Feverfew ( Tanacetum parthenium ) Feverfew traditionally has been used for the prevention a nd treat- ment of migraine headaches, arthritis, fever and menstrual irregu- larities. Feve rfew inhibits platelet aggregation, serotonin release from platelets and leukocytes, and th e production of prostaglan- dins and leukotrienes in rat and human leukocytes (Sumner et al ., 1992). It also has serotonin 5-HT receptor blocking eff ects which has relevance as sero tonin dysregulation is thought to contribute to headache initiation (Shrivastava et al., 20 06). One of the major active constituents in feverfew, parthenolide, inhibits the infl ux For patients with migraine or tension headaches, target a serum 25(OH) D level of 50 to 60 ng/ml. Many children may need higher SECTION 9 special topics 616 of extracellular calcium into vascular smooth muscle cells decreas- ing spasm (Pareek et al ., 2011). also be integrated into the regimens for infl ammatory bowel dis- ease (IBD) to quell infl ammation and subsequently reduce pain. Randomized trials of feverfew in adult patients reduced the number and severity of migraine attacks when used singularly (Murphy et al., 1988) or in combination with ginger (Cady et al., 2011). In the 1988 study, 72 volunteers were randomly allocated to receive either drie d feverfew leaves (82 mg/day) or matching placebo for 4 months with cross-over for the foll owing 4 months. Feverfew treatment had a 24% reduction (P <0.005) in attack fre- quency and a signifi cant decrease (P <0.02) in migraine-associated nausea and vomiting compared with placebo. Visual analog scale (VAS) scores of pain also improved with feverfew. Chamomile ( Matricaria recutita ) Chamomile traditionally has been used to treat nausea, ne rvous diarrhea, gastrointestinal spasms, restlessness and insomnia. Active ingredients, alp ha-bisabolol and bisabolol oxide, inhibit cyclo-oxygenase and lipo-oxygenase thereby reduci ng the produc- tion of infl ammatory prostaglandins and leukotrienes. Th ey also inhibit hi stamine release from mast cells and have antispasmodic eff ects on smooth muscle (Hormann a nd Korting, 1994). Another active ingredient, apigenin, binds to gamma-aminobutyric acid (G ABA) receptors, the primary receptor sites of benzodiazepines in the central nervous system , to exert anxiolytic eff ects without sedation (Viola et al., 1995). In a prospective doub le-blind study in 33 infants with colic, an herbal preparation containing chamo- mile was e ff ective in reducing colic episodes without side eff ects. Th e tea eliminated the colic i n 19 (57%) of 33 infants, whereas placebo was helpful in only 9 (26%) of 35 (P <0.01) (Weiz man et al., 1993). Th ere have been no trials of feverfew in any pediatric popu- lations, although it is frequ ently recommended for pediatric headache management. No signifi cant adverse eff ects have been reported with long-term use of feverfew (Pittler et al., 2000). Th e recommended dosin g is 50 to 150 mg of feverfew extract stand- ardized to 0.2% to 0.4% parthenolides, or two to three fresh leaves daily. Use the 50 mg dose for children 25 to 50 kg and the 150 mg dos e for larger children and adults (>70 kg). Coenzyme Q 10 (CoQ 10 ) CoQ 10 defi ciency occur s in many pediatric patients with migraine headache (Hershey et al., 2007). Th ere are two major factors that lead to defi ciency of CoQ 10 in humans: reduced biosynthesis and increa sed utilization by the body when consumed by oxygen free- radicals. Oxydative stress (indic ated by low CoQ 10 levels) with mitochondrial dysfunction (indicated by low ATP levels in b lood mononuclear cells) are found in pain disorders such as migraine and fi bromyalgia (Cor dero et al., 2012). CoQ 10 functions as an anti-oxidant, a membrane stabilizer, as well as a co-factor in many metabolic pathways, and is necessary for generating ATP in mito- chondr ial oxidative respiration (Turunen et al., 2004). One heaping teaspoon of dried fl ower heads in half a cup of boil- ing water steeped for 10 min yields about 3 g of chamomile extract. For infants with colic, give 1 ounce of this pr eparation (approxi- mately 0.75 g) three