Integrative therapies for multiple sclerosis

Disease-a-Month 59 (2013) 290–301

Contents lists available at SciVerse ScienceDirect

Disease-a-Month journal homepage: www.elsevier.com/locate/disamonth

Integrative therapies for multiple sclerosis Geeta Maker-Clark, MD, Smita Patel, DO, FAASM

1. Introduction People afflicted with Multiple Sclerosis (MS) commonly seek out complementary and alternative treatments in addition to their conventional therapy.1,2 The integration of both types of treatment is a very promising strategy and is the one that requires further study. While the cause of MS has yet to be fully elucidated, the most compelling theories engage many variable possible risk factors and etiologies for MS. These include diet, genetics, geography, autoimmunity, and viral infection. With this multifactorial picture, it behooves us as clinicians to consider all possible useful treatments for MS patients. As patients are already looking outside of what conventional medicine offers, familiarizing ourselves with what has been studied for MS only will help us provide more complete and thorough care of our patients. This chapter includes those therapies, for which some research on areas such as diet and supplements, as well as healing modalities, that have been of benefit to patients but do not have evidence-based research to support their use. Many alternative therapies are very useful as adjuncts to conventional care and can offer stress reduction, mind– body connection, and physical relief from pain and symptoms.

2. Dietary interventions While study in the field of nutrition for MS is lacking, there is some consensus around healthful dietary measures that can improve well-being of a person with MS. While diet does not seem to prevent exacerbation or promote regression, there are significant implications for overall health. The most commonly accepted view is that multiple sclerosis is an autoimmune disorder that ultimately causes inflammation in the CNS. It would thus follow that a diet that is anti-inflammatory in nature will be of benefit. The anti-inflammatory diet is one that is based on applied nutritional science and proposes a plant-based diet that is high in omega-3 fats, vegetables, fruits, beans and legumes, and whole grains and low in processed and refined foods, dairy, and other animal products. This diet has been adopted and used widely for patients with many types of inflammatory conditions and postulates that excessive ingestion of animal products like beef, eggs, and dairy, as seen in a typical American diet, produces large amounts of the omega-6 fatty acid, arachidonic acid. As arachidonic acid is more readily converted to inflammatory compounds, excess levels of AA have been associated with increased inflammation and reduced anti-inflammatory effects of omega-3 fatty acids.3 Processed foods 0011-5029/$ - see front matter & 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.disamonth.2013.03.017

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that contain hydrogenated oils, high fructose corn syrup, and highly refined grains have high levels of omega-6 fatty acids, as well as contribute to the increased sugar content and glycemic index of foods. In the body, chemical reactions between these sugars and protein produce proinflammatory compounds called AGEs (advanced glycation end products), which expectedly increase inflammation as well.3 The anti-inflammatory diet has not been well studied as a treatment, or adjunct for patients with MS, but is being increasingly utilized for patients with chronic inflammatory disease processes. A similar version of this diet has been studied and is quite controversial in the field of neurology: the Swank diet. The Swank diet was formulated by the neurologist Dr. Roy Swank in the late 1940s and deserves mention. It has received mixed reception in the medical community over the years, although it is still used widely by patients with MS. The diet is based on the idea that high levels of saturated fat in the diet contribute to increased platelet aggregation, which promotes demyelination of neurons via direct cell death, as well as increased permeability of the blood brain barrier, and microembolization.4 An autoimmune etiology for the disease prevails in the medical community, and thus, there is a disagreement in this treatment for MS. Dr. Swank has pursued several other studies, which he cites as evidence for his disease theory, including observing that high-fat meals cause blood cells to clump and slow circulation.5 The Swank diet shares many similar aspects to the anti-inflammatory diet and includes 10 g or less of saturated fat daily, 40–50 g of PUFA, 1 teaspoon of cod liver oil, and 3 or more servings of fish per week. It goes further by banning all dairy, gluten, legumes, and saturated fat from animal sources.6 Some of the difficulty in evaluation of the treatments of MS stem from its highly variable course, which can range from mild to severe symptoms alternating with periods of remission that may be short or prolonged. The Swank diet, while often cited by MS patients as helpful, does not have any controlled studies. Dr. Swank has argued that a double-blind RCT cannot be done that includes all of the eating habits of a patient for 35 years. His early studies in 1970s followed 150 patients with varying levels of disability. Patients were put on high-fat and low-fat diets and asked to keep food diaries; all lapses were noted. He compared his Swank diet patients to patients enrolled in a Mayo Clinic study that were on a high-fat intake diet. According to Swank, 50% of the Mayo Clinic patients were unable to work or walk after 10 years, whereas only 25% of the dieting patients were similarly disabled.4 The Cochrane Collaboration group looked at dietary interventions for multiple sclerosis and concluded that more research is required to assess the effectiveness of diets and dietary supplements in MS. The recommendation called for a better well-designed parallel group, double-blind trials of diets and dietary supplements on people with MS, carried out for sufficient time periods. Outcome measures that include adverse events, a sensitive comprehensive, reliable measure of patient disability over time, and the doses of the supplements should also be evaluated. Consumers will welcome the evidence gained from these trials, as will physicians.7

