CVS, Pain, Inflammation and Drugs

1. CVS, Pain, Inflammation and Drugs 1This review provides an overview of 59 randomized placebo-controlled trials that examined the analgesic effect of antidepressants Data from 41 controlled trials indicate that tricyclic antidepressants (TCAs) areeffective analgesics.Amitriptyline is the most thoroughly studied (1964-2000) agent; Note: The chronic pain diagnoses was for primarily, chronic tension headaches, migraine, psychogenic headache, Chronic organic pain ("usuallymusculoskeletal"), postherpetic *neuralgia (reactivation of the varicella zoster virus), fibromyalgia, primary fibrosis, Rheumatoid Arthritis(RA), Diabeticneuropathy, chronic intractable pain Selective serotonin reuptake inhibitor (SSRI) group of antidepressantshave been disappointing. These agents are not superior analgesicsas was hoped in the later 1980s and early 1990’s when it was assumed that analgesic mechanism of the antidepressantswere monaminergic In studies examining both SSRIs (Fluoxitine, Citalopram, Zimeldine, Paroxetine, Famoxetine) and TCAs, the analgesia obtained with TCAs was superior in every case. There is concern that SSRIs may actually enhance responses to noxious stimulation. *Neuropathic pain is pain caused by damage or disease affecting the somatosensory nervous system 12000. Antidepressantsas analgesics: a review of randomized controlled trials

2. Bendsten et al demonstrated an improvement in tension headache with amitriptyline, but not with citalopram. Max and co-workers found desipramineandamitriptyline, but not fluoxetine, to be effective in treatment of diabetic *neuropathy, Venlafaxineand tramadolexhibit pharmacological similarities as well; both inhibit reuptake of serotonin and norepinephrine, both are enantio selectively metabolizedby cytochrome oxidase isoenzymeP450 2D6 Summary: There is significant evidence that the TCAs are good analgesics, but data for the SSRIs are conflicting; data available to date indicate trazodoneis not analgesic, and although venlafaxineshows significant promise, clinical trials are needed. So, up to 2000, this selection as options for treatment for painwere few, but amitriptylinewas superior. Next we’ll look at the last 20 years meta-studies and see if developments have been made in understanding neurological pathways of painand which drugs are being used and why for CVS *Neuropathic pain is pain caused by damageor disease affecting the somatosensory nervous system

3. 2The year 1999 marked the 100th anniversary of the development of aspirin as a pharmaceutical compound used for the treatmentof rheumatic diseases. On this anniversary, new drugs developed as a result of advances in the understanding of prostanoid biosynthetic pathways have become available for clinical use. These drugs were specifically designed to inhibit the cyclooxygenase (COX) activity of the inducible isoform of prostaglandin H (PGH) synthase, or COX-2. NSAIDs non-specifically inhibit theCOX enzymes. Understanding of COX-2biology provides a rationale for the use of specific COX-2 inhibitorsin patients with rheumatic diseases, as well as cautionsrelated to the physiologic functions of COX-2. The common mode of action of these compounds was described in 1971 by Sir John Vane, who recognized that aspirinand NSAIDsinhibitproduction of PGs (Prostaglandins). He proposed that the therapeutic effects and the main side effects of these compounds result from blocking formation of PGs 21999, BASIC BIOLOGY AND CLINICAL APPLICATION OF SPECIFIC CYCLOOXYGENASE-2 INHIBITORS

5. 2The enzymesinvolved in the biosynthesis of prostaglandinsinclude the phospholipases that release Arachidonic Acidfrom phospholipid membranes, particularly phospholipase A2(PLA2). Arachidonate is metabolized to PGby the bi-functional enzyme cyclooxygenase (COXor PGH synthase), after which stable PGsare formed by a group of synthases. (See Vagus Nerve Presentation introduction slides) The principal mechanism of action for aspirinand NSAIDs is inhibitionof the enzymatic activity of COX. Until 1990, it was thought that the rate-limiting step in prostanoid biosynthesis was the availability of Arachidonic Acid (AA) substrate. However, Masferrer et al,in the laboratory of Dr. Philip Needleman, made the observation that COXproteinin micewas increased by exposure to bacterial endotoxinand, furthermore, that the levels of COX protein were decreased by glucocorticoids(corticosteroids) 21999, BASIC BIOLOGY AND CLINICAL APPLICATION OF SPECIFIC CYCLOOXYGENASE-2INHIBITORS