to four times daily. Use higher doses for older ch ildren and adolescents \200\2241 to 3 g taken three to four times daily \200\224to reduce a bdominal and/or menstrual cramps, or induce relaxation. Ginger ( Zingiber o \203 cinale ) Historically ginger has been used for stomach aches, hea daches, nausea, and to stimulate appetite, reduce gas formation, and pro- mote bile secreti on for digestion. Its active constituent, 6-gingerol, reduces nausea and vomiting by increa sing gastric motility (Ali et al., 2007). Ginger \200\231s antispasmodic eff ect on the vis ceral smooth muscle is the result of antagonism of serotonin receptor sites in the gastroin testinal tract (Murray, 1995). Twenty-four healthy volun- teers were studied twice in a ran domized double-blind manner and given ginger capsules (total 1200 mg) or placebo followed b y a soup meal. Ginger accelerated gastric emptying (13.1 1.1 ver- sus 26.7 3.1 min, P <0. 01) and stimulated antral contractions (P <0.005) compared to placebo (Wu et al., 2008). CoQ 10 supplementation reduced headache frequency and related disability in children with m igraine when CoQ 10 blood levels were normalized. CoQ 10 was measured in 1550 paediat- ric patients, aged 3 to 22 years, with migraine. Patients with low CoQ 10 (<0.70 mcg/ml; normal levels 0.5 \200\2231.5 mcg/ml), were started on 1 to 3 mg/kg per day of CoQ 10 in liquid g el capsule formula- tion. In 3 months, the total CoQ 10 level improved to 1.20 0.59 mcg/ml (P <0.0001), while the headache frequency decreased from 19.2 10.0 to 12.5 10.8 (P <0.00 1) and headache disability assessed with PedMIDAS reduced from 47.4 50.6 to 22.8 30.6 (P <0.001) (Hershey et al., 2007). Ginger is well tolerated and considered safe when used in typi- cal doses in children older than 2 years old. Ginger can be given by brewing 0.5 \200\2231 g of dried root in 150 ml b oiling water for 5 \200\22310 min, then straining. Powered root in capsule form can also be used and dosed 250 \200\223500 mg 3 \200\2234 times daily up to the maximum of 4 g per day . It is generally recommended that intake not exceed 4 g per day in adults as side eff ects such as abdominal discomfort, heart- burn, or diarrhea may develop with doses greater than 5 g per day (Srivastava and Mustafa, 1989). CoQ 10 is generally well tolerated and has no signifi cant adverse eff ects. Small amounts are derived from dietary meats and seafood; however, the amounts ingested from foods do not approach thera- peutic doses. Th e recommended dosing when used for migraine prevention is 100 to 300 mg daily. Functional abdominal pain/in \202 ammatory bowel disease Th e causes of functional abdomin al pain are multifactorial and oft en diffi cult to treat with only one modality. Change of diet, cognitive- behavioral therapy, and use self-regulation techniques (guided imagery, h ypnosis, meditation) used concurrently can help relieve pain (Weydert, 2012). Along with th ese modalities, certain herbs and dietary supplements have been shown to be safe and eff ec tive in treating abdominal pain. Many of these same supplements can Peppermint ( Mentha piperita ) Th ere are over 40 diff erent compounds found in peppermint oil. Most research has focused on menthol which decreases the infl ux of extracellular calc ium ions through potential-dependent channels thus inhibiting smooth muscle contractions (H ills and Aaronson, 1991). In a randomized, double-blind controlled trial, 42 children aged 8 to 17 years with irritab le bowel syndrome (IBS) were given pH-dependent, enteric-coated capsules containing 187 mg of peppermint oil per capsule or placebo. Children weighing CHAPTER 59 complementary drugs \200\224herbs, vitamins, and dietary supplements 617 between 30 and 45 kg received one capsule three times a day whereas patients weighing more than 45 kg received two pep- permint oil or placebo capsules three times a day. Aft er 2 we eks, 75% of patients receiving peppermint oil had reduced severity of pain compared to only 19% of the placebo group (P <0.001) (Kline et al., 2001). fatty acid important for the health of colonocytes, particularly the epithelial cells in