Aims To examine the role of acupuncture in the treatment of diabetic painful neuropathy (DPN) using a single-blind, placebo-controlled RCT and to collect data that would be required in a future definitive study of the efficacy of acupuncture in DPN.
Methods 45 patients were allocated to receive a 10-week course either of real (53%) or sham (47%) acupuncture. Five standardised acupuncture points on the lower limb of each leg were used in the study: LR3, KI3, SP6, SP10 and ST36. Outcome measures included the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale, lower limb pain (Visual Analogue Scale, VAS); Sleep Problem Scale (SPS); Measure Yourself Medical Outcome Profile (MYMOP); 36-item Short Form 36 Health Survey and resting blood pressure (BP).
Results Over the 10-week treatment period, small improvements were seen in VAS −15 (−26 to −3.5), MYMOP −0.89 (−1.4 to −0.3), SPS −2.5 (−4.2 to −0.82) and resting diastolic BP −5.2 (−10.4 to −0.14) in the true acupuncture group. In contrast, there was little change in those receiving sham acupuncture. A moderate treatment effect in favour of active acupuncture was detected in MYMOP scores −0.66 (−0.96 to −0.35) but non-significant effect sizes in LANSS Pain Scale −0.37 (−2.2 to 1.4), resting diastolic BP −0.50 (−3.0 to 1.99) and the SPS −0.51 (−2.2 to 1.16).
Conclusions We have demonstrated the practicality and feasibility of acupuncture as an additional treatment for people with DPN. The treatment was well tolerated with no appreciable side effects. Larger randomised trials are needed to confirm the clinical and cost-effectiveness of acupuncture in the treatment of DPN.
Trial registration number ISRCTN number: 39740785.
- PAIN RESEARCH
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Diabetic painful neuropathy (DPN) is a distressing and disabling complication of diabetes mellitus. A recent study showed that nearly one-third of patients with type 2 diabetes have DPN.1 The causes of this condition are not yet fully understood, but age, duration of diabetes and diabetes control have all been shown to be associated with DPN.1 Typical symptoms include nocturnal burning or shooting pains in the legs and feet, indicating impairment or damage to small nerve fibres. Symptoms often persist for years and are associated with disrupted sleeping patterns and a poor quality of life.2 No treatment that can reverse the development or progression of diabetic peripheral neuropathy is available.3 Treatment, therefore, relies on the use of medication to manage the pain. The most commonly prescribed drugs for DPN are tricyclic antidepressants and anticonvulsants. Clinical trials have shown these drugs to be effective in controlling the pain but they have important side effects, including dizziness and nausea. Up to two-thirds of patients may have at least one side effect from taking these drugs, of which 15% will be serious enough for them to stop taking the drugs, leaving them with no effective treatment.4 A number of other, non-pharmacological treatments have been tried, including the application of topical capsaicin and opsite film dressing. Although there is some evidence that capsaicin can lead to a reduction in pain score, the effectiveness of topical treatments is yet to be determined.5
Acupuncture has been shown to be effective in treating back pain and shoulder pain.6 ,7 There is also some evidence that it may be beneficial in the management of peripheral neuropathy and painful neuropathy in diabetes.8–10 However, the evidence to support this use of acupuncture is deficient because of poor methodology, variability of treatment protocols and small sample sizes.11 ,12
To date, most studies have concentrated on the analgesic properties of acupuncture. For example, a meta-analysis of 29 acupuncture RCTs in the treatment in chronic pain showed that acupuncture produces small but clinically relevant reductions in pain.13
The objective of this sham-controlled single-blind RCT was to examine the practicality and feasibility of integrating acupuncture into the management of lower limb painful neuropathy in diabetes. The study also considered a range of different outcomes for their suitability for a future definitive clinical trial, and to derive point and variability estimates to inform future sample size calculations.
Patients and methods
Sixty-five patients with type 1 or type 2 diabetes, aged between 18 and 80 years, with a clinical diagnosis of DPN and taking a prescribed drug for DPN were identified from primary and secondary care patient databases and invited to attend a screening visit held in the recruiting centre of a local district general hospital. Other inclusion criteria were patients taking a prescribed drug for their neuropathic pain; having at least one palpable pedal pulse per foot; not having previously received acupuncture treatment for DPN; being free of foot ulcers at the start of the study and having signs of peripheral sensory neuropathy, defined as the absence of any two of sharp/blunt sensations (measured using a NeuroTip)14; impaired light touch (10 g monofilament)15 or a vibration perception threshold on either foot >25 V, measured with a neurosthesiometer.16 Data were collected between July 2008 and March 2010.
