Effects of Repetitive Transcranial Magnetic Stimulation in the Treatment of Phantom Limb Pain in Landmine Victims: ANTARES

NCT01872481 | Completed Phase 3 DMC

• 1 other identifier: fcv195
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

Brief Summary

Phantom Limb Pain (PLP) is a neuropathic chronic syndrome, characterized by a painful sensation in a body part that has been amputated. The incidence of phantom limb pain is between 50-80% of all amputees, however, additional risk factors as psychological trauma, blood loss, and infection increases its incidence after a traumatic amputation in landmine victims. Satisfactory management is often difficult to achieve and different clinical trials with medical and surgical measures have yielded unsatisfactory results. The response rate with pharmacologic treatment is around 30% using conventional medication as opiates and N-methyl-D-aspartate (NMDA) receptor antagonists, which is not significantly different from response rates with placebo. Recent case series have shown that repetitive Transcranial Magnetic Stimulation (rTMS) of the motor cortex can display an effectiveness that goes from 52% to 88% in the treatment of some refractory neurogenic pain cases which is quite superior to conventional management. However, the use of this type of treatment has not been studied in patients with phantom limb pain secondary to landmine injuries. The main objective of this trial is to evaluate the efficacy and safety of rTMS in the treatment of phantom limb pain in landmine victims. A double blind randomized placebo-controlled clinical trial, including 54 landmine victims with PLP will be performed. At the time of enrollment, a complete medical evaluation will be performed and those patients who meet the inclusion criteria will be randomly assigned to one of two groups, to receive rTMS in series of 20 trains of 6 s in duration (54-s intertrain interval) at a stimulation rate of 10 Hz (1200 pulses) and an intensity of 90% rest motor threshold using an "active" coil or a "sham" coil. Sessions will be administered 5 days a week (Monday to Friday) during two consecutive weeks. The stimulation will be directed to the primary motor cortex contralateral to the amputated limb. Response will be evaluated by measuring the pain intensity at baseline and after each session using a visual analog scale. These measurements will be repeated 2 weeks after the end of the treatment scheme, in order to determine the duration of the analgesic effect of rTMS

Conditions

Phantom Limb Pain

Keywords

Phantom limb pain syndrome; Neuropathic pain; Antipersonnel landmines; Transcranial Magnetic Stimulation

Outcome Measures

Primary Outcomes (1)

• Percentage reduction in the intensity of neuropathic pain.

  four weeks after beginning the treatment

Secondary Outcomes (1)

• Presence of adverse events related to the administration of rTMS.

  four weeks after beginning the treatment

Study Arms (2)

Sham stimulation

PLACEBO COMPARATOR

rTMS with "sham" coil. Sessions will be administered 5 days a week (Monday to Friday) during two consecutive weeks.

Device: Sham rTMS

Active stimulation

EXPERIMENTAL

rTMS in series of 20 trains of 6 s in duration (54-s intertrain interval) at a stimulation rate of 10 Hz (1200 pulses) at an intensity of 90% rest motor threshold. Sessions will be administered 5 days a week (Monday to Friday) during two consecutive weeks.

Device: rTMS

Interventions

rTMS DEVICE

rTMS in series of 20 trains of 6 s in duration (54-s intertrain interval) at a stimulation rate of 10 Hz (1200 pulses) at an intensity of 90% rest motor threshold. Sessions will be administered 5 days a week (Monday to Friday) during two consecutive weeks.

Active stimulation

Sham rTMS DEVICE

A coil with similar appearance to the active coil in shape and weight, producing a similar sound artifact but without emission of a magnetic pulse is used for the control group.

Sham stimulation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women 18 years or older
• Amputation at any level of one lower limb by anti-personnel land mines
• Symptoms compatible with PLP, defined as painful sensation, sensation of shooting, stabbing, boring, boring, sqeezing, throbbing and burning or paresthesia or any other pain sensation in a limb that doesn't exist anymore.
• Willingness to participate in the study and to sign the informed consent form.