th e rectum and left colon. Probiotics activate reg- ulatory T cells and regulatory pathways, leading to down regulation of infl ammation (Sartor, 2011). Two recent double-blind randomized placebo-controlled tri- als found diff erent types of pr obiotics ( Lactobacillus GG and VSL#3 \200\224a commercial brand containing eight diff er ent strains) reduced both the frequency and intensity of pain in children with recurrent ab dominal pain/IBS (Francavilla et al., 2010; Guandalini et al., 2010). In the Francavilla st udy, 141 children with IBS or func- tional pain received either oral LGG (3 \227 10 9 colo ny-forming units) or oral placebo twice per day. Th e number of episodes of pain per week d ecreased in the probiotic group from 3.7 to 1.1 (P <0.01) at 12 weeks, and to 0.9 at week 2 0 (P <0.02). Pain severity decreased from 4.3 to 2.3 at week 12 (P <0.01) and to 0.9 at wee k 20 (P <0.001). Th ese decreases were not seen in the placebo group. Peppermint is widely used as a tea. Due to its eff ect on calcium channels it can cause rel axation of the lower oesophageal sphincter leading to heartburn. Use of the enteric coated capsules will prevent this side eff ect. Typical dosage of the enteric coated capsules is 2 00 to 400 mg three times a day. Slippery elm ( Ulmus fulva ) Slippery elm inner bark, from the slippery elm or red elm tree native to North America, is known to sooth infl ammation of the gastroin- testinal tract. Slippery elm has demulcent and anti-oxidant proper- ties that can protect the gastrointesti nal tract from irritation. When taken internally, slippery elm causes refl ex stimulation o f the gob- let cell nerve endings in the gastrointestinal tract producing extra mucous (Nat ural Medicine Comprehensive Database, 2012). It is popular among IBD patients in the UK (La ngmead et al., 2000). Typical dose is 10 to 100 billion colony forming units (CFU) once or twice daily. Th ese pr eparations can be of a single strain ( Lactobacillis GG, Saccharomyces , etc.) or made of m ultiple strains combined to treat both small and large intestines. Digestive enzymes Digestive enzymes, amylase, lipase, protease and others, are neces- sary to facilitate proper breakdown of foods for utilization in our bodies. Incomplete digestion of food in the gastrointestinal tract leads to gas formation, bloating, abdominal cramps a nd diarrhea, and food allergies/sensitivities. Chronic hyposecretion of these enzymes not o nly causes maldigestion, but also malabsorption of micronutrients leading to defi ciencies and increased intestinal per- meability. Impaired gastric acid and pancreatic function has been reported in Crohn \200\231s disease contributing to malnutrition (Winter et al., 2004) . Th ese may also help for rehabilitation of the malnour- ished patient with IBD. Signifi cant improvement in IBS symptoms were noted with use of slippery elm. Th irty-one s ubjects received daily formulations of slippery elm. Twenty-one were classifi ed as suff er ing from diar- rhoea-predominant (DA) or alternating bowel habit IBS, and ten classifi ed a s constipation-predominant (C) IBS. In the DA group, abdominal pain scores decreased by 19% (P = 0.006), bloating scores decreased by 28% (P <0.0001), and global IBS symptoms decreas ed 21% (P = 0.002) during the treatment period. In the C group, there was a 14% decrease in abdominal pain scores (P = 0.032), a 13% decrease in bloating severity (P = 0.034), and a 34% reduction in global IBS symptom severity (P = 0.0005) when mean baseline scores were co mpared to mean scores over the treatment period (Hawrelak and Myers, 2010). In one study, administration of a digestive enzyme product sig- nifi cantly reduced the blo ating, fl atulence, and abdominal pain, with a slight increase of urgency for bowel movemen ts in patients with IBS (Ciacci et al., 2011). A tea can be made with adding one tablespoon of powdered inner bark to one cup of boiling w ater for 15 min. Use 2 to 5 ml three times a day. Capsules: 250 \200\223500 mg three to fou r times daily. Whole bark should not be used as it is considered an abortifacient. A trial of a broad-spectrum digestive