The study was approved by the north west ethics committee (ref: 08/H1011/16A) and all patients gave written informed consent before taking part in the study. ISRCTN Number: 39740785.
Before the recruitment, a computer-generated randomised list of numbers was prepared allocating participants to receive either real or sham acupuncture. The allocation was placed inside sequentially ordered sealed opaque envelopes, opened only after enrolment. The treatment allocation was revealed to the acupuncturists out of sight of the participants to ensure blinding. To reduce the risk of observer bias, the acupuncture practitioners were discouraged from discussing the treatments or previous results with the patients.
Weekly afternoon clinics were arranged allowing sufficient time for the collection of study outcome data and for the acupuncture treatments to be completed.
A total of five standardised acupuncture points on the foot and lower limb of each leg (total 10) were used in the study; LR3, KI3, SP6, SP10 and ST36 (figure 1). The chosen points are based on traditional Chinese medicine diagnosis for diabetes and neuropathy—that is, kidney deficiency, de qi and blood stagnation. These acupuncture points have also commonly been used in other similar clinical studies.8 ,9 ,17 ,18
The point location and depth of needle insertion were based on traditional acupuncture methods and good clinical practice.19 The depth of needle insertion varied according to point, but was usually 0.5–1.5 cun (about 0.25–2 cm).
The acupuncture treatments were carried out by any one of three trained acupuncturists who were either members of the British Acupuncture Council or the Acupuncture Association of Chartered Physiotherapists. Two of the acupuncturists (BV and LFW) were UK trained with nearly 10 years’ experience of treating patients in the NHS and in private practice. The third practitioner (MX) was trained in integrated medicine in China and has worked as a consultant doctor in Western and Chinese medicine. She has also been a senior lecturer in traditional Chinese medicine and acupuncture since 2001.
A series of training sessions were carried out before the start of the study to allow practitioners to become familiar with the sham acupuncture devices and to standardise point location and technique.
The sham device used in the study was the Park sham device (Dong Bang Acupuncture Inc, Korea), which has been validated for use in randomised clinical trials.20 In brief, both the real and sham disposable needles look identical; the sham needle, however, is blunt and slides into the handle rather than penetrating the skin when the needle is tapped. Before needling, a sliding plastic tube is adhered to each of the acupuncture points to mask the allocation of needles from the patients.
We did not ask patients whether they felt de qi to avoid the risk of patients in the placebo group becoming unblinded to their treatment allocation.21
After insertion, the needles remained in place for 30 min and both real and sham needles were manipulated after 15 min, which is in keeping with normal acupuncture practice.19
The intervention consisted of a total of 10 weekly sessions during which diabetes and blood pressure management continued as normal. The protocol permitted changes in medication as required, including those taken for DPN.
All patients were provided with a patient information sheet which informed them that they were taking part in a randomised trial in which they could be treated with real acupuncture or an inactive treatment that looked like real acupuncture. They were also informed that they would not be told which treatment they had received until all study visits had been completed.
As this was a feasibility study, a primary outcome measure and a formal power calculation were not required. Outcomes selected for this study were based on measures used in previous studies of DPN. Assessments of neuropathic pain were carried out using the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) Pain Scale.22 Although originally developed as a screening instrument, the LANSS has been used as an outcome measure in previous neuropathic pain RCTs.23 The instrument contains questions pertaining to five neuropathic sensory disturbance domains and two sensory examination items. The maximum score on the LANSS scale is 24, with scores >12 indicating that neuropathic mechanisms are likely to be contributing to patients’ pain.
Lower limb pain intensity was measured on a 100 mm Visual Analogue Scale (VAS), and the Measure Yourself Medical Outcome Profile (MYMOP) was used to measure changes in health over time. The instrument was developed specifically for use in studies of complementary medicine24 and collects information on symptoms considered by the patient to be important. Sleep quality was assessed using the Sleep Problem Scale (SPS), a short standardised measure of sleep disturbance.25 General health status was measured using the 36-item Short Form 36 Health Survey (SF-36), which produces three subscale scores: physical health score, a mental health score and a bodily pain score (BPS).26
At each study visit, all patients had their blood pressure taken before and after treatment and completed a copy of the MYMOP and a VAS for pain. In addition, the LANSS pain scale, SPS and SF-36 were completed at the baseline visit, week 5 and week 10.