6. Arachidonate is metabolized to PGby the bifunctional enzyme cyclooxygenase (COXor PGH synthase), after which stable PGsare formed by a group of synthases. (See Vagus Nerve Presentation introduction slides)

7. 1The prostaglandinswere discovered over 40 years ago when it was noted that seminal fluid had smooth muscle contracting activity. Since then, considerable progress has been made in understanding their biochemistry, metabolic pathways and physiological roles in the various tissuesof the body. In the body the predominant precursor is arachidonic acid, an integral component of cell membranes. In 1976 a new prostaglandin, initially called prostaglandin Xand now known as prostaglandin L (PGL), or prostacyclin, was described (4). This prostaglandin, which is synthesized by the blood vessel wall, is a potent inhibitor of platelet aggregation and a powerful vasodilator. Because of the unique properties of PG12 it has been the subject of intense investigation. It has been designated PG12 because it was the next prostaglandin in alphabetical order after prostaglandin H to be characterized, and the subscript 2 indicates that it is derived from fatty acids with two unsaturated bonds. The substrates for its synthesis are the endoperoxides, prostaglandin G2(PGG2) and prostaglandin H (PGH2). The effect of PGI2 on platelets is augmented by agents that inhibit cyclic AMP degradation.' 11980. Prostaglandin I2 (prostacycin)

10. The [de novo] synthesis of PGI2by the blood vessel wall may be important in limitingplatelet-augmented thrombosis (42). We have demonstrated in rabbits that the inhibition of the production of PG12 by the vessel wall with large doses of acetylsalicylic acid, hydrocortisone or tranylcypromine augments *thrombus formation. A role for PGI2in the development of atherosclerosishas also been suggested. Lipid peroxides that are present in atherosclerotic plaques have been demonstrated to be potent inhibitors of PGI2synthetase. However, some investigators have questioned this hypothesis, and therefore the potential role of PGI2 in the pathogenesis of atherosclerosisremains unresolved. PGI2 may influence many organ systems in addition to hemostasis and thrombosis. PG12 is produced by the human renal cortex 52) and rabbit kidneys synthesize PG12from bothendogenous and exogenous arachidonic acid. Although thekidney cansynthesizePGI2, it preferentially synthesizesthromboxane A2(a potent vasoconstrictor and inducer of platelet aggregation) following ureteric obstruction (52) Thus, PG12may act as the vasodilatory balance to the vasoconstriction produced by the kidney's thromboxane A2. Both PGE2 and PG12may play a role as blood pressure regulators. Indeed, PGI2may be the prostaglandin of prime importance since it is more potent than PGE and, unlike PGE2, is not completely inactivated in the pulmonarycirculation. The infusion of PG12into hypertensive animals normalizes the blood pressure.

11. 1Inflammation- Prostaglandinsof the E series (PGE1 and PGE) are released during inflammation and enhance the reaction by increasing vascular permeability. PGI2also potentiates the inflammatory response but, unlike PGE, does not alter vascular permeability but potentiates the vascular permeability induced by histamineand serotonin Drugs that inhibit the prostaglandin pathwayand block PGI2 production have the potential to alter the physiological effects of PGI2. Because of the potent vasodilatory activity of PGI2 and its analogues, PGI2 has been suggested for clinical use in a wide variety ofdisorders, including myocardial infarction, angina, vascular occlusive diseases and hypertension. PG12 has recently been used successfully in the treatment of patients with advanced arteriosclerosis obliterans. Conclusion – PGI2, a recently discovered potent prostaglandin, may play a fundamental physiological role in a number of organ systems in addition to hemostasis andthrombosis. Its depletion by disease and drugs may also be important in a number of disorders. However, as yet the exact physiological function of PGI2is unclear. 11980. Prostaglandin I2 (prostacycin)