enzyme consisting of a ratio of 25:2:25 of amylase:li pase:protease USP units respectively, given with meals may be of benefi t in those with the described symptoms. Gradually increase to the dosage recommended by the manufac- turer dep endant on strength. Marshmallow ( Althaea o \203 cinalis ) Marshmallow is used commonly for infl ammation of t he gastric mucosa, peptic ulcers, respiratory tract mucous membrane infl am- mation, and dr y cough. Marshmallow leaf and root contain muci- lage polysaccharides that form a protectiv e layer to shield mucous membranes from local irritation. Th e mucilage also has antimi- cr obial, antispasmotic, antisecretory, and wound-healing eff ects (Newall et al., 1996). Fibromyalgia/widespread myofacial pain Patients with fi bromyalgia (FM) frequently have mus culoskeletal pain, fatigue, headache, anxiety, weakness, and IBS amongst other symptoms. Ma ny of these symptoms can be treated with the use of herbs and dietary supplements while the underlying dysfunction is addressed for long-lasting relief. Th e leaf tea is prepared by steeping one to two teaspoons of the dried leaf in 150 ml boil ing water for 5 to 10 min and then strain- ing. Th e root tea is prepared by steeping one t o two teaspoons of the dried root in 150 ml cold water for 1 to 1 h, straining, and then warming before consumption (Natural Medicine Comprehensive Database, 2012). Each preparatio n yields 2 to 5 g to be taken three to four times a day. Vitamin D \200\224cholecalciferol (vitamin D 3 ) Vitamin D defi ciency is frequently seen i n patients diagnosed as FM and non-specifi c musculoskeletal pain (Bhatty et al., 2010). Vi tamin D defi ciency causes muscle pain and proximal muscle weakness with reports of heavine ss in the legs, rapid fatigue, and problems with climbing stairs and mobility. Vitamin D se ems to increase muscle protein synthesis, possibly by activating second messengers and phos phorylation (Pfeifer et al., 2002). In paediat- rics, vitamin D defi ciency can present as atypical muscular pain. Probiotics Th e human intestinal tract is populated with various microbial spe- cies that a re non-pathogenic but necessary for metabolizing foods and certain drugs, absorbing nutrien ts, and preventing colonization by pathogenic bacteria. Probiotics produce butyrate, a shor t-chain SECTION 9 special topics 618 Th e child at risk of this is typically white, breastfed, protected from the sun, and obese (Clarke and Page, 2012). lactate production and decreased adenosine triphosphate (ATP) (Eisinger, 1994). Several case reports suggest vitamin D therapy can provide prompt relief of muscle weakness and restore mobility (Prabhala et al., 2000). In a study of 61 women with FM and 25-hydrox y- vitamin D (25(OH) D) levels <20 ng/ml, signifi cant improvement was noted when their blo od level of 25(OH) D became greater than or equal to 30 ng/ml. Th is improvement became mor e signifi cant when their blood level of 25(OH) D exceeded 50 ng/ml (Matthana, 2011). Rather than supplement with separate B vitamins, it would be more eff ective to supplement with daily B-50 complex formulation which would provide 50 mg of vitamins B 1 , -2 , -3 , - 5 , -6 ; 50 mcg of cobalamin and biotin; and 400 mcg of folic acid. Coenzyme Q 10 CoQ 10 defi ciency, mitochondrial dysfunction, oxidative stress, and mitophag y activation in blood mononuclear cells have been observed in FM patients. CoQ 10 transfers electrons in the mito- chondrial respiratory chain and fulfi ls a critical role in mitocho n- drial ATP energy production and cellular metabolism (Cordero et al., 2010). Aft er measuring 25(OH) D levels, dose oral vitamin D 3 to target a level of 50 to 60 ng/ml . Knowing that each 100 IU only raises the 25(OH) D level by 1 IU, doses of 2000 to 4000 IU may be needed to increase levels 20 to 40 ng/ml. Very few foods naturally contain vitamin D. Dietary sources include fortifi ed eggs, fatty fi sh such as herrings, mackerel, sardine s, and tuna, and some fortifi ed foods, though these are minor sources overall. In a case series of fi ve patients with a diagnosis of FM and CoQ 10 defi ciency, there was a