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A neurobiological basis of social attachment. Am J Psychiatry , 154 , 726 \200\223735 . Joesten, M. D., Hogg, J. L., and Castellion, M. E. (2007). Th e world of chemisty: essentials . Belmont, CA : Th omson . Johnston, C., Byron, J., Filion, F., Campbell-Yeo, M., Gibbins, S., and NG, E. (2012). Alte rnative female kangaroo care for procedural pain in preterm neonates: a pilot study. Acta P aediatr , 101 (11), 1147 \200\2231150 . Nishitani, S., Miyamura, T., Tagawa, M., Sumi, M., Takase, R., Doi, H., et al . (2009). Th e calming eff ect of a maternal breast milk odor on the human newborn infant. Neurosci Res , 63 , 66 \200\22371 . Johnston, C., Campbell-Yeo, M., Fernandes, A., Inglis, D., Streiner, D., and Zee, R. (2010) . Skin-to-skin care for procedural pain in neonates. Cochrane Database Syst Rev , 3 , CD008 435 . doi: 10.1002/14651858.CD008435. Johnston, C. C., Campbell-Yeo, M., and Filion, F. (20 11). Paternal vs maternal kangaroo care for procedural pain in preterm neonates: a randomiz ed crossover trial. Arch Pediatr Adolesc Med , 165 , 792 \200\223796 . Obeidat, H., Kahalaf, I., Callister, L. C., and Froelicher, E. S. (2009). Use of facilitate d tucking for nonpharmacological pain management in preterm infants: a systematic review. J Perinat Neonatal Nurs , 23 , 372 \200\223377 . Ockleford, E. M., Vince, M. A., Layton, C., and Reader, M. R. (1988). Response of neonates to parent \200\231s and other \200\231s voi ces. Early Hum Dev , 18 , 27 \200\22336 . Ors, R., Ozek, E., Baysoy, G., Cebeci, D., Bilgen , H., Turkuner, M., and BASARAN, M. (1999). Comparison of sucrose and human milk on pain re sponse in newborns. Eur J Pediatrics , 158 , 63 \200\22366 . Johnston, C. C., Filion, F., Campbell-Yeo, M., Goulet, C., Bell, L., McNaughton, K., et al . (2009). Enhanced kangaroo mother care for heel lance in preterm neonates: a crossover tri al. J Perinatol , 29 , 51 \200\22356 . Osinaike, B. B., Oyedeji, A. O., Adeoye, O. T., Dairo, M. D., and Aderinto, D. A. (2007). E ff ect of breastfeeding during venepuncture in neonates. Ann Trop Paediatr , 27 , 201 \200 \223205 . Johnston, C. C., Filion, F., Campbell-Yeo, M., Goulet, C., Bell, L., McNaughton, K., et al . (2008). Kangaroo mother care diminishes pain from heel lance in very preterm neonates: a crossover trial. BMC Pediatr , 8 , 13 . Panksepp, J., Herman, B. H., Vilberg, T., Bishop, P., and Deeskinazi, F. G. (1980). Endogen ous opioids and social behavior. Neurosci Biobehav Rev , 4 , 473 \200\223487 . Johnston, C. C., Filion, F., and Nuyt, A. M. (2007). Recorded maternal voice for preterm ne onates undergoing heel lance. Adv Neonatal care , 7 , 258 \200\223266 . Panksepp, J., Nelson, E., and Siviy, S. (1994). Brain opioids and mother-infant Johnston, C. C., Stevens, B., Pinelli, J., Gibbins, S., Filion, F., Jack, A., et al . (2003 ). Kangaroo care is eff ective in diminishing pain response in preterm neonates. Arch Pedia tr Adolesc Med , 157 (11), 1084 \200\2231088 . Kashaninia, Z., Sajedi, F., Rahgozar, M., an d Noghabi, F. A. (2008). Th e eff ect of Kangaroo Care on behavioral responses to pain of a n intramuscular injection in neonates. J Specialists Pediatr Nurs , 13 , 275 \200\223280 . social motivation. Acta Paediatr Suppl , 397 , 40 \200\22346 . Piira, T., Champion, G. D., Bustos, T., Donnelly, N., and Lui, K. (2007). Factors associate d with infant pain response following an immunization injection. Early Hum Dev , 83 , 319 \200\223326 . Pillai Riddell, R., Campbell, L., Flora, D. B., Racine, N., Din Osmun, L., Garfi eld, H., e t al . (2011). Th e relationship between caregiver sensitivity and infant pain behaviors ac ross the fi rst year of life. Pain , 152 , 2819 \200\2232826 . Konner, M. (2004). Th e ties that bind. Nature , 429 , 705 . Kostandy, R. R., Ludington-Hoe , S. M., Cong, X., Abouelfettoh, A., Bronson, C., Stankus, A, et al . (2008). Kangaroo Care (skin contact) reduces crying response to pain in preterm neonates: pilot results. Pain Ma nag Nurs , 9 , 55 \200\22365 . Rattaz, C., Goubet, N., and Bullinger, A. (2005). Th e calming eff ect of a familiar odor o n full-term newborns. J Dev Behav Pediatr , 26 , 86 \200\22392 . Sajedi, F., Kashaninia, Z. , Rahgozar, M., and Noghabi, F. A. (2007). Th e eff ect of Kangaroo Care on physiologic res ponses to pain of an intramuscular injection in neonates. Iranian J Pediatr , 17 , 339 \200 \223344 . Kurihara, H., Chiba, H., Shimizu, Y., Yanaihara, T., Takeda, M., Kawakami, K., et al . (199 6). Behavioral and adrenocortical responses to stress in neonates and the stabilizing eff e cts of maternal heartbeat on them. Early Hum Dev , 46 , 117 \200\223127 . Schaal, B., Marlier, L., and Soussignan, R. (1998). Olfactory function in the human fetus: evidence from selective neonatal responsiveness to the odor of amniotic fl uid. Behav Neuro sci , 112 , 1438 \200\2231449 . Liaw, J. J., Yang, L., Katherine Wang, K. W., Chen, C. M., Chang, Y. C., and Yin, T. (2012) . Non-nutritive sucking and facilitated tucking relieve preterm infant pain during heel-sti ck procedures: a prospective, randomized controlled crossover trial. Int J Nurs Stud , 49 , 300 \200\223309 . Scher, M. S. and Loparo, K. A. (2009). Neonatal EEG/sleep state analyzes: a complex phenoty pe of developmental neural plasticity. Dev Neurosci , 31 , 259 \200\223275 . Ludington-Hoe, S. M., Hosseini, R., and Torowizc, D. L. (2005). Skin-to-skin contact (Kanga roo Care) analgesia for preterm infant heelstick. AACN Clin Issues , 16 , 373 \200\223387 . Shah, P. S., Aliwalas, L., and Shah, V. (2007). Breastfeeding or breastmilk to alleviate pr ocedural pain in neonates: a systematic review. Breastfeed Med , 2 , 74 \200\22382 . Ludington-Hoe, S. M., Johnson, M. W., Morgan, K., Lewis, T., Gutman, J., Wilson, P. D., et al . (2006). Neurophysiologic assessment of neonatal sleep organization: preliminary result s of a randomized, controlled trial of skin contact with preterm infants. Pediatrics , 117 , e909 \200\223e923 . Shah, P. S., Aliwalas, L. L., and Shah, V. (2008). Breastfeeding or breast milk for procedu ral pain in neonates. Cochrane Database Syst Rev , 1 , CD004950 . Standley, J. M., and Mase n, C. K. (1990). Comparison of infant preferences and responses to auditory stimuli: music, mother, and other female voices. J Music Th er , 27 , 54 \200\22397 . Madrazo, I., Franco-Bourland, R. E., Leon-Meza, V. M., and Mena, I. (1987). Intraventricula r somatostatin-14, arginine vasopressin, and oxytocin: analgesic eff ect in a patient with intractable cancer pain. Applied Neurophysiol , 50 , 427 \200\223431 . Stevens, B., Johnston, C., Taddio, A., Gibbins, S., and Yamada, J. (2010). Th e premature i nfant pain profi le: evaluation 13 years aft er development. Clin J Pain , 26 , 813 \200 \223830 . Marlier, L. and Schaal, B. (2005). Human newborns prefer human milk: conspecifi c milk odor is attractive without postnatal exposure. Child Dev , 76 , 155 \200\223168 . Stevens, B. J., Johnston, C., Petryshen, P., and Taddio, A. (1996). Premature infant pain p rofi le: development and initial validation. Clin J Pain , 12 , 13 \200\22322 . McDaniel, M. R., Barker, E., and Lederer, C. L. (1989). Sensory characterization of human milk. J Dairy Sci , 72 , 1149 \200\2231158 . CHAPTER 58 mother care for procedural pain in infants 609 Ward-Larson, C., Horn, R. A., and Gosnell, F. (2004). Th e effi cacy of facilitated tucking for relieving procedural pain of endotracheal suctioning in very low birthweight infants. MCN Am J Matern Child Nurs , 29 , 151 \200\223156 . Sweet, S. D., Mcgrath, P. J., and Symons, D. (1999). Th e roles of child reactivity and parenting context in infant pain response. Pain , 80 , 655 \200\223661 . Upadhyay, A., Aggarwal, R., Narayan, S., Joshi, M., Paul, V. K., and Deorari, A. K. (2004). Analgesic eff ect of expressed breast milk in procedural pain in term neonates: a randomiz ed, placebo-controlled, double-blind trial. [see comment] . Acta Paediatr , 93 (4), 518 \200\22322 . Yang, J. (1994). Intrathecal administration of oxytocin induces analgesia in low back pain involving the endogenous opiate peptide system. Spine , 19 , 867 \200\223871 . Varendi, H., Christensson, K., Porter, R. H., and Winberg, J. (1998). Soothing eff ect of a mniotic fl uid smell in newborn infants. Early Hum Dev , 51 , 47 \200\22355 . This page