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Acupuncture for PTSD, Naturopathy for Cardiovascular Risk; Yoga for Osteoarthritis; Chasteberry for PMS; and Antioxidants for Cardiovascular Events
EVIDENCE-BASED INTEGRATIVE MEDICINE UPDATES
ACUPUNCTURE FOR PTSD, NATUROPATHY FOR CARDIOVASCULAR RISK; YOGA FOR OSTEOARTHRITIS; CHASTEBERRY FOR PMS; AND ANTIOXIDANTS FOR CARDIOVASCULAR EVENTS
| Richard Glickman-Simon, MD, Brian S. Alper, MD, MSPH, FAAFP | ACUPUNCTURE MAY IMPROVE SYMPTOMS OF PTSD, AND MAY BE AS EFFECTIVE AS COGNITIVE BEHAVIORAL THERAPY AND SELECTIVE SEROTONIN REUPTAKE INHIBITORS Level 2 [mid-level] evidence Evid Based Complement Altern Med 2013;(2013):615857 Post-traumatic stress disorder (PTSD) occurs in 25–30% of those who survive a
DynaMed is an evidence-based clinical reference, which is updated daily through systematic surveillance and critical appraisal of the research literature. DynaMed editors and reviewers select content of interest for integrative medicine, summarize the current evidence, and describe challenges in evidence analysis and application. Evidence quality is rated level 1 (likely reliable) evidence for studies with clinical outcomes and minimal risk of bias, level 2 (mid-level) evidence for studies with clinical outcomes and significant methodological or statistical limitations, and level 3 (lacking direct) evidence for reports that do not include scientific analysis of clinical outcomes. When applicable, the number of patients needed to be treated to lead to one patient having an improved outcome (NNT for number needed to treat) or a worse outcome (NNH for number needed to harm) is presented. DynaMed is available at http:// www.ebscohost.com/dynamed. For more information, contact Brian S. Alper, MD, MSPH, FAAFP, at DynaMedEditor@ebsco host.com.
life-threatening or otherwise catastrophic event.1 It is characterized by three clusters of symptoms: re-experiencing, hyper-arousal, and marked avoidance.2 First-line therapy includes a combination of cognitive behavioral therapy (CBT) and psycho-pharmaceuticals. Inadequate response and/or drug intolerance have caused many patients with PTSD and their advocates to seek alternative or supplementary treatments. Acupuncture has emerged as one of the more actively researched modalities for this purpose. Two previous reviews (one of them on acupressure), however, were unable to draw reliable conclusions about its benefits.3,4 In the present study, researchers set out to perform a systemic review of currently available prospective trials investigating the effectiveness of classical acupuncture, electroacupuncture, acupuncture with moxibustion (needle warming), or auricular (ear) acupuncture for PTSD.5 (Studies on acupressure were excluded.) Four randomized controlled trials (N ¼ 543) and two uncontrolled clinical trials (N ¼ 103) were included. All but one of the trials were performed on earthquake victims. In one trial with 56 patients, acupuncture significantly improved scores for PTSD symptoms, depression, anxiety, and functional impairment compared with wait-list control. The addition of acupuncture to CBT significantly improved PTSD symptom scores compared to CBT alone in
Evidence-Based Integrative Medicine Updates
one trial with 91 patients, and there were no significant differences in scores for PTSD symptoms, depression, or anxiety in another trial with 57 patients comparing acupuncture vs. CBT. Similarly, no differences were found in another trial with 256 patients comparing electroacupuncture (alone or in combination with auricular acupuncture or moxibustion) vs. selective serotonin reuptake inhibitors (SSRIs). But in a meta-analysis, combining data from two trials with 115 patients, electroacupuncture plus moxibustion was associated with significantly improved scores for PTSD symptoms, depression, and anxiety compared to SSRIs. Only one RCT had a low risk of bias. The two uncontrolled trials reported improvement with acupuncture in 4 90% of patients. The results of this review suggest that acupuncture may be at least as effective as CBT and SSRIs in the management of PTSD. Since all of the studies compared acupuncture with either no treatment or other forms of therapy, we cannot conclude anything about the efficacy of acupuncture compared to a placebo. The reliability of these results is further diminished by the high risk of bias in the uncontrolled trials and most of the RCTs. Despite these limitations, a trial of acupuncture may be worth considering for patients whose response to conventional therapy has been disappointing.
