Clinical Therapeutics/Volume 36, Number 12, 2014
Complementary and Alternative Medical Therapies in Multiple Sclerosis—The American Academy of Neurology Guidelines: A Commentary Vijayshree Yadav, MBBS, MCR1; and Pushpa Narayanaswami, MBBS, DM, FAAN2 1
MS Center at OHSU, Department of Neurology, Oregon Health & Science University; Department of Neurology, Veterans Affairs Medical Center, Portland, Oregon; and 2Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
ABSTRACT Background: Complementary and alternative medicine (CAM) use in individuals with multiple sclerosis (MS) is common, but its use has been limited by a lack of evidence-based guidance. Methods: In March 2014, the American Academy of Neurology published the most comprehensive literature review and evidence-based practice guidelines for CAM use in MS. The guideline author panel reviewed and classiﬁed articles according to the American Academy of Neurology therapeutic scheme, and recommendations were linked to the evidence strength. Findings: Level A recommendations were found for oral cannabis extract effectiveness in the short term for spasticity-related symptoms and pain and ineffectiveness of ginkgo biloba for cognitive function improvement in MS. Key level B recommendations included: Oral cannabis extract or a synthetic cannabis constituent, tetrahydrocannabinol (THC) is probably ineffective for objective spasticity improvement in the short term; Nabiximols oromucosal cannabinoid spray is probably effective for spasticity symptoms, pain, and urinary frequency, but probably ineffective for objective spasticity outcomes and bladder incontinence; Magnetic therapy is probably effective for fatigue reduction in MS; A low-fat diet with ﬁsh oil supplementation is probably ineffective for MS-related relapses, disability, fatigue, magnetic resonance Accepted for publication October 10, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.10.011 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.
imaging lesions, and quality of life. Several Level C recommendations were made. These included possible effectiveness of gingko biloba for fatigue; possible effectiveness of reﬂexology for MS-related paresthesias; possible ineffectiveness of the Cari Loder regimen for MS-related disability, symptoms, depression, and fatigue; and bee sting therapy for MS relapses, disability, fatigue, magnetic resonance imaging outcomes, and health-related quality of life. Implications: Despite the availability of studies evaluating the effects of oral cannabis in MS, the use of these formulations in United States may be limited due to a lack of standardized, commercial US Food and Drug Administration–regulated preparations. Additionally, signiﬁcant concern about prominent central nervous system–related adverse effects with cannabis was emphasized in the review. (Clin Ther. 2014;36:1972–1978) & 2014 Elsevier HS Journals, Inc. All rights reserved.
INTRODUCTION Multiple sclerosis (MS) is a chronic, disabling neurologic illness that affects 2.5 million individuals worldwide and 4400,000 Americans.1,2 MS is usually classiﬁed into 3 different types: relapsing-remitting MS (RRMS), secondary progressive MS with or without relapses, or primary progressive MS. In the past 20 years, signiﬁcant progress in the treatment of Scan the QR Code with your phone to obtain FREE ACCESS to the articles featured in the Clinical Therapeutics topical updates or text GS2C65 to 64842. To scan QR Codes your phone must have a QR Code reader installed.