You may not qualify if:

• Diagnosis of complex regional pain syndrome.
• Any pathology that based on the judgment of the researcher that could alter the course of PLP (neoplasias, immunological disorders, etc.)
• Previous diagnosis of cancer.
• Renal insufficiency requiring dialysis treatment.
• Pregnancy
• History of epilepsy.
• Cardiac arrhythmias.
• Metallic prostheses in the skull.
• History of severe head trauma.
• Use of tricyclic antidepressants (amitriptyline, imipramine, clomipramine).
• Use of antipsychotic medication (chlorpromazine, levomepromazine, haloperidol, clozapine, olanzapine, etc.).
• Mentally or neurologically disabled patients that are considered not fit to approve their participation in the study.

Sponsors & Collaborators

• Fundación Cardiovascular de Colombia: lead
• Universidad Industrial de Santander: collaborator
• Spaulding Rehabilitation Hospital: collaborator

Study Sites (1)

Fundacion Cardiovascular de Colombia

Floridablanca, Santander Department, 0, Colombia

Location

Related Publications (59)

• Landmine monitor. International Campaign to Ban Landmines. (http://www.lm.icbl.org/index.php/LM/The-Issues/FAQs). Fecha de Consulta: 22 de Julio de 2010

  BACKGROUND

• Walsh NE, Walsh WS. Rehabilitation of landmine victims--the ultimate challenge. Bull World Health Organ. 2003;81(9):665-70. Epub 2003 Nov 14.

  PMID: 14710508 BACKGROUND

• Andersson N, da Sousa CP, Paredes S. Social cost of land mines in four countries: Afghanistan, Bosnia, Cambodia, and Mozambique. BMJ. 1995 Sep 16;311(7007):718-21. doi: 10.1136/bmj.311.7007.718.

  PMID: 7549685 BACKGROUND

• Strada G. The horror of land mines. Scientific American 1996; 274(5): 40-45.

  BACKGROUND

• Doswald-Beck L, Herby P, Dorais-Slakmon J. Basic facts: the human cost of landmines. Geneva: International Committee of the Red Cross; 1995. ICRC Fact Sheet 1-01-1995.

  BACKGROUND

• Rosenfeld JV. Landmines: the human costs. ADF Health 2000; 1: 93-8.

  BACKGROUND

• Coupland RM, Korver A. Injuries from antipersonnel mines: the experience of the International Committee of the Red Cross. BMJ. 1991 Dec 14;303(6816):1509-12. doi: 10.1136/bmj.303.6816.1509.

  PMID: 1838290 BACKGROUND

• Meier RH 3rd, Smith WK. Landmine injuries and rehabilitation for landmine survivors. Phys Med Rehabil Clin N Am. 2002 Feb;13(1):175-87. doi: 10.1016/s1047-9651(03)00077-9.

  PMID: 11878082 BACKGROUND

• Ketz AK. The experience of phantom limb pain in patients with combat-related traumatic amputations. Arch Phys Med Rehabil. 2008 Jun;89(6):1127-32. doi: 10.1016/j.apmr.2007.11.037.

  PMID: 18503810 BACKGROUND

• Nikolajsen L, Jensen TS. Phantom limb pain. Br J Anaesth. 2001 Jul;87(1):107-16. doi: 10.1093/bja/87.1.107. No abstract available.

  PMID: 11460799 BACKGROUND

• Muller A, Sherman R, Weiss J, Addison R, Carr D, Harden RN. Neurophysiology of pain from landmine injury. Pain Med. 2006 Nov-Dec;7 Suppl 2:S204-8. doi: 10.1111/j.1526-4637.2006.00234_5.x. No abstract available.

  PMID: 17112353 BACKGROUND

• Whyte AS, Niven CA. Psychological distress in amputees with phantom limb pain. J Pain Symptom Manage. 2001 Nov;22(5):938-46. doi: 10.1016/s0885-3924(01)00352-9.

