VOLUME 103 NUMBERS 1—2 MAY 2003
`
`PUBLISHED MONTHLY
`
`ISSN 0304—3959 &
`
`103 (1-2) 1—228
`
`®
`
`ELSEVIER
`
`HEALTH 5c
`UMP-s’E'ngr-IENCES LIBRAR‘
`1’ OF 'III’ISCONSIN
`
`NORTH AMERICAN EDITION
`
`IPR2015—00410
`
`Petitioners' EX. 1015
`
`Page 1
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`IPR2015-00410
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`SCOPE AND PURPOSE
`
`PAIN“
`
`This journal is the olTIcial publication of the International Association for the Study of Pain ( IASP) and it publishes original research on the
`nature, mechanisms and treatment of pain. The journal provides a forum for the dissemination of research in the basic and clinical sciences of
`multidisciplinary interest.
`Editor-in-Chief
`
`Dr. Allan J. Basbaurn, Editor—in-Chief PAt'N'”. Depanntenl of Anatomy and W.M. Keck Foundation Center for Integrative Neuroscience.
`University of Calil'ontia. San Francisco, CA. USA.
`Editorial Office
`
`Ms. Kathy Havers. 909 NE. 43rd Street. Suite 306. Seattle. WA 90105—6020. USA.
`
`TYPES OF PAPERS
`
`— Clinical/Basic Science Research Reports (research reports of not more than 2—3000 words).
`« Clinical Notes (brief reports on clinical cases).
`— Letters to the Editor.
`
`- Topical Reviews will be invited articles on new findings and issues in clinical and basic research related to pain.
`
`The reviewing promo; for all articles will he handled by the Editor-in-Chief. Allan l. Basbaum and 7 Section Editors:
`
`Neurobiology:
`Phamtttt'ology:
`Clinical Science:
`Clinical Psychology:
`Pain Measurement and imaging:
`Clinical Notes:
`Pain Clinical Updates:
`
`Marshall Devor. Jerusalem. Israel
`Frank Porreca, Tucson. AZ. USA
`Henry McQuay, Ox ford. UK
`Francis J. Keefe, Durham, NC, USA
`Karen Davis, Toronto. Canada
`J. Edmond Charlton. Newcastle upon Tyne. UK
`Daniel Carr. Boston. MA. USA
`
`Authors are requested, upon submission of their article, to recommend to which Section their article should be assigned to. They also should
`include the names (with address, phone. Fax and e-mail details) of four potential reviewers.
`
`Cover material. Suggestions for future photographs or diagrams of clinical or basic research data are invited. The illustration may be from a
`manuscript submitted for publication. at previous paper published in PA INS", or material not published previously. Photographs ol~ historical
`interest would also be welcome.
`
`Attttotmcetttents will not be published in the journal and should he sent to: Ms. L.E. Jones. Executive Oificer [AS P. 909 NE. 43rd Street, Sttite
`306, Seattle. WA 98105. USA (fax: +1 206 54lli'03: e—mail: IASP@juno.com: www address: http:llwww.iasp—pain.org). for possible
`inclusion in the IASP Newsletter.
`
`INSTRUCTIONS TO AUTHORS
`
`Submission of a paper to PALM?“ is understood to imply that it has not previously been published (except in abstract form) and that it is not
`being considered for publication elsewhere. Manuscripts submitted under multiple authorship are reviewed on the assumption that (ll all
`authors listed concur with the submitted version of tile manuscript and with the listing of the authors: (2) authorship credit is based on
`important contributions in one or more of the following areas: conception and design, analysis and interpretation of data. drafting of the
`manuscript or making intellectual contributions to its content; (3) the linal manuscript has been tacitly or explicitly approved by the
`responsible authorities in the laboratory or institution where the work was carried out.
`II‘ illustrations or other small parts of articles or
`books already published elsewhere are used in papers submitted to PAlN'H' the written permission of author and publisher concerned must be
`included with the manuscript. The original source must be indicated in the legend of the illustration in these cases. The letter accompanying
`the manuscript should include a statement oi‘any financial or other relationships that might lead to :1 conflict of interest. the recommended
`Section Editor to which the manuscript should be assigned to. and the names of four potential reviewers with complete contact details.
`
`The Publisher and Editor—in—Chiel‘ regret that they are unable to return copies of submitted manuscripts.
`
`Articles should be written in English and should be complete in all respects. The layout and style should adhere strictly to the instructions
`given under ‘Organisation ol‘ the Article' and. in particular. the reference style of raw“.
`
`No revisions or updates will be incorporated after the article has been accepted and sent to the Publisher (un less approved by the Editors}.
`t..
`
`For all types of papers the preferred method of submission is electronic via the WWW using the SM ARTWorks" website:
`
`hit
`
`
`:llwww.smartwork52000.comtst-nartZtltltltstarttstarttts.
