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Cochrane Database of Systematic Reviews Protocol - Intervention

Acupuncture for symptomatic treatment of diabetic peripheral neuropathy

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the beneficial and harmful effects of acupuncture therapy for symptomatic diabetic peripheral neuropathy compared with placebo, no treatment or other treatments.

Background

Prevalence and causes

Peripheral neuropathy is a common complication of diabetes mellitus. On average the onset of symptoms occurs 10 to 20 years after diabetes has been diagnosed. Common symptoms of diabetic peripheral neuropathy (DPN) include numbness and/or insensitivity; prickling and/or tingling sensation; burning sensation; aching pain and/or tightness; sharp, shooting, lancinating pain; and allodynia and/or hyperalgesia (Bastyr 2005). Abnormal sensations and pain are features of approximately 10% of all cases of diabetic neuropathy and can cause marked diminution in quality of life for these patients. It is a chronic progressive disease accounting for considerable morbidity. Diabetic neuropathy was observed in 56% of patients with type 1 diabetes (Iwanicka 2000). It is the most common peripheral neuropathy in developed countries (Yasuda 2003). In the United States, diabetic symmetrical distal neuropathy or diabetic polyneuropathy is the most common form of neuropathy (Poncelet 2003).
The mechanisms of this disease include persistent hyperglycaemia, microvascular disease, modification of proteins critical to neural function by glycation and glycosylation, altered metabolism of fatty acids, increased activity in the polyol pathway and decreased neurotrophic factors.

Pathology

The pathogenesis of diabetic neuropathy has not been fully elucidated but is multifactorial. Some people with diabetes experience painful diabetic neuropathy (PDN), while others experience an asymptomatic, progressive loss of peripheral nerve function (Page 1997). Painful diabetic neuropathy is a major cause of morbidity in diabetes mellitus (Emanuele 1997). Painful diabetic neuropathy tends to develop in stages. Early on, intermittent pain and tingling is noted in the extremities, particularly the feet. In later stages, the pain is more intense and constant. In the second type of neuropathy, a painless neuropathy develops. This greatly increases the risk of severe tissue injury because pain no longer alerts the person to injury. Loss of sensation predisposes the patient to the development of diabetic foot ulcers and infection. Resulting infections may lead to serious sequelae of cellulitis, osteomyelitis, or gangrene, with amputation as the only possible cure in some instances (Hemstreet 2001).

Treatment

Glucose control has been proven to prevent or slow the progression of diabetic neuropathy. The goals of treating diabetic neuropathy are to prevent progression and reduce the symptoms of the disease. Treatment options include oral medication and insulin. Supportive therapies, including pain management and podiatric care, can improve quality of life and prevent chronic ulcerations (Poncelet 2003). Until now, there has not been an effective therapy for this disease.

Acupuncture for diabetic peripheral neuropathy

Acupuncture has been used for a long time in China to treat symptoms of diabetic neuropathy. Acupuncture therapy includes body acupuncture, scalp acupuncture, acupoint injection, electroacupuncture, laser acupuncture, moxibustion (an external method of preventing and treating diseases by ignition of moxa to stimulate the acupuncture points. It has the function of warming channels, to expel cold, and to induce the smooth flow of Qi and blood) or a combination of the above approaches. This ancient therapy hinges on the belief that a person's state of health depends on the balance and level of energy in the body.

It is known that acupuncture relieves pain by controlling the activities of the autonomic nervous system. It has been shown that opioid‐signaling events are involved in both neuropathic pain and the analgesic effects of acupuncture (Ko 2002), and the analgesic effect of acupuncture has a physiological basis. Using neurophysiological, neuropharmacological, neurobiochemical and neuromorphological methods, the neurohumoral mechanism of the analgesic effect of acupuncture was studied from the peripheral neural pathway of acupuncture sensation De‐Qi (needling sensation in Chinese Traditional Medicine (CTM)) to the central neuromodulatory effect (Cao 2002). This study indicated that needling of the acupuncture point could elicit De‐Qi sensation. De‐Qi refers to induction of the channel Qi after the needle is inserted. During the needling sensation, the patients have soreness, numbness, and a feeling of distension or heaviness around the point. This means acupuncture could activate nerve fibres ascending in the anterolateral spinothalamic tract which conduct pain and temperature sensation and activate the anti‐nociceptive system causing release of opioid peptides which stimulate descending inhibitory pathways resulting in analgesia (Cao 2002).