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V. Yadav and P. Narayanaswami relapsing forms of MS has been made. More than 10 disease-modifying therapies are now approved by the US Food and Drug Administration (FDA). Although disease-modifying therapies availability has remarkably changed how neurologists treat relapsing forms of MS, a signiﬁcant gap in the overall care of MS exists due to inadequate treatment options for progressive forms of MS and symptom management. These inadequately treated and disabling symptoms of MS include pain, stiffness, spasms, cognitive impairment, fatigue, depression, bladder and bowel dysfunction, imbalance, tremor, and insomnia. The resulting poor quality of life (QOL) also remains a concern for many patients with MS. It is reported that individuals with MS try to use many treatment modalities that are normally not prescribed by their conventional MS care providers. Therapies that individuals with MS use in conjunction with or in lieu of their conventional treatments are called complementary and alternative medical (CAM) therapies. The prevalence of CAM therapy use in MS is reported in the literature to vary from 33% to 80%.3,4 CAM therapies have been classiﬁed into different categories such as mind-body medicine, biologically based practices, manipulative and body-based practices, and energy medicine.5 Examples of CAM therapies are shown in the Table. Recognizing the signiﬁcance of the use of CAM therapies by individuals with MS and the need for evidence-based practice guidance, the American
Academy of Neurology published guidelines for their use in March 2014.6 This guideline is the ﬁrst and the most comprehensive evidence-based review of the CAM therapies for MS. The guideline addressed 3 key questions relevant to individuals with MS: 1) Do CAM therapies reduce speciﬁc symptoms and prevent relapses or disability? 2) Can CAM therapies use worsen MS or cause serious adverse effects (AEs)? 3) Can CAM therapy use interfere with MS diseasemodifying therapies? The guideline included studies pertaining to these questions published from 1970 until September 2013. The guideline development panel’s initial search for the relevant studies included 291 articles, 115 of which were subsequently found relevant to the questions asked. These studies then underwent data extraction, and their ﬁndings resulted in the published guideline. The individual articles included in the guideline development were classiﬁed as class I, II, III, or IV according to the American Academy of Neurology therapeutic scheme, and recommendations were then linked to the evidence strength.7 Class I studies are considered to have the least risk of bias and therefore provide the highest quality of evidence. This review articles highlights the key ﬁndings from the guidelines.
Ginkgo Biloba Ginkgo biloba is a Chinese herb that may improve cognitive function and memory in patients with Alzheimer’s disease and cerebral insufﬁciency.8–10
Table. Examples of CAM therapies. Category of CAM Mind-body medicine Biologically based practice
Manipulative and bodybased practice Energy medicine Other
Examples of CAM Therapies Biofeedback, hypnosis, music therapy, mindfulness training Herbs: Padma 28, ginkgo biloba, cannabis Dietary supplements: low-fat diet, omega-3 fatty acid, linoleic acid, creatine, acetyl-L-carnitine, inosine, Cari Loder regimen, threonine, glucosamine, lowdose naltrexone Others: bee venom, transdermal histamine with caffeine, hyperbaric oxygen Hippotherapy, reﬂexology, yoga, massage therapy, acupuncture, progressive muscle relaxation Magnetic therapy, neural therapy Naturopathic medicine
CAM ¼ complementary and alternative medicine.
Clinical Therapeutics Gingko biloba is of interest because MS-related cognitive impairment affects a signiﬁcant population of MS patients, for which currently there are no effective therapies. The guideline reviewed 4 studies evaluating ginkgo biloba in MS. Two of these studies were rated class I,11,12 and 2 were rated class II.13,14 The symptoms evaluated in these studies included cognitive function and fatigue. Based on 2 class I studies of 12-week duration evaluating cognitive function in MS (N = 39 and N = 121, respectively), there was no signiﬁcant improvement in cognitive function. Ginkgo biloba was established to be ineffective for cognition in MS.11,12 One class II study of 4-week duration that involved 22 MS subjects suggests possible effectiveness of ginkgo biloba for fatigue in MS.13 Ginkgo biloba appeared to have no signiﬁcant adverse events in the studies reviewed in this guideline.
Cannabis The cannabis plant is a source of compounds called cannabinoids, which include psychoactive delta-9tetrahydrocannabinol and nonpsychoactive cannabidiol. The studies involving cannabis used different formulations of cannabis, and, hence, the evidence was described based on the type of cannabis used. The different forms of cannabis included oral cannabis extract (OCE), which contains tetrahydrocannabinol (THC) and cannabidiol, synthetic THC, oromucosal cannabinoid spray (nabiximols*), and smoked cannabis. The guideline reviewed 19 studies related to cannabis,6 of which 6 were rated class I, 4 were rated class II, and 9 were rated class III by the guideline authors. Studies involving OCE and synthetic THC† included all types of MS. There were 3 class I,15–17 2 class II,18,19 and 4 class III20–23 studies that evaluated the effects of OCE and synthetic THC compared with placebo on a variety of MS symptoms. MS symptoms (measured by patients’ reported standardized questionnaires) or signs (measured by physicians/researchers using standardized scales) evaluated in these studies varied from study to study and included spasticity, stiffness, pain, spasms, disability, tremor, bladder symptoms, and sleep. Based on class I *
Trademark: Sativexs (Salisbury, Wiltshire, United Kingdom). Trademark: Marinols (Solvay Pharmaceuticals, Marietta, GA).
