By Melissa Quick, DO
Integrative Medicine Fellow, Mount Sinai Beth Israel Medical Center, New York City
Synopsis: According to Zhou’s recent research, acupuncture is a safe option that may be effective at improving cognitive function in patients with Alzheimer’s disease when used in conjunction with certain pharmaceutical treatments.
Source: Zhou J, et al. The effectiveness and safety of acupuncture for patients with Alzheimer disease: A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 2015;94:e933. doi: 10.1097/MD.0000000000000933.
Dr. Quick reports no financial relationships relevant to this field of study.
Summary Points
- Management of the cognitive and behavioral symptoms of dementia is a growing concern, as the prevalence of Alzheimer’s disease is expected to increase in the coming years.
- Current conventional treatment consists primarily of pharmaceuticals with limited efficacy and a high risk of adverse effects.
- Acupuncture is a safe modality that may be offered alone or in conjunction with pharmaceutical treatment to possibly improve cognitive function in individuals with Alzheimer’s disease.
To evaluate the effectiveness and safety of acupuncture in Alzheimer’s disease (AD), two authors independently searched databases and extracted data for this meta-analysis. The inclusion criteria were randomized, controlled trials (RCTs) with participants diagnosed with AD by common diagnostic criteria, including the International Classification of Diseases and the Diagnostic and Statistical Manual of Mental Disorders. Studies using acupuncture were included unless the trials compared different types of acupuncture or acupoints.
The initial search yielded 1703 results. After removing duplicates and eliminating review articles, animal experiments, papers focusing on the mechanism of AD, and unrelated topics, 10 RCTs were ultimately selected. From these trials, 585 participants were included in the meta-analysis. The included studies had sample sizes ranging from 16 to 49 participants, participants ages 46 to 81 years, and trial durations of 4 to 24 weeks. The specific acupuncture points used most frequently were noted, with the most common two (GV20 and ST36) used 40% among the 10 studies. Although each RCT utilized randomization, the details were unclear in half of the trials, even after the authors of the original trials were contacted. None of the RCTs blinded acupuncturists or participants, and there was no mention whether any of the studies used sham acupuncture.
Zhou accounted for the risk of bias in each study using the Cochrane Handbook for Systematic Reviews of Interventions. The 10 RCTs were evaluated in three groups based on comparisons: Group 1: “acupuncture versus drugs;” Group 2: “acupuncture plus donepezil versus the same donepezil alone;” and Group 3: “acupuncture versus no treatment.” Multiple different neurocognitive scales were used to evaluate treatment endpoints. These scales included the Mini Mental State Examination (MMSE) Scale, Hasegawa’s Dementia Scale, Alzheimer’s Disease Assessment Scale-Cognition (ADAS-cog), Activities of Daily Living (ADL) Scale, Functional Activities Questionnaire (FAQ), and the Montreal Cognitive Assessment (MoCA). All of the 10 trials used the MMSE and seven used the ADL scale for outcome assessments. For simplicity in this review, we will only mention Zhou’s analysis of these two scales in the above three groups.
In Group 1, the RCTs included a variety of “drugs:” donepezil, almitrine and raubasine, dihydroergotoxine, nimodipine, and piracetam. For the MMSE outcome of Group 1, Zhou found a large amount of heterogeneity (I2 = 57%) but noted that this may primarily be due to one particular study that was an unpublished master’s thesis with shorter duration than the other five studies. The mean differences (MD) of MMSE scores for the six RCTs was 1.05 (95% confidence interval [CI], 0.16-1.93; P = 0.02) using the random model and 0.54 (95% CI, 0.02-1.07; P = 0.04) using the fixed model, neither of which was significantly different. For the ADL outcome of Group 1, the MD was -2.80 (95% CI, -4.57 to -1.02; P = 0.002) using the fixed model.
The results of Group 2 combined three RCTs and showed a MD of 2.37 (95% CI, 1.53-3.21; P < 0.0001) for the MSSE scale, indicating a statistically significant difference between the “acupuncture plus donepezil” and “donepezil alone” groups in improving the MMSE score.
Group 3 involved only one RCT evaluating the MMSE and ADL scores and, thus, was not a true meta-analysis. The MD of the MMSE outcome was statistically significant (3.74; 95% CI, 1.34-6.14; P = 0.002), but the MD of the ADL outcome was not (-8.82; 95% CI, -19.83 to 2.19; P = 0.12).