3. PUFA supplementation There is some preclinical evidence that a diet low in saturated fats and supplemented by omega3 (from fatty fishes, cod liver oil, or flaxseed oil) and omega-6 (fatty acids from sunflower or safflower seed oil and possibly evening primrose oil) may have some benefit for people with MS.8 3.1. Omega-3 Research about dietary fats has focused predominately on polyunsaturated fatty acid (PUFA). PUFAs have already been extensively studied, specifically omega-3 fatty acids, for their benefits in lowering cholesterol level and heart disease risk. There have also been clinical trials related to omega-3 supplementation and some evidence pointing to benefits for relapsing-remitting MS. Omega-3 fatty acids are ALA (alpha linoleic acid), DHA (docosahexanoic acid), and EPA (eicosapentaenoic acid). They are obtained primarily through the consumption of fish or from fish

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oil supplements. Fish like salmon, mackerel, herring, sardines, tuna, and cod that live in cold water are rich sources of omega-3s. Uncontrolled studies of PUFAs in people with MS have been reported, and clinical improvement was noted in many. No worsening of MS or other serious side effects was noted.8,9–14 There have been 5 prospective randomized controlled clinical trials (RCCT) of PUFAs among people with relapsing-remitting (RR) MS.15–19 Two of these involved supplementation with EPA and DHA (omega-3) in fish oil as an intervention for MS.18,19 The larger study, with over 300 patients, used 10-g fish oil supplementation daily as the intervention and olive oil as a placebo.18 Although no statistically significant difference was observed, there was a trend favoring the omega-3 group, with fewer people progressing one point on the Disability Status Scale (DSS), a scale used to measure disability change in clinical trials. Other statistically non-significant trends favoring the treatment group were observed. Although the findings in the fish oil study were not statistically significant, it is interesting to note that supplementation with fish oil provided an absolute risk reduction of 10% and a relative risk reduction of 18% of progressing one point on the DSS. This is similar to the risk reductions reported for standard medical therapies.8,20 The study, with only 312 people however, is possibly underpowered to detect a 10% absolute risk reduction of disability progression.20 Larger studies are needed to evaluate whether fish oil supplementation truly has definite therapeutic effect in MS. Another small randomized study investigated fish oil and other dietary fat changes as a treatment among users of approved MS conventional therapies.19 Patients who had been using FDA-approved therapies for at least 2 months were assigned to receive either six fish oil capsules (1-g capsules) along with instructions to maintain a very-low-fat diet (o15% of calories from fat) or six olive oil capsules (1-g capsules) along with instructions to maintain a low-fat diet (o30% of calories from fat). The primary outcome measure was the Physical Component Scale (PCS) of the Short Form Health Survey Questionnaire (SF-36). The study reported a trend on the PCS favoring the fish oil group that was not statistically significant at the end of the year-long study. EDSS scores worsened in the olive oil group and improved in the fish oil group, which the authors described as a ‘weak trend.’8,19 Since there is no conclusive evidence to demonstrate whether omega-3 PUFA supplementation has a therapeutic benefit for people with MS, a standard dosage is not known. In the clinical studies using fish oil, the combined daily intake of EPA and DHA was 0.9–2.85 g.9,18,19 Omega-3 fatty acids can be obtained from the diet; however, an intake of this level of EPA and DHA entirely from the diet may be impractical as it requires up to one-and-a-half servings of salmon or other fish per day as well as raises concerns about contaminants, such as mercury.8 It has been determined through studies of other conditions that a total daily intake of 3 g or less of EPA and DHA is well tolerated.21 3.2. Contraindications and safety Contraindications for omega-3 fatty acids are few. People with allergy or hypersensitivity to fish should avoid fish oil or omega-3 fatty acid products derived from fish. Fish oil may have an anticoagulant effect, although there is little evidence of significant bleeding risk at lower doses. Still they should be used with caution by people who take anti-platelet or anticoagulant medications, have bleeding disorders, or are undergoing surgical procedures.22 High doses ( 46 g combined daily intake of EPA and DHA) may reduce the efficacy of insulin, and thus, diabetic patients should be more cautious with its use. The Food and Drug Administration has stated that it is generally safe to consume fish oil supplements when the combined daily intake of EPA and DHA is o3 g.6–8 As a result, fish oils are classified as “Generally Regarded as Safe.” The most common side effects are heartburn, halitosis, nosebleeds when consumed at doses above 6 g/day, and fishy taste after consumption.22 3.3. PUFA-omega-6 fatty acids Omega-6 fatty acids have also been looked at for MS. These include linoleic acid, which is an essential fatty acid, and gamma-linolenic acid (GLA) and arachidonic acid. There are multiple