  PMID: 11728797 BACKGROUND

• Flor H. Phantom-limb pain: characteristics, causes, and treatment. Lancet Neurol. 2002 Jul;1(3):182-9. doi: 10.1016/s1474-4422(02)00074-1.

  PMID: 12849487 BACKGROUND

• Woolf CJ, Shortland P, Coggeshall RE. Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature. 1992 Jan 2;355(6355):75-8. doi: 10.1038/355075a0.

  PMID: 1370574 BACKGROUND

• Devor M, Govrin-Lippmann R, Angelides K. Na+ channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J Neurosci. 1993 May;13(5):1976-92. doi: 10.1523/JNEUROSCI.13-05-01976.1993.

  PMID: 7683047 BACKGROUND

• Sandkuhler J. Learning and memory in pain pathways. Pain. 2000 Nov;88(2):113-118. doi: 10.1016/S0304-3959(00)00424-3. No abstract available.

  PMID: 11050365 BACKGROUND

• Florence SL, Kaas JH. Large-scale reorganization at multiple levels of the somatosensory pathway follows therapeutic amputation of the hand in monkeys. J Neurosci. 1995 Dec;15(12):8083-95. doi: 10.1523/JNEUROSCI.15-12-08083.1995.

  PMID: 8613744 BACKGROUND

• Pons TP, Garraghty PE, Ommaya AK, Kaas JH, Taub E, Mishkin M. Massive cortical reorganization after sensory deafferentation in adult macaques. Science. 1991 Jun 28;252(5014):1857-60. doi: 10.1126/science.1843843.

  PMID: 1843843 BACKGROUND

• Elbert T, Flor H, Birbaumer N, Knecht S, Hampson S, Larbig W, Taub E. Extensive reorganization of the somatosensory cortex in adult humans after nervous system injury. Neuroreport. 1994 Dec 20;5(18):2593-7. doi: 10.1097/00001756-199412000-00047.

  PMID: 7696611 BACKGROUND

• Flor H, Elbert T, Knecht S, Wienbruch C, Pantev C, Birbaumer N, Larbig W, Taub E. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature. 1995 Jun 8;375(6531):482-4. doi: 10.1038/375482a0.

  PMID: 7777055 BACKGROUND

• Florence SL, Taub HB, Kaas JH. Large-scale sprouting of cortical connections after peripheral injury in adult macaque monkeys. Science. 1998 Nov 6;282(5391):1117-21. doi: 10.1126/science.282.5391.1117.

  PMID: 9804549 BACKGROUND

• Jones EG, Pons TP. Thalamic and brainstem contributions to large-scale plasticity of primate somatosensory cortex. Science. 1998 Nov 6;282(5391):1121-5. doi: 10.1126/science.282.5391.1121.

  PMID: 9804550 BACKGROUND

• Chen R, Corwell B, Yaseen Z, Hallett M, Cohen LG. Mechanisms of cortical reorganization in lower-limb amputees. J Neurosci. 1998 May 1;18(9):3443-50. doi: 10.1523/JNEUROSCI.18-09-03443.1998.

  PMID: 9547251 BACKGROUND

• Ralston HJ 3rd, Ohara PT, Meng XW, Wells J, Ralston DD. Transneuronal changes of the inhibitory circuitry in the macaque somatosensory thalamus following lesions of the dorsal column nuclei. J Comp Neurol. 1996 Jul 22;371(2):325-35. doi: 10.1002/(SICI)1096-9861(19960722)371:23.0.CO;2-R.

  PMID: 8835736 BACKGROUND

• Melzack R. Phantom limbs and the concept of a neuromatrix. Trends Neurosci. 1990 Mar;13(3):88-92. doi: 10.1016/0166-2236(90)90179-e.