Although acupuncture was traditionally not recommended in patients with diabetes due to fear of infection and subsequent gangrene, modern advances in needle manufacture and sterilization have allowed practitioners to perform acupuncture safely on patients with diabetes.

Present status

Drug treatment for the symptoms of diabetic peripheral neuropathy is often inadequate. Uncontrolled studies of TENS and of acupuncture have been reported to decrease pain in >75% of patients with diabetic neuropathy (Julka 1998). Limited evidence from previous studies of acupuncture for pain relief suggests that 50 to 80% of patients appear to benefit from treatment and that some pain relief may be maintained after treatment ends. One recent study indicated that acupuncture has the action of improving the metabolism of blood sugar and blood‐lipid, lowering blood viscosity, and restoring the functions of peripheral nerve cells, thus giving definite therapeutic effects for diabetic peripheral neuropathy (Jiang 2006). Very few adverse effects are associated with acupuncture.

Our preliminary searches identified about 90 trials on treatment of diabetic peripheral neuropathy with acupuncture in the Chinese Biomedical Database (December 2001). The role and efficacy of acupuncture for treatment of the symptoms of diabetic peripheral neuropathy are still unclear. A systematic review of controlled trials comparing acupuncture to placebo, no treatment or other treatments is needed.

Objectives

To assess the beneficial and harmful effects of acupuncture therapy for symptomatic diabetic peripheral neuropathy compared with placebo, no treatment or other treatments.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) or quasi‐randomised trials (ie trials in which allocation is by alternation or day of the week or some other systematic system) of acupuncture therapy in the treatment of diabetic peripheral neuropathy will be included regardless of language and type of publication.

Types of participants

We will include participants with diabetic peripheral neuropathy. Diabetic peripheral neuropathy will be defined according to the diagnostic criteria of the World Health Organization (WHO 1999).

Types of interventions

Any type of acupuncture therapy alone compared with placebo, no treatment or any other treatment. Acupuncture includes:

  1. body acupuncture

  2. electroacupuncture

  3. acupoint injection

We will include trials where acupuncture is combined with another treatment provided the control group receives the same treatment.

We will consider four types of acupuncture separately and together. The different types of acupuncture are:

  1. acupuncture

  2. electroacupuncture

  3. acupuncture and moxibustion

  4. acupoint injection.

Types of outcome measures

Primary outcomes

The primary outcome measure will be change in a symptom score after four weeks because the focus of the review is on treatment of symptoms. Studies where scores have not been adjusted for baseline values will also be used if necessary and feasible. The Total Symptom Score (Ametov 2003) at four weeks after randomisation is an acceptable symptom score. Where this outcome is not available, we will use clinically significant improvement with whatever scale was used by the authors, as the primary outcome measure. In the event that data are only available for a period shorter than four weeks, then the average change in score per week will be used.

Secondary outcomes

Secondary outcome measures include:

  1. Change in nerve conduction attributes at least four weeks after randomisation.

  2. Change in sum score of an impairment scale, such as the Neuropathy Impairment Score (Young 1993), at least six months after randomisation.

  3. Change in quality of life at least six months after randomisation.

  4. Adverse events occurring as a result of acupuncture treatment, for example, fainting due to acupuncture.

Search methods for identification of studies

We will attempt to identify all relevant studies regardless of language and publication status (published, unpublished, in press, and in progress).
We will search the Trials Register of the Cochrane Neuromuscular Disease Group. In addition, we will also search the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library.

(1) Electronic databases

We will search the following electronic databases: MEDLINE (1966 to 2006), EMBASE (1980 to 2006), and the China National Knowledge Infrastructure database (CNKI) (1960 to 2006).

(a) Search Strategy for MEDLINE:

A.Search strategy to locate RCTs
search terms 1‐30, as given in the Cochrane Handbook , appendix 5 (Higgins 2005).