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sources of omega-6 fatty acids. Most studies of omega-6 PUFA supplementation in MS have used sunflower seed oil, which contains relatively high concentration (about 70%)8 of LA. Other LA sources include soybean oil, corn oil, walnut oil, wheat germ oil, grapeseed oil, safflower seed oil, and flaxseed oil. GLA may be found in relatively high concentrations in evening primrose oil (EPO), borage seed oil, blackcurrant seed oil, and spirulina (blue–green algae).8,23,24 Three small prospective clinical studies of LA (linoleic acid) supplementation in people with MS have been undertaken.15–17 The trials used similar doses of LA, ranging from 17 g to 23 g daily as sunflower oil, while oleic acid, as olive oil, was used as a placebo. The duration of each trial was between 24 and 30 months, and between 58 and 96 people were involved in each, most of whom had relapsing-remitting MS. Results showed no effect on disability progression or exacerbation frequency in any of the three studies.15–17 Two of the three LA studies reported statistically significant reductions in exacerbation severity and duration.15 In one study, the P values were reported as o0.025 for reduction in duration of exacerbations and o0.01 for reduction in severity of exacerbations.17 A grading system was used for measuring exacerbation severity using point amounts based on specific symptoms. The use of a grading system that was of limited value and has poor reporting makes it difficult to evaluate the data used to support conclusions that LA supplementation decreased MS exacerbation severity or duration.8 These studies were later pooled and reanalyzed.25 The reanalysis concluded that patients with little or no disability at the start of the trial (DSS 2 or less) had a significantly smaller increase in disability than did those in the control group (P ¼ 0.05).8,25 Dosing in these studies of RRMS was in the form of sunflower seed oil, between 17 and 23 g daily.15–17 In the MS clinical trials, evening primrose oil was given at doses that provided 0.34–0.36 g of GLA daily.15,16 Doses up to 2.8 g of GLA daily are well tolerated.26 3.4. Contraindications and safety Contraindications for omega-6 fatty acid supplements are considered to be few. Similar to omega-3 fatty acids, they may prolong bleeding7 and, as a result, should be used with caution by people receiving anticoagulant or anti-platelet agents, who have bleeding disorders or are undergoing surgery. EPO may decrease seizure threshold and provoke seizures when used in patients who have epilepsy or schizophrenia.21 Borage seed oil should be avoided in patients who have liver disease or take hepatotoxic medications as it may contain pyrrolizidine alkaloids (PAs),21 which have possible multiple toxic effects, including hepatotoxicity. PA-free borage seed oil is commercially available. Preliminary studies also suggest that borage oil has a teratogenic effect and that its prostaglandin E agonist action may cause premature labor.27 The long-term safety of supplementation with LA or GLA has not been studied. In the short term, omega-6 fatty acid supplements are generally well tolerated. The safety of blackcurrant seed oil has not been well studied. Some spirulina products contain contaminants including heavy metals, microbes, and microcystins.21 Microcystin contamination can cause hepatotoxicity, renal failure, and neurotoxicity. Products should be certified free from contamination. Supplementation with LA, GLA, and other PUFAs may cause vitamin E deficiency, and vitamin E supplementation may be necessary (0.6–0.9 IU/g of PUFA).8 The Cochrane Collaboration reviewed this topic as well and concluded that dietary supplementation with PUFAs seems to have no major effect on disease progression, the main clinical outcome in MS, and it does not substantially affect the risk of clinical relapses over 2 years. However, the data available are insufficient to assess the real benefit or harm that might result from PUFA supplementation.7