EXPLORE November/December 2013, Vol. 9, No. 6 385
ADDITION OF NATUROPATHIC CARE TO USUAL CARE MIGHT REDUCE ESTIMATED CARDIOVASCULAR RISK Level 3 [lacking direct] evidence CMAJ 2013;185(9):E409–E416. The practice of naturopathic medicine is based on the principle of vis medicatrix naturae, or nature's healing power. A naturopath views disease largely as a departure from the natural way of living and, therefore, believes that the most sensible way to restore health is to return to nature. This underlying philosophy manifests itself in a great variety of treatment strategies, some of which are identical to current evidence-based recommendations (e.g., eating a well-balanced diet and exercising regularly). Where naturopathic medicine departs from conventional medicine is in its emphasis on dietary supplements (most notably herbs) and its use of a variety of other interventions intended, for example, to detoxify the liver and support the immune and endocrine systems. In this trial, researchers investigated the effect of adjuvant naturopathic care on the risk of cardiovascular disease in 246 highrisk Canadian postal workers (total cholesterol-to-HDL cholesterol ratio 4 1.8).6 Participants were randomized to usual care (with a primary care physician) plus seven sessions with a naturopathic physician vs. usual care alone for one year. Naturopathic care consisted of individualized health promotion with diet and lifestyle counseling during an initial one-hour session followed by six 30minute sessions at work-site clinics, plus nutritional medicine and/or dietary supplementation. Differences in the rate of metabolic syndrome (as defined by the Adult Treatment Panel III recommendations7) and 10-year risk of cardiovascular events (as determined by the Framingham Heart Study algorithm8) were used as primary outcomes. (An insufficient number of actual cardiovascular events precluded the use of this patientoriented outcome instead.) Thirty-nine patients (16%) were lost to follow-up and not included the analysis. Comparing adjuvant naturopathic care vs. usual care at one year (adjusted for nonsignificant baseline differences), the rate of metabolic syndrome was 31.6% vs. 48.5% (risk reduction [RR] 16.9% [95% CI: 29.6% to 4.3%], NNT 6). The
estimated 10-year cardiovascular event risk was 7.7% vs. 10.8% (RR 3.1% [95% CI 4.4 to 1.8%]). This appears to be a seriously flawed trial with no attention control, no allocation concealment, and non-standardized treatments, among other risks of bias. It should be noted that the researchers did not set out to investigate what specific aspects of naturopathic care would benefit patients at high risk for cardiovascular disease. Since we do not know what the naturopathic physicians recommended to their patients, we do not know whether the observed benefits are unique to naturopathy. It is plausible that the same results could have been obtained by having the primary care physicians themselves make a set of standardized recommendations (based on naturopathic principles or not) to one group and not the other. But even if the results were the same, their real world applicability would be questionable. Primary care physicians cannot and do not spend an additional four hours with their patients at risk for cardiovascular disease. Naturopaths, on the other hand, can and do. An interesting followup study would be to directly compare the benefits of primary allopathic vs. naturopathic care in this patient population. Although measuring cardiovascular events would be far preferable to the surrogate risk markers used in this trial, the necessary size and duration of such a study would be prohibitive.
HATHA YOGA THERAPY MAY BE MORE EFFECTIVE THAN EXERCISE THERAPY FOR OSTEOARTHRITIS OF THE KNEE Level 2 [mid-level] evidence J Altern Complement Med 2012;18 (5):463–472. Hatha yoga, a popular form of the ancient Indian philosophy and practice, is based principally on asanas, which are characterized by the effortless maintenance of postures by internal awareness.9 Like most styles of yoga, it also incorporates rhythmic breathing (pranayama), relaxation techniques, and deep meditation. A key management strategy for patients with osteoarthritis of the lower extremities is to improve muscle strength, flexibility, range of motion, and coordination. There is evidence that exercise
386 EXPLORE November/December 2013, Vol. 9, No. 6
therapy can effectively achieve these goals.10,11 Hatha yoga, which theoretically can produce many of these effects, may have the added benefit of promoting adaptive joint positioning and suppressing nociceptive pathways through meditation and stress reduction. To compare their relative benefits, researchers randomized 250 Indian patients between the ages 35 and 80 with knee osteoarthritis to integrated hatha yoga vs. exercise therapy.9 During a 15-day supervised phase, all patients received conventional physiotherapy daily, consisting of transcutaneous electrical nerve stimulation (TENS) and ultrasound treatments followed immediately by the yoga or exercise interventions. Yoga therapy included 40 min of supervised strengthening and loosening followed by asanas, relaxation techniques with devotional singing, and counseling on yoga philosophy. Exercise therapy included 40 min of supervised strengthening and loosening of all joints followed by a brief rest period, specific knee exercises, and further rest. Hatha yoga and exercise therapy groups were taught yoga and non-yoga exercises, respectively, to do at home every day for 12 weeks following completion of the supervised phase. Compared to the exercise group, the yoga group showed significantly greater improvements in all outcomes tested: walking pain, walking time, knee flexion, clinical examination (i.e., tenderness, swelling, and crepitus), and knee disability score (WOMAC) on days 15 and 90 (P o .001). The strengths of this trial, compared to previous yoga studies, include its relatively large size, attention control, and integration with physical therapy. Although the attrition rate was low (6%), it was not clear how these dropouts were handled and if differences would be significant in a full intentionto-treat analysis. Also, it is not possible to determine what aspect of hatha yoga produced the beneficial effects. Nevertheless, it is interesting and reasonable to speculate that the added focus on meditation and postural awareness promoted an enhanced therapeutic effect. While the favorable outcomes persisted beyond the active treatment phase, further studies are required to determine long-term outcomes.