statistically signifi cant reduction of symp- toms aft er receiving CoQ 10 300 mg daily for 9 months (Cordero et al., 2011). All patients reported an improvement in sleep, men- ta l alertness, and a marked decrease in joint pain. Th ere were also signifi cant decreases i n the number of tender points, the VAS for pain, the Fibromyalgia Impact Questionnaire (FIQ ), the Headache Impact Test (HIT-6), and the Migraine Disability Assessment (MIDAS). Magnesium As mentioned previously, magnesium is a natural muscle relax- ant and pain reliev er which achieves its mechanism of action by antagonizing primarily N-type calcium-mediated channels at nerve endings, reducing noradrenaline release, thereby depressing nerve transm ission and muscle contractility (Shimosawa et al., 2004). It is also a cofactor driving man y enzymatic reactions necessary for mitochondrial function and energy production. CoQ 10 is generally well tolerated and has no signifi cant adverse eff ects. Th e recommend ed dosing when used for treatment of FM is 300 mg daily. Serum and RBC magnesium levels were signifi cantly lower in patients with FM than in contro ls with a negative correlation between the magnesium levels and FM symptoms (Bagis et al., 2013). Supplemental magnesium has been used in its various salt forms to treat myalgias. Or al magnesium citrate treatment, 300 mg a day, was eff ective in reducing tender points and pain intensity of FM (Bagis et al., 2013). It was also helpful in reducing pain and tendern ess in adult FM patients when taken orally as magnesium hydroxide with malic acid (Russell et al., 1995). L-Carnitine It has been suggested that FM may be associated with mitochon- drial dysfunctio n from a defi cit of carnitine. L-carnitine plays a key role in cellular energy production. Long-chain fatty acids are too large to cross the internal mitochondrial membrane and rely on L-carnitine dependant enzymatic transportation. Once in the mitochondria, fatty acids u ndergo beta-oxidation to adenosine triphosphate (ATP), and L-acetyl-carnitine is excreted t o begin a new transportation cycle (Natural Medicine Comprehensive Database, 2012). Typical dosing is 250 to 500 mg orally twice a day. Dietary sources of magnesium include le gumes, whole grains, vegetables, seeds, and nuts, though it is diffi cult to get adequate a mounts daily from food alone. Magnesium \200\231s effi cacy is dependent on its absorption from the gastrointestinal tract. Supplement with magnesium salts, glyci- nate, aspartate, g luconate, citrate, or malate to promote absorption without causing diarrhea which can occur with magnesium oxide. Epsom salts, which are 100% magnesium sulfate, can also be used as a compress or a bath soak to relieve muscle pain. One multicenter randomized trial compared acetyl L-carnitine (LAC) versus placebo in patien ts with overt FM. A statistically signifi cant improvement was observed for depression and muscu- loskeletal pain in the treatment group receiving 500 mg LAC three times daily over 1 0 weeks. Treatment was well-tolerated (Rossini et al., 2007). Th e body obtains some carnitine from red meats and dairy prod- ucts and can synthesize car nitine from the amino acids, lysine, and methionine. A typical total dose of LAC is 1000 to 2000 mg daily in three divided doses. Th is dose would be safe in children as doses of 100 mg/kg/day are used in children with Rett syndrome (Ellaway et al., 1999). Vitamin B complex Many of the B vitamins are cofactors in the Krebs cycle. Th ey serve as f acilitators of specific biochemical reactions, i.e. niacin \206\222 nicotinamide dinucleot ide (NAD), ribofl avin \206\222 fl avin- adenine-dinucleotide (FAD), and therefore necessa ry for mito- chondrial energy production. Defi ciencies cause defi cits of ATP leading to f atigue, reduce glutathione and nitric oxide synthesis leading to myalgias, and reduce serot onin production causing pain and mood disturbances (Eisinger, 1998). Sleep disorders, anxiety, restlessness Th ese comorbid conditions are commonly seen in pati ents dealing with pain and can aggravate the pain experience. Th ere are several calming he rbs