  PMID: 1691874 BACKGROUND

• Merzenich MM, Nelson RJ, Stryker MP, Cynader MS, Schoppmann A, Zook JM. Somatosensory cortical map changes following digit amputation in adult monkeys. J Comp Neurol. 1984 Apr 20;224(4):591-605. doi: 10.1002/cne.902240408.

  PMID: 6725633 BACKGROUND

• Oakley DA, Whitman LG, Halligan PW. Hypnotic imagery as a treatment for phantom limb pain: two case reports and a review. Clin Rehabil. 2002 Jun;16(4):368-77. doi: 10.1191/0269215502cr507oa.

  PMID: 12061470 BACKGROUND

• Wiech K, Kiefer RT, Topfner S, Preissl H, Braun C, Unertl K, Flor H, Birbaumer N. A placebo-controlled randomized crossover trial of the N-methyl-D-aspartic acid receptor antagonist, memantine, in patients with chronic phantom limb pain. Anesth Analg. 2004 Feb;98(2):408-413. doi: 10.1213/01.ANE.0000096002.53818.BD.

  PMID: 14742379 BACKGROUND

• Lierz P, Schroegendorfer K, Choi S, Felleiter P, Kress HG. Continuous blockade of both brachial plexus with ropivacaine in phantom pain: a case report. Pain. 1998 Nov;78(2):135-137. doi: 10.1016/S0304-3959(98)00128-6.

  PMID: 9839824 BACKGROUND

• Bergmans L, Snijdelaar DG, Katz J, Crul BJ. Methadone for phantom limb pain. Clin J Pain. 2002 May-Jun;18(3):203-5. doi: 10.1097/00002508-200205000-00012.

  PMID: 12048424 BACKGROUND

• Wilson JA, Nimmo AF, Fleetwood-Walker SM, Colvin LA. A randomised double blind trial of the effect of pre-emptive epidural ketamine on persistent pain after lower limb amputation. Pain. 2008 Mar;135(1-2):108-18. doi: 10.1016/j.pain.2007.05.011. Epub 2007 Jun 20.

  PMID: 17583431 BACKGROUND

• Bone M, Critchley P, Buggy DJ. Gabapentin in postamputation phantom limb pain: a randomized, double-blind, placebo-controlled, cross-over study. Reg Anesth Pain Med. 2002 Sep-Oct;27(5):481-6. doi: 10.1053/rapm.2002.35169.

  PMID: 12373695 BACKGROUND

• Schwenkreis P, Witscher K, Janssen F, Addo A, Dertwinkel R, Zenz M, Malin JP, Tegenthoff M. Influence of the N-methyl-D-aspartate antagonist memantine on human motor cortex excitability. Neurosci Lett. 1999 Aug 6;270(3):137-40. doi: 10.1016/s0304-3940(99)00492-9.

  PMID: 10462113 BACKGROUND

• Pridmore S, Oberoi G, Marcolin M, George M. Transcranial magnetic stimulation and chronic pain: current status. Australas Psychiatry. 2005 Sep;13(3):258-65. doi: 10.1080/j.1440-1665.2005.02197.x.

  PMID: 16174199 BACKGROUND

• Hallett M. Transcranial magnetic stimulation and the human brain. Nature. 2000 Jul 13;406(6792):147-50. doi: 10.1038/35018000.

  PMID: 10910346 BACKGROUND

• Hallett M. Transcranial magnetic stimulation: a primer. Neuron. 2007 Jul 19;55(2):187-99. doi: 10.1016/j.neuron.2007.06.026.

  PMID: 17640522 BACKGROUND

• Baker SN, Olivier E, Lemon RN. Recording an identified pyramidal volley evoked by transcranial magnetic stimulation in a conscious macaque monkey. Exp Brain Res. 1994;99(3):529-32. doi: 10.1007/BF00228989.

  PMID: 7957732 BACKGROUND

• Griskova I, Hoppner J, Ruksenas O, Dapsys K. Transcranial magnetic stimulation: the method and application. Medicina (Kaunas). 2006;42(10):798-804.