Evidence-Based Integrative Medicine Updates
CHASTEBERRY MAY IMPROVE SYMPTOMS IN WOMEN WITH PMS Level 2 [mid-level] evidence Phytomedicine 2012;19(14):1325–1331. Premenstrual syndrome (PMS) regularly affects up to 20% of menstruating women.12 Symptoms occur during the luteal phase of the menstrual cycle and include irritability, mood alteration, anger, bloating, headache, fatigue, and breast pain (mastodynia). As the name implies, fruit of the chasteberry tree (Vitex agnus castus, VAC) has been used for centuries to suppress sexual desire. More recently, its most common use has been for cyclic mastodynia and other symptoms of PMS. While its exact mechanism of action remains unknown, there is evidence that VAC suppresses the release of pituitary prolactin. However, additional mechanisms are likely responsible for the full range of its effects.13 In a previous trial, 178 women with premenstrual syndrome were randomized to receive either the VAC fruit extract ZE 440 (standardized to casticin 20 mg) or placebo orally once daily for three consecutive cycles.14 ZE 440 was associated with a greater improvement from baseline (128.5 vs. 78.1 mm, P ¼ .001) using a visual analog self-assessment score combining six PMS symptom categories (irritability, mood alteration, anger, headache, other menstrual symptoms, including bloating, and breast fullness). In the present study, 162 women between the ages of 18 and 45 with PMS were randomized into one of four groups: placebo, 8-mg, 20-mg, or 30-mg extracts of ZE 440 taken orally daily for three menstrual cycles. Based on the same six-item visual analog scale, mean differences from baseline were 32.5, 14.4, 211.1, and 190.3, respectively.13 Compared to the 20-mg dose, these differences were statistically significant for placebo and the 8-mg dose (P o .0001) but not for the 30mg dose (P ¼ .60). Defining response to treatment as Z 50% reduction in total symptom score, 11% of the placebo group and 14% of the 8-mg group responded (no significant difference). In the 20-mg group, 81% responded (P o .001 vs. placebo, P o .05 vs. 8 mg, NNT 2 for both), and 61% responded in the 30-mg group (P o .001 vs. placebo,
NNT 2, not significant vs. 20 mg). These treatment effects were no different in a sub-analysis of women (23%) who were taking oral contraceptives during the study period. There were no serious adverse effects in any group. Although both trials were placebo controlled, it is unclear if investigators enrolling patients were blinded to assignment on trial entry. Nevertheless, their results suggest that a daily 20-mg extract of VAC (standardized to casticin) is effective for the relief of PMS symptoms. Increasing the dose to 30 mg adds no benefit. These results are consistent with two other trials from China supporting the benefits of chasteberry for this indication.15,16 Although mastodynia would be expected to respond to a suppression of prolactin release, other, as yet unidentified, mechanisms are probably involved in the more global improvements observed in PMS. Given its safety and tolerability, it seems reasonable to recommend ZE 440 20 mg (or similar VCA product standardized to casticin) to women with PMS who experience inadequate relief from oral contraceptives or who do not wish to take them.
VITAMIN AND ANTIOXIDANT SUPPLEMENTS DO NOT APPEAR TO REDUCE RISK FOR CARDIOVASCULAR DISEASE Level 2 [mid-level] evidence BMJ 2013;346:f10. Preclinical studies have long supported the theory that supplementation with vitamins and antioxidants inhibit the development of atherosclerosis.17,18 According to the oxidative modification model of atherogenesis, the complete oxidation of accumulated subendothelial low-density lipoprotein (LDL) causes macrophages to aggressively devour cholesterol, stimulates the endothelial binding of monocytes, and promotes lipid and liposomal enzyme release.17 Increasing the endothelial concentration of antioxidants by dietary supplementation theoretically decelerates atherogenesis. Observational studies over the past few decades have given credence to this theory by consistently demonstrating an association between higher intake of antioxidant-rich fresh fruits and vegetables and lower incidence
Evidence-Based Integrative Medicine Updates
of cardiovascular events.19 However, the findings from numerous randomized controlled trials investigating the clinical efficacy of the antioxidant constituents of these foods have been inconsistent.20 In the present meta-analysis, researchers set out to compile a single, comprehensive report on the efficacy of dietary vitamin and antioxidant supplementation for preventing major cardiovascular events.21 After evaluating all pertinent randomized controlled trials from the past 24 years, they ultimately included 50 studies with 294,478 patients between the ages of 49 and 82. Supplementation and follow-up periods ranged from 6 months to 12 years. Of the studies included, 30 were primary prevention trials and 20 were secondary prevention trials. Supplements included vitamins A, B6, B12, C, D, E, β-carotene, folic acid, and selenium. Methodologic quality of the trails averaged 4.3 on the Jadad scale (range 2–5). Outcomes