studies that ranged between 12 and 15 weeks, OCE and THC were established as effective for reducing patient-reported spasticity symptoms and pain but were found to be probably ineffective for reducing physician-measured spasticity outcomes.15,17 Based on 1 class II study, OCE and THC were found to be possibly effective for reducing patient-reported spasticity symptoms and physician-documented spasticity measures over a 12-month period.18 OCE and THC were found to be probably ineffective for reducing symptoms of MS-related tremor, and there were insufﬁcient data to support or refute the use of OCE/oral THC for bladder symptoms.15,19 Oromucosal cannabinoid spray (nabiximol) is a special formulation of cannabis that is not FDA approved or available in the United States at present but is available in Canada and few other countries. The review included 3 class I, 2 class II, and 3 class III studies using oromucosal cannabinoid spray in MS. The symptoms addressed in these studies included spasticity, spasms, bladder problems, tremor, pain, mood, disability, fatigue, and sleep. The evidence from these studies shows probable effectiveness of cannabinoid spray for improving patient-reported spasticity symptoms over 6 weeks (1 class I study),24 central neuropathic pain over 5 weeks (1 class I study),25 and daily bladder frequency over 10 weeks (1 class I study).26 The oromucosal cannabinoid spray was probably ineffective for improving objective spasticity measured over 6 weeks (1 class I study)24 or bladder incontinence over 10 weeks (1 class I study).26 The oromucosal cannabinoid spray was possibly ineffective for reducing MS-related tremor over a 15-week period.27 Additionally, the current data appear insufﬁcient to support or refute oromucosal cannabinoid spray use for overall bladder symptoms, anxiety symptoms, sleep problems, or symptoms related to cognition, QOL, or fatigue. Studies evaluating smoked cannabis for MS symptoms such as spasticity, pain, balance, posture, and cognition were inconclusive with regard to beneﬁt.28,29 Although cannabis was generally well tolerated in the studies reviewed, the primary concern with its use in individuals with MS involves AEs of the central nervous system (eg, dizziness, somnolence, drowsiness, lightheadedness, memory disturbance, and poor concentration).6 The guideline found increased AEs in the subjects receiving cannabinoids than in the placebo groups. Dizziness was the most common
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V. Yadav and P. Narayanaswami AE, reported by 15% to 50% of subjects. The cannabinoids’ well-known psychoactive properties increase the risk of psychopathological and neurocognitive AEs. This can be especially concerning in individuals with MS who may be more susceptible to these AEs due to underlying disorders. Sativex oromucosal cannabinoid spray is not approved by the FDA and is therefore not available in the United States. The guideline authors suggested careful consideration of the applicability of the conclusions regarding the use of various formulations of cannabis because the clinical trials used standardized OCEs, which are not commercially available in the United States. Hence, extrapolating the conclusions to nonstandardized forms available in the United States may not be appropriate in terms of efﬁcacy or safety. Additionally, medical marijuana is not legally available in all US states, and, hence, the relevant laws should be carefully considered by the patients and discussed in depth with their clinicians.