12. 1Masferrer and co-workers further hypothesized that the presence of different COXenzymescould havefunctional consequences, that is, one isoform could be responsible for the PGs produced in pathologic situations whereas physiologic PGs might be the product of another COX isoform If this is indeed the case, then specific inhibition of COX-2might provide the therapeutic benefits associated withNSAIDswithout the usual side effects. Note: Reducing the amount of toxicity incurred by drugs is part of the paradox. Almost, if not all pharmaceutical drugs, are either affecting the Liver or Kidneys, losing function of either leads to inflammation and dysfunction over time. The most striking difference between the COXisoformswas at the level of basal expression and regulation of the messenger RNA (mRNA) (9). The promoter region of COX-1 has the characteristics of a housekeeping gene, a gene that is continuously transcribed and stably expressed COX-1 is the only isoform expressed in platelets, and is responsible for production of PGsthat maintain the integrity of normal gastric mucosa(12). COX-1 is also available to increase PG production acutely when an abrupt increase in arachidonate substrate occurs 11999, BASIC BIOLOGY AND CLINICAL APPLICATION OF SPECIFIC CYCLOOXYGENASE-2 INHIBITORS

13. Expression of cyclooxygenase-1(COX-1) and COX-2. COX-1expression is constitutive in most tissues. There are a few situations in which COX-1 is modestly increased during cellular differentiation. COX-2 exhibits restricted expression under basal conditions, but can be markedly induced in response to stimulation by cytokines, mitogens/growth factors, hormones, and many other pathologic and physiologic stimuli.

14. As would be predicted, COX-2 expression is highly induced by a number of cytokines, including interleukin-1 (IL-1), tumor necrosis factor a (TNF-a) and other stimuli associated with inflammation and growth (9,19) It has been confirmed that COX-2 expression is inhibited by glucocorticoids in all cells and tissues studied to date (9). Note: That date being 1999/2000 and data available up to that point (9)  In animal models of inflammatory arthritis, COX-2 increases in parallel with PG production and clinical inflammation. In vitro experiments have revealed increased COX-2 expression after stimulation with pro-inflammatory cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), in many cell types, including synoviocytes, endothelial cells, chondrocytes, osteoblasts, and monocytes/macrophages. Another distinguishing characteristic of COX-2is decreased expression in response to glucocorticoids. COX-2 is also increased in some types of human cancers, particularly colon cancer. IL-1 increases COX-2 mRNA half-life in addition to increasing transcription. However, the mechanisms by which glucocorticoidsinhibitCOX-2 expression have not yet been completely elucidated. Many agents that stimulate arachidonate release, such as cytokines and growth factors, also stimulate transcription of COX-2, and full prostanoid biosynthetic capacity is reached only when COX-2 is induced(24). (9) 1997, CroffordLJ. COX-1and COX-2tissue expression: implications and predictions. J Rheumatol;24 Suppl 49:15–9.

16. (24) Prostaglandin synthesis is initiatedwhen agonists such as histamine [1], bradykinin[2-4], leukotrienes [5,6], angiotensin[7], cytokines [8-11), thrombin[41) or growth factors [12-14] activate specific phospholipases causing the release of arachidonatefrom membranes. Released arachidonate is converted to PGH2 byprostaglandin H (PGH) synthase, the central enzyme in the prostaglandin biosynthetic pathway arachidonate Prostacyclin PGI2 (24) 1991, Prostaglandin endoperoxidesynthase: regulation of enzyme expression. BiochimBiophysActa083:121–34

18. COX-2

20. Add 15 year old case file on CVS and CYTOCHROME SNP MUTATIONS

21. In virtually all models studied, COX-2 expression increases in response to inflammatory stimuli and other types of tissue damage. Since NSAIDsare efficaciousin the treatment of arthritisand other forms of acute and chronic inflammation, examination of the relative expression of COX-1 and COX-2 in these types of disorders provides some insight into potential roles for the isoformsand potential therapeutic benefits of specific COX-2inhibition. BothCOX-1 and COX-2 are expressed in synovial tissuesof patients with arthritis Note: With Idiopathic Adhesive Capsulitis that I am currently dealing with, the synovium is inflamed, so thetissues would be also which induces the pain. Its not RheumatoidArthritis, but without treatment may well lead to fibrosisat the least, and osteoarthritisat the worst COX-1 is localized at the synovial lining layer, and there is no difference in the level of expression in inflammatoryversus non-inflammatory arthritides(32). COX-2 is localized to the sublininglayers, particularly the vascular endothelial cells, infiltrating mononuclear inflammatory cells, and fibroblast-like synoviocytes. Its expression is increased in inflammatory forms of arthritis (32,33).

