The translation of therapeutic interventions to humans with spinal cord injury with the goal of promoting growth and repair in the central nervous system could, inadvertently, drive mechanisms associated with the development of neuropathic pain. A framework is needed to evaluate the probability that a therapeutic intervention for acute spinal cord injury modifies the progression of neuropathic pain. We analyzed a large, longitudinal dataset from the European Multi-Center Study about Spinal Cord Injury (EMSCI) and compared these observations with a previously published Swedish/Danish cohort. A meta-analysis was performed to produce aggregate estimates for the transition period between 1–6 months and the transition period between 1–12 months after injury. A secondary analysis used logistic regression to explore associations between the progression of neuropathic pain and demographics, pain characteristics, and injury characteristics. For overall neuropathic pain, 72% presenting with pain symptoms at one month reported persisting symptoms at six months, and 23% who did not have neuropathic pain at one month later had it develop. From 1–12 months, there was a similar likelihood of pain persisting (69%) and slightly higher rate of pain developing (36%). Characteristics that were significantly associated with the progression of pain included age and sensory and motor preservation. We provide historical benchmarks for estimating the progression of neuropathic pain during the first year after acute SCI. This information will be useful for comparison and evaluating safety during early phase acute spinal cord injury trials.
Get full access to this article
View all access options for this article.
References
1.
CoteD.J., BredenoordA.L., SmithT.R., AmmiratiM., BrennumJ., MendezI., AmmarA.S., BalakN., BollesG., EseneI.N., MathiesenT., and BroekmanM.L. (2017). Ethical clinical translation of stem cell interventions for neurologic disease. Neurology, 88, 322–328.
2.
AndersonK.D., GuestJ., DietrichW.D., Bartlett BungeM., CurielR., DididzeM., GreenB.A., KhanA., PearseD.D., Saraf-LaviE., Widerstrom-NogaE., WoodP., and LeviA.D. (2017). Safety of autologous human Schwann cell transplantation in subacute thoracic spinal cord injury. J. Neurotrauma, 34, 2950–2963.
3.
Gomes-OsmanJ., CortesM., GuestJ., and Pascual-LeoneA. (2016). A systematic review of experimental strategies aimed at improving motor function after acute and chronic spinal cord injury. J. Neurotrauma, 33, 425–438.
4.
AssinckP., DuncanG.J., HiltonB.J., PlemelJ.R., and TetzlaffW. (2017). Cell transplantation therapy for spinal cord injury. Nat. Neurosci. 20, 637–647.
5.
FanC., ZhengY., ChengX., QiX., BuP., LuoX., KimD.H., and CaoQ. (2012). Transplantation of D15A-expressing glial-restricted-precursor-derived astrocytes improves anatomical and locomotor recovery after spinal cord injury. Int. J. Biol. Sci. 9, 78–93.
6.
HofstetterC.P., HolmströmN.A., LiljaJ.A., SchweinhardtP., HaoJ., SpengerC., Wiesenfeld-HallinZ., KurpadS.N., FrisénJ., and OlsonL. (2005). Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat. Neurosci. 8, 346–353.
7.
LeviA.D., OkonkwoD.O., ParkP., JenkinsA.L.3rd, KurpadS.N., ParrA.M., GanjuA., AarabiB., KimD., CashaS., FehlingsM.G., HarropJ.S., AndersonK.D., GageA., HsiehJ., HuhnS., CurtA., and GuzmanR. (2018). Emerging safety of intramedullary transplantation of human neural stem cells in chronic cervical and thoracic spinal cord injury. Neurosurgery, 82, 562–576.
8.
FinnerupN.B., NorrbrinkC., TrokK., PiehlF., JohannesenI.L., SørensenJ.C., JensenT.S., and WerhagenL. (2014). Phenotypes and predictors of pain following traumatic spinal cord injury: a prospective study. J. Pain, 15, 40–48.
9.
SiddallP.J., TaylorD.A., McClellandJ.M., RutkowskiS.B., and CousinsM.J. (1999). Pain report and the relationship of pain to physical factors in the first 6 months following spinal cord injury. Pain, 81, 187–197.
10.
KirshblumS.C., BurnsS.P., Biering-SorensenF., DonovanW., GravesD.E., JhaA., JohansenM., JonesL., KrassioukovA., MulcaheyM., Schmidt-ReadM., and WaringW. (2011). International standards for neurological classification of spinal cord injury (revised 2011). J. Spinal Cord Med. 34, 535–546.
11.
CraggJ.J., HaefeliJ., JutzelerC.R., RöhrichF., WeidnerN., SaurM., MaierD.D., KalkeY.B., SchuldC., CurtA., and KramerJ.K. (2016). Effects of pain and pain management on motor recovery of spinal cord-injured patients: a longitudinal study. Neurorehabil. Neural Repair, 30, 753–761.
12.
WarnerF.M., CraggJ.J., JutzelerC.R., RöhrichF., WeidnerN., SaurM., MaierD.D., SchuldC.; EMSCI sites, MaierD.D., CurtA., and KramerJ.K. (2017). Early administration of gabapentinoids improves motor recovery after human spinal cord injury. Cell Rep. 18, 1614–1618.
13.
SiddallP.J., TaylorD.A., and CousinsM.J. (1997). Classification of pain following spinal cord injury. Spinal Cord, 35, 69–75.
14.
HassanpourK., Hotz-BoendermakerS., DokladalP.; European Multicenter Study for Human Spinal Cord Injury Study group, CurtA. (2012). Low depressive symptoms in acute spinal cord injury compared to other neurological disorders. J. Neurol. 259, 1142–1150.