`
`
`However. it you are having dithculty with the on-line submission. please contact Putt: at: tinny@iasp-painorg. It you are not able to make
`e-mail contact. you may send out: hartlcopy ot‘thc manuscript. iuculding copies ol'all illustrations. ncctmipattietl by a disk containing tiles ol‘
`all the text and illustrations. to the attention of the Etlitor—in-Chicf at the Editorial Ollire.
`
`For funher extensive instructions to authors see prelim pages \' & vi ot' this issue.
`
`
`
`
`
`The instructions can also be l'otunl ou the World Wide Web: access ttndcr http:t'lwww,clscviencom
`
`l
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`IPR2015-00410
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`l"—___
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`'
`
`\‘UL.
`
`'01 N03 1_3
`
`PAIN"
`
`CONTENTS
`
`MAY 2:103
`
`TOPICAL REVIEW
`
`Anccr and persistent pain: current status and future directions
`KA. Greenwood. R. Thurston. M. Rumble. SJ. Waters. FJ. Keefe (USA:
`RES EA RC H PAPERS
`
`1
`
`'l
`
`I
`
`|
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`21
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`3|
`
`4t
`
`49
`
`5?
`
`()5
`
`:5
`
`33
`
`93
`
`99
`
`[11
`
`I I‘)
`
`13|
`
`139
`
`15]
`
`l5?
`
`lo}
`
`1?5
`
`l8?
`
`I99
`
`HEALTH SCIENCES HERA!“
`unwessm or WISCONSIN
`
`Chronic intrathecul cannulas inhibit some and potentiate olhcr behaviors elicited by formalin injection
`J. Satvynok. A. Reid I'Canada}
`‘i. -e differences in postoperative pain are scale dependent: a comparison of measures of pain intensity and quality in younger and older surgical
`patients
`1.. Gugliese. J. Kalz (Canada!
`Multiple phases of relief from experimental mechanical aliodynia by systemic lidocaine: responses to early and late infusions
`NLC. Araujo. C‘J. Sinnott. GR. Striclnn‘tz tUSA)
`.-‘\s.<essment of nociceptive trigeminal pathways by laser-evoked potentials and laser silent periods in patients with painful temporotnandihular
`disorders
`A. Romanieilo. G. Crucctt. G. Frisardi. L. Arendt'Nielsen. P. Svcnsson (Denmark. Italy]
`t'jltronic pain. \vork perl‘omtancc and litigation
`!-'-' M. Blyth. L.M, March. MK. Nicholas. M]. Cousins tAustralial
`'l'rteyclic antidepressants as long-acting local anesthetics
`‘-' Strdoh. E.E. Cahoon. P. Gerner. GK. Wang (USA)
`Altersensations in experimental and clinical hypersensitivity
`‘ Gotttup. AD. Kristenscn. PW. Bach. TS. Jensen {Denmark}
`Development of motor system dysfunction following whiplash injury
`1. Sterling. G. Jull. B, Vicenzino. J. Kenardy. R. Darnell tAustralia]
`Differential recruitment of endogenous pain inhibitory systems in neuropatltic pain patients
`Wining. P. Sven-soon. T.S. Jensen iDEllmilrkJ
`Convergence of cutaneous. muscular and visceral noxious inputs onto ventroniedial thalamic neurons in the rat
`L. Monconduit. L. Bourgcals. J.—F. Bernard. L. Villanueva {France}
`Susceptibility loci for complex regional pain syndrome
`ts'.-.l.T. van de Beck. BO. Rocp. AR. van der Slik. MJ. Giphart. 13.]. van Hilton {The Netherlands]
`r‘--‘-1:'al representation of visceral and cutaneous hypersensitivity in the irritahle bowel syndrome
`UN, Verne. NC, Himes. ME. Robinson. K.S. Gopinath. KW. Briggs. B. Crosson. DD. Price {USA}
`venous adenosine alleviates neuropatllic pain: a double blind placebo controlled crossover trial using an enriched enrolment design
`ME. Lynch. AJ. Clark. J. Sawynok [Canada]
`yesia by electrostiinulation ol' the trigeminal ganglion in patients with trigeminopathic pain: a PET activation study
`F. Willoch. U. Gamringer. R. Medele. U. Sieude. TR. Toile (Germany. Norway}
`('I.. ..-__'cs in sensory processing in the spinal dorsal horn accompany vincristine—induccd hyperalgesia and allodynia
`|l.-R. Wang. LV, Cordella. PM. Dougherty (USAl