and dietary supplements that may off er the desired eff ects to help with symptom contr ol. A number of similarities exist between FM and thiamin defi - ciency. Th ey include irritabi lity, frequent headaches, unusual fatigue, muscle tenderness, muscular weakness, IBS, and s leep disturbances. Studies have demonstrated abnormalities of thia- min metabolism in FM wi th increased pyruvate, decreased Chamomile ( Matricaria recutita ) As discussed previously, Chamomile is used commonly to tr eat nausea, nervous diarrhea, gastrointestinal spasms, restlessness, CHAPTER 59 complementary drugs \200\224herbs, vitamins, and dietary supplements 619 and insomnia. Its mechanism of action is through a known active ingredient, apigenin, which binds to benzodiazepine receptors in the central nervous system, to exert anxiolytic eff e cts (Viola et al., 1995). other sleep hygiene strategies (removal of environmental stimulants 1 to 2 h before bedtime , dusk simulation, quiet evening activities, etc.) to improve eff ectiveness. L-tryptophan/5-HTP L-tryptophan is an essential amino acid absorbed from dietary protein so urces that is converted to serotonin and melatonin by the earlier described pathway. People typically use this orally for insomnia, sleep apnoea, depression, anxiety, and myofascial pain. Th ere were mixed results of effi cacy in a double-blind, ran- domized trial of 34 adults w ith insomnia. A dose of 270 mg of chamomile given twice a day was used in this trial (Zick et al., 2011). Given that 1 to 3 g taken three to four times daily is the usual recommended dose to help induce relaxation or sleep (Robbers and Tyler, 1999), the dose in this trial may have been inadequate. In clinical studies, 1 g of L-tryptophan signifi cantly reduced sleep latency, with lower d oses (0.25 \200\2230.5 g) producing a trend in the same direction (Hartmann and Spinweber, 1979). Clinical evidence sug- gests L-tryptophan is as helpful as light therapy in the trea tment of seasonal eff ective disorder (Ghadirian et al., 1998). One heaping teaspoon of dried fl ower heads in half a cup of boil- ing water steeped for 10 min yields about 3 g of chamomile extract which can be taken up to four times a day. Th e dose suggested for children under 18 is one-half the adult dose. Th e essential oils of cha momile can also be used as aromatherapy to promote relaxa- tion and reduce pain (Buckle, 19 99). Th eoretically, concomitant use with benzodiazepines or other sedatives might cause ad ditive eff ects and side eff ects. Th eoretically, concomitant use with medications that cause seda- tion may have additive ef f ects. Also, combining serotonergic anti- depressants with L-tryptophan/5-HTP may increase the risk of serotonin syndrome. Consider a starting dose of 50 mg 30 min before bedtime. If not eff ective, increase by 50 mg each night to a maximum of 300 mg per night for children and adolescents. Occasionally i ndividuals may feel more energized taking this at night. In that case, dose with 50 to 100 mg three times a day with meals. Lemon balm ( Melissa o \203 cinalis ) Lemon balm commonly is used for anxiety, insomnia, a nd rest- lessness. As an inhalant, lemon balm is used as aroma therapy for calming patients with Alzheimer \200\231s disease. Behavioral effects are attributable to a number of possi ble active components of the dried leaf and essential oil of the herb. Some research sug- g ests lemon balm has acetylcholine receptor activity with both nicotinic and muscarinic bind ing properties (Kennedy et al., 2002). Valerian ( Valeriana o \203 cinalis ) Valerian, also known as \200\230nature \200\231s Va lium \200\231, has been used for insom- nia, anxiety-associated restlessness and sleeping d isorders, mood disorders, and chronic fatigue syndrome. Valerenic acid and other constituen ts of valerian are GABA agonists (Natural Medicine Comprehensive Database, 2012). One RCT found signifi cant improvements in quality of sleep dur- ing 30 days of treatment w ith 600 mg/day of M. offi cinalis (Cerny and Schmid, 1999). An extract of valerian and lemon balm reduced restlessness and diffi culties falling asleep in an