4. Vitamin D The characteristic geographic clustering of MS is particularly interesting and has spurred a multitude of studies around vitamin D and its relationship to the disease. Individuals who grow up in higher latitudes show an increased susceptibility to MS, occurrence ratios being 1:2000, as

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opposed to people who live in tropical latitudes until age 15 and rarely develop the disease, with an occurrence ratio of 1:10,000.28 A recent study that utilized geospatial analysis also found a significant increase in MS risk in areas with low-level UV radiation.29 ○ More recent literature suggests vitamin D status can be an influential factor affecting prevalence and severity of diseases considered to be autoimmune. For instance, in the cases of psoriasis, inflammatory bowel disease, vitamin D has been shown to improve symptoms. RA and SLE are also associated with deficiency of vitamin D.30,31 Vitamin D is obtained primarily through skin synthesis, followed by dietary intake. Egg yolk, mushrooms, fish, and enriched foods like milk, juice, and bread are all sources of vitamin D. It is the exposure of UVB irradiation from sunlight that catalyzes vitamin D3 synthesis, which is then hydroxylated in the liver to 25-hydroxyvitamin D and further hydroxylated to its active form 1,25-dihydroxyvitamin D within the kidney. Vitamin D receptors are found not only in the epithelial cells but also in the myocytes, osteoblasts, APC, cortical neurons and glia, cerebellum, and pancreatic islet cells, and thus, it acts more like a hormone in nature than a vitamin.30 Only a few clinical trials of vitamin D therapy in individuals with MS have been completed, and most report data from unblinded, uncontrolled study designs. In a recent open-label safety study, 12 individuals with MS and active gadolinium-enhancing lesions received dose escalation therapy with vitamin D3 (cholecalciferol) over 28 weeks.32 Serum concentrations of vitamin D averaging 155 ng/mL and a dosage of 40,000 IU/d of vitamin D3 for 5 weeks were found to be safe and without toxicity. Relapse rate and EDSS remained stable, and gadolinium-enhancing lesions were significantly decreased by the study's end. An extension of this study included 25 treated individuals and 25 controls. After receiving doses up to 40,000 IU/d of vitamin D3 over 4 months, the study participants received 10,000 IU/d for 3 months, then 8000 IU/d for the next 2 months, followed by a 1-month washout, for a mean dosage of 14,000 U/d for 52 weeks.33,34 The maximum mean serum vitamin D level approached 156 ng/mL without adverse effects, and fewer relapses were observed in the treatment group compared with the controls.33 ○ Two additional small open-label safety studies, one investigating α-hydroxy-D3 (alfacalcidol) supplementation in 5 individuals with MS for 6 months and the other studying 1,25dihydroxyvitamin D (calcitriol) in 15 individuals with MS for 12 months, reported good tolerability and mild hypercalcemia.34–36 It is important to note that no double-blinded randomized placebo-controlled trials of vitamin D for the treatment of MS have been completed. The Cochrane group only found 1 out of 16 RCTs on the use of vitamin D for the management of MS that met their criteria for review. The sample size comprised 49 participants (40 females, 9 males) with a mean age of 40.5 years. Of these participants, 45 had relapsing-remitting MS and 4 had secondary progressive MS. The baseline mean serum 25(OH)D was 78 nmol/L, and the mean score on the Expanded Disability Status Scale (EDSS) was 1.34 for both groups. The participants in the treatment group25 were seen every 6 weeks and received escalating vitamin D doses to assess tolerability, up to 40,000 IU/day over 28 weeks to raise serum 25(OH)D rapidly, followed by 10,000 IU/day (12 weeks) and were then down-titrated to 0 IU/day. Supplementation with tricalcium phosphate (1200 mg/day) was provided throughout the study period. Participants in the control group24 were allowed to take the regular dose of 4000 IU of vitamin D and “supplemental calcium if desired,” and were seen only at the start and completion of the study and at two intermediate time points. In the group treated with escalating doses of vitamin D compared to control, there was a reduction in annualized relapse rate as well as a higher proportion of relapse-free patients at the end of the study period. The escalating dose group also had a reduction of the mean EDSS scores and a lower proportion of patients with an increase in EDSS scores at the end of the study.37,38 Their conclusion was that the present consensus on the use of vitamin D in the management of MS is based on the hypothesis that vitamin D could potentially reduce the inflammatory activity