included cardiovascular death, fatal or non-fatal myocardial infarction, angina, sudden cardiac death, fatal or non-fatal stroke, and transient ischemic attack. In the overall analysis there was no association between vitamin and antioxidant supplementation and risk of any major cardiovascular event. The same was true for subset analyses by type of prevention (primary vs. secondary), type of supplement (vitamin only, antioxidant only, and singly or in combination), methodologic quality (Jadad r 4 vs. 5), duration of treatment (o 5 vs. Z 5 years), funding source (pharmaceutical industry vs. independent organization), supplement supplier (pharmaceutical vs. non-pharmaceutical industry), control (placebo vs. no placebo), and number of trial participants (o 10,000 vs. Z 10,000). Low-dose vitamin B6 (3–25 mg/day) slightly decreased the risk of major cardiovascular events (relative risk [RR] 0.92, 95% CI 0.85–0.99) in eight trials, but the effect disappeared when the analysis was restricted to five high-quality trials. Vitamin B6 and vitamin E (any dose) were associated with lower risk of cardiovascular death (eight trials, RR 0.91, 95% CI 0.83–0.99) and myocardial infarction (12 trials, RR 0.77, 95% CI 0.65–0.91), respectively. Both of these effects disappeared, however, when the analysis
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was restricted to non-industry-supported trials. High-dose vitamin A (25,000 IU daily) increased the risk of major cardiovascular events in one trial (RR 1.41, 95% CI 1.15–1.73). It is clear, based on the results of this meta-analysis, that vitamin and antioxidant supplementation has no effect on major cardiovascular outcomes in men and women who are 49 to 82 years old and should not be recommended for this purpose. The discrepancy between the findings from clinical trials vs. preclinical and observational studies has at least two possible explanations.21 First, the cardiovascular effects of these substances depend on their interaction with numerous other nutrients in fresh fruits and vegetables and lose their beneficial effects when administered in isolation. Second, for these supplements to be helpful they must be administered at the earliest stages of atherogenesis (say, prior to the age of 40 years). Importantly, vitamin and antioxidant supplementation may not be without risk. Although this systematic review did not find an increase risk in mortality, other studies have. In a Cochrane review of 78 randomized trials (N ¼ 296,707), an increase in mortality was found in subgroup analyses of high-quality trials for vitamin E and β-carotene.22 The authors theorized that enhanced antioxidation may interfere with critical defense mechanisms, such as apoptosis, phagocytosis, and detoxification.
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REFERENCES 1. National Collaborating Centre for Mental Health (UK), Post-Traumatic Stress Disorder. The Management of PTSD in Adults and Children in Primary and Secondary Care. Br Psychol Soc 2005. 2. Shalev AY. What is posttraumatic stress disorder? J Clin Psychiatry. 2001;62(suppl 17):4–10. 3. Feinstein D. Rapid treatment of PTSD: why psychological exposure with acupoint tapping may be effective. Psychotherapy. 2010;47(3):385–402. 4. Hollifield M. Acupuncture for posttraumatic stress disorder: conceptual, clinical, and biological data support further
12.
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research. CNS Neurosci Ther. 2011;17: 769–779. Young-Dae Kim, In Heo, Byung-Cheul Shin, Cindy Crawford, Hyung-Won Kang, Jung-Hwa Lim. Acupuncture for posttraumatic stress disorder: a systematic review of randomized controlled trials and prospective clinical trials. Evid Based Complement Altern Med 2013:615857 (2013). Seely D, Szczurko O, Cooley K, et al. Naturopathic medicine for the prevention of cardiovascular disease: a randomized clinical trial. CMAJ. 2013;185(9): E409–E416. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735–2752. D'Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743–753. Ebnezar J, Nagarathna R, Yogitha B, Nagendra HR. Effects of an integrated approach of hatha yoga therapy on functional disability, pain, and flexibility in osteoarthritis of the knee joint: a randomized controlled study. J Altern Complement Med. 2012;18(5):463–472. Ettinger WH, Bums R, Messier SPA. Randomized trial comparing aerobic exercise and resistance exercise with a health education program in older adults with knee osteoarthritis: the Fitness Arthritis and Seniors Trial (FAST). J Am Med Assoc. 1997;277:25–31. Bashaw RT, Tingstad EM. Rehabilitation of the osteoarthritic patient: focus on the knee. Clin Sports Med. 2005;24:101–131. Rapkin AJ, Winer SA. Premenstrual syndrome and premenstrual dysphoric disorder: quality of life and burden of illness. Exp Rev Pharmacoeconomics Outcomes Res. 2009;9(2):157–170. Schellenberg R, Zimmermann C, Drewe J, Hoexter G, Zahner C. Dose-dependent efficacy of the Vitex agnus castus extract Ze 440 in patients suffering from premenstrual syndrome. Phytomedicine. 2012; 19(14):1325–1331. Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised,
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15.