23. In peripheral tissues, PGs (Prostaglandins) prolong pro-inflammatory actions of bradykinin, histamine, nitric oxide, and othermediators. Centrally, there is constitutive expression ofCOX-2in the spinal cord,which is up-regulated during inflammation (34) The anti-inflammatory and analgesic activity of specific COX-2 inhibition correlated with decreased cerebrospinal fluid PG levels (35). Nevertheless, COX-2 in the central nervous system seems to play an important role in the therapeutic efficacy ofNSAIDsand specific COX-2 inhibitors. Feveroccurs in response to inflammation and induction of cytokines. PGs have long been known to mediate the fever. COX-2 expression is induced inthe brain vasculature, with temporal correlation to the development of fever(40). Moreover, mice with targeted COX-2 gene disruption fail to develop fever in response to inflammatory stimuli (41). Patients with Helicobacter pylori–associated ulceration have increased COX-2 expression ingastric mucosa. After treatment of the infection, COX-2 levels are decreased (43). The significance of COX-2 for producing protective prostanoidsin these settings relative to COX-1–mediated PG production is not clear, although it has been shown that specific inhibition of COX-2delays healingof gastric mucosal erosions and ulcers in mice (46). Further clinical evaluation is needed to determine what role COX-2 may play in the healing of damaged GI mucosa.

24. The fact that only COX-1is expressed in platelets and is responsible for thromboxane A2(TXA2) productionduring platelet activation, while endothelial cells have the capacity to express both COX-1 and COX-2, may have implications regarding vascularphysiology in patients treated with specificCOX-2 inhibitors. PGs influence the balance between collagendepositionand matrix metalloproteinase production in fibroblasts (53), indicates that failure to induce COX-2 normally may contribute to the development of fibrosis in IPF (Idiopathic Pulmonary Fibrosis). Although use of NSAIDsis known to prolong labor, the extent of COX-2 involvement in reproductive function was perhaps not fully appreciated until it was shown that COX-2 knockout mice had impaired fertility (57). In addition, there is a focal increase of COX-2 expression at the site of blastocyst attachment in the uterus (60). COX-2 is highly expressed constitutively in the vas deferens of the adult male rat. Expression appears to be dependent on androgen since castration depletes COX-2and androgenreplacement after castration restores levels of COX-2 (61). COX-1 and COX-2 are expressed in different cells and tissues of the lung. COX-2 is expressedunderbasal conditions inmacrophage and mast cell–like cells in proximity to bronchial epithelium.

25. COX-2is hypothesizedto play a role in development of Alzheimer’s disease, although data are conflicting as to whether COX-2 is actually increased or decreased in the brainof patients with this disease(69–72). The critical role of PGsin renal physiology is demonstrated by the fact that alterations in renal function develop in some patients treated with NSAIDs. Further studies are needed to clarify whether COX-2 is similarly localized in the human kidney but preliminary studies have indicated that COX-2 is present in the glomerular podocytesand the vasculature(74,75) Evidence that COX-2 plays a role in renal function in humans is provided by clinical trials demonstrating an excess of edema (bloating, swelling of the ankles, water retention) when high doses of specific COX-2 inhibitors are given (76). Additionally, in healthy elderly volunteers, specific COX-2 inhibitors decreasedrenal prostacyclin production and led to a significant transient decline in urinary sodium excretion (77,78). Clinical implications of these biologic observations are currently unknown, For the purpose of this discussion, Celecoxiband Rofecoxibwill be considered specific COX-2inhibitors(47,82).