B.Search strategy to locate diabetic peripheral neuropathy
31. exp diabetes mellitus/
32. diabet$.mp.
33. 31 or 21
34. neuropath$.mp.
35. exp peripheral nervous system diseases/
36. peripheral$ nervous$ system$ disease$.mp.
37. polyneuropath$.mp.
38. or/34‐37
39. 33 and 38
40. exp Diabetic Neuropathies/
41. diabetic neuropath$.mp.
42. diabetic polyneuropath$.mp.
43. or/39‐42

C.Search Strategy to locate acupuncture intervention:
44. exp acupuncture/
45. exp electroacupuncture/
46. exp meridians/
47. exp acupuncture points/
48. exp acupuncture therapy/
49. acupuncture$.mp.
50. acupoint injection.mp.
51. electroacupuncture.mp.
52. acupuncture therapy.mp.
53. acupuncture points.mp.
54. or/44‐53
55. 30 and 43 and 54

(b) We will adapt this strategy as necessary to search EMBASE.

(2) Hand searching

We will hand search the following Chinese Journals: Chinese Journal of Integrated Traditional and Western medicine; Research of Traditional Chinese Medicine; Modern Traditional Chinese Medicine; Modern Journal of Integrated Traditional and Western Medicine; New Journal of Traditional Chinese Medicine; Forum on Traditional Chinese Medicine; Chinese Acupuncture; Journal of Tianjin University of Traditional Chinese Medicine; Journal of Beijing University of Traditional Chinese Medicine; Clinical Research of Acupuncture; Journal of Shanghai Acupuncture‐Moxibustion; Hebei Journal of Traditional Chinese Medicine; Shanxi Traditional Chinese Medicine; Acupuncture Research; Journal of World Acupuncture.

We will also check the citations of existing reviews and of all trials identified by the above methods.

Data collection and analysis

Selection of studies

Two authors (TZ, RZ) will retrieve the full articles for further assessment if the title, abstract and the keywords given suggest that the study: (1) was for treating diabetic peripheral neuropathy, (2) referred to a quasi‐randomised or randomised controlled trial, (3) compared acupuncture with other another active intervention, placebo or no treatment. We will measure interrater agreement for study selection using the kappa statistic, and reach agreement by consensus, with reference to a third author if necessary.

Data extraction and management

Two authors (TZ, RZ) will independently enter data into a data extraction form about the details of study population, intervention, and outcomes. The data extraction form will include the following items:

  1. General information: title, authors, reference source, contact address, year of publication.

  2. Trial characteristics: design, method of randomisation, allocation concealment, blinding (participants, people administering treatment, outcome assessors).

  3. Intervention(s): interventions(s) (dose, route, timing), comparison intervention(s) (dose, route, timing).

  4. Participants: total number and number in comparison groups, age.

  5. Primary and secondary outcomes described above.

We will resolve all matters emerging during data extraction by referring back to the original article and consensus. If necessary, we will contact the authors of the primary studies to request information.

For binary outcomes, we will extract the number of events and total number in each group. For continuous outcomes, we will extract or impute the mean, standard deviation, and sample size of each group.

Assessment of risk of bias in included studies

The quality assessment will include an evaluation of the following components for each included study. Each component will be categorised as Adequate, Unclear, Inadequate or Not used.

  • Randomisation (allocation generation) ‐ adequate when the allocation sequence protects against biased allocation to the comparison groups

  • Randomisation (allocation concealment) ‐ adequate when clinicians and participants are unaware of future allocations

  • Observer blinding (masking) ‐ adequate when the outcome assessor is unaware of the allocation.

  • Participant blinding ‐ adequate when the participant is unaware of the allocation.

  • Loss to follow‐up ‐ adequate when >80% of participants are followed up.

Two authors (TZ, RZ) will independently assess each trial.

Data synthesis

If the data are dichotomous, we will report relative risks (RR) with 95% confidence intervals. If data are continuous, we will report weighted mean difference (WMD and 95% CI) for continuous outcomes. We will test for heterogeneity by using the Chi‐square test. If the result is P<= 0.10, we will use a random‐effects model. If not, we will use a fixed‐effect model. We will assess possible sources of heterogeneity by sensitivity and subgroup analyses as described below. We will test for publication bias by using the funnel plot or other corrective analytical methods depending on the number of included trials.

We will consider adverse events and costs and cost‐effectiveness of acupuncture for diabetic peripheral neuropathy in the Discussion section with reference to the non‐randomised literature.

Sensitivity analysis

If heterogeneity results from low quality studies, we will undertake sensitivity analyses by repeating the analysis after omitting studies lacking specific quality attributes.