`.tTects of hi glt- and low-intensity percutaneous stimulation on nitric oxide levels and spike activity in the superficial laminae of the spinal cord
`D. Schulte. J. Millar (Germany. UK)
`'l'J.-. social context of gastrointestinal cancer pain: a preliminary study examining the relation of patient pain catastrophizing to patient perceptions
`of social sttpport and caregiver stress and negative responses
`tJ. Keefe, l. Lipkus. J.C. laei'ehvre. H. Hurtvitz. E. Clipp. J. Smith. l.. Porter (USA)
`sell—efficacy of family caregivers for helping cancer patients manage pain at end—oI'-liic
`1".J. Keefe. TA. Allies. LS. Porter. LM. Sutton. CM. McBride. MS. Pope. E.T, McKinstry.C.P. Furstenherg. J. Dalton. 11H. Baucont tUSAl
`!vement of the anterior pretectal nucleus in the control of persistent pain: a behavioral and c—Fos expression study in the rat
`C.F. Villarreal. EA. Del Bcl. WA. Prado {Brazil}
`:tnahinoid agonist differentially attenuates deep tissue liyperalgesia in animal models of cancer and inflammatory muscle pain
`LJ. Kohl. D,T. Hanminom. Rw. Wacnik. 0.1.. Cmfi. B.D. Norsted. G.L. Wilcox. [1A, Simone (USA:
`«tiring pain in children with cognitive impairment: pain response to surgical procedures
`C. Terstegen. HM. Koot, LB. de Boer. D. Tibhoel {The Netherlands}
`['i..si]1lex regional pain syndrome type I: incidence and prevalence in Olmsted county. a population-based study
`P. Snndroni. L.M, Benrud-Lurson. R.L. McClelland. PA. Low {USA}
`
`F“
`
`~.
`
`Tl.
`
`Th.
`
`It"
`
`i\
`
`.\i
`
`Available online at wwwsciencedirectcom
`
`SCIENOE@DIHI§¢TI
`for onltne access v1a your library
`
`JUN 0 2 2003
`ifimmm
`
`
`
`ELSEVIER
`
`
`l Cital in Current Crintt’iiio'itfe Sciences. Current C(Jirreirrsi’Cliiiir‘ril Practice. Biological Alamo-rs. Psyr'lmlogicitl Alon-art‘s FPS-v.
`t‘lllllffi‘l. E:lrlBA.§'E.-"E\‘ccr‘pfu Mcdica. index Medium. Behavioural Medicine Alrrrrrrcrr. Reffi’l't’iit‘e“ Whittle. Elsevier BlOBASEJCnr-
`rem Awareness in Biological Sciences. Full tart available in Selena-Direct 3" imrl Nelri‘GS'FltHLl
`
`IPR2015—00410
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`(fume-ms continued1
`
`CLINICAL NOTES
`
`Facet joint injection: :1 ran; l‘urm cause of epidural abscess formation
`E. Alcnck. A, chaard. .I. Browne (UK)
`Cervical [rimsl‘ummina] injection of corticosteroids inlu u rildlt‘uléll' artery: :1 possible mechanism For spinal cord injury
`R. Baker. P. Drcyfuss. S. Mercer. N, Bogduk {USA. New Zealand. Auslmlia}
`Encapsulation of an inumhccal calhclcr
`J. Gaermcr. R. Subatnwzski. F. Elsner. L. Radhrucli {Germany}
`Diabelic thoracic radiculopalhy: an unusual cause 01‘ pust—thomcammy pain
`R. Brewer LUSAJ
`LETTERS TO THE EDITOR
`
`Spinal cord stimulmiun for central pain
`S. Canzivcro. V. Boniculzi I'IIzIIyJ
`Reply to Canavem and Bonicalzi‘s comments on Eiscnbcrg and Bracken Lumbar spinal cord stimulation for cervical-origituucd ccnlml pain: a case
`report (Pain 20023002299401)
`E. Eisenberg. C. Breaker (Israelj
`Cummenl an: Serpcll cl 211.. gabupenlin in neurnpathiu pain syndromes: :1 randomised duublc-blind. placebo controlled lriul {Pain 2002199: SST—6(3)
`GJ. McClczanc (UK)
`Neuropuihic Pain Study Group
`ML}. Serpel] (UK)
`
`209
`
`3“
`
`317"
`
`321
`
`225
`
`226
`
`22?
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`223
`
`
`
`J
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`l P
`
`AIN
`
`
`www.clsevier.com/locate/pain
`
`
`U pd ION [0
`
`$4? “xx"
`
`‘1 or;
`
` Pain 103 (2003) 277—283
`
`Efficacy of the NMDA-receptor antagonist memantine in patients with
`chronic phantom limb pain — results of a randomized double—blinded,
`placebo-controlled trial
`
`Christoph Maiera’*, Roman Dertwinkelb, Noushin Mansourian“, Ingolf Hosbachb,
`Peter Schwenkreisc, Isabel Sennea, Guido Skipkad, Michael Zenzb, Martin TegenthoffC
`.