26. Note: A few things to consider is that using NSAIDSto target COX-2 (COX-1 too) has its issues, such as processes involving basal operations concerning bone formulation and remodelling, fertility, collagen and anti-inflammatory processes. There is also the toxicity of the drugs, and most NSAIDS should not be taken long term due to its effects on the liver and kidneys, and the body’s ability for sudden expression of intolerance to the drug Nevertheless, from a clinical standpoint, there are two key questions for evaluating the specific COX-2inhibitors in comparison with other NSAIDs: Are they equally effective forarthritis and/or pain? Are there differences in the side effect profiles? These early clinical trials demonstrate that endoscopic ulcerationis significantly reduced with specificCOX-2 inhibitors. However, too few patients have been studied to be able to definitively demonstrate a reduction in clinically significant GI events. It bears repeating that data do not demonstrate a significant reductionof non–ulcer related GI symptoms (nausea, dyspepsia, abdominal pain) with the specificCOX-2inhibitors. The addition of aspirin to a regimen of treatment with a specificCOX-2 inhibitorwill, of course, alter the overall risk for GIside effects and other bleeding complications (84,85).

27. Amitriptyline 1It is well established that the tricyclic anti-depressant amitriptyline possess analgesic activity in various chronic pain conditions and that the analgesic action of this drug is independent of its anti-depressant effect (3,4). However, the exact analgesic mode of action is unknown. The blockade of serotonin and noradrenaline reuptake in the Central Nervous System (CNS) probably plays an essential role (3,5), but other mechanisms such as reduction of central sensitization, i.e., increased excitability of neurons in the Central Nervous System, may also be important The primary aim of the present study was to examine whether amitriptylinemainly inhibits muscle painas reflected by a reduction of myofscial tenderness, or whether it reduces pain sensitivity in general as reflected by an increase in electrical or extracranial mechanical pain threshold. Note: This study compared Citalopramand Amitriptylinein an 8 week period and “compared with placebo, there were no significant effects of citalopram on actual headache intensity”. 12000, Amitriptyline reduces myofascial tenderness in patients with chronic tension-type headache

28. 2Amitriptylinedid not modulate the sensitivity to pressure or electrical pain stimuli applied to various parts of the body, indicating that pain sensitivity in general was unaffected. Thus, the present data indicate that amitriptylinereducesnociceptionfrom myofascial tissues rather than pain sensitivity in general Thus, while citalopram is an extremely specific serotonin reuptake inhibitor (39) amitriptylinealso has several other effects, e.g. effects on reuptake of noradrenaline as well as effects on serotonergic (40), adrenergic (41), cholinergic(40), and histaminergic(34) receptors. Of these effects, especially inhibition of noradrenalinereuptake(42, 43), and the effects in various serotonin subtypes (44, 45) have been considered important Therefore, it is most likely that the reduction of tenderness exerted byamitriptyline, at least in part, is caused by a segmental action in the Central Nervous System, probably at the level of the spinal Dorsal Horn/trigeminal nucleus. An electro-physiological study by Su & Gebhart (55) points towards a direct analgesic effect of tricyclic anti-depressants on afferent nerves, while studies by Esser & Sawynok (56) and Sawynok et al. (57) indicate that interaction with endogenous nociceptive mediators effectamitriptyline 2(26) 1986, A RANDOMIZED, CONTROLLED TRIAL OF AMITRIPTYLINEAND NAPROXENIN THE TREATMENT OF PATIENTS WITH FIBROMYALGIA