open multicenter post marketing sur- veillance study of 918 children under age 12 wi th sleep disorders. Patients took one to two tablets, each containing 160 mg of valerian an d 80 mg of lemon balm, twice a day. Th ere were no signifi cant side eff ects (M ller an d Klement, 2006). A systematic review of the available literature suggests that valerian im proves sleep quality without producing side eff ects (Bent et al., 2006). Some evidence sho ws that valerian reduces self-reported stress in social anxiety (Kohnen and Oswald, 1998). Capsules containing 100 to 200 mg of dried herb can be taken three times daily or as needed . A tea can be made steeping to 1 teaspoon of dried herb in one cup of hot water for 10 min yield- ing 1 to 2 g taken in divided doses four times a day. It has a long history of s afe usage with no worrisome side eff ects (Wong et al., 1998). Melatonin Melatonin traditionally has been used for insomnia, delayed sleep phase syndrome (DSPS), circadian rhythm disorders in the blind, and jet lag. Melatonin is a hormone synthe sized endogenously in the pineal gland produced from tryptophan \206\222 5-hydroxytryptoph an \206\222 serotonin \206\222 N-acetylserotonin \206\222 melatonin. In the brain, melat onin appears to increase the binding of GABA, the primary inhibitory neurotransmitter, to i ts receptors (Munoz- Hoyos et al., 1998). Melatonin production is infl uenced by day/ night cycles. Light, both natural and artifi cial, inhibits melatonin secretion and darkness sti mulates secretion (Brzezinski, 1997). Dosing of 100 to 300 mg 30 min before bedtime is recommended for sleep. It can also be dose d on a three-times-a-day schedule for anxiety. Valerian has been safely used in children in studies lasting 4 to 8 weeks. Use of valerian with other herbs and supplements with sedati ve properties might have synergistic eff ects, therefore caution should be used. L-Th eanine L-Th eanine is the major amino acid found in green tea and histori- cally been used for its relaxation and anti-anxiety eff ects. L-theanine works to reduce anxiety by in creasing levels of GABA and sero- tonin (Lu et al., 2004). It also antagonizes glutamate an d NMDA receptors (Kakuda et al., 2000). A meta-analysis of data of randomized controlled trials which included four studies totalin g 226 children showed that melatonin treatment advanced mean endogenous melatonin onset by 1.18 h (95% confi dence interval (CI): 0.89 \200\2231.48 h) and clock hour of sleep onset b y 0.67 h (95% CI: 0.45 \200\2230.89 h). Melatonin decreased sleep-onset latency by 23.27 mi n (95% CI: 4.83 \200\22341.72 min) (van Geijlswijk et al., 2010). One study evaluated the acute eff ects of alprazolam and L-theanine under a relaxed and exp erimentally induced anxiety condition. L-theanine 200 mg was superior to alprazolam 1 mg in producing a relaxed state under resting conditions (Lu et al., 2004). A typical dose for insomnia is 0.3 to 5 mg at bedtime. Start with the lowest dose and incre ase to higher levels if needed. Implement Typical dosing would be 100 to 200 mg once or twice daily. SECTION 9 special topics 620 Conclusion Th e goal of this chapter is to introduce clinicians to the use of com- mon herb s, vitamins, and dietary supplements that can be inte- grated into the care of children and adolescents experiencing pain. As clinicians we need to have an understanding of the benef i ts or potential side eff ects these supplements have so that we can best advise our patie nts in their use. Th e supplements outlined in this chapter, with their mechanisms of actio n and recommended doses, have been found to be eff ective and are generally regarded as saf e to use in the pediatric population for various pain syndromes or symptoms associated with pain. h each night and felt rested when she woke in the morning. She stopped taking naps during t he day, no longer had the achy mus- cles and was walking without fatigue about 40 min a day . She still had occasional headaches, but these were shorter in duration and intensity and could be relieved by acetaminophen. Both she and her mother reported an improved mood. Suza nne was