15.
LevitanY., ZeiligG., BondiM., RinglerE., and DefrinR. (2015). Predicting the risk for central pain using the sensory components of the International Standards for Neurological Classification of Spinal Cord Injury. J. Neurotrauma, 32, 1684–1692.
16.
KishkN.A., GabrH., HamdyS., AfifiL., AbokreshaN., MahmoudH., WafaieA., and BilalD. (2010). Case control series of intrathecal autologous bone marrow mesenchymal stem cell therapy for chronic spinal cord injury. Neurorehabil. Neural Repair, 24, 702–708.
17.
Oraee-YazdaniS., HafiziM., AtashiA., AshrafiF., SeddighiA.S., HashemiS.M., SeddighiA., SoleimaniM., and ZaliA. (2016). Co-transplantation of autologous bone marrow mesenchymal stem cells and Schwann cells through cerebral spinal fluid for the treatment of patients with chronic spinal cord injury: safety and possible outcome. Spinal Cord, 54, 102–109.
18.
MaciasM.Y., SyringM.B., PizziM.A., CroweM.J., AlexanianA.R., and KurpadS.N. (2006). Pain with no gain: allodynia following neural stem cell transplantation in spinal cord injury. Exp. Neurol. 201, 335–348.
19.
SchulzerM., and ManciniG.B. (1996). “Unqualified success” and “unmitigated failure”: number-needed-to-treat-related concepts for assessing treatment efficacy in the presence of treatment-induced adverse events. Int. J. Epidemiol. 25, 704–712.
20.
KramerJ.L., MinhasN.K., JutzelerC.R., ErskineE.L., LiuL.J., and RamerM.S. (2017). Neuropathic pain following traumatic spinal cord injury: models, measurement, and mechanisms. J. Neurosci. Res. 85, 1295–1306.
21.
BurkeD., FullenB.M., StokesD., and LennonO. (2017). Neuropathic pain prevalence following spinal cord injury: a systematic review and meta-analysis. Eur. J. Pain, 21, 29–44.
22.
Thibault-HalmanG., RiversC.S., BaileyC.S., TsaiE.C., DrewB., NoonanV.K., FehlingsM.G., DvorakM.F., KuerbanD., KwonB.K., and ChristieS.D. (2017). Predicting recruitment feasibility for acute spinal cord injury clinical trials in Canada Using National Registry data. J. Neurotrauma, 34, 599–606.
23.
FaulF., ErdfelderE., LangA.G., and BuchnerA. (2007). G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav. Res. Methods, 39, 175–191.
24.
De OliveiraG.S.Jr., AlmeidaM.D., BenzonH.T., and McCarthyR.J. (2011). Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology, 115, 575–588.
25.
SalinasF.A., LugoL.H., and GarcíaH.I. (2012). Efficacy of early treatment with carbamazepine in prevention of neuropathic pain in patients with spinal cord injury. Am. J. Phys. Med. Rehabil. 91, 1020–1027.
26.
CardenasD.., NieshoffE.C., SudaK., GotoS.I., SaninL., KanekoT., SpornJ., ParsonsB., SoulsbyM., YangR., WhalenE., ScavoneJ.M., SuzukiM.M., and KnappL.E. (2013). A randomized trial of pregabalin in patients with neuropathic pain due to spinal cord injury. Neurology, 80, 533–539.
27.
Margot-DuclotA., TournebiseH., VenturaM., and FattalC. (2009). What are the risk factors of occurence and chronicity of neuropathic pain in spinal cord injury patients?. Ann. Phys. Rehabil. Med. 52, 111–123.
28.
BoogaardS., HeymansM.W., de VetH.C., PetersM.L., LoerS.A., ZuurmondW.W., and PerezR.S. (2015). Predictors of persistent neuropathic pain—a systematic review. Pain Physician, 18, 433–457.
29.
JungB.F., JohnsonR.W., GriffinD.R., and DworkinR.H. (2004). Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology, 62, 1545–1551.
30.
BrackenM.B., ShepardM.J., CollinsW.F., HolfordT.R., YoungW., BaskinD.S., EisenbergH.M., FlammE., Leo-SummersL., and MaroonJ., et al. (1990). A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N. Engl. J. Med., 322, 1405–1411.
31.
InadaT., TakahashiH., YamazakiM., OkawaA., SakumaT., KatoK., HashimotoM., HayashiK., FuruyaT., FujiyoshiT., KawabeJ., MannojiC., MiyashitaT., KadotaR., SomeyaY., IkedaO., HashimotoM., SudaK., KajinoT., UedaH., ItoY., UetaT., HanaokaH., TakahashiK., and KodaM. (2014). Multicenter prospective nonrandomized controlled clinical trial to prove neurotherapeutic effects of granulocyte colony-stimulating factor for acute spinal cord injury: analyses of follow-up cases after at least 1 year. Spine (Phila. Pa. 1976). 39, 213–219.
32.
FehlingsM.G., TheodoreN., HarropJ., MauraisG., KuntzC., ShaffreyC.I., KwonB.K., ChapmanJ., YeeA., TigheA., and McKerracherL. (2011). A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J. Neurotrauma, 28, 787–796.
33.
FinnerupN.B., JensenM.P., NorrbrinkC., TrokK., JohannesenI.L., JensenT.S., and WerhagenL. (2016). A prospective study of pain and psychological functioning following traumatic spinal cord injury. Spinal Cord, 54, 816–821.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
