A rational combination for the prophylaxis of migraine, the nociceptive modulation and the reduction of tension states

Transcription

1 A rational combination for the prophylaxis of migraine, the nociceptive modulation and the reduction of tension states

2 2 VULNERABILITY TRIGGERING PAIN MODULATION Headache is a painful disorder of the head (sometimes associated with painfullness of the face and/or neck). It is the most common pain syndrome. In Italy, it affects about ten million people in an episodic way, two million chronically. The primary headache can be divided into three main groups: Migraine Tension-type headache (CTT) Cluster headache Migraine is present in 18% of women and 6% of men, manifested in recurrent attacks, with moderate to severe intensity, associated with autonomic symptoms such as nausea, vomiting, photophobia, phonophobia, separated by free intervals (periods of well-being), and chronic. In recent years there have been many studies on the origin of migraine but a unitary model has not yet been reached. To explain the pathophysiology of migraine four main theories have been proposed over the years: 1) Peripheral vascular theory: alteration of cerebral vessels with a mechanism of constriction/dilatation leading to the classic throbbing pain. 2) Trigeminal-vascular theory, according to which the stimulation of trigeminal fibers would lead releasing from axon, collateral, of certain substances (neuropeptides) as substance P, neurokinin A and CGRP inducing the so-called neurogenic inflammation. 3) Central theory, according to which there would exist a condition of impaired cerebral neuronal excitability due to dysfunction of calcium channels or mitochondrial defects or other. 4) Unified theory that considers the migraine a polygenic and multifactorial disease, caused both by environmental factors and genetic factors involving different genes. According to this theory there would exist events which, starting from the posterior areas of the brain would spread to other areas including the brainstem trigeminal-vascular system and promote platelet changes, modifications of the diameter of the vessels and release of algogenic substance. A prophylactic therapy is indicated not only when the attacks are believed to be frequent (>3-6/months) but also when they are present two or three times per month (48-72 hours) and/or very disabling. Prophylaxis is defined to be positive when it lead to a reduction of 50% of frequency in the number of attacks/month or their intensity.

3 3 vulnerability THEORY OF CHANNELLOPATHIES METABOLIC THEORY FHM-1 Ca ++ GENETIC RISK FACTORS FHM-2 ATP-pump FHM-3 Na + channel Cerebral metabolism is altered in all types of headaches, generating, as a direct therefore, a generalized hyperexcitability and the progressive lowering of the so-called migraine threshold. ATTACK THRESHOLD GLU / MIDBRAIN 5-HT This alteration appears to result from a compromised oxidative metabolism. Mg ++ Mg ++ is actively involved in control of NMDA receptors, resulting in the inhibition of calcium entry within the cell. Various experimental methods have highlighted as the levels of Mg ++ are [1, 2] lower in patients with migraine. The Role of Magnesium in the prophylaxis and in migraine pain has been documented in numerous clinical [3, 5, 6, 7, 11, 12] studies. The muscle relaxant activity of Magnesium helps to reduce the stress-associated states. Riboflavin is the most important cofactor involved in the oxidative mitochondrial chain. Numerous double-blind, randomized, placebo controlled clinical studies have confirmed the clinical benefits in the reduction of the frequency of attacks [4, 5, 6, 7, 11] and the degree of severity. Coenzyme Q10, like riboflavin, plays a central role in the electron transport in the mitochondria. In recent years Coenzyme Q10 has been the subject of several clinical studies that have confirmed the efficacy in the prophylaxis [4, 5, 6, 7, 8, 10, 11, 12] of headaches.

4 4 NEUROVASCULAR THEORY Triggering Cortex Hypothalamus Dura NO 5-HT, Histamine PG, CGRP vasodilation protein extravasation macrophage activation

5 5 Thalamus Dorsal raphe nucleus Locus coeruleus Superior salivatory nucleus Parthenolides, active components of the parthenium extract, powerful inhibitors of the expression of NOS and the subsequent synthesis of nitric [5, 6, 7, 9, 11, 12, 13] oxide. Parthenolides showed in experimental models, both in vitro and in vivo, to inhibit in a specific manner the activation of NF-kB, the proinflammatory cytokine synthesis (IL-1beta, IL-6 and TNFalpha) and the activation of microglia in the CNS. [17,18] Trigeminal ganglion First Author No. Patients/ Dropouts Magnus raphe nucleus Dosage Parthenium In vitro and animal models experiments have also documented significant effects on the release of serotonin (5-HT) from platelets, and inhibition of [5, 6, 7, 9, 11, 12, 13] phospholipase A. The primary endpoint Results Johnson et al. 17/02 50 mg/die Frequency of attacks; Incidence of nausea and vomit The frequency of attacks was significantly higher in patients compared with placebo (p<0.02). Pterygopalatine ganglion Murphy et al. 72/12 82 mg/die Frequency, duration and severity of attacks; Incidence of nausea and vomit 24% reduction in the frequency of attacks (p<0.005). Significant reduction (p<0.02) of nausea and vomiting. No changes in the severity of the attacks. Palevitch et al. 57/nr 100 mg/die Intensity of pain; Degree of severity of nausea and vomiting Significant reduction (p<0.01) for each endpoint.