spending more time with friends and attending school half-days with plans to return full time the following week. Since she was clinically improved, no further laboratory tests were done. She was encourage d to continue the current regimen of supplements until she had full resolution of the sympt oms and was back to her usual level of physical activity. At that time she could consider c oming off the supplements and monitor for any recurrence of the symptoms. Case example Suzanne presented with a 6-month history of headache, myal- gias, and fatigue. Th is previo usly healthy and energetic 16-year- old developed symptoms aft er a prolonged viral illness . She described her headache as \200\230all over pressure \200\231, rated the pain as \200\2307 \200\231 on the VAS, and made worse with bright lights and noise. She stated all her muscles were achy, \200\230felt heavy \200\231, and worse with any physical activity. She was sleeping 12 h every night but did not feel rested when she woke and oft en needed t o take naps during the day. Because of the fatigue and pain, she had not attended school fo r over 3 months and stopped all physical activity. She rarely went outside the family home. Her mother was concerned that Suzanne was becoming more depressed because she wasn \200 \231t doing her normal activities nor was she able to be with her friends. References Abraham, G. E., Schwartz, U. D., and Lubran, M. M. (1981). Eff ect of vitamin B- 6 on plasma and red blood cell magnesium levels in pre-menopausal women. Ann Clin Lab Sci , 11 (4), 333 \200\223336 . Ali, B. H., Blunden, G., Tanira, M. O., and Nemmar, A. (2007). Some phytochemical, pharmaco logical and toxicological properties of ginger (Zingiber offi cinal Roscoe): a review of re cent research. Food Chem Toxicol , 46 (2), 409 \200\223420 . Altura, B. T., Shirley, T., Young, C. C., Hiti, J., Dell \200\231Orfano, K., Handwerker, S. M., et al . (1992). A new method for the rapid determination of ionized Mg2+ in whole bloo d, serum and plasma. Meth Find Exp Clin Pharmacol , 14 (4), 297 \200\223304 . Astin, J. (1998). Why patients use alternative medicine: results of a national study. JAMA , 279 (19), 1548 \200\2231553 . On physical examination Suzanne appeared tired and had fl at aff ect. Her skin was pale, bu t she had no rashes or bruises. She had multiple tender areas with palpation of her head, n eck, and upper back. She also had tenderness all along her paraspinus muscles and of the la rge muscle groups of her extremities. Th e remainder of her examination was otherwise norma l. Bagis, S., Karabiber, M., As, I., Tamer, L., Erdogan, C., and Atalay, A. (2012). Is magnesi um citrate treatment eff ective on pain, clinical parameters and functional status in patie nts with fi bromyalgia? Rheumatol Int , 33 (1), 167 \200\223172 . Bent, S., Padula, A., Moore, D., Patterson, M., and Mehling, W. (2006). Valerian for sleep: a systematic review and meta-analysis. Am J Med , 119 (12), 1005 \200\2231012 . Laboratory investigations done to assess for anemia, infec- tion, thyroid dysfunction, and autoimmune diseases were all normal. Her RBC magnesium level was low at 3.5 mg/dL (normal 4 .7 \200\2237.0 mg/dL), homocysteine level high at 12 mol/L (normal <8 mol/L), 25-hydrox yvitamin D level low at 17 ng/ml (ideal 50 \200\22360 ng/ml), and coenzyme Q 10 level was l ow-normal at 0.6 mcg/ml (normal 0.5 \200\2231.5 mcg/ml). Bhatty, S.A., Shaikh, N.A., Irfan, M., Kashif, S. M., Vaswani, A. S., Sumbhai, A, et al . ( 2010). Vitamin D defi ciency in fi bromyalgia. J Pak Med Assoc , 60 (11), 949 \200\223951 . Bruijn, J., Duivenvoorden, H., Passchier, J., Locher, H., Dijkstra, N., and Arts, W. F. (20 10). Medium-dose ribofl avin as a prophylactic agent in children with migraine: a prelimina ry placebo-controlled, randomized, double- blind, cross-over trial Cephalalgia , 30 (12), 1 426 \200\2231434 . She was started on vitamin D 3 4000 IU daily, magnesium malate 500 mg twice daily, and CoQ 10 300 mg daily for the obvious defi - ciencies and for their known eff ects on headache pa in and myal- gias. 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