`aDepartment of Pain Management, Ruhr University, Bachum, Germany
`hDepartment ofAnesthesiology. Intensive Care and Pain Therapy, Ruhr University, Bachum, Germany
`CDepartment of Neurology, Berufsgenassenschaftliche Kliniken Bergmannrheil, Ruhr University, Bochum, Germany
`dDepartment of Medical Informatics, Biometry and Epidemiology, Ruhr University, Bachum, Germany
`Received 3 July 2002; accepted 13 November 2002
`
`
`’
`
`Abstract
`
`Phantom limb pain (PLP) associated neuroplastic changes are partly mediated by excitatory amino acids at NMDA receptor sites. This
`study was undertaken to deduce if NMDA-receptor antagonists may be effective in patients with chronic PLP. Therefore a four week double-
`blinded, randomized placeb0<controlled trial was performed to evaluate the efficacy of 30 mg memantine/day, an orally administrable
`NMDA receptor antagonist.
`Thirty—six patients, 18 per group, with a history of at least 12 months PLP and an average pain of at least 4 on the 11-point numeric rating
`scale (NRS) were enrolled. The patients completed a standardized questionnaire before the trial. PLP intensity and the level of eight
`complaints were assessed during the trial. Number needed to treat (NNT) was calculated based on the average PLP during the 3rd week
`(steady state). In both groups, PLP declined significantly in comparison with the baseline (verum: 5.1 ($2.1) to 3,8 (:23), placebo from 5.1
`(i 2.0) to 3.2 (i 1,46) NRS) without a re-rising of the PLP during the washout period. Mean pain relief was 47% in the memantine group (10
`patients reported more than 50% relief), 40% in the placebo group (6 > 50%): NNT were 4.5 (KI: 2.1—10.6). Analysis of covariance
`demonstrated a signifiCant impact only on the prior PLP intensity, but no treatment effect. Two patients have demonstrated long-term
`pain relief under memantine until now (16 months). The total number of slight adverse events were comparable in both groups, but the overall
`number of severe events was higher in the memantine group (P < 0.05). This trial failed to demonstrate a significant clinical benefit of the
`NMDA-receptor antagonist memantine in chronic PLP. The administration of a higher dosage is probably not tolerable.
`© 2002 International Associaiton for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.
`
`Keywords: Phantom limb pain; N-MethyI-D-aspartate receptor antagonist; Memantine; Placebo-controlled randomized trial
`__—______—_____—_—____.___—_—_____—.—.———————-——
`
`1. Introduction
`
`Phantom limb pain (PLP) is a common complaint follow-
`ing upper and lower limb amputation with an incidence of
`60—70% (Jensen ct al., 1985; Kooijman et al., 2000). Periph-
`eral, spinal and cerebral neuronal mechanisms may generate
`and maintain PLP, including plastic changes occurring in
`the primary somatosensory cortex (Flor et al., 1995, 1998;
`Birbaumer et al., 1997). Rapid cortical ncuroplasticity and
`the hyperexcitabily in dorsal horn neurons after deafferen—
`tiation are partly mediated by excitatory amino acids at N-
`methyl-D-aspartate (NMDA) receptor sites (Garraghty and
`Muja, 1996; Woolf and Salter, 2000; Ji and Woolf, 2001).
`
`* Corresponding author.
`
`NMDA-receptor antagonists reduce on-going pain, allody—
`nia and pathologically decreased pain thresholds in experi-
`mental and clinical studies in humans (Nikolajsen et al.,
`1996; Warncke et al., 1996; Dickenson and Sullivan,
`1987; Treede et al., 1992). Ketamine is the most powerful
`NMDA-receptor antagonist. Using a low-dose regimen, it
`seems
`to prevent
`tactile hyperalgesia
`after
`surgery
`(Wamcke et al., 1996; Stubhaug et al., 1997). Using the
`same ketamine dosage 72h postoperatively, we demon-
`strated recently in an open pilot study a reduced intensity
`of PLP 6—12 months after amputation in comparison to a
`historical control group (Dertwinkel et al., 2002). However,
`the feasibility of ketamine in the treatment of chronic neuro-
`pathic pain is limited due to its psychotomimetic effects
`(restlessness, hallucinations, anxiety disturbances). Further-
`
`0304—3959/03/$30.00 © 2002 International Associaiton for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. '
`doi:10.1016/80304-3959(02)00456-6
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`278
`
`C. Maier et a]. /Pat'n 103 (2003) 277—283
`
`more, ketamine is only available for parenteral administra-
`tion. Some case reports and one ‘N of 1
`trial’ revealed
`disappointing reSults of orally administered ketamine
`(Nikolajsen et al., 1997; Haines and Gaines, 1999; Kannan
`et al., 2002; Fitzgibbon et al., 2002). Therefore there is need
`for orally administrable NMDA receptor antagonists like
`dextromctorphan, amantadine or its derivate memantine,
`The latter has been administered long term in the treatment
`of dementia and Parkinson’s disease (Pantev et al., 1993;
`Ditzler, 1991; Jain, 2000). The effects of memantine in
`animal studies are comparable to those of ketamine (Eisen-
`berg et al., 1993, 1995). However, memantine failed to have
`significant analgesic effects
`in two placebo-controlled
`studies dealing with patients suffering from neuropathic
`(including PLP after surgery) and postherpetic pain (Niko-
`lajsen et al., 2000; Eisenberg et al., 1998). In both trials, the
`daily dosage of memantine was titrated up to a maximum of
`20 mg. The frequency of side effects was not higher than in
`each placebo group. It is possible that the treatment failed to
`be effective in these studies, due to too low a dosage.