Table: Acupuncture Groups Based on Comparisons |
||
|
Group 1 |
Group 2 |
Group 3 |
|
Acupuncture vs drugs |
Acupuncture plus donepezil vs the same donepezil alone |
Acupuncture vs no treatment |
The safety of acupuncture was addressed separately, evaluating 141 studies consisting of 3416 AD patients treated either with acupuncture or acupuncture and another therapy. No studies reported severe adverse events. Adverse reactions related to acupuncture occurred in only seven cases. Of these seven, the reactions were described as tolerable and not severe.
Commentary
AD is an irreversible, progressive form of dementia that causes memory loss and cognitive decline. AD is the most common form of dementia and is a complex disease characterized by an accumulation of ß-amyloid (Aß) plaques and neurofibrillary tangles composed of tau amyloid fibrils.1 Today, of the 5.3 million Americans with AD, 5.1 million are ≥ 65 years of age and 81% are ≥ 75 years of age.2 Two-thirds of patients with AD are women.3 The prevalence of AD increases annually across the globe. It is estimated that worldwide, the number of individuals suffering from dementia will increase to 75.6 million in 2030, and 135.5 million in 2050.4 Individuals with AD, along with their family, friends, and caregivers, are tremendously affected on personal, emotional, financial, and social levels. In 2010, the total estimated worldwide cost of dementia was $604 billion.5
Given the incredible burden that AD puts on all of us — as family members, friends, and clinicians — the search for adequate symptom control and ultimately prevention is crucial. In particular, managing the behavioral aspects of AD, such as sleep disorders, anxiety, depression, and agitation, pose significant challenges for providers. Indeed, in 2010, a group called Alzheimer’s Disease International urged governments to take a more prominent role in research and care for those affected by AD.5 In 2011, President Barack Obama signed into law the National Alzheimer’s Project Act (NAPA) with the mission of funding research, provider education, and awareness of AD.6 Acupuncture, among other integrative approaches, offers promise to ameliorate some of the cognitive and behavioral symptoms associated with AD.
Zhou’s meta-analysis exemplifies the type of research necessary to evaluate the utility of acupuncture. Acupuncture, the insertion and stimulation of needles at specific points on the body to facilitate recovery of health, is gaining popularity in the United States.7 Acupuncture is part of a larger system of healing within traditional Chinese medicine (TCM) and has been around for thousands of years. In addition to TCM acupuncturists, contemporary acupuncturists also include medical doctors who integrate physiologic aspects of the needling process along with traditional Chinese teachings.8
Understanding risk factors and the pathology of AD are paramount to prevention, early recognition, and monitoring and controlling symptoms. Briefly, the major risk factors2 for AD include:
- Age older than 65 (though AD is not a normal part of aging)
- Genetics (a first-degree relative with AD along with inheriting one or two copies of the e4 form of apolipoprotein E [APOE] gene may increase the likelihood of developing AD)
- Mild cognitive impairment; cardiovascular disease (growing evidence links the health of the heart and blood vessels to brain health)
- Fewer years of formal education; decreased social and cognitive engagement
- Personal history of traumatic brain injury
The diagnosis of AD is largely clinical and historically has been made by a patient’s primary care physician. A physician generally makes a diagnosis by assessing a patient’s complete medical and family history, gaining insight from family members, physical and neurologic examinations, and neurocognitive tests such as those listed above.
In 2011, the National Institute on Aging and the Alzheimer’s Association suggested revised criteria and guidelines for diagnosing AD. These modified guidelines categorize AD into three categories (preclinical Alzheimer’s, mild cognitive impairment due to Alzheimer’s, and dementia due to AD), and also propose the use of biomarkers to both identify and treat those with the disease.9 It should be emphasized that these guidelines have not been validated but do show promise in our clinical approach to AD. The participants in Zhou’s meta-analysis were likely in the latter two categories.
The 10 trials included in Zhou’s study were primarily within the last decade, ranging from 2001-2014. Perhaps unsurprisingly, given that acupuncture originated in China, all 10 studies were in Chinese. Zhou notes that none of the reviewed RCTs contained information about the degree of hippocampal atrophy, as no study utilized magnetic resonance imaging (MRI). MRI, along with certain biomarkers such as the e4 form APOE gene, are gaining momentum as additional ways in which to both diagnose and monitor the progression of AD.2 Future acupuncture studies would benefit from reviewing additional objective endpoints such as imaging and serum biomarkers.