intentionally left blank SECTION 9 Special topics This page intentionally left blank CHAPTER 59 Complementary drugs \200\224 herbs, vitamins, and dietary supplements for pain a nd symptom management Joy A. Weydert Summary Because of the interest of patients and physicians, there has been increasing resea rch into the use of botanical agents, nutritional sup- plements, and diet as a means to man age pain. Pharmacological agents typically are chosen as fi rst-line therapy for pain and s ymp- tom management; however, for some patients these agents may not work well long term or have side eff ects that are not tolerated. Other patients may prefer non-pharmacological t herapies. Most clinicians are not trained or may not be comfortable recommend- ing these co mplementary agents. Th e herbs that will be discussed have \200\230Generally Recognized As Safe \200\231 statu s (GRAS) for use in the US. GRAS is the US Food and Drug Administration (FDA) designation t hat a chemical or substance is considered safe by experts, and so exempted from the usual F ederal Food, Drug, and Cosmetic Act (FFDCA) food additive tolerance requirements. GRAS exem ptions are granted for substances that are generally recognized, among experts quali- fi ed by scientifi c training and experience to evaluate their safety, as having been adequately shown through scientifi c procedures to be safe under the conditions of their intended use (Food and Drug Administration, 2012). Common dosages of herbs, vitamins, and dietary suppl ements are shown in Table 59.1 . Introduction and background Th e use of complementary and alternative medicine (CAM) has in creased considerably in the pediatric population (Tsao and Zeltzer, 2005). Approximately 20 % to 40% of healthy children seen in pediatric clinics and more than 50% of children with c hronic illnesses use CAM in conjunction with conventional medical care (Kemper et al., 2008 ). Th ose groups that report higher use of CAM oft en have chronic disorders in which pain is a signifi cant problem (Hagen et al., 2003; Heuschkel et al., 2002). Pain syndromes and suggested complementary drugs Headaches Chronic primary headaches, wheth er tension-type or migraine, are the most common pain problems in children aff ecting as ma ny as one in fi ve children (Perquin et al., 2000). Recent theories of head- ache etiology increasingly point to similarities between migraine and tension-type headache, with both su ggesting an underlying heightened central nervous system sensitivity (Peres et al., 2007). Th e goal for treatment, therefore, is to target the underlying prob- lem within the nervou s system to lessen reactivity. Families who use CAM state they do so \200\230not so much as a result of being dissatisfi ed with conventional medicine, but largely because they found these health care alternative s to be more congruent with their own values, beliefs, and philosophical orientations towar d health and life \200\231 (Astin, 1998, p. 1548). Magnesium Magnesium is regarded as a natural muscle relaxant and pain reliever. Its mechani sm of action is through antagonizing N-type calcium-mediated channels at nerve endings. Thi s prevents noradrenaline release, thereby depressing nerve transmission and muscle contract ility (Shimosawa et al., 2004). Magnesium also has voltage-gated antagonist action at the N -methyl-D-aspartate The National Center on Complementary and Alternative Medicine (NCCAM), a division of the Na tional Institutes of Health (NIH), funds various studies on CAM. Research on the eff ective - ness of various CAM therapies for children is small but growing. Much of our knowledge of these therapies is extracted from adult studies, however pediatric studies will be reviewe d in this chapter when available. SECTION 9 special topics 614 Table 59.1 Common dosages of herbs, vitamins, dietary supplements \200\224please refer to t ext for more details on dosing, side e \200 ects, interactions defi ciency. Normal RBC magnesium levels for children are 4.7 to 7.0 mg/dL. In one study, 86 children between the ages of 3 and 17 years with migraine headaches were r andomly assigned to receive magnesium or placebo for 16 weeks to prevent headache pain. Bas eline mean IMg 2+ levels in both treatment and placebo groups were similar at 0.5 and 0.49 mg/dL, respectively. Th ere was a signifi cant reduction in both headache frequency (p = 0. 