  PMID: 17090978 BACKGROUND

• Speer AM, Kimbrell TA, Wassermann EM, D Repella J, Willis MW, Herscovitch P, Post RM. Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biol Psychiatry. 2000 Dec 15;48(12):1133-41. doi: 10.1016/s0006-3223(00)01065-9.

  PMID: 11137053 BACKGROUND

• Ben-Shachar D, Belmaker RH, Grisaru N, Klein E. Transcranial magnetic stimulation induces alterations in brain monoamines. J Neural Transm (Vienna). 1997;104(2-3):191-7. doi: 10.1007/BF01273180.

  PMID: 9203081 BACKGROUND

• Keck ME, Sillaber I, Ebner K, Welt T, Toschi N, Kaehler ST, Singewald N, Philippu A, Elbel GK, Wotjak CT, Holsboer F, Landgraf R, Engelmann M. Acute transcranial magnetic stimulation of frontal brain regions selectively modulates the release of vasopressin, biogenic amines and amino acids in the rat brain. Eur J Neurosci. 2000 Oct;12(10):3713-20. doi: 10.1046/j.1460-9568.2000.00243.x.

  PMID: 11029641 BACKGROUND

• Keck ME, Welt T, Muller MB, Erhardt A, Ohl F, Toschi N, Holsboer F, Sillaber I. Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system. Neuropharmacology. 2002 Jul;43(1):101-9. doi: 10.1016/s0028-3908(02)00069-2.

  PMID: 12213264 BACKGROUND

• Kole MH, Fuchs E, Ziemann U, Paulus W, Ebert U. Changes in 5-HT1A and NMDA binding sites by a single rapid transcranial magnetic stimulation procedure in rats. Brain Res. 1999 May 1;826(2):309-12. doi: 10.1016/s0006-8993(99)01257-3.

  PMID: 10224311 BACKGROUND

• Daskalakis ZJ, Christensen BK, Fitzgerald PB, Chen R. Transcranial magnetic stimulation: a new investigational and treatment tool in psychiatry. J Neuropsychiatry Clin Neurosci. 2002 Fall;14(4):406-15. doi: 10.1176/jnp.14.4.406.

  PMID: 12426408 BACKGROUND

• Li X, Nahas Z, Kozel FA, Anderson B, Bohning DE, George MS. Acute left prefrontal transcranial magnetic stimulation in depressed patients is associated with immediately increased activity in prefrontal cortical as well as subcortical regions. Biol Psychiatry. 2004 May 1;55(9):882-90. doi: 10.1016/j.biopsych.2004.01.017.

  PMID: 15110731 BACKGROUND

• Bestmann S. The physiological basis of transcranial magnetic stimulation. Trends Cogn Sci. 2008 Mar;12(3):81-3. doi: 10.1016/j.tics.2007.12.002. Epub 2008 Feb 1.

  PMID: 18243042 BACKGROUND

• Maeda F, Pascual-Leone A. Transcranial magnetic stimulation: studying motor neurophysiology of psychiatric disorders. Psychopharmacology (Berl). 2003 Aug;168(4):359-76. doi: 10.1007/s00213-002-1216-x. Epub 2003 Jun 26.

  PMID: 12830365 BACKGROUND

• Counter SA, Borg E, Lofqvist L, Brismar T. Hearing loss from the acoustic artifact of the coil used in extracranial magnetic stimulation. Neurology. 1990 Aug;40(8):1159-62. doi: 10.1212/wnl.40.8.1159.

  PMID: 2381522 BACKGROUND

• Pascual-Leone A, Cohen LG, Shotland LI, Dang N, Pikus A, Wassermann EM, Brasil-Neto JP, Valls-Sole J, Hallett M. No evidence of hearing loss in humans due to transcranial magnetic stimulation. Neurology. 1992 Mar;42(3 Pt 1):647-51. doi: 10.1212/wnl.42.3.647.