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responsible for relapses and the neuronal damage implicated in disability and thereby slow the progression of the disease. Although this one trial provided some evidence of the safety of high dosing regimens of vitamin D, there is a need for further randomized controlled trials, which can help provide insight into the real benefits of such dosing regimens in people with MS.37 A vitamin D level ≥30 ng/mL is commonly recommended,30 although the above literature suggests that there may be additional benefits at higher levels. Excess vitamin D causes increased intestinal calcium absorption and induction of bone resorption.34,39) As a result, toxic levels of vitamin D are associated with hypercalcemia, renal calcinosis, and renal injury. Clinically, toxicity may present with drowsiness, polyuria, polydipsia, anorexia, nausea, vomiting, constipation, hypertension, and ultimately coma.40 These symptoms have been mistaken for gastroenteritis, and hypercalciuria may be a more sensitive marker for toxicity than hypercalcemia.34,39 Excessive sunlight and adipose stores do not cause toxicity. Although a recent small study of individuals with MS reported no toxicity with high doses of vitamin D3,32 vitamin D intoxication in the form of hypercalcemia and hyperphosphatemia has been observed at levels of 150 ng/mL and oral vitamin D3 supplementation of 50,000 IU/d.30,39 Most literature on vitamin D emphasizes the evidence that supplementation of up to 10,000 IU/d of vitamin D3 for up to 5 months has not been associated with toxicity.30 Reference ranges for laboratory testing commonly reflect levels less than 100 ng/mL as safe based on existing data. Oral supplementation is widely recommended for deficiency and insufficiency, and cholecalciferol (vitamin D3) has been found to be superior to ergocalciferol (vitamin D2) in terms of potency and duration of action.40 However, prescription-strength vitamin D2 is also commonly recommended, particularly in severe deficiency.30 A variety of supplementation approaches have been recommended to raise serum vitamin D levels. However, authors in the field of MS do acknowledge that no optimal dose or level is yet known for benefits for people with MS. Emerging literature has strengthened the association between vitamin D and MS. This relationship may have important consequences for the risk of developing MS, as well as subsequent disease activity and severity. Given the strength of published studies thus far, it appears reasonable and safe for the practicing physician to consider screening for and treating vitamin D deficiency or insufficiency in patients with MS. A 25-hydroxyvitamin D level of 30–60 ng/mL appears safe and may have benefits for people with MS. It is important to consider alternative etiologies for vitamin D deficiency or insufficiency, including renal disease, hepatic disease, and malabsorption syndromes. Although the medical community has been greatly concerned about vitamin D intoxication, it is one of the rarest reported medical conditions and is usually not observed until 4 10.000 IU of vitamin D is ingested per day for 4 5 months.30 Blood 25(OH)D concentrations are usually 4 200 mg/L before manifestations of vitamin D intoxication are observed. There is no downside to increasing vitamin D intake by increasing the consumption of foods that naturally contain or are fortified with vitamin D.30