6 6 NEUROVASCULAR THEORY Altered modulation and neurogenic inflammation Cortex Hypothalamus Dura Midbrain dysfunction pronociceptive state Reduced filter of peripheral sensory and central input Trigeminal reflexes may act as feed-forward system causing vasodilation

7 7 Thalamus Trigeminal ganglion Dorsal raphe nucleus Locus coeruleus Superior salivatory nucleus Magnus raphe nucleus Andrographolide, an active constituent extracted from the leaves of Andrographis paniculata, has shown, both in vitro and in vivo, a marked antinociceptive and anti-inflammatory activity comparable to NSAIDs and [14, 15, 16] opioids. Andrographolide is a potent inhibitor of NF-kB and the synthesis of proinflammatory cytokines. [19] 20 ANDROGRAPHOLIDE * p < 0,05 16 Pterygopalatine ganglion Writhing (number) * * * 0 Control * Morphine (5 mg/kg) Andrographolide (25 mg/kg) Andrographolide (50 mg/kg) Andrographolide (100 mg/kg) Writhing Test (central pain)

8 SWALLOWABLE TABLETS COLORED FILM Coenzyme Q10, RIBOFLAVIN, MAGNESIUM and dry extracts of PARTHENIUM and ANDROGRAPHIS PANICULATA A rational combination for the prophylaxis of migraine, the nociceptive modulation and the reduction of tension states NUTRITIONAL INFORMATION Substances with nutritional or physiological effect 1 CPR %VNR* MAGNESIUM 281,25 mg 75 PARTHENIUM dry extract 150 mg ANDROGRAPHIS PANICULATA dry extract 100 mg COENZYME Q10 20 mg VITAMIN B2 4,8 mg 342,857 *Nutritional values of reference for daily vitamins and minerals within the meaning of Regulation (EU) No. 1169/2011 HOW TO USE: 1 or 2 tablets per day, swallowed with a sip of water. Bibliography 1. Pan Afr Med J. 2012;11:46. Epub 2012 Mar 15. Blood Magnesium levels in migraineurs within and between the headache attacks: a case control study. Samaie A, Asghari N, Ghorbani R, Arda J. 2. Neurosciences (Riyadh) Oct;16(4): Relation between serum magnesium level and migraine attacks. Talebi M, Savadi-Oskouei D, Farhoudi M, Mohammadzade S, Ghaemmaghamihezaveh S, Hasani A, Hamdi A. 3. J Neural Transm May;119(5): doi: /s Epub 2012 Mar 18. Why all migraine patients should be treated with magnesium. Mauskop A, Varughese J. 4. Headache Oct;52 Suppl 2:81-7. doi: /j x. CoEnzyme Q10 and riboflavin: the mitochondrial connection. Markley HG. 5. Can J Neurol Sci Mar;39(2 Suppl 2):S1-59. Canadian Headache Society guideline for migraine prophylaxis. Pringsheim T, Davenport W, Mackie G, Worthington I, Aubé M, Christie SN, Gladstone J, Becker WJ; Canadian Headache Society Prophylactic Guidelines Development Group. 6. Headache Mar;51(3): doi: /j x. Nutraceuticals and headache: the biological basis. Taylor FR. 7. Clin J Pain Jun;25(5): doi: /AJP.0b013e31819a6f65. Foods and supplements in the management of migraine headaches. Sun-Edelstein C, Mauskop A. 8. J Child Neurol Nov;23(11): doi: / High-dose riboflavin for migraine prophylaxis in children: a double-blind, randomized, placebo-controlled trial. MacLennan SC, Wade FM, Forrest KM, Ratanayake PD, Fagan E, Antony J. 9. Headache Mar;46(3):531. Feverfew for migraine prophylaxis. Henneicke-von Zepelin HH. 10. Neurology Feb 22;64(4): Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial. Sándor PS, Di Clemente L, Coppola G, Saenger U, Fumal A, Magis D, Seidel L, Agosti RM, Schoenen J. 11. Headache Jun;52(6): doi: /j x. The 2012 AHS/AAN guidelines for prevention of episodic migraine: a summary and comparison with other recent clinical practice guidelines. Loder E, Burch R, Rizzoli P. 12. Neurology Apr 24;78(17): doi: /WNL.0b013e d0c. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. 13. Pharmacogn Rev Jan;5(9): doi: / Feverfew (Tanacetum parthenium L.): A systematic review. Pareek A, Suthar M, Rathore GS, Bansal V. 14. Arch Pharm Res Sep;32(9): doi: /s x. Epub 2009 Sep 26. Analgesic, antipyretic, anti-inflammatory and toxic effects of andrographolide derivatives in experimental animals. Suebsasana S, Pongnaratorn P, Sattayasai J, Arkaravichien T, Tiamkao S, Aromdee C. 15. Biol Res Nurs Jan;11(3): doi: / Epub 2009 Aug 18. Antinociceptive and antiedematogenic activities of andrographolide isolated from Andrographis paniculata in animal models. Sulaiman MR, Zakaria ZA, Abdul Rahman A, Mohamad AS, Desa MN, Stanslas J, Moin S, Israf DA. 16. Phytother Res Jul;23(7): doi: /ptr Antioxidant, antioedema and analgesic activities of Andrographis paniculata extracts and their active constituent andrographolide. Lin FL, Wu SJ, Lee SC, Ng LT. 17. Cephalalgia : 612; Parthenolide is the component of tanacetum parthenium that inhibits nitroglycerin-induced Fos activation: studies in an animal model of migraine. Tassorelli et al. 18. Phytother. Res Parthenolide Inhibits the LPS-induced Secretion of IL-6 and TNF-a and NF-kB Nuclear Translocation in BV-2 Microglia. Magni et al. 19. Plos One 2013 Andrographolide Protects against LPS-Induced Acute Lung Injury by Inactivation of NF-kB. Zhu et al. FB Health S.p.A. Via dei Sabini, Ascoli Piceno Tel Fax fb-health@fb-health.com