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placebo controlled study. Br Med J. 2001;322(7279):134–137. He Z, Chen R, Zhou Y, et al. Treatment for premenstrual syndrome with Vitex agnus castus: a prospective, randomized, multi-center placebo controlled study in China. Maturitas. 2009;63(1):99–103. Ma L, Lin S, Chen R, Zhang Y, Chen F, Wang X. Evaluating therapeutic effect in symptoms of moderate-to-severe premenstrual syndrome with Vitex agnus castus (BNO 1095) in Chinese women. Aust N Z J Obstet Gynaecol. 2010;50 (2):189–193. Diaz MN, Frei B, Vita JA, Keaney JF Jr.. Antioxidants and atherosclerotic heart disease. N Engl J Med. 1997;337:408–416. Farbstein D, Kozak-Blickstein A, Levy AP. Antioxidant vitamins and their use in preventing cardiovascular disease. Molecules. 2010;15:8098–8110. Dauchet L, Amouyel P, Dallongeville J. Fruits, vegetables and coronary heart disease. Nat Rev Cardiol. 2009;6: 599–608. Bhupathiraju SN, Tucker KL. Coronary heart disease prevention: nutrients, foods, and dietary patterns. Clin Chim Acta. 2011;412:1493–1514. Myung SK, Ju W, Cho B, et al. Korean Meta-Analysis Study Group. Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. Br Med J. 2013;346:f10. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2012;3.
Richard Glickman-Simon, MD, is a family physician, Integrative Medicine Editor of DynaMed, and Assistant Professor of Public Health and Community Medicine at Tufts University School of Medicine in Boston, MA, and a contributor to DynaMed in Ipswich, MA. Brian S. Alper, MD, MPSH, FAAFP, is a family physician, Editor-in-Chief of DynaMed and Medical Director for EBSCO Publishing, Inc.
Evidence-Based Integrative Medicine Updates
ACUPUNCTURE FOR PTSD, NATUROPATHY FOR CARDIOVASCULAR RISK; YOGA FOR OSTEOARTHRITIS; CHASTEBERRY FOR PMS; AND ANTIOXIDANTS FOR CARDIOVASCULAR EVENTS
| Richard Glickman-Simon, MD, Brian S. Alper, MD, MSPH, FAAFP | ACUPUNCTURE MAY IMPROVE SYMPTOMS OF PTSD, AND MAY BE AS EFFECTIVE AS COGNITIVE BEHAVIORAL THERAPY AND SELECTIVE SEROTONIN REUPTAKE INHIBITORS Level 2 [mid-level] evidence Evid Based Complement Altern Med 2013;(2013):615857 Post-traumatic stress disorder (PTSD) occurs in 25–30% of those who survive a
DynaMed is an evidence-based clinical reference, which is updated daily through systematic surveillance and critical appraisal of the research literature. DynaMed editors and reviewers select content of interest for integrative medicine, summarize the current evidence, and describe challenges in evidence analysis and application. Evidence quality is rated level 1 (likely reliable) evidence for studies with clinical outcomes and minimal risk of bias, level 2 (mid-level) evidence for studies with clinical outcomes and significant methodological or statistical limitations, and level 3 (lacking direct) evidence for reports that do not include scientific analysis of clinical outcomes. When applicable, the number of patients needed to be treated to lead to one patient having an improved outcome (NNT for number needed to treat) or a worse outcome (NNH for number needed to harm) is presented. DynaMed is available at http:// www.ebscohost.com/dynamed. For more information, contact Brian S. Alper, MD, MSPH, FAAFP, at DynaMedEditor@ebsco host.com.
life-threatening or otherwise catastrophic event.1 It is characterized by three clusters of symptoms: re-experiencing, hyper-arousal, and marked avoidance.2 First-line therapy includes a combination of cognitive behavioral therapy (CBT) and psycho-pharmaceuticals. Inadequate response and/or drug intolerance have caused many patients with PTSD and their advocates to seek alternative or supplementary treatments. Acupuncture has emerged as one of the more actively researched modalities for this purpose. Two previous reviews (one of them on acupressure), however, were unable to draw reliable conclusions about its benefits.3,4 In the present study, researchers set out to perform a systemic review of currently available prospective trials investigating the effectiveness of classical acupuncture, electroacupuncture, acupuncture with moxibustion (needle warming), or auricular (ear) acupuncture for PTSD.5 (Studies on acupressure were excluded.) Four randomized controlled trials (N ¼ 543) and two uncontrolled clinical trials (N ¼ 103) were included. All but one of the trials were performed on earthquake victims. In one trial with 56 patients, acupuncture significantly improved scores for PTSD symptoms, depression, anxiety, and functional impairment compared with wait-list control. The addition of acupuncture to CBT significantly improved PTSD symptom scores compared to CBT alone in
Evidence-Based Integrative Medicine Updates
one trial with 91 patients, and there were no significant differences in scores for PTSD symptoms, depression, or anxiety in another trial with 57 patients comparing acupuncture vs. CBT. Similarly, no differences were found in another trial with 256 patients comparing electroacupuncture (alone or in combination with auricular acupuncture or moxibustion) vs. selective serotonin reuptake inhibitors (SSRIs). But in a meta-analysis, combining data from two trials with 115 patients, electroacupuncture plus moxibustion was associated with significantly improved scores for PTSD symptoms, depression, and anxiety compared to SSRIs. Only one RCT had a low risk of bias. The two uncontrolled trials reported improvement with acupuncture in 4 90% of patients. The results of this review suggest that acupuncture may be at least as effective as CBT and SSRIs in the management of PTSD. Since all of the studies compared acupuncture with either no treatment or other forms of therapy, we cannot conclude anything about the efficacy of acupuncture compared to a placebo. The reliability of these results is further diminished by the high risk of bias in the uncontrolled trials and most of the RCTs. Despite these limitations, a trial of acupuncture may be worth considering for patients whose response to conventional therapy has been disappointing.