`For this reason, we performed a placebo-controlled study
`with a daily dosage of 30 mg memantine in patients with
`chronic PLP. This dosage has had the efficacy proven in
`studies for dementia and decreased withdrawal symptoms
`in opioid dependent humans. The same dosage has been
`shown to influence intracortical
`intemeuronal circuits in
`
`Table 1
`Demographic data
`
`N
`Gender (f/m)
`Age (years; median, range)
`Site of amputation
`Upper extremity
`Shoulder/upper arm
`Forearm
`Hand
`Lower extremity
`Hip/thigh
`Lower leg
`Ankle/foot
`Cause of amputation
`Vascular disease
`Infection
`Tumour
`Trauma
`Other
`Pretreatment
`Medical
`Invasive
`Physical
`Complementary
`No treatment
`Social aspects
`Retired
`Early retired due to
`amputation/PLP
`Working
`
`Memantine group
`
`Placebo group
`
`18
`14/4
`62 (28—76)
`
`10 (56%)
`5 (28%)
`l (6%)
`4 (22%)
`
`6 (33%)
`2(11%)
`No
`
`4 (22%)
`1 (6%)
`2 (l 1%)
`9 (50%)
`2 (11%)
`
`13 (72%)
`7 (39%)
`2 (l 1%)
`6 (33%)
`5 (28%)
`
`13 (72%)
`8 (44%)
`
`5 (28%)
`
`18
`15/3
`61 (35—77)
`
`10 (56%)
`5 (28%)
`2 (11%)
`3 (17%)
`
`s (28%)
`2(11%)
`l (6%)
`
`2 (11%)
`1 (6%)
`(0%)
`15 (83%)
`no
`
`16 (89%)
`6 (33%)
`1 (6%)
`4 (22%)
`2 (11%)
`
`12 (67%)
`1 (6%)
`
`6 (33%)
`
`healthy humans without an increase in adverse events
`(Ditzler. 1991; Pantev et al., 1993; Schwenkreis et a1.,
`1999', Bisaga et a1., 2001).
`
`2. Methods
`
`The study was approved by the Ethical Committee of the
`Ruhr University, Bochum. Patients were recruited from the
`pain clinic and by an advertisement in the local newspaper.
`All patients gave their written informed consent.
`Inclusion criteria was an amputation of the upper or lower
`limb (at least more than 3 fingers or toes, see Table 1), a
`history of at least 12 months PLP and an average pain of at
`least 4 on the 11-point numeric rating scale (NRS, 0: no
`pain, 10: worst imaginable pain). Exclusion criteria were
`any changes in PLP treatment within the last 4 weeks
`prior to the investigation, disturbance of the renal function,
`a history of seizures, severe depression, panic disorders or
`other contra-indications to memantine.
`
`2.1. Study design
`
`A doctor not involved in the study performed the rando-
`mization, using a computerized random generator. The
`study medication was prepared in the hospital pharmacy,
`so that placebo and verum had the same color and size
`(5 mg/capsule).~
`
`2.2. Instruments
`
`including the
`The patients completed a questionnaire,
`German validated depression scale (ADS), Pain Disability
`Index (PDI), numeric pain scales (NRS) for recent, average
`and maximum painduring the previous 4 weeks. Additional
`questions mainly concerned the reason for the amputation,
`the quality and the history of PLP and other complaints, the
`use of prothesis, and the effectiveness of prior treatment.
`During the study, the patients assessed used a daily dairy
`to enter the following parameters three times daily: PLP
`intensity (NRS) and the level Of eight complaints (vertigo,
`tiredness, headache, nausea, excitation,
`inner and motor
`restlessness (like crampi) and others), using a 5—point Likert
`scale (0, no; 1, very slight; 2, slight; 3, severe; 4, most
`severe). Complaints rating two or higher were noted as
`severe adverse events. The daily average PLP pain relief
`was calculated from the daily assessment. Number needed
`to treat (NNT) and their 95% confidence interval (using
`Wilson score method) were calculated based on the Change
`in the average PLP at the end of the 3rd week in comparison
`to the average pain assessed at the baseline questionnaire
`(Cook and Sackett, 1995; McQuay and Moore, 1998,
`Bender, 2001).