In Zhou’s review, neurocognitive tests were the only way in which interventions were monitored. Six different neurocognitive assessments were used and compared in the 10 studies above. This variety of outcome measurements leads to an unavoidable degree of heterogeneity in this meta-analysis, except when evaluating the MMSE, which was the only outcome used in all of the studies. The small sample sizes of studies utilizing other assessments, such as the MoCA, HDS, ADAS-cog, and FAQ, made meta-analysis impossible and thus effectiveness could not be sufficiently determined.
Interestingly, a recent study compared different cognitive and behavioral assessments in patients with AD and found similar correlations between test results.10 This indicates that the perceived heterogeneity between outcome measurements in this meta-analysis may be more homogenous than they initially appear to be. Furthermore, educational differences influence cognitive performance and may affect baseline and outcome scores.10 Future meta-analyses that utilize neurocognitive scales may benefit from including education levels as additional data points for interpretation.
Unfortunately, no pharmacologic or non-pharmacologic treatments available today slow or stop the neuronal damage or symptoms associated with AD.2 Given the current suboptimal state of therapies for AD, many nonconventional modalities, such as mind-body therapies, botanicals, and dietary approaches, are being further explored as effective care options.11 Indeed, a recently published National Health Statistics Report shows a linear increase in the use of acupuncture in general over the last decade.12
Interestingly, many of the medications used in the RCTs in Group 1 (acupuncture vs drugs) are not used in the United States to treat AD. For example, dihydroergotoxine, nimodipine, piracetam, and almitrine and raubasine are not frequently used to treat AD in the United States. The FDA currently has approved five medications to treat AD symptoms: donepezil, galantamine, rivastigmine, memantine, and a combination pill including donepezil and memantine.13 Correspondingly, the applicability of the results of the meta-analysis of Group 1 to the U.S. population is limited.
Frustratingly, current medication regimens have limited efficacy and questionable short- and long-term clinical significance.14 Additionally, there have been significant adverse effects associated with commonly used pharmaceuticals for AD. Medications such as donepezil come with a long list of possible significant adverse reactions, the most significant of which include insomnia (2-14%) and gastrointestinal upset (nausea 3-19% and diarrhea 5-15%).15 In comparison, acupuncture is generally considered safe, with the most common risks consistent with those that could occur whenever penetrating the body with a sharp instrument, but quite rare in practice under a well-trained acupuncturist. A patient on anticoagulation should be vigilantly observed for deep bleeding, although there are no reported cases to date.8 Because acupuncture can sometimes be associated with an acute onset of euphoria, anxiety, or lightheadedness, all patients should be monitored during and after a treatment.
The analysis of Group 2, where a statistically significant difference was found in the improvement of the MD of MMSE scores between the “acupuncture plus donepezil” and the “donepezil alone” group, represents a truly admirable aspect of Zhou’s study. Group 2 analyzes studies using the FDA-approved drug donepezil. This medication is considered a current front-line treatment for AD in the United States; thus, these results offer more relevance to patients in this country. Group 2 integrates treatment modalities, rather than focusing on therapies individually. Indeed, Zhou points out that their systematic review is the only such review to evaluate the idea that acupuncture (an “alternative” modality) being used in conjunction with pharmaceuticals (a more “conventional” treatment) may enhance the effect of pharmaceuticals.
Another novel aspect of Zhou’s study is that it is the first systematic review of acupuncture treatment for AD patients assessing safety. As discussed above, side effects were minimal in the meta-analysis. In general, acupuncture is considered safe in a geriatric population (those most likely to have AD), with the most common risks consistent with those that could occur whenever penetrating the body with a sharp instrument. A patient on anticoagulation should be vigilantly observed for deep bleeding, although there are no reported cases to date.8 Because acupuncture can sometimes be associated with an acute onset of euphoria, anxiety, or lightheadedness, all patients should be monitored during and after a treatment.
One aspect not addressed in Zhou’s study is the feasibility of actually performing acupuncture in challenging populations. Patients with dementia represent a unique challenge to acupuncture, as patients must cooperate with their acupuncturist (i.e., lying calmly and still) during a treatment. Interestingly, this study and the research reviewed does not address this aspect of treatment, perhaps because their participants were all in an earlier stage of AD and thus more capable of controlling their behavior. Further information on the practical approach to performing acupuncture on a patient with an altered sensorium would be beneficial for acupuncturists interested in helping this population.