5. Other supplements Other supplements that are often recommended and have been studied are selenium, vitamin B6, and lipoic acid. 5.1. Vitamin B6 When a vitamin B6 deficiency is present, various symptoms can occur, most commonly depression. One theory proposed is that a deficiency of vitamin B6 may predispose individuals to develop MS. The theory is based on evidence of carbon-monoxide poisoning, which depletes vitamin B6 causing MS-like symptoms.41 In one study, a vitamin B6 analog was placed in vitro with various cell types. The researchers found that oxidative damage was reduced and improvements were seen in the MS model cells.42

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5.2. Selenium Selenium as an antioxidant has been studied in depth in relation to MS. There have been a number of studies that it explored the increased lipid peroxidation in patients with MS and the corresponding reduction in the antioxidant enzyme glutathione peroxidase (GSH-Px).43 Selenium is the mineral attached to one of the two forms of GSH-Px, and its function is to protect cell from free-radical damage. If there are low levels of GSH-Px, then the cell, in this case the myelin cell, forms more lipid peroxides leading to increased cellular damage. In studies that documented low levels of GSH-Px in patients with MS, selenium and other antioxidants increased the levels of GSH-Px in some of these patients.44 Some practitioners use 200 mcg daily for MS patients. 5.3. Lipoic acid The naturally occurring antioxidant lipoic acid (LA) was first described as an essential cofactor for the conversion of pyruvate to acetyl-CoA, a critical step in respiration. LA is now recognized as a compound that has many biological functions. Along with its reduced form dihydrolipoic acid (DHLA), LA reduces and recycles cellular antioxidants, such as glutathione, and chelates zinc, copper, and other transition metal ions in addition to heavy metals. LA can also act as a scavenger of reactive oxygen and nitrogen species. These diverse actions suggest that LA may be therapeutically effective in treating oxidative stress-associated diseases like MS. The only placebo-controlled clinical trial looking at the effects of oral racemic LA in MS subjects was a phase 1 clinical trial.45 The study included 37 subjects who were randomly assigned to four groups including placebo. The other three groups included subjects receiving 600 mg LA twice a day, 1200 mg LA once a day, or 1200 mg LA twice a day, given for 14 days. The study found LA to be generally well tolerated but found significant variation of peak plasma levels of LA among the subjects. Higher serum peak levels of LA were seen in subjects taking 1200-mg LA than those taking 600 mg. As would be expected with a short duration safety/dose finding investigation, subjects taking LA had no change in disability caused by MS as assessed by the Expanded Disability Status Score (EDSS). Longer duration trials with a larger number of MS subjects are needed to establish the ability of LA to decrease disease activity.

6. Botanicals 6.1. Withania somnifera (Ashwagandha) Ashwagandha, also known as the winter cherry, is the root of W. somnifera, family Solanaceae. Ashwagandha is a small shrub widely distributed throughout the drier regions of India. This herb has been considered ideal for treating multiple sclerosis due to the anti-inflammatory, antioxidant, anxiolytic, immunomodulatory, and rejuvenating properties of ashwagandha.46 The dosage for MS is 1–2 g of the whole herb in powdered form given two or three times a day. 6.2. Cannabis There have been a number of studies evaluating the use of cannabinoids for spasticity in MS. The major psychoactive constituent in cannabis is δ-9-tetrahydrocannabinol (THC). THC binds to cannabinoid receptors (CBs) in the CNS and acts as a partial agonist to both CB1 and CB2 receptors. In MS, the mechanism of action of THC is unknown, although there is limited evidence that it has anti-inflammatory and neuroprotective properties.47 Cannabidol (CBD) is a nonpsychoactive constituent in cannabis and is the major constituent in the plant. It is thought to decrease the clearance of THC by affecting liver metabolism. It binds to both CB1 and CB2 receptors in the CNS, with a higher affinity to the CB2 receptor.