`
`2.3. Flow of the study (Fig. I)
`
`The maximum dosage of 30 mg/day was titrated from
`5 mg in the beginning with a daily increment of 5 mg.
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`c. Mafzr et at [Pain 103 (2003) 277—283
`
`279
`
`3. Results
`
`3. I . Patient demographics
`
`Thirty—six patients, 18 per group, were enrolled. In both
`groups, the majority had an amputation after an accident or
`other trauma (Table 1). The clinical data did not differ in
`both groups significantly, except for a longer time period
`since amputation in the verum group. However, the duration
`of PLP was comparable as well as the number of patients
`with limb pain prior to amputation. A further evaluation of
`the baseline questionnaire revealed no relevant differences
`between groups with regard to intensity and frequency of
`PLP, the duration of pain-free episodes, the use of prothesis
`or other relevant items (Table 2).
`
`Table 2
`Phantom limb pain and other complaints (baseline questionnaire)a
`
`Memantine group Placebo group
`
`en ”Ned
`n=40
`
`randomized
`n= 36
`
`4 patients
`
`
`“event=.8 n -'- 18placebo
`
`
`
`1st week
`titration
`
`2 pat. (day 3)
`
`2 pat. (day14)
`
`2nd and 3'U wee k
`30/ mglday
`
`4st week
`wash-out
`
`1 pat. (day 10)
`
`
`
`
`pEacebo
`n = 15
`
`Fig. 1. Flow chart of the trial.
`
`After 2 weeks, the end dosage of 30 mg memantine/day was
`achieved, followed by a 2-week steady-state period. In the
`4th week, the drug was gradually withdrawn. Patients were
`allowed to continue their medication in an open add-on
`study.
`
`2.4. Measurement of serum concentration of memantine
`
`Three weeks after the onset of memantine (or placebo)
`therapy, blood samples were drawn and the memantine
`serum concentration was measured in the Department of
`Pharmacological Research Laboratory of Merz and Co
`(Frankfurt, Germany).
`
`2.5. Statistical analysis
`
`Statistical analysis was carried out using Statview©;
`SAS©. Differences between the active treatment and
`placebo arm were proved by Wilcoxon U-test and Chiz-
`test. The data of drop-outs, that means patients that with—
`drew prematurely, were also included in the analysis
`employing the method ‘last observation carried forward’
`(intent-to-treat). The change in NRS during the 4 weeks
`was
`analyzed with covariance
`analysis
`(ANCOVA;
`repeated measures), using treatment, baseline NRS, age
`and the duration of PLP before the study as independent
`factors.
`
`Phantom pain
`Patients (n)
`Average intensity (mean i SD)
`Patients with 35 NRS
`Maximum intensity (mean i SD)
`Patients with 27 NRS
`
`Times free of PLP (last 6 months)
`More <1 week
`Few days/week
`Less
`
`Change of PLP since amputation
`Deteriorated
`Constant
`Improved
`
`Stump pain
`Patients (n)
`Average intensity (mean : SD)
`Patients with 25 NRS
`Maximum intensity (mean : SD)
`Patients with 27NRS
`
`Phantom dysaesthesia
`Patients (n)
`Patients with pain prior
`amputation
`Years since amputation
`(mean. range)
`Patients >5 years since amputation
`History of PLP (years; mean,
`range)
`Patients with >5 years PLP
`
`Use of prothesis
`Patients using prothesis
`Prothesis induced pain
`
`18
`5.1 ($2.13)
`6 (33%)
`7.8 ($1.57)
`13 (72%)
`
`No
`3 (16%)
`12 (83%)
`
`5 (38%)
`12 (66%)
`1 (6%)
`
`18
`5.2 ($202)
`9 (50%)
`7.7 ($1.8)
`13 (72%)
`
`No
`6 (33%)
`12 (67%)
`
`9 (50%)
`6 (33%)
`3 (17%)
`
`10 (56%)
`4,8 (:1,94)
`6 (33%)
`6.4 ($15)
`3 (17%)
`
`'
`
`10 (56%)
`3.6 (:2,29)
`4 (22%)
`6 (i119)
`2 (11%)
`
`9 (50%)
`1 (6%)
`
`8 (44%)
`7 (39%)
`
`23.5 (1—49)*
`
`6 (2—57)
`
`15 (83%)
`10 (1—49)
`'
`
`11
`
`6 (33%)
`3 (16%)
`
`8 (44%)
`12.5 (2—49)
`
`13
`
`12 (67%)
`8 (44%)
`
`29.5 (10—64)
`4 (22%)
`
`Pain disability index (mean t SD)
`Patients with score 240
`
`24 (6—47)
`3 (16%)
`
`17.5 (5—36)
`14.5 (3—41)
`Depression score (mean t SD)
`
`
`6 (33%)Patients with score 218 9 (50%)
`7‘ P < 0.05.