Although the main focus of this study was to examine the benefits of acupuncture for the treatment of DPN, there is now some evidence and growing interest in the potential benefits of acupuncture in the management of hypertension.27 ,28 As resting blood pressure is routinely measured in the diabetic clinic, systolic and diastolic blood pressures were recorded before each acupuncture treatment.
Adverse event reporting
At the beginning of each study visit, patients were asked if they had had any side effects as a result of the acupuncture treatment. In addition, patients were provided with a telephone number to report any concerns they had about the study. Any adverse events were recorded on the case report forms and reported to the principal investigator (EBJ) and the research and development department according to the hospital's standard operating procedures. All patients with suspected adverse events received a referral appointment with the study principal investigator, a consultant in diabetes, to determine whether the event was related to the acupuncture treatment.
Power calculation and sample size
As this was a feasibility study, a power calculation was not required. Our target sample of 60 people was based on the recommendations of Lancaster et al.29
We considered the availability and willingness of patients to be recruited; the number of adverse events and losses to follow-up.
Baseline characteristics are presented using means and SDs and categorical data are presented as proportions. χ2 Tests were performed on categorical data and t tests on continuous variables. The analyses were conducted on an ‘intention-to-treat’ basis. Last observation carried forward was used to replace missing values. The proportions in each group showing at least a 25% improvement in LANSS and VAS pain scores were also compared. As outcome values were likely to be strongly correlated with baseline values, analyses of covariance were carried out.30 Group differences between the means are presented together with their 95% CIs. For each of the outcome measures, an effect size estimate comparing real and sham acupuncture groups was calculated as the difference between the 10-week mean values divided by the pooled SD, with values ≤0.4 considered small effects, 0.4–0.7 considered moderate and >0.7 considered large effects.31
All patients were enrolled into the study within the 18-month target recruitment period. The primary care medical staff and administrators supported the project and readily agreed to identify potentially suitable patients from the databases, make the initial contact with the patients and send out the patient information sheets.
Of the 65 patients considered eligible, six refused, resulting in 59 being enrolled into the study. The baseline demographic and clinical characteristics are displayed in table 1.
Forty-five (76%) patients completed a baseline and final assessment: 24 (53%) received active acupuncture and 21 (47%) sham acupuncture treatment. A total of four patients in the active group and 10 patients in the sham group failed to complete the study (figure 2).
In total, three adverse events were reported resulting in patients withdrawing from the study. In the group receiving active treatment, one participant developed chest pains while undergoing acupuncture treatment, related to a chronic heart condition, and another withdrew as she felt that the acupuncture exacerbated her leg pain. In the sham group, one participant withdrew because she developed a localised swelling in her leg, which was considered unrelated to the study. No incidents of infections associated with the administration of acupuncture were seen or reported.
Two patients in the group receiving active acupuncture had their blood pressure medication stopped owing to low blood pressure and two patients had their medication dose increased. One person in the sham group stopped taking their medication owing to low blood pressure. None of the patients changed their neuropathic pain medication during the 10-week study period.
Patients in the active acupuncture group showed a 16% improvement in LANSS score after acupuncture. In contrast, those in the sham group showed a 7.2% deterioration in LANSS symptoms (table 2). Six of 24 (25%) patients in the active acupuncture group showed at least a 25% improvement compared with four of 21 (19%) in the sham group. In the analysis of covariance, the LANSS score improved by an average of 2.1 points more in the treatment group than the sham group which would be considered as a moderate treatment effect (table 3).
In the active acupuncture group, improvements over 10 weeks were found for VAS pain intensity, MYMOP score, SPS and diastolic blood pressure. Thirteen of 28 (46.4%) in the group receiving active treatment showed at least a 25% improvement in VAS pain intensity score compared with four of 31 (12.9%) in the sham treatment group. Improvements were also seen for SF-36 physical component and BPS and systolic blood pressure. Sham group participants also showed improvements in VAS score, resting blood pressure and SPS but these were much smaller than those found in the active treatment group. The largest change seen in the sham group was a 6.3 unit improvement in SF-36 BPS (table 2).