EXPLORE November/December 2013, Vol. 9, No. 6 385
ADDITION OF NATUROPATHIC CARE TO USUAL CARE MIGHT REDUCE ESTIMATED CARDIOVASCULAR RISK Level 3 [lacking direct] evidence CMAJ 2013;185(9):E409–E416. The practice of naturopathic medicine is based on the principle of vis medicatrix naturae, or nature's healing power. A naturopath views disease largely as a departure from the natural way of living and, therefore, believes that the most sensible way to restore health is to return to nature. This underlying philosophy manifests itself in a great variety of treatment strategies, some of which are identical to current evidence-based recommendations (e.g., eating a well-balanced diet and exercising regularly). Where naturopathic medicine departs from conventional medicine is in its emphasis on dietary supplements (most notably herbs) and its use of a variety of other interventions intended, for example, to detoxify the liver and support the immune and endocrine systems. In this trial, researchers investigated the effect of adjuvant naturopathic care on the risk of cardiovascular disease in 246 highrisk Canadian postal workers (total cholesterol-to-HDL cholesterol ratio 4 1.8).6 Participants were randomized to usual care (with a primary care physician) plus seven sessions with a naturopathic physician vs. usual care alone for one year. Naturopathic care consisted of individualized health promotion with diet and lifestyle counseling during an initial one-hour session followed by six 30minute sessions at work-site clinics, plus nutritional medicine and/or dietary supplementation. Differences in the rate of metabolic syndrome (as defined by the Adult Treatment Panel III recommendations7) and 10-year risk of cardiovascular events (as determined by the Framingham Heart Study algorithm8) were used as primary outcomes. (An insufficient number of actual cardiovascular events precluded the use of this patientoriented outcome instead.) Thirty-nine patients (16%) were lost to follow-up and not included the analysis. Comparing adjuvant naturopathic care vs. usual care at one year (adjusted for nonsignificant baseline differences), the rate of metabolic syndrome was 31.6% vs. 48.5% (risk reduction [RR] 16.9% [95% CI: 29.6% to 4.3%], NNT 6). The
estimated 10-year cardiovascular event risk was 7.7% vs. 10.8% (RR 3.1% [95% CI 4.4 to 1.8%]). This appears to be a seriously flawed trial with no attention control, no allocation concealment, and non-standardized treatments, among other risks of bias. It should be noted that the researchers did not set out to investigate what specific aspects of naturopathic care would benefit patients at high risk for cardiovascular disease. Since we do not know what the naturopathic physicians recommended to their patients, we do not know whether the observed benefits are unique to naturopathy. It is plausible that the same results could have been obtained by having the primary care physicians themselves make a set of standardized recommendations (based on naturopathic principles or not) to one group and not the other. But even if the results were the same, their real world applicability would be questionable. Primary care physicians cannot and do not spend an additional four hours with their patients at risk for cardiovascular disease. Naturopaths, on the other hand, can and do. An interesting followup study would be to directly compare the benefits of primary allopathic vs. naturopathic care in this patient population. Although measuring cardiovascular events would be far preferable to the surrogate risk markers used in this trial, the necessary size and duration of such a study would be prohibitive.
HATHA YOGA THERAPY MAY BE MORE EFFECTIVE THAN EXERCISE THERAPY FOR OSTEOARTHRITIS OF THE KNEE Level 2 [mid-level] evidence J Altern Complement Med 2012;18 (5):463–472. Hatha yoga, a popular form of the ancient Indian philosophy and practice, is based principally on asanas, which are characterized by the effortless maintenance of postures by internal awareness.9 Like most styles of yoga, it also incorporates rhythmic breathing (pranayama), relaxation techniques, and deep meditation. A key management strategy for patients with osteoarthritis of the lower extremities is to improve muscle strength, flexibility, range of motion, and coordination. There is evidence that exercise
386 EXPLORE November/December 2013, Vol. 9, No. 6
therapy can effectively achieve these goals.10,11 Hatha yoga, which theoretically can produce many of these effects, may have the added benefit of promoting adaptive joint positioning and suppressing nociceptive pathways through meditation and stress reduction. To compare their relative benefits, researchers randomized 250 Indian patients between the ages 35 and 80 with knee osteoarthritis to integrated hatha yoga vs. exercise therapy.9 During a 15-day supervised phase, all patients received conventional physiotherapy daily, consisting of transcutaneous electrical nerve stimulation (TENS) and ultrasound treatments followed immediately by the yoga or exercise interventions. Yoga therapy included 40 min of supervised strengthening and loosening followed by asanas, relaxation techniques with devotional singing, and counseling on yoga philosophy. Exercise therapy included 40 min of supervised strengthening and loosening of all joints followed by a brief rest period, specific knee exercises, and further rest. Hatha yoga and exercise therapy groups were taught yoga and non-yoga exercises, respectively, to do at home every day for 12 weeks following completion of the supervised phase. Compared to the exercise group, the yoga group showed significantly greater improvements in all outcomes tested: walking pain, walking time, knee flexion, clinical examination (i.e., tenderness, swelling, and crepitus), and knee disability score (WOMAC) on days 15 and 90 (P o .001). The strengths of this trial, compared to previous yoga studies, include its relatively large size, attention control, and integration with physical therapy. Although the attrition rate was low (6%), it was not clear how these dropouts were handled and if differences would be significant in a full intentionto-treat analysis. Also, it is not possible to determine what aspect of hatha yoga produced the beneficial effects. Nevertheless, it is interesting and reasonable to speculate that the added focus on meditation and postural awareness promoted an enhanced therapeutic effect. While the favorable outcomes persisted beyond the active treatment phase, further studies are required to determine long-term outcomes.