0037) and severity (p = 0.0029) in the children taking magnesium oxide (9 mg elemental Mg 2 + /kg/ day) compared with those who took the placebo. Th e only reported side eff ect was l oose stools \200\22419% in magnesium oxide group and 7% in the placebo group (Wang et al., 2003). Oral magnesium sup- plementation has also been found to decrease pain in children du e to tension-type headache (Grazzi et al., 2007). Twenty-two patients were given magnesium pidolate 2.25 g twice a day for 3 months. Th ere was signifi cant reduction in number of he adache days (69.6% improvement, p = 0.001), analgesic consumption (65.4% improvement, p = 0 .0001), and Migraine Disability Assessment scale (MIDAS) score (75.5% improvement, p = 0.00 1) at 12 months compared to baseline. Th e treatment was well tolerated and free from serio us side eff ects. Butterbur 50 \200\223100 mg two to three times a day Chamomile 1 \200\2233 g three to four times a day Coenzyme Q 10 Digestive enzymes 100 \200\223300 mg a day 1 capsule before meals (25:2:25 ratio of amylase:lipase:protease) Feverfew 50 \200\223150 mg a day Ginger 250 \200\223500 mg three times a day L-Carnitine 1000 \200\2232000 mg in divided doses three times a day L-Th eanine 100 \200\223200 mg one to two times a day L-Tryptophan/5-HTP 50 \200\223300 mg a day Lemon balm 100 \200\223200 mg three times a day Magnesium 250 \200\223500 mg twice a day Marshmallow 2 \200\2235 g three to four times a day Acute treatment with intravenous magnesium has been used in adults to abort headache pain i n an outpatient clinic setting (Demirkaya et al., 2001; Mauskop et al., 1996). Of 40 patien ts given intravenous (IV) infusion of 1 g of magnesium sulfate, 80% had complete eliminatio n of pain within 15 min of infusion (P <0.001). Th ey also had complete elimination of phot ophobia, phonophobia, and nausea for 24 h (Mauskop et al., 1996). Th ese patients subse- qu ently were found to have low serum IMg 2+ levels. Th ere are no clinical trials using IV ma gnesium acutely to terminate migraine in children. Melatonin 0.3 \200\2235 mg 30 min before bedtime Peppermint (enteric coated) 200 \200\223400 mg three times a day Probiotics 10 \200\223100 billion CFU one to two times a day Slippery elm 400 \200\223500 mg 3 \200\2234 times daily Valerian 100 \200\223300 mg before bedtime Vitamin B complex One tablet a day Vitamin D 3 1000 \200\2234000 IU a day Oral magnesium \200\231s effi cacy is dependent on its absorption from the gastrointestinal tract. Magnesium oxide is poorly absorbed and can cause diarrhea. Use of the magnesium sal ts glycinate, aspar- tate, gluconate, citrate, malate, will yield better results without ca using diarrhea (Ranade and Somberg, 2001). Typical dosing for children is 250 to 500 mg ora lly twice a day \200\224start with the lower dose and gradually increase the dose for eff e ct. For acute manage- ment of migraine in a hospital or emergency department setting, 1 g o f magnesium sulfate can be given IV over 15 min in patients with normal cardiovascular and renal function. (NMDA) receptors preventing excessive neuronal depolariza- tion (Sun et al., 2005). Defi ci encies in magnesium play an impor- tant role in the pathogenesis of migraine headaches by p romoting cortical spreading depression, altering neurotransmitter release, promoting hypera ggregation of platelets, and causing vasoconstric- tion, all of which are relevant features of our current understanding of migraine pathophysiology. Magnesium defi ciency also resul ts in the generation and release of substance P, which is believed to act on sensory fi bre s and produce headache pain (Sun-Edelstein and Mauskop, 2009). Vitamin B complex Mitochondrial function has been found to be impaired in migraine patients (Gaby, 2011; Pieczenik and Neustad, 2007) and may be related to the B vitamins thiamin (B 1 ), ribofl avin (B 2 ), niacin (B 3 ), pantothenic acid (B 5 ), pyridoxine (B 6 ), and bio tin which are needed in mitochondrial energy