Cari Loder Regimen The idea of a regimen of lofepramine plus phenylalanine with vitamin B12 as treatment for MS, also known as the Cari Loder regimen, was ﬁrst proposed by Cari Loder in a 1996 book.36 The theory behind this regimen is that reduced norepinephrine levels may play a role in MS35 and that lofepramine (which limits uptake of norepinephrine) and L-phenylalanine (a precursor of norepinephrine) increase norepinephrine levels.36 The guideline included one 24-week long, class II, randomized, controlled trial (RCT) that involved 138 MS subjects. The active regimen included twice-daily oral intake of 10 mg lofepramine and 500 mg L-phenylalanine, with weekly intramuscular injections of 1 mg vitamin B12. The placebo arm consisted of placebo pills and weekly intramuscular injections of 1 mg vitamin B12.37 The active intervention was ineffective in reducing MS-related disability, symptoms, depression, and fatigue. AEs reported in the study included constipation, dry mouth, nausea, and insomnia.
Low-Fat Diet with Fish Oil Supplementation The use of a low-fat diet supplemented with omega-3 fatty acids was introduced by Dr. Roy Swank30,31 as a treatment for MS in 1948. The diet was based on the (unproven) hypothesis that MS was the result of a modern diet that was high in saturated fat. The guideline review included 3 studies, with one each from class I,32 II,33 and III.34 The class I study was 24 months long and included 92 subjects with RRMS, and its active intervention consisted of daily oral intake of omega-3 fatty acids (1350 mg of eicosapentaenoic acid and 850 mg of docosahexaenoic acid).32 This study did not show any beneﬁcial effect on the cumulative number of lesions seen on gadolinium-enhanced brain magnetic resonance imaging (MRI) at 6 months, MS relapse rates at 6 and 24 months, disability progression, fatigue, or QOL. This study, however, was limited by a small sample size, so a possible moderate beneﬁt of the intervention cannot be excluded. The other 2 studies did not show improvements in the active intervention (omega-3 supplement and diet) in health-related QOL (HRQOL), MS relapse rate, or disability. Therefore, based on these studies, a low-fat diet with omega-3 fatty acid was probably ineffective for relapses, disability, fatigue, the number of lesions seen on MRI, or QOL. Although a low-fat diet may yield general health beneﬁts, these outcomes were not evaluated in the MS populations in these studies.
Bee Sting Therapy Bee venom therapy involves is the use of live bee stings or injected bee venom. Interest in the use of bee sting therapy to relieve MS-related symptoms and disability came about because compounds in the bee venom are thought to have anti-inﬂammatory properties.38,39 One class II crossover study40 of bee venom involving 26 subjects with MS was included in the guideline. The active intervention involved getting 20 stings from live bees 3 times weekly for 24 weeks. The study outcomes included the effect of the active intervention versus placebo on the new lesions seen on gadolinium-enhanced MRI or the total lesion volume seen on the T2 weighted MRI, the number of MS relapses, and MS-related disability, fatigue, and QOL. The study did not ﬁnd signiﬁcant effects of the bee sting therapy on any of these outcomes. Therefore, based on this 1 class II study, bee sting therapy was possibly ineffective for reducing MS-related relapses, disability, fatigue, total lesion burden seen on MRI, new lesion volume seen on gadolinium-enhanced MRI, or HRQOL. AEs related to the bee sting included tenderness, swelling, and redness at the sting sites. Four subjects reported itching, and 5 subjects reported ﬂulike symptoms.
Reflexology Reﬂexology is the method of manually stimulating reﬂex points on the feet with the notion that stimulating corresponding pressure points will increase circulation and energy to ailing organ systems. Interest in reﬂexology has come about in part because of positive results reported for somatic symptoms in a previous RCT of reﬂexology for another indication.41 The guideline evaluated 4 RCTs (1 class I,42 2 class II,43,44 and 1 class III45). These studies evaluated effects of reﬂexology on MS-related pain, HRQOL, disability, spasticity, fatigue, cognition, bowel/bladder function, depression, anxiety, or insomnia. Of these 4 studies, 1 class II RCT that included 71 subjects with MS found signiﬁcantly greater reductions in paresthesia with 11 weekly reﬂexology treatments plus calf massage compared with calf massage alone.43 The other 3 studies did not show any effects of reﬂexology on the MS-related outcomes. Therefore, based on the 1 class II study, reﬂexology was possibly effective for reducing paresthesia associated with MS. Reﬂexology appeared to cause no signiﬁcant safety concern in these studies.