Evidence-Based Integrative Medicine Updates
CHASTEBERRY MAY IMPROVE SYMPTOMS IN WOMEN WITH PMS Level 2 [mid-level] evidence Phytomedicine 2012;19(14):1325–1331. Premenstrual syndrome (PMS) regularly affects up to 20% of menstruating women.12 Symptoms occur during the luteal phase of the menstrual cycle and include irritability, mood alteration, anger, bloating, headache, fatigue, and breast pain (mastodynia). As the name implies, fruit of the chasteberry tree (Vitex agnus castus, VAC) has been used for centuries to suppress sexual desire. More recently, its most common use has been for cyclic mastodynia and other symptoms of PMS. While its exact mechanism of action remains unknown, there is evidence that VAC suppresses the release of pituitary prolactin. However, additional mechanisms are likely responsible for the full range of its effects.13 In a previous trial, 178 women with premenstrual syndrome were randomized to receive either the VAC fruit extract ZE 440 (standardized to casticin 20 mg) or placebo orally once daily for three consecutive cycles.14 ZE 440 was associated with a greater improvement from baseline (128.5 vs. 78.1 mm, P ¼ .001) using a visual analog self-assessment score combining six PMS symptom categories (irritability, mood alteration, anger, headache, other menstrual symptoms, including bloating, and breast fullness). In the present study, 162 women between the ages of 18 and 45 with PMS were randomized into one of four groups: placebo, 8-mg, 20-mg, or 30-mg extracts of ZE 440 taken orally daily for three menstrual cycles. Based on the same six-item visual analog scale, mean differences from baseline were 32.5, 14.4, 211.1, and 190.3, respectively.13 Compared to the 20-mg dose, these differences were statistically significant for placebo and the 8-mg dose (P o .0001) but not for the 30mg dose (P ¼ .60). Defining response to treatment as Z 50% reduction in total symptom score, 11% of the placebo group and 14% of the 8-mg group responded (no significant difference). In the 20-mg group, 81% responded (P o .001 vs. placebo, P o .05 vs. 8 mg, NNT 2 for both), and 61% responded in the 30-mg group (P o .001 vs. placebo,
NNT 2, not significant vs. 20 mg). These treatment effects were no different in a sub-analysis of women (23%) who were taking oral contraceptives during the study period. There were no serious adverse effects in any group. Although both trials were placebo controlled, it is unclear if investigators enrolling patients were blinded to assignment on trial entry. Nevertheless, their results suggest that a daily 20-mg extract of VAC (standardized to casticin) is effective for the relief of PMS symptoms. Increasing the dose to 30 mg adds no benefit. These results are consistent with two other trials from China supporting the benefits of chasteberry for this indication.15,16 Although mastodynia would be expected to respond to a suppression of prolactin release, other, as yet unidentified, mechanisms are probably involved in the more global improvements observed in PMS. Given its safety and tolerability, it seems reasonable to recommend ZE 440 20 mg (or similar VCA product standardized to casticin) to women with PMS who experience inadequate relief from oral contraceptives or who do not wish to take them.