  PMID: 1549231 BACKGROUND

• Wassermann EM, Grafman J, Berry C, Hollnagel C, Wild K, Clark K, Hallett M. Use and safety of a new repetitive transcranial magnetic stimulator. Electroencephalogr Clin Neurophysiol. 1996 Oct;101(5):412-7.

  PMID: 8913194 BACKGROUND

• Pascual-Leone A, Houser CM, Reese K, Shotland LI, Grafman J, Sato S, Valls-Sole J, Brasil-Neto JP, Wassermann EM, Cohen LG, et al. Safety of rapid-rate transcranial magnetic stimulation in normal volunteers. Electroencephalogr Clin Neurophysiol. 1993 Apr;89(2):120-30. doi: 10.1016/0168-5597(93)90094-6.

  PMID: 7683602 BACKGROUND

• Homberg V, Netz J. Generalised seizures induced by transcranial magnetic stimulation of motor cortex. Lancet. 1989 Nov 18;2(8673):1223. doi: 10.1016/s0140-6736(89)91835-7. No abstract available.

  PMID: 2572937 BACKGROUND

• Wassermann EM, Cohen LG, Flitman SS, Chen R, Hallett M. Seizures in healthy people with repeated "safe" trains of transcranial magnetic stimuli. Lancet. 1996 Mar 23;347(9004):825-6. doi: 10.1016/s0140-6736(96)90898-3. No abstract available.

  PMID: 8622349 BACKGROUND

• Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol. 1998 Jan;108(1):1-16. doi: 10.1016/s0168-5597(97)00096-8.

  PMID: 9474057 BACKGROUND

• Bobadilla H, Fierro M. Transcraneal magnetic stimulation. Rev Colomb Psiquiatr 2002; 31(4): 271-85.

  BACKGROUND

• Lefaucheur JP, Drouot X, Keravel Y, Nguyen JP. Pain relief induced by repetitive transcranial magnetic stimulation of precentral cortex. Neuroreport. 2001 Sep 17;12(13):2963-5. doi: 10.1097/00001756-200109170-00041.

  PMID: 11588611 BACKGROUND

• Lefaucheur JP, Drouot X, Menard-Lefaucheur I, Zerah F, Bendib B, Cesaro P, Keravel Y, Nguyen JP. Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain. J Neurol Neurosurg Psychiatry. 2004 Apr;75(4):612-6. doi: 10.1136/jnnp.2003.022236.

  PMID: 15026508 BACKGROUND

• Khedr EM, Kotb H, Kamel NF, Ahmed MA, Sadek R, Rothwell JC. Longlasting antalgic effects of daily sessions of repetitive transcranial magnetic stimulation in central and peripheral neuropathic pain. J Neurol Neurosurg Psychiatry. 2005 Jun;76(6):833-8. doi: 10.1136/jnnp.2004.055806.

  PMID: 15897507 BACKGROUND

• Lefaucheur JP, Hatem S, Nineb A, Menard-Lefaucheur I, Wendling S, Keravel Y, Nguyen JP. Somatotopic organization of the analgesic effects of motor cortex rTMS in neuropathic pain. Neurology. 2006 Dec 12;67(11):1998-2004. doi: 10.1212/01.wnl.0000247138.85330.88.

  PMID: 17159107 BACKGROUND

MeSH Terms

Conditions

Phantom Limb; Neuralgia

Condition Hierarchy (Ancestors)

Perceptual Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Pain, Postoperative; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain; Peripheral Nervous System Diseases; Neuromuscular Diseases

Study Officials

• Federico A Silva, Neurologist

  Fundacion Cardiovascular de Colombia

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 5, 2013
• First Posted: June 7, 2013
• Study Start: June 1, 2013
• Primary Completion: September 1, 2013
• Study Completion: October 1, 2014
• Last Updated: February 8, 2016

Record last verified: 2013-06

Locations

CO (1)