`
`IPR2015—00410
`
`Petitioners' EX. 1015
`
`Page 7
`
`IPR2015-00410
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`Page 7
`
`

`

`280
`
`C. Mater at a], /Pain 103 (2003) 277—283
`
`3.2. Compliance/violation of study protocol/withdrawals
`
`Five patients (three under placebo, two under memantine)
`interrupted the study medication within the first or second
`week (Fig.
`1). The two patients under memantine
`complained of a higher degree of vertigo, nausea, excitation,
`restlessness and moderate headache (onset of all symptoms:
`day 3—5). One of them reported no pain relief and the other
`presented more than 50% pain reduction before withdrawal.
`Three patients on placebo interrupted the trial due to insuf-
`ficient analgesia (two on day 3 and one on day14). However,
`they reported similar side effects on a lower level.
`The measurements of the memantine serum concentra—
`
`tions revealed values within therapeutic levels in all of the
`patients in the verum group (Komhuber and Quack, 1995).
`No violation of the protocol was observed.
`
`no re—rising of the PLP intensity during the washout period
`of memantine or placebo (4th week). ANCOVA analysis
`demonstrated a significant impact only on the prior phantom
`pain level (P = 0.018), however, no effect of treatment.
`Mean pain relief was also similar in both groups (47%
`memantine, 40% placebo group). Ten patients under
`memantine therapy (56%) and six under placebo (33%)
`experienced pain relief of more than 50%, resulting in a
`NNT of 4.5 (95%-confidence interval: 2.1—10.6). Two
`patients in the verum group, none taking placebo were
`free of PLP within the 3rd week. PDI (verum: 22.1 t 12;
`placebo: 17 i7) and the depression scale (22 i 12 vs.
`31 i 18) did not change significantly in either group. Inten—
`sity of stump pain was not assessed during the study,
`however, no patient reported any improvement sponta-
`neously.
`
`3.3. Validation of blinding
`
`3.5. Adverse events
`
`Twenty-six patients (12 under placebo, 14 under meman-
`tine) believed they were receiving placebo. The remaining
`ten patients (six under placebo) believed they were being
`administered memantine.
`
`3.4. Analgesic efects
`
`In both groups, PLP intensity declined significantly
`compared to baseline, which was assessed a few days
`prior to the study entry (Fig. 2). The first day of titration
`was the only one with significant differences between
`groups. However, the further course of PLP intensity and
`of percentage pain relief during the 4 weeks was similar in
`both groups. After a comparable slope in both groups within
`the first week of titration, the mean PLP intensity was low
`without any'differences between groups (Fig. 2). There was
`
`daily average pain intensity (NR5)
`
`1|]
`
`. placebo group I mmtine group
`
`
`
`
`”3““ 1
`
`7
`
`n
`days of treatment
`
`21
`
`2:
`
`Fig. 2. Pain intensity (NRS) at baseline (questionnaire before the trial) and
`during the study (daily mean i standard error of mean; day 1-7: titration
`period, day 7—21: steady state, day 21—28 wash-out period)
`
`The total number of slight adverse events and the number
`of patients, reporting at least one severe side effect were
`comparable in both groups (Table 3). The overall number
`of severe events were higher in the memantine group
`(P < 0.05) due to more than one severe complaint occurring
`at the same time in some of these patients.
`
`3.6. Follow-up
`
`Two patients decided to continue the memantine medica-
`tion untill now (16 months). All other patients preferred to
`terminate the study medication.