VITAMIN AND ANTIOXIDANT SUPPLEMENTS DO NOT APPEAR TO REDUCE RISK FOR CARDIOVASCULAR DISEASE Level 2 [mid-level] evidence BMJ 2013;346:f10. Preclinical studies have long supported the theory that supplementation with vitamins and antioxidants inhibit the development of atherosclerosis.17,18 According to the oxidative modification model of atherogenesis, the complete oxidation of accumulated subendothelial low-density lipoprotein (LDL) causes macrophages to aggressively devour cholesterol, stimulates the endothelial binding of monocytes, and promotes lipid and liposomal enzyme release.17 Increasing the endothelial concentration of antioxidants by dietary supplementation theoretically decelerates atherogenesis. Observational studies over the past few decades have given credence to this theory by consistently demonstrating an association between higher intake of antioxidant-rich fresh fruits and vegetables and lower incidence
Evidence-Based Integrative Medicine Updates
of cardiovascular events.19 However, the findings from numerous randomized controlled trials investigating the clinical efficacy of the antioxidant constituents of these foods have been inconsistent.20 In the present meta-analysis, researchers set out to compile a single, comprehensive report on the efficacy of dietary vitamin and antioxidant supplementation for preventing major cardiovascular events.21 After evaluating all pertinent randomized controlled trials from the past 24 years, they ultimately included 50 studies with 294,478 patients between the ages of 49 and 82. Supplementation and follow-up periods ranged from 6 months to 12 years. Of the studies included, 30 were primary prevention trials and 20 were secondary prevention trials. Supplements included vitamins A, B6, B12, C, D, E, β-carotene, folic acid, and selenium. Methodologic quality of the trails averaged 4.3 on the Jadad scale (range 2–5). Outcomes included cardiovascular death, fatal or non-fatal myocardial infarction, angina, sudden cardiac death, fatal or non-fatal stroke, and transient ischemic attack. In the overall analysis there was no association between vitamin and antioxidant supplementation and risk of any major cardiovascular event. The same was true for subset analyses by type of prevention (primary vs. secondary), type of supplement (vitamin only, antioxidant only, and singly or in combination), methodologic quality (Jadad r 4 vs. 5), duration of treatment (o 5 vs. Z 5 years), funding source (pharmaceutical industry vs. independent organization), supplement supplier (pharmaceutical vs. non-pharmaceutical industry), control (placebo vs. no placebo), and number of trial participants (o 10,000 vs. Z 10,000). Low-dose vitamin B6 (3–25 mg/day) slightly decreased the risk of major cardiovascular events (relative risk [RR] 0.92, 95% CI 0.85–0.99) in eight trials, but the effect disappeared when the analysis was restricted to five high-quality trials. Vitamin B6 and vitamin E (any dose) were associated with lower risk of cardiovascular death (eight trials, RR 0.91, 95% CI 0.83–0.99) and myocardial infarction (12 trials, RR 0.77, 95% CI 0.65–0.91), respectively. Both of these effects disappeared, however, when the analysis
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was restricted to non-industry-supported trials. High-dose vitamin A (25,000 IU daily) increased the risk of major cardiovascular events in one trial (RR 1.41, 95% CI 1.15–1.73). It is clear, based on the results of this meta-analysis, that vitamin and antioxidant supplementation has no effect on major cardiovascular outcomes in men and women who are 49 to 82 years old and should not be recommended for this purpose. The discrepancy between the findings from clinical trials vs. preclinical and observational studies has at least two possible explanations.21 First, the cardiovascular effects of these substances depend on their interaction with numerous other nutrients in fresh fruits and vegetables and lose their beneficial effects when administered in isolation. Second, for these supplements to be helpful they must be administered at the earliest stages of atherogenesis (say, prior to the age of 40 years). Importantly, vitamin and antioxidant supplementation may not be without risk. Although this systematic review did not find an increase risk in mortality, other studies have. In a Cochrane review of 78 randomized trials (N ¼ 296,707), an increase in mortality was found in subgroup analyses of high-quality trials for vitamin E and β-carotene.22 The authors theorized that enhanced antioxidation may interfere with critical defense mechanisms, such as apoptosis, phagocytosis, and detoxification.
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placebo controlled study. Br Med J. 2001;322(7279):134–137. He Z, Chen R, Zhou Y, et al. Treatment for premenstrual syndrome with Vitex agnus castus: a prospective, randomized, multi-center placebo controlled study in China. Maturitas. 2009;63(1):99–103. Ma L, Lin S, Chen R, Zhang Y, Chen F, Wang X. Evaluating therapeutic effect in symptoms of moderate-to-severe premenstrual syndrome with Vitex agnus castus (BNO 1095) in Chinese women. Aust N Z J Obstet Gynaecol. 2010;50 (2):189–193. Diaz MN, Frei B, Vita JA, Keaney JF Jr.. Antioxidants and atherosclerotic heart disease. N Engl J Med. 1997;337:408–416. Farbstein D, Kozak-Blickstein A, Levy AP. Antioxidant vitamins and their use in preventing cardiovascular disease. Molecules. 2010;15:8098–8110. Dauchet L, Amouyel P, Dallongeville J. Fruits, vegetables and coronary heart disease. Nat Rev Cardiol. 2009;6: 599–608. Bhupathiraju SN, Tucker KL. Coronary heart disease prevention: nutrients, foods, and dietary patterns. Clin Chim Acta. 2011;412:1493–1514. Myung SK, Ju W, Cho B, et al. Korean Meta-Analysis Study Group. Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. Br Med J. 2013;346:f10. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2012;3.
Richard Glickman-Simon, MD, is a family physician, Integrative Medicine Editor of DynaMed, and Assistant Professor of Public Health and Community Medicine at Tufts University School of Medicine in Boston, MA, and a contributor to DynaMed in Ipswich, MA. Brian S. Alper, MD, MPSH, FAAFP, is a family physician, Editor-in-Chief of DynaMed and Medical Director for EBSCO Publishing, Inc.
Evidence-Based Integrative Medicine Updates