production through synthesis of coen- zyme A, transfer of amino groups, donation of methyl groups, and activation of other enzymes. In ad dition, elevated homocysteine levels and lower serum and red blood cell folate levels are s een in both adult and pediatric patients with migraines (Nelson et al., 2010; Oterino et al ., 2010). Homocysteine accumulation leads to impaired fatty acid synthesis, infl ammation, vascular damage, and nervous system dysfunction. Other B vitamins (folic acid, cobala- min (B 12 ), pyridoxine (B 6 ), and pantothenic acid (B 5 )) may play a role in mitigating migr aine headache by lowering homocysteine levels. Vitamin B 6 , 100 mg given twice a day, doub led RBC mag- nesium levels aft er 4 weeks of therapy in pre-menopausal women Th ere have been confl icting reports in the literature regarding the actual magnesium leve ls in relation to reports of headache pain. Only 1% of the total body magnesium is in the m easurable extracellular space, therefore the levels found on routine blood testing do not r efl ect total body stores. It is the serum ionized magnesium level (IMg 2+ ) that truly ref l ects disturbed magne- sium metabolism. Patients who have low IMg 2+ may have normal serum levels, therefore, IMg 2+ levels provide more consistent and reliable results (Altura et a l., 1992). Normal IMg 2+ for children ranges from 1.09 to 1.51 mg/dL and typically does not vary with age (Hoshino et al., 1998). Levels of red blood cell (RBC) magne- sium have also been shown to be decreased in migraineurs (Gallai et al., 1993) as well as in juvenile mig raine patients with and with- out aura (Soriani et al., 1995). Given its commercial availab ility, the RBC magnesium assay may be a better way of assessing for CHAPTER 59 complementary drugs \200\224herbs, vitamins, and dietary supplements 615 (Abraham et al., 1981) so could have eff ects in treating migraine through this mechanism a s well. than the current AAP recommendation of 400 IU daily as 100 IU of vitamin D 3 only raises th e serum level by 1 ng/ml. It is safe to give 2000 to 4000 IU daily if levels are monitored every 6 to 8 weeks. Symptoms of vitamin D toxicity (levels >150 ng/ml) might include nausea , vomiting, poor appetite, weakness, confusion, or tingling around the mouth, and are relat ed to hypercalcaemia and hypercal- ciuria. Published cases of toxicity revealed intake of g reater than 40 000 IU per day (Vieth, 1999). Studies in children using single supplementation of ribofl avin (B 2 ) at doses 50 to 200 m g have been equivocal (Bruijn et al., 2010; MacLennan et al., 2008). However, a retrospecti ve study of 41 chil- dren given ribofl avin 200 to 400 mg daily found a signifi cant reduc- tion in both migraine frequency and intensity (Cond et al., 2009). In another study of 16 pediatric patients with migraine, hyper- homocysteinaemia, and methylenetetrahydrofolate reductase (MTHFR) polymorphisms, ten out of 16 patients had complete resolution of the mig raine episodes using folic acid 5 mg daily for 6 months. Th e plasma levels of homocysteine dropped to the nor- mal range in 100% of patients (Di Rosa et al., 2007). Butterbur ( Petasites hybridus ) Butterbur is a perennial shrub that historically has been used to treat migraine, allergic rhinitis, chronic cough, and urinary tract spasms. Th e ac tive constituents of butterbur, petasin and isopeta- sin, have antispasmodic eff ects on sm ooth muscle and vascular walls by non-competitive inhibition of histamine (Ko et al., 2001) . Th ey also inhibit leukotriene synthesis, and decrease the priming of mast cells, which l owers the concentration of histamine in vitro (Lee et al., 2003). Histamine is a key compon ent of the neuroin- fl ammatory process contributing to migraine acting mainly on H1 recept ors which mediate infl ammation and H3 receptors which serve as negative feedback to inhibi t further excessive release of his- tamine by C-fi bres (Gupta et al., 2011). Butterbur the reby impacts migraine pain via these mechanisms. Adult studies have shown effi cacy in using sustained release niacin (B 3 ) 375 mg twice a day or vitamin B 12 , either 1 mg intra- nasally daily or 1000 mcg intramuscularly