29. 3Patients with cyclic vomiting syndrome plus have many of the same neuromuscular conditionsfrequently reported in individuals with mitochondrial disease, and many are evaluated for the possibility of a mitochondrial disorder Most cases of cyclic vomiting syndrome plus also demonstrate lactic acidosis, energy-deficient patterns on urine organic acid analysis, and pedigrees suggestive of maternal inheritance, suggesting that cyclic vomiting syndrome plus is a phenotyperelated to mitochondrial dysfunction secondary to predisposing mitochondrial DNA sequence variants. Maternal inheritanceis suggestive of mitochondrial DNA involvement because mitochondrial DNA is asexually inherited from the Ova, without recombination, and cyclic vomiting syndrome in general is related to the mitochondrial DNA sequence and, hence, to energy metabolism Note: As seen in various other papers and in other parts to this thesis (powerpoints Parts 1-5, Vagus Nerve and Vitamin D/Omega-3/Omega-6), the connection with dysfunction with some Cytochrome P450 enzymes in metabolising certain drugshas been cited. More on this later. This raises the following question: Is cyclic vomiting syndrome plus a distinct entity either clinically or genetically, or is neuromusculardiseasesimply another potential phenotype secondary to the mitochondrial dysfunction that is related to cyclic vomiting syndrome? All subjects report being Caucasian, with one being of Hispanic ethnicity. 32006, Cyclic Vomiting Syndrome Plus,

31. 1One of the most clinically important causes of drug interactions is the inhibition or induction of the activity of cytochrome P450[5], a superfamily of enzymescatalyzing the metabolism of a large number of drugs. the most important forms are CYP2D6 and CYP3A4. (SeeCyclic Vomiting Syndrome case involving CYP2D6, CYP2C9, and CYP2C19) 12004, Potential for drug interactions involving cytochromes P450 2D6 and 3A4 on general adult psychiatric and functional elderly psychiatric wards

32. This study from 2004 cited poor metabolism of a certain drug, Doxepin,due to polymorphic changes in Cytochrome450 enzymes(CYP) CYP1A2, CYP2C19, and CYP2D6, but there are others

33. 1This paper presents 6 patients who responded to I-carnitine administration. Average time between episodes was 1.7 months before carnitine administration and increased to 1.1 years after carnitine administration. Average dose of carnitine administered was 50 mg/kg. Oral carnitine may be useful to control the symptoms in patients with cyclic vomiting syndrome. The incidence of CVSranges from 1.7 to 2.7 percent of school children, (2-4) and the etiology remains largely unknown. Proposed causative factors include epilepsy, irritable bowel syndrome, and psychiatric factors (5), classic migraine, abdominal migraine, and CVS may be related (6,7). There is no known cure for CVS, but several therapies to alleviate symptoms have been tried. Prophylactic agents have included anti-migraine agents such as beta-blockers (propranolol) and Tricyclic Anti-depressant 5-HT2 antagonist amitriptyline and GABA inhibitors have also been prescribed. These agents ameliorate symptoms in about 70% of cases.(8-11) This paper presents another possible prophylactic agent for CVS: I-carnitine. free plasma carnitine normal levels: 39 umol/L 12002, L-Carnitine Administration Reduces Number of Episodes in Cyclic Vomiting Syndrome

34. 1After starting carnitine at 30 mg/kg, the number of episodes was greatly reduced and he missed no school for over 1 month. After a few months on the carnitine regimen, he (12.5 year old) had a setback, but increasing carnitine to 55 mg/kg reduced the episodes again. Because of the association between vomitingand the diagnosis of inborn errors of metabolism, all 6 subjects were evaluated for metabolic disorders. Fatty acid oxidation defects and mitochondrial DNA mutationshave been diagnosed in individuals with CVS(12-14). In this study, none of the subjects were diagnosed with an inborn error of metabolism (IEM). However, since mitochondrial DNA was not sequenced in any of the subjects, a mitochondrial defect was not entirely ruled out. Initially, subjects were given carnitine supplementation anda low-fat diet because of the possibility that they had a fatty acid oxidation defect. It was noted that their episodes of vomiting decreased substantially or stopped completely with carnitine. Later, CVSsubjectswere prescribed a trial of carnitine alone. They too responded to the treatment. Vomiting episodes resumed after Patient 5 stopped taking carnitineand after Patient 6 decreased the dose. In both cases, returning the carnitine dose to its original level decreased the frequency of vomiting episodes. 12002, L-Carnitine Administration Reduces Number of Episodes in Cyclic Vomiting Syndrome

35. A mechanism for the effect of carnitine on cyclic vomiting is unknown. Possibly some noxious compound is being bound by carnitine as a carnitine ester, thus reducing its toxicity. This is the mechanism that is believed to underlie carnitine'seffectiveness in treatment of organic acidemias(15,16). Whatever the mechanism, carnitine may prove to be another drug for the prophylactic treatment of CVS. A double-blind placebo-controlled trial would formally determine the effectiveness of carnitine in the treatment of CVS. For a CVS patient to respond to carnitine administration, it does not appear that a low plasma carnitine concentrationis a prerequisite for carnitine to help reduce vomiting frequency and severity. Three of 5 subjects had normal carnitine concentrations before starting carnitine treatment.