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In a review of six controlled studies evaluating a combination of THC and CBD for spasticity in MS, it was found that THC–CBD was well tolerated and improved patient's self-reports of spasticity.48–54 Objective measures did not show significant improvement compared with placebo.48 Three of the six studies were placebo controlled; the sample size range was 12– 295 MS patients; the dose range was less than 10 mg/day to 120 mg/day; and the intervention range was 2–15 weeks.51,52,54 Only one study reported a significant improvement in Ashworth score,53 and none of the studies reported a significant improvement in timed walk. The authors noted that side effects were mild and reported in both treatment and placebo groups. The authors concluded that there was significant improvement in patient-reported spasticity combined and that the combination of THC and CBD was well tolerated in MS. They noted that objective measures of spasticity showed no significant improvement. Sativex is a commercial, cannabis-based medicine composed primarily of CBD and THC. It is sprayed under the tongue or on the cheeks. Sativex has had trials for overactive bladder, neuropathic pain, and spasticity in MS with promising results. A recent study with sixty-six subjects who received either Sativex or placebo was completed. The treatment group reported an average reduction in pain intensity of 2.7 points, as opposed to 1.4 in the placebo group.55,56 In another study, patients required fewer daily doses of Sativex and reported lower median pain scores the longer they took the drug. Authors also reported that the drug's administration was not associated with an increase in patient's use of other analgesics. Many patients reduced or ceased their use of pharmaceutical pain medications while taking Sativex.57 The National MS Society established a task force to examine the use of cannabis in MS and review what is currently known about its potential. This task force made specific recommendations on the research that still needs to be done to answer pressing questions about the potential effectiveness and safety of marijuana and its derivatives in treating MS.

7. Physical and complementary therapies A natural, drug-free way of self-treating is to use an all embracing approach covering every aspect of life and lifestyle—dietary interventions and supplements (as discussed above), exercise, thoughts, and emotions. It may also mean receiving some complementary treatments, such as acupuncture, massage, and reflexology, which may be a very beneficial adjunct to the conventional treatment for MS. 7.1. Exercise Though multiple sclerosis can be a challenging health condition both physically and psychologically, research has shown that a person's level of physical fitness, psychological disposition, and general quality of life can improve with regular physical activity, strength training, and flexibility exercises.58 Some of the functions of exercise are to keep muscles strong, keep joints mobile, and prevent stiffness and help with coordination and balance. Pilates, yoga, tai chi, and aquatic activities seem to be well tolerated in those with MS. Pilates can increase core stability, strength, fitness, and stamina. Yoga involves stretching and holding your body in various poses (asanas, in Sanskrit) while simultaneously controlling your breathing and quieting your mind. Yoga and the yogic breath has many advantages for those with MS since it can help the body's own self-healing mechanism, stills the mind, and improves fatigue and mood. In addition, yoga asanas have been shown to improve circulation, balance, relaxation, and flexibility and reduce muscle tension. A study on nine MS patients who did 6 months of yoga or aerobic exercise showed significant improvement in fatigue, compared to controls.59,60 The gentle exercises of tai chi are ideal in improving body awareness, balance, coordination, and strength. In 2003, the National Institute for Clinical Excellence in the United Kingdom issued guidelines stating that tai chi may be helpful for people with MS in terms of a general sense of well-being.61