every we ek, but these studies have not been done in children or adolescents (van der Kuy et al., 20 02). It is unlikely that any individual would have a single vitamin B defi ciency. Various B vit amins share similar but not identical functions, therefore, supplementation with a daily B- 50 complex formulation could be used when treating headache in children. Th is would provid e 50 mg of vitamins B 1 , -2 , -3 , -5 , -6 ; 50 mcg of cobalamin and biotin; and 400 mcg o f folic acid. All B vitamins are water-soluble, so excess amounts are readily excreted by t he kid- neys rather than accumulate in fatty tissue which can occur with fat-soluble vitami ns \200\224A, D, E, K. Butterbur contains hepatotoxic pyrrolizidine alkaloids (PAs) which are most concentrated in the plant roots, but may be found in all plant parts. Toxic PAs are removed from butterbur extracts. Th ese PA-free extracts are available for use and are considered safe. Butterbur root extract was found to be an eff ective and well-tol- erated migraine prophylaxis for c hildren and teenagers (Pothmann and Danesch, 2005). 108 children and adolescents between th e ages of 6 and 17 were included in a multicenter prospective open-label study of butterbur . Children 6 to 9 years of age initially received 50 mg of the butterbur extract once a day and adolescents aged 10 to 17 years received 50 mg twice a day. Aft er 2 months the dose f or non-responders increased to 75 mg daily (6 \200\2239-year-olds) or 75 mg twice a day (10 \200\22317-year-olds). Th e number of monthly migraine attacks was reduced 63.2% for the t otal sample population at the end of 4 months in relation to pre-study baseline measures an d the duration of pain was reduced, on average, from 10 h to 7 h. No seri- ous adverse even ts occurred. Vitamin D \200\224cholecalciferol (vitamin D 3 ) Very low vitamin D levels have been found in a survey of children with migraine (O \200\231Brien et al., 2010). Vitamin D defi ciency is asso- ciated with higher levels of pro-infl ammatory and pro-coagulatory biomarkers \200\224high sensitivity C-reactive protein, homocysteine, tissue plasminogen activator ant igen, and von Willebrand factor. Th ese same biomarkers are known to be elevated in adult a nd pae- diatric patients with migraine indicative of endothelial activation and vascular re activity caused by infl ammation and oxidative stress (Nelson et al., 2010; Tietjen et al., 2009). Vitamin D, important for neurovascular stability, immune modulation, and antithromb otic eff ects which lessen cardiovascular and stroke risks, is likely impor- tant, too, in decreasing the incidence of migraine. For migraine headache prophylaxis, a PA-free butterbur rhizome extract standardized to 15% petasin and isopetasin (Petadolex ) can be used in doses of 50 to 100 mg twice daily with meals. Th ree times daily dosing has been used in children who don \200\231t respond to the twice daily dose. Th e most commonly reported adverse events related to butterbur were bel ching, drowsiness, fatigue, nausea, and abdominal pain. Th ese adverse events are generally considered mild and self-limiting. Th us far no randomized, placebo controlled studies have been conducted using vitamin D how ever several case reports sug- gest that vitamin D may indeed be eff ective in reducing pai n in migraines and related conditions in adults. Vitamin D and calcium supplementation were used to successfully treat premenopausal and postmenopausal women with migraines who previ ously did not get relief with conventional therapies (Th ys-Jacobs, 1994a, 1994b). Other ca se reports also demonstrated reduction of headache pain with vitamin D (1000 \200\2231500 I U) and calcium (1000 \200\2231500 mg) sup- plementation within 4 to 6 weeks. Th ough the ro le of calcium in suppressing these headaches could not be ruled out, they surmised that vit amin D was more vital for headache relief in that serum calcium levels normalized within th e fi rst week of therapy, but headache pain only abated with normalization of the 25-hydrox y vitamin D (25(OH)D) levels at 4 to 6 weeks of treatment (Prakash and Shah, 2009). 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