36. 1CVSis generally believed to be a variant of migraine based on overlapping symptoms such as headache, nausea, and photophobia. There is also frequent progression of CVS to migraine headache, and a very high prevalence of migraine among close relatives of CVS patients [4]. Furthermore, CVS and migraine respond to many of the same medications including amitriptyline, cyproheptadine, propranololand triptans. Amitriptyline(Elavil), a tricyclic “antidepressant” is the most widely prescribed prophylactic medication used for the treatment of CVS. In a recent consensus statement on management, amitriptyline was recommended as the first-line treatment choice for CVSprophylaxis in patients age 5 years and older (1) Three reasons prompted us to study whether Co-Q has efficacy in CVSprophylaxis: 1) demonstrated efficacy of Co-Q in migraine prophylaxis; 2) its increasingly popular usage in CVS; and 3) the association of both conditions with mitochondrial dysfunction. In this retrospective study, we compare the efficacy, tolerabilityand patientsatisfaction of Co-Q with the current standard-of-care in CVStherapy: amitriptyline. 12010, Treatment of cyclic vomiting syndrome with coenzyme Q10and amitriptyline, a retrospective study

37. 1Our result of 72% efficacy (defined by compound measure) in those taking prophylactic amitriptyline agrees with the 52 to 73% efficacy rates reported in four previous studies [4-7]. This result also supports the overall validity of our on-line survey methodology. Our data is also consistent with our own clinical experience, in that overall efficacy is good (72%), yet side effects are frequent (50%), and often result in discontinuation of treatment (21%). Overall, approximately half(47%) of 134 subjects taking amitriptylinereported that the benefits outweighed the side effectsof treatment. Furthermore, our data regarding the preventative treatment of CVSwith Co-Q is consistent with our clinical experience, in that overall efficacy is good (69%), with side effects being rare (0/22). Three-quarters (77%) of subjects taking Co-Q reported that the benefits outweighed the side effects, asignificantly higher portion than that with amitriptyline. There are substantial child versus adult-related differences in clinical CVS, such as longer and more frequent episodes and more severe inter-episodic nausea among adults [29]. Furthermore, a strong association with the 16519T and 3010AmtDNApolymorphismswas noted 12010, Treatment of cyclic vomiting syndrome with coenzyme Q10and amitriptyline, a retrospective study

38. Interestingly, both amitriptyline and Co-Q seem to affect different parameters in different people, including episode frequency, episode duration, number of emeses, and severity of nausea. Neither therapy appears to affect the prodrome The authors’ clinical practice for treatment of CVSwith Co-Q is 10 mg/kg/day divided *bid, up to 200 mg bid(either in liquid or gel capsule formulation). It also includes obtaining a blood Co-Q level in the case of an inadequate response, and increasing the dose for blood levels less than 3 mg/L. Additional mitochondrial-targeted dietary supplements have also been used to prevent CVS attacks including L-carnitine, and riboflavin, which has demonstrated efficacy in migraine headache [32] (authors’ practice: 100-400 mg/day) Anecdotally, in the authors’ practice while some CVS patients respond well to cofactor therapy alone, many patients require drug therapy (generally amitriptyline) in addition. Our data suggest that the naturally-occurring food supplement Co-Q (ubiquinone) has potential therapeutic efficacy and excellent tolerability in the treatment of CVS. *bid = “bisin die” or twice a day. Tid = three times a day 12010, Treatment of cyclic vomiting syndrome with coenzyme Q10and amitriptyline, a retrospective study