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Aquatic activities are an appropriate form of exercise for the MS population. Water can provide adequate support for those with gait and balance problems, allowing movement that may be difficult to achieve on land and keeping the body cool during exercise.62 7.2. Acupuncture Acupuncturists believe that illness is an imbalance in the body's energy. The aim of acupuncture is to restore this balance. In traditional Chinese medicine, it balances the yin and yang. Fine needles are inserted into the skin at particular points along invisible energy channels called “meridians,” which are named after the organs they represent. The needles help unblock chi, or life force energy. By stimulating these points, blockages are released and energy flow is restored. Heat or electrical stimulation can sometimes be applied at acupuncture points. A 2011 review of review articles concluded that, except for neck pain, acupuncture was of doubtful efficacy in the treatment of pain and accompanied by small but serious risks and adverse effects including death, particularly when performed by untrained practitioners. Pneumothorax and infections were the most frequently reported adverse effects.63,64 However, there is a general agreement that acupuncture is safe when done by well-trained practitioners using sterile needles.65 One study that looked at acupuncture as a treatment for spasticity in MS found the results “encouraging enough to invite further investigation.”66 In another study that explored acupuncture for bladder dysfunction, forty one people with MS were divided into four groups, receiving no intervention, conventional treatment, acupuncture, or conventional treatment plus acupuncture. Those receiving either conventional treatment plus acupuncture or acupuncture alone benefited most.67,68 As recommended by the National MS Society: Acupuncture may provide relief for some MS-related symptoms, including pain, spasticity, numbness and tingling, bladder problems, and depression. There is no evidence, however, that acupuncture can reduce the frequency of MS exacerbations or slow the progression of disability. If acupuncture is used, it should be as an addition to, rather than as a substitute for, standard medical treatments, and should only be used after consultation with one's physician or other MS healthcare professional. In addition, the treatment should be provided by a licensed acupuncturist.69 7.3. Massage It has been estimated that 23.3% of the MS patients in the United States have used massage therapy.70,72 The American Massage Therapy Association defines massage as “manual soft tissue manipulation that includes holding, causing movement, and/or applying pressure to the body,” and massage therapy as “ a profession in which the practitioner applies manual techniques, and may apply adjunctive therapies, with the intention of positively affecting the health and well being of the client.” Various types of massage can be useful for MS, including traditional Swedish, Thai, acupressure, and shiatsu. Peer-reviewed medical research has shown that the benefits of massage include pain relief, reduced trait anxiety and depression, and temporarily reduced blood pressure, heart rate, and state of anxiety. In one small study, twenty-four adults with MS were randomly assigned to either massage therapy for 45-min massages twice a week, or standard medical treatment. The massage group was found to have less anxiety, improved mood, increased self-esteem and body image, increased ambulation, and improved physical and social functioning. They also had a more positive attitude about having MS.71 7.4. Reflexology Reflexology is based on the principle that every part of the body is represented in the feet. Gentle hand pressure to specific areas of the feet, hands, or ears is applied. By working on the parts of the feet

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Graph. Picture of foot.

that correspond to the head and the neck, they stimulate healing in the referral area. Reflexology foot charts show in detail where the different parts of the body are represented on the feet.73 Reflexologists usually think of health problems as occurring because of a blockage of life force, or chi, at various points in the body. Massaging, squeezing, or pushing on the appropriate parts of the feet help to restore the flow of energy through channels or meridians, which have been blocked or disrupted by illness. It also relieves tension and improves circulation (Graph). Reflexology appears to have created a space for patients to talk about their worries and concerns, and to receive advice and support from the nurse therapists.74 A small study by Siev-Ner et al.75 of 53 MS patients showed the effectiveness of reflexology for improving spasticity, paresthesias (numbing and tingling sensations), and urinary symptoms. The treatment included manual pressure on specific points in the feet and massage of the calf area. The control group received non-specific massage of the calf. Both groups were tested for numbness, bladder problems, muscle strength, and spasticity. The results showed a significant improvement in the group given reflexology.75 In addition, reflexology has a relaxation effect from the moment the treatment begins. Several studies have reported relaxation based on EEG brain activity, reducing pain, and can help with mental health by reducing depression and anxiety.76–78

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