Magnesium Oral Supplementation to Reduce Pain Inpatients With Severe Peripheral Arterial Occlusive Disease

Summary

Magnesium exerts analgesic effects in several animal pain models and in patients affected by acute postoperative pain and chronic pain of neuropathic origin. There is no evidence that magnesium can modulate pain in patients with peripheral arterial occlusive disease (PAOD). We describe the protocol of a single-center randomized double-blind clinical trial aimed at assessing the efficacy of oral magnesium supplementation in controlling severe pain in patients with advanced PAOD.

Timeline

Start

2015-09

Primary completion

2017-12

Completion

2017-12

Publications

• Background Dowell D, Kunins HV, Farley TA. Opioid analgesics--risky drugs, not risky patients. JAMA. 2013 Jun 5;309(21):2219-20. doi: 10.1001/jama.2013.5794. No abstract available.
• Background Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, Norman PE, Sampson UK, Williams LJ, Mensah GA, Criqui MH. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013 Oct 19;382(9901):1329-40. doi: 10.1016/S0140-6736(13)61249-0. Epub 2013 Aug 1.
• Background Iseri LT, French JH. Magnesium: nature's physiologic calcium blocker. Am Heart J. 1984 Jul;108(1):188-93. doi: 10.1016/0002-8703(84)90572-6. No abstract available.
• Background Kew JN, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl). 2005 Apr;179(1):4-29. doi: 10.1007/s00213-005-2200-z. Epub 2005 Feb 25.
• Background Recio-Pinto E, Castillo C. Peripheral N-methyl-D-aspartate receptors as possible targets for chronic pain treatment. Techniques in Reg Anesth & Pain Manag 2010;14:48-58
• Background Fisher K, Coderre TJ, Hagen NA. Targeting the N-methyl-D-aspartate receptor for chronic pain management. Preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage. 2000 Nov;20(5):358-73. doi: 10.1016/s0885-3924(00)00213-x.
• Background Hewitt DJ. The use of NMDA-receptor antagonists in the treatment of chronic pain. Clin J Pain. 2000 Jun;16(2 Suppl):S73-9. doi: 10.1097/00002508-200006001-00013.
• Background De Kock MF, Lavand'homme PM. The clinical role of NMDA receptor antagonists for the treatment of postoperative pain. Best Pract Res Clin Anaesthesiol. 2007 Mar;21(1):85-98. doi: 10.1016/j.bpa.2006.12.006.
• Background Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg. 2003 Oct;97(4):1108-1116. doi: 10.1213/01.ANE.0000081061.12235.55.
• Background Nechifor M. Magnesium involvement in pain. Magnes Res. 2011 Dec;24(4):220-2. doi: 10.1684/mrh.2011.0296. No abstract available.
• Background Hasanein P, Parviz M, Keshavarz M, Javanmardi K, Mansoori M, Soltani N. Oral magnesium administration prevents thermal hyperalgesia induced by diabetes in rats. Diabetes Res Clin Pract. 2006 Jul;73(1):17-22. doi: 10.1016/j.diabres.2005.12.004. Epub 2006 Jan 18.
• Background Rondon LJ, Privat AM, Daulhac L, Davin N, Mazur A, Fialip J, Eschalier A, Courteix C. Magnesium attenuates chronic hypersensitivity and spinal cord NMDA receptor phosphorylation in a rat model of diabetic neuropathic pain. J Physiol. 2010 Nov 1;588(Pt 21):4205-15. doi: 10.1113/jphysiol.2010.197004.
• Background Begon S, Pickering G, Eschalier A, Dubray C. Magnesium increases morphine analgesic effect in different experimental models of pain. Anesthesiology. 2002 Mar;96(3):627-32. doi: 10.1097/00000542-200203000-00019.
• Background Bujalska M, Makulska-Nowak H, Gumulka SW. Magnesium ions and opioid agonists in vincristine-induced neuropathy. Pharmacol Rep. 2009 Nov-Dec;61(6):1096-104. doi: 10.1016/s1734-1140(09)70172-0.
• Background Ulugol A, Aslantas A, Ipci Y, Tuncer A, Hakan Karadag C, Dokmeci I. Combined systemic administration of morphine and magnesium sulfate attenuates pain-related behavior in mononeuropathic rats. Brain Res. 2002 Jul 5;943(1):101-4. doi: 10.1016/s0006-8993(02)02618-5.