Magnetic Therapy Interest in the use of magnetic therapy in MS came from research showing that electromagnetic ﬁelds can normalize visual evoked potentials46 and affect spasticity and bladder function.47 The guideline evaluated 1 class I study,48 2 class II studies,49,50 and 3 class III studies51–53 for the use of magnetic therapy in MS. The various modalities for providing magnetic therapy included the use of a metal mat, wristwatch-size magnetic pulsing devices, and a magnetic-ﬁeld mattress and pillow. The class I study, a 12-week RCT of 41 subjects with RRMS, evaluated the effect on fatigue of low-frequency, pulsed electromagnetic ﬁeld therapy using a metal mat (measured by a modiﬁed fatigue impact score). The subjects lay on the metal mat for 8 minutes twice daily for 12 weeks. The study showed that subjects who received the active intervention had signiﬁcantly less fatigue than those who received placebo. No change in depression or disability measurements was seen in the study participants. The other magnetic therapy studies evaluated disability, spasticity, fatigue, and self-assessment of activities of daily living, but did not show any evidence of magnetic therapy effectiveness. Therefore, based on evidence from these studies, magnetic therapy was found to be probably effective in reducing MS fatigue, but probably ineffective for reducing depression in RRMS.
Magnetic therapy was generally well-tolerated in these studies.
Other CAM Therapies The guidelines reviewed evidence related to additional CAM therapies, including biofeedback, music therapy, mindfulness-based training, hypnosis, Padma 28, linoleic acid, creatine, acetyl-L-carnitine, inosine, threonine, glucosamine sulfate, low-dose naltrexone, transdermal histamine with caffeine, hyperbaric oxygen, hippotherapy, yoga, massage therapy, acupuncture, progressive muscle relaxation therapy, neural therapy, and naturopathic medicine, but found insufﬁcient evidence to support any speciﬁc practice recommendation.
DISCUSSION Based on my personal clinical experience with CAM use in the MS population, I believe that this guideline with evidence-based information will greatly beneﬁt and educate the individuals with MS, MS care providers, and related stakeholders. Even though the current guideline does not provide enough evidence at the present time regarding the use of certain CAM therapies such as yoga, massage therapy, meditation, and mindfulness-based relaxation techniques, it is likely that these therapies will remain popular among the individuals with MS who use these therapies for balance, muscle strengthening, stiffness, pain, stress, and mood dysfunction. I believe that as long as such therapies are used under supervision and safe conditions, are not cost prohibitive, and patients ﬁnd them beneﬁcial, their use can be a reasonable complementary approach to MS care. At present, most CAM therapies are not FDA regulated; thus, the quality of individual CAM therapy may vary tremendously. At present, the interaction of various CAM therapies with disease-modifying therapies for MS remains unknown, and this should be kept in mind when discussing the use of CAM therapies with patients. Due to tremendous public interest in CAM therapies, further research should continue to promote rational therapies and sound decision making by all the stakeholders.
ACKNOWLEDGMENTS Vijayshree Yadav and Pushpa Narayanaswami contributed to the study concept and design, data collection, data interpretation, writing/revising the manuscript, critical revision of the manuscript for important intellectual content, and study supervision.
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CONFLICTS OF INTEREST V. Yadav serves as a section editor for Current Neurology and Neuroscience Reports; served as consultant for Bayer Healthcare Pharmaceutical, Teva Neurosciences, and Biogen Idec; is on the speakers’ bureau of Novartis; and receives research support from the McDougall Foundation, National Multiple Sclerosis Society Foundation, Nancy Davis Center Without Walls Foundation, and Biogen Idec. The authors have indicated that they have no other conﬂicts of interest regarding the content of this article.
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Address correspondence to: Vijayshree Yadav, MBBS, MCR, Department of Neurology, Oregon Health & Science University, L 226 SW Sam Jackson Park Road, Portland, OR 97239. E-mail: [email protected]
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