blood rheology.
  • b.The RCTs included in this review utilized various methods of acupuncture point stimulation including manual acupuncture, acupuncture with and without moxabustion, and electroacupuncture.
  • c.Polyneuropathy studies included those of diabetic and HIV related type.
  • d.RCTs on treatment of diabetic neuropathy with acupuncture did not demonstrate any benefit to neuropathic symptoms.
  • e.The polyneuropathy trials analyzed commonly used the extra points Baxie (EX‐UE‐9) and Bafeng (EX‐LE‐10) in addition to points on the principal acupuncture channels.

• 4. Identify the incorrect statement

  • a.Review of these trials reports on safety and adverse effects suggest that acupuncture is safe in the treatment of neuropathies.
  • b.Trials of the treatment of mono‐neuropathic conditions demonstrated an emphasis on local points related to the effected nerve.
  • c.The authors analyzed RCTs of trials for Bell's Palsy and Carpal Tunnel Syndrome.
  • d.The trials for Bell's Palsy most commonly used ipsilateral hand Yangming Stomach points such as ST4, ST6, ST7 and bilateral LI 4 Hegu.
  • e.The acupuncture points used in the trial for Bell's Palsy are commonly known to be near the branches of the Occipital nerve.

• 5. Identify the incorrect statement

  • a.The acupuncture points commonly used for Bell's Palsy are closely related to the facial nerve.
  • b.Trials for Carpal Tunnel Syndrome (CTS) routinely employed acupuncture points that have close association with the median nerve.
  • c.Commonly employed points for CTS were ipsilateral hand Jueyin Pericardium channel points PC6, PC 7, and PC 8.
  • d.The authors propose that for mono‐neuropathies, a structural approach of use of acupuncture points can be used to create simple but effective standardized treatment protocols.
  • e.The authors propose that based on their systematic review Traditional Chinese Medicine theory is the suggested evidence‐based approach to treatment of neuropathies.

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