This is one of very few studies that have investigated the role of acupuncture in the management of lower limb DPN. This report follows STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) guidelines.32
This study has provided a model of how acupuncture can be easily incorporated into the routine management of people with DPN. Acupuncture was also well tolerated by patients with few if any side effects, suggesting that it is a safe treatment.
The study was carried out on a fairly typical sample of patients with long-term DPN who might be found in primary and secondary care. The patients who received active acupuncture were slightly older and also had higher levels of sensorimotor impairment. Because of the small numbers, we were unable to determine whether these differences influenced the results of the study.
Overall, the non-completion rate was in line with expectation but found to be higher amongst those allocated to receive sham treatment. Bias resulting from inadequacies in blinding could lead to exaggerated treatment effects.33 In a post hoc analysis 3 months after their final treatment, participants were asked whether they thought they had received active or sham treatment. Forty per cent in the active acupuncture group thought they had received sham treatment and 42% in the sham group thought they received real treatment. These data suggest that our results were not unduly biased owing to any blinding effects.
Observed improvements in the active acupuncture group, but not in the sham group, suggest that acupuncture may have a role in the treatment of some of the unpleasant symptoms associated with DPN. The study included only 59 participants and therefore some of the results may be susceptible to type II errors —that is, the sample size was too small for the observed differences between groups to appear statistically significant.
Our findings showing small to moderate treatment effects of active acupuncture are comparable with randomised studies of headache and low back pain.34 ,35 The results are also consistent with the findings of a recent systematic review of the analgesic effects of acupuncture in chronic pain.13
It has previously been suggested that non-penetrating sham needles could cause some level of sensory stimulation when the needles are tapped and rotated and therefore stimulate the acupuncture points.36 In this study, however, over 90% of patients had loss of sharp/blunt and light touch sensation in their lower limbs (table 1), it is unlikely, therefore, that the study patients would have been able to differentiate between real or sham needles. Evidence for this is provided in table 2, which shows only small changes in eight of the nine outcome measures in the sham group between baseline and 10 weeks, results which suggest that the sham treatment was relatively therapeutically inactive. The exception to this was the SF-36 BPS, which showed a small six-unit improvement over 10 weeks. This result may occur because the BPS items relate to general pain changes in the previous month and therefore BPS is likely to reflect the episodic nature of chronic musculoskeletal pain commonly found in people of this age.37
Our results also suggest that the 10-week course of acupuncture may lead to a 5 mm Hg reduction in diastolic blood pressure. The evidence for the efficacy of acupuncture in controlling blood pressure is controversial and inconclusive. Similar results, however, were reported in the findings of a systematic review of 11 studies.38 Although our results should be treated with caution, they do support the inclusion of blood pressure as an outcome in future acupuncture studies.
This study has shown that acupuncture can be successfully incorporated into the management of patients with DPN. Although the attendance was in line with expectations, in future studies we would recommend the adoption of additional measures to reduce the non-attendance rate, such as the use of reminder texts and telephone calls.
As our results suggested improvements in a variety of troublesome symptoms, future studies should collect information on the different signs and symptoms associated with DPN rather than concentrating on detecting unit reductions in pain intensity.
The findings of this study will be useful in the planning of larger RCTs that are needed to determine the therapeutic and cost-effectiveness of acupuncture in the treatment of DPN.
Painful diabetic neuropathy is difficult to treat.
We tested the feasibility of a sham-controlled acupuncture trial.
Patients were willing and standardised treatment was deliverable in the diabetic clinic.
Improvements in symptoms were promising, and a trial feasible.
Correction notice This article has been corrected since it was published Online First. Figure 1 has been amended.
Contributors All authors contributed to the design of the pilot RCT. APG produced draft copies of the manuscript and the final version for submission. APG and EBJ performed the statistical analysis. All other authors contributed and approved the final version of the manuscript. EBJ is guarantor of the paper taking responsibility for the integrity of the work as a whole from inception to published article.
Funding This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (grant reference number PBPG-0706-10595). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Competing interests None.
Ethics approval Ethical approval was obtained from the north west ethics committee (ref: 08/H1011/16A). ISRCTN number: 39740785.
Provenance and peer review Not commissioned; externally peer reviewed.
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