• Background Chen Y, Zhang Y, Zhu YL, Fu PL. Efficacy and safety of an intra-operative intra-articular magnesium/ropivacaine injection for pain control following total knee arthroplasty. J Int Med Res. 2009 Nov-Dec;37(6):1733-41. doi: 10.1177/147323000903700609.
• Background Bondok RS, Abd El-Hady AM. Intra-articular magnesium is effective for postoperative analgesia in arthroscopic knee surgery. Br J Anaesth. 2006 Sep;97(3):389-92. doi: 10.1093/bja/ael176. Epub 2006 Jul 11.
• Background Cizmeci P, Ozkose Z. Magnesium sulphate as an adjuvant to total intravenous anesthesia in septorhinoplasty: a randomized controlled study. Aesthetic Plast Surg. 2007 Mar-Apr;31(2):167-73. doi: 10.1007/s00266-006-0194-5.
• Background Nechifor M. Magnesium in major depression. Magnes Res. 2009 Sep;22(3):163S-166S.
• Background Murck H. Ketamine, magnesium and major depression--from pharmacology to pathophysiology and back. J Psychiatr Res. 2013 Jul;47(7):955-65. doi: 10.1016/j.jpsychires.2013.02.015. Epub 2013 Mar 26.
• Background Albrecht E, Kirkham KR, Liu SS, Brull R. Peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis. Anaesthesia. 2013 Jan;68(1):79-90. doi: 10.1111/j.1365-2044.2012.07335.x. Epub 2012 Nov 1.
• Background Seyhan TO, Tugrul M, Sungur MO, Kayacan S, Telci L, Pembeci K, Akpir K. Effects of three different dose regimens of magnesium on propofol requirements, haemodynamic variables and postoperative pain relief in gynaecological surgery. Br J Anaesth. 2006 Feb;96(2):247-52. doi: 10.1093/bja/aei291. Epub 2005 Nov 25.
• Background Ryu JH, Kang MH, Park KS, Do SH. Effects of magnesium sulphate on intraoperative anaesthetic requirements and postoperative analgesia in gynaecology patients receiving total intravenous anaesthesia. Br J Anaesth. 2008 Mar;100(3):397-403. doi: 10.1093/bja/aem407.
• Background Tramer MR, Schneider J, Marti RA, Rifat K. Role of magnesium sulfate in postoperative analgesia. Anesthesiology. 1996 Feb;84(2):340-7. doi: 10.1097/00000542-199602000-00011.
• Background Song JW, Lee YW, Yoon KB, Park SJ, Shim YH. Magnesium sulfate prevents remifentanil-induced postoperative hyperalgesia in patients undergoing thyroidectomy. Anesth Analg. 2011 Aug;113(2):390-7. doi: 10.1213/ANE.0b013e31821d72bc. Epub 2011 May 19.
• Background Tugrul S, Degirmenci N, Eren SB, Dogan R, Veyseller B, Ozturan O. Analgesic effect of magnesium in post-tonsillectomy patients: a prospective randomised clinical trial. Eur Arch Otorhinolaryngol. 2015 Sep;272(9):2483-7. doi: 10.1007/s00405-014-3219-8. Epub 2014 Aug 6.
• Background Borazan H, Kececioglu A, Okesli S, Otelcioglu S. Oral magnesium lozenge reduces postoperative sore throat: a randomized, prospective, placebo-controlled study. Anesthesiology. 2012 Sep;117(3):512-8. doi: 10.1097/ALN.0b013e3182639d5f.
• Background Brill S, Sedgwick PM, Hamann W, Di Vadi PP. Efficacy of intravenous magnesium in neuropathic pain. Br J Anaesth. 2002 Nov;89(5):711-4.
• Background Crosby V, Wilcock A, Corcoran R. The safety and efficacy of a single dose (500 mg or 1 g) of intravenous magnesium sulfate in neuropathic pain poorly responsive to strong opioid analgesics in patients with cancer. J Pain Symptom Manage. 2000 Jan;19(1):35-9. doi: 10.1016/s0885-3924(99)00135-9.
• Background Suresh S, Lozono S, Hall SC. Large-dose intravenous methotrexate-induced cutaneous toxicity: can oral magnesium oxide reduce pain? Anesth Analg. 2003 May;96(5):1413-1414. doi: 10.1213/01.ANE.0000057140.33744.65.
• Background Kroin JS, McCarthy RJ, Von Roenn N, Schwab B, Tuman KJ, Ivankovich AD. Magnesium sulfate potentiates morphine antinociception at the spinal level. Anesth Analg. 2000 Apr;90(4):913-7. doi: 10.1097/00000539-200004000-00025.
• Background Yousef AA, Al-deeb AE. A double-blinded randomised controlled study of the value of sequential intravenous and oral magnesium therapy in patients with chronic low back pain with a neuropathic component. Anaesthesia. 2013 Mar;68(3):260-6. doi: 10.1111/anae.12107. Epub 2012 Dec 17.