`
`4. Discussion
`
`This study in patients with chronic PLP failed to demon-
`strate a significant clinical benefit of the NMDA-receptor
`antagonist memantine with a daily dosage of 30 mg. This
`result is in line with three other double-blinded and placebo-
`controlled cross—over studies. Two of them used a lower
`maximum dosage of 20 mg/d memantine in 24 patients
`suffering from postherpetic neuralgia (PHN), the other in
`19 patients with traumatic nerve injury, including 15 ampu-
`tees (Nikolajsen et al., 2000; Eisenberg and Pud, 1998). The
`third cross-over trial, published recently just after the end of
`our trial, compared the efficacy of memantine (maximum
`daily dose: 58 mg, mean: 50mg), dextrometrophan and
`placebo in 19 patients with diabetic neuropathy and 17
`with PHN. No comparison with placebo reached statistical
`significance and also not in a subgroup of patients with
`allodynia (Sang et al., 2002)
`The lack of efficacy of memantine in the treatment of
`chronic neuropathic pain may have three explanations: (i)
`the dosage used so far was too low to block increased activ-
`ity of the NMDA-receptor effectively; (ii) the potency of
`memantine is too low to reduce NMDA-receptor-mediated
`synaptic excitability in chronic pain states; (iii) chronic PLP
`
`IPR2015—00410
`
`Petitioners' EX. 1015
`
`Page 8
`
`IPR2015-00410
`Petitioners' Ex. 1015
`Page 8
`
`

`

`C. Maier e! a!. /Pain 103 (2003) 277—283
`
`281
`
`Table 3
`Number of patients with slight or severe adverse events during the titration (lst week) and steady-state period (2nd + 3rd week)a
`Adverse event
`Placebo group
`
`Memantine group
`
`Severity of adverse events
`
`Slight
`
`Severe
`
`
`Slight
`Severe
`
`6 (33%)
`6 (33%)
`
`5 (28%)
`9 (50%)
`
`2 (11%)
`6 (33%)
`
`4 (22%)
`' 4 (22%)
`
`7 (39%)
`4 (22%)
`
`4 (22%)
`1 (6%)
`
`no
`2 (11%)
`
`3 (17%)
`3 (17%)
`
`1 (6%)
`2 (11%)
`
`3 (17%)
`2 (11%)
`
`1 (6%)
`2 (11%)
`
`2 (11%)
`3 (17%)
`
`3 (17%)
`4 (22%)
`
`3 (17%)
`l (6%)
`
`7 (39%)
`8 (44%)
`
`8 (44%)
`11 (61%)
`
`5 (28%)
`5 (28%)
`
`1 (6%)
`4 (22%)
`
`6 (33%)
`5 (28%)
`
`2 (11%)
`2 (11%)
`
`2 (11%)
`l (6%)
`
`N0
`No
`
`No
`N0
`
`2 (11%)
`1 (6%)
`
`No
`No
`
`2 (11%)
`2 (11%)
`
`2 (11%)
`3 (17%)
`
`No
`No
`
`Vertigo
`1st week
`2nd + 3rd week
`Tiredness
`Est week
`2nd + 3rd week
`Headache
`151 week
`2nd + 3rd week
`Nausea
`lst week
`2nd + 3rd week
`Restlessness
`lst week
`2nd + 3rd week
`Excitation
`lst week
`2nd + 3rd week
`
`Crampi
`1st week
`2nd + 3rd Week
`Others
`1st week
`2nd + 3rd week
`
`1 (6%)
`no
`1 (6%)
`2 (11%)
`7
`39
`18*
`35
`Number of adverse events
`
`10 (56%) S (23%)
`7 (39%)
`8 (44%)
`Number of patients with at least one event
`“P<am.
`
`5 (28%)
`2 (11%)
`
`1 (6%)
`l (6%)
`
`is (additionally) maintained by mechanisms independent
`from the NMDA-receptor activation.
`The first hypothesis cannot be excluded. However, 30 mg
`memantine daily has been proven to be effective in the
`treatment of dementia and decreased withdrawal symptoms
`in morphine-dependent humans (Ditzler, 1991; Pantev et a1.,
`1993; Bisaga et a1., 2001). Furthermore, the serum concen-
`trations of all patients were within the level, which has
`proved to be effective in humans (Kornhuber and Quack,
`1995).
`that a higher dosage of
`it seems unlikely,
`Moreover,
`In contrast
`to previous
`memantine would be tolerable.
`studies using 20 mg/day,
`the overall number of severe
`adverse events increased in the verum group,
`indicating
`that a dosage of 30 mg/day is the limit of its clinical toler-
`ability. In RCTs for the treatment of dementia, the maxi—
`mum dosage was 20—30 rug/day with an acceptable level of
`side effects, mostly inner or motoric restlessness, headache
`and sleeping disorder (Ditzler, 1991; Pantev et a1., 1993), as
`also reported in our study as well as in the above cited pain
`studies. Using a higher dose of 50 mg memantine, 83% 0f
`
`the patients reported adverse events without an increase of
`efficacy (Sang et a1., 2002).
`The very narrow therapeutical window seems to be a
`common problem of all clinically used NMDA-receptor
`antagonists (Nikolaj sen et a1., 1996; Sang, 2000). For exam-
`ple. dose—limiting side effects of ketamine limited its effec—
`tiveness
`significantly in experimental pain models,
`in
`patients with allodynia and also in the treatment of refrac-
`tory cancer pain (Max et a1., 1995; Park et a1., 1995; Jackson
`et a1., 2001). There are comparable findings in studies deal—
`ing with the treatment of dementia or with neuroprotection
`after stroke (Lodder, 2000; Jain, 2000).
`The generalization of the present results is limited by
`some confusing findings:
`
`0 Despite randomization, pain intensity on day 1 signifi-
`cantly differed between groups. This cannot be explained
`by group differences concerning clinical or demographi—
`cal data. In particular, there were no differences between
`groups with regard to risk factors for severe PLP, such as
`pain prior to amputation, underlying