Despite the positive intentions of this meta-analysis, several concerns within the study question its validity. Zhou acknowledges that selection and publication bias may decrease the quality of his evidence. All studies analyzed in this review were from China, thereby potentially limiting the applicability to other countries and other more heterogeneous populations. Also the paucity of information on randomization and allocation aspects of the 10 RCTs examined raise concerns of the methodology used in the original studies.
Although any acupuncture trial has difficulty adequately blinding providers and recipients of acupuncture, this aspect was also not addressed in Zhou’s 10 RCTs and may impact the results. Conversely, it could be argued that participants with dementia may not recall that they had acupuncture, and therefore the concern of inadequate blinding on the patient’s part may be somewhat reduced in this unique population. A final consideration for the limitations of Zhou’s review is that none of the RCTs assess short- or long-term follow-up of their participants. Arguably one of the most important aspects of research for modalities to help patients with AD is to search for long-term amelioration of symptoms. Future studies with long-term follow up of patients with any intervention will be the most useful.
Meta-analyses such as Zhou’s are paramount to evaluating the safety and effectiveness of interventions of integrative treatments for AD. Though biases, small sample sizes, and heterogeneity of studies may have detracted from the significant outcomes in this study, acupuncture remains a promising adjunct treatment for patients with AD. Compared to the adverse effects of pharmaceuticals, the risks associated with acupuncture seem to be insignificant. Given the limited effectiveness of current conventional treatment approaches to AD, acupuncture seems to be a safe modality that may be offered alone or in conjunction with pharmaceutical treatment to possibly improve cognitive function and ADLs in individuals with AD.
REFERENCES
- Hardy J. Alzheimer’s disease: The amyloid cascade hypothesis: An update and reappraisal. J Alzheimers Dis 2006;9(Suppl 3):151-153.
- Alzheimer’s Association. 2015 Alzheimer’s Disease Facts and Figures. Alzheimers Dementia 2015;11:332-384.
- Hebert LE, et al. Alzheimer disease in the United States (2010–2050) estimated using the 2010 Census. Neurology 2013;80:1778-1783.
- Alzheimer’s Disease International. Dementia statistics. Available at: www.alz.co.uk/research/statistics. Accessed June 29 2015.
- Alzheimer’s Disease International. World Alzheimer Report 2010. The Global Economic Impact of Dementia. Available at: www.alz.co.uk/research/files/WorldAlzheimerReport2010.pdf. Accessed June 29, 2015.
- National Alzheimer’s Project Act. Available at: http://aspe.hhs.gov/national-alzheimers-project-act. Accessed June 30, 2015.
- Vickers AJ, et al. Acupuncture for chronic pain: Individual patient data meta-analysis. Arch Intern Med 2012;172:1444-1453.
- Helms J. Acupuncture Energetics: A Clinical Approach for Physicians. Stuttgart, Germany: Thieme Publishers; 1995.
- Jack CR, et al. Introduction to the recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7:257-262.
- De Oliveira FF, et al. Correlations among cognitive and behavioural assessments in patients with dementia due to Alzheimer’s disease. Clin Neurol Neurosurg 2015;135:27-33. doi: 10.1016/j.clineuro.2015.05.010.
- Sierpina VS, et al. Complementary and integrative approaches to dementia. South Med J 2005;98:636-645.
- Clarke TC, et al. Trends in the Use of Complementary Health Approaches Among Adults: United States 2002-2012. National Health Statistics Report Hyattsville, MD: National Center for Health Statistics; 2015: no 79.
- Alzheimer’s Association. What We Know Today About Alzheimer’s Disease. Available at: www.alz.org/research/science/alzheimers_disease_treatments.asp#approved. Accessed June 30, 2015.
- Winslow BT, et al. Treatment of Alzheimer disease. Am Fam Phys 2011;83:1403-1412.
- Donepezil. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: http://online.lexi.com. Accessed June 30, 2015.
According to Zhou’s recent research, acupuncture is a safe option that may be effective at improving cognitive function in patients with Alzheimer’s disease when used in conjunction with certain pharmaceutical treatments.
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