• Background Lysakowski C, Dumont L, Czarnetzki C, Tramer MR. Magnesium as an adjuvant to postoperative analgesia: a systematic review of randomized trials. Anesth Analg. 2007 Jun;104(6):1532-9, table of contents. doi: 10.1213/01.ane.0000261250.59984.cd.
• Background Pickering G, Morel V, Simen E, Cardot JM, Moustafa F, Delage N, Picard P, Eschalier S, Boulliau S, Dubray C. Oral magnesium treatment in patients with neuropathic pain: a randomized clinical trial. Magnes Res. 2011 Jun;24(2):28-35. doi: 10.1684/mrh.2011.0282.
• Background Felsby S, Nielsen J, Arendt-Nielsen L, Jensen TS. NMDA receptor blockade in chronic neuropathic pain: a comparison of ketamine and magnesium chloride. Pain. 1996 Feb;64(2):283-291. doi: 10.1016/0304-3959(95)00113-1.
• Background Mikkelsen S, Dirks J, Fabricius P, Petersen KL, Rowbotham MC, Dahl JB. Effect of intravenous magnesium on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers. Br J Anaesth. 2001 Jun;86(6):871-3. doi: 10.1093/bja/86.6.871.
• Background Ruger LJ, Irnich D, Abahji TN, Crispin A, Hoffmann U, Lang PM. Characteristics of chronic ischemic pain in patients with peripheral arterial disease. Pain. 2008 Sep 30;139(1):201-208. doi: 10.1016/j.pain.2008.03.027. Epub 2008 May 9.
• Background Shechter M, Bairey Merz CN, Stuehlinger HG, Slany J, Pachinger O, Rabinowitz B. Effects of oral magnesium therapy on exercise tolerance, exercise-induced chest pain, and quality of life in patients with coronary artery disease. Am J Cardiol. 2003 Mar 1;91(5):517-21. doi: 10.1016/s0002-9149(02)03297-6.
• Background FONTAINE R, KIENY R, GANGLOFF JM, CUNY A, SUHLER A, GONZALES I, PARAMODIAZ M. LONG-TERM RESULTS OF RESTORATIVE ARTERIAL SURGERY IN OBSTRUCTIVE DISEASES OF THE ARTERIES. J Cardiovasc Surg (Torino). 1964 Nov-Dec;5:463-72. No abstract available.
• Background Caraceni A, Cherny N, Fainsinger R, Kaasa S, Poulain P, Radbruch L, De Conno F. Pain measurement tools and methods in clinical research in palliative care: recommendations of an Expert Working Group of the European Association of Palliative Care. J Pain Symptom Manage. 2002 Mar;23(3):239-55. doi: 10.1016/s0885-3924(01)00409-2.
• Background Frampton CL, Hughes-Webb P. The measurement of pain. Clin Oncol (R Coll Radiol). 2011 Aug;23(6):381-6. doi: 10.1016/j.clon.2011.04.008. Epub 2011 May 14.
• Background Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale. Neurology. 1997 Feb;48(2):332-8. doi: 10.1212/wnl.48.2.332.
• Background Bonezzi C, Nava A, Barbieri M, Bettaglio R, Demartini L, Miotti D, Paulin L. [Validazione della versione italiana del Brief Pain Inventory nei pazienti con dolore cronico]. Minerva Anestesiol. 2002 Jul-Aug;68(7-8):607-11. Italian.
• Background Negri E, Bettaglio R, Demartini L, Allegri M, Barbieri M, Miotti D, Paulin L, Buonocore M, Bonezzi C. [Validation of the Italian version of the "Neuropathic Pain Scale" and its clinical applications]. Minerva Anestesiol. 2002 Mar;68(3):95-104. Italian.
• Background Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-83. doi: 10.1016/0021-9681(87)90171-8.
• Background Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994 Nov;47(11):1245-51. doi: 10.1016/0895-4356(94)90129-5.
• Background Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, Glaser SE, Vallejo R. Opioid complications and side effects. Pain Physician. 2008 Mar;11(2 Suppl):S105-20.
• Venturini MA, Zappa S, Minelli C, Bonardelli S, Lamberti L, Bisighini L, Zangrandi M, Turin M, Rizzo F, Rizzolo A, Latronico N. MAGnesium-oral supplementation to reduce PAin in patients with severe PERipheral arterial occlusive disease: the MAG-PAPER randomised clinical trial protocol. BMJ Open. 2015 Dec 16;5(12):e009137. doi: 10.1136/bmjopen-2015-009137.

Drugs

Indications