{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T08:05:48Z","timestamp":1773821148863,"version":"3.50.1"},"reference-count":119,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,10,8]],"date-time":"2018-10-08T00:00:00Z","timestamp":1538956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mucopolysaccharidosis (MPS) are a group of lysosomal storage disorders that are caused by the deficiency of enzymes involving in the catabolism of glycosaminoglycan (GAGs). GAGs incompletely degraded accumulate in many sites, damaging tissues and cells, leading to a variety of clinical manifestations. Many of these manifestations are painful, but few data are available in the literature concerning the prevalence, etiology, and pathogenesis of pain in children with MPS. This review, through the analysis of the data available the in literature, underscores the relevant prevalence of pain in MPSs\u2019 children, provides the instruments to discern the etiopathogenesis of the disease and of pain, illustrates the available molecules for the management of pain and the possible advantages of non-pharmacological pain therapy in MPSs\u2019 patients.<\/jats:p>","DOI":"10.3390\/ijms19103063","type":"journal-article","created":{"date-parts":[[2018,10,8]],"date-time":"2018-10-08T10:44:53Z","timestamp":1538995493000},"page":"3063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Pain in Mucopolysaccharidoses: Analysis of the Problem and Possible Treatments"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2098-7896","authenticated-orcid":false,"given":"Sabrina","family":"Congedi","sequence":"first","affiliation":[{"name":"Dipartimento di Salute della Donna e del Bambino, Universit\u00e0 degli studi di Padova, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcello","family":"Orzalesi","sequence":"additional","affiliation":[{"name":"Scuola di Formazione Maruzza in Cure Palliative Pediatriche \u201cMaruzza Lyceum\u201d, Fondazione Maruzza Lefebvre D\u2019Ovidio Onlus, 00135 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Di Pede","sequence":"additional","affiliation":[{"name":"Centro di Riferimento Veneto di Terapia del Dolore e Cure Palliative Pediatriche, Dipartimento di Salute della Donna e del Bambino, Universit\u00e0 degli studi di Padova, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franca","family":"Benini","sequence":"additional","affiliation":[{"name":"Dipartimento di Salute della Donna e del Bambino, Universit\u00e0 degli studi di Padova, 35128 Padua, Italy"},{"name":"Centro di Riferimento Veneto di Terapia del Dolore e Cure Palliative Pediatriche, Dipartimento di Salute della Donna e del Bambino, Universit\u00e0 degli studi di Padova, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,8]]},"reference":[{"key":"ref_1","unstructured":"Neufeld, E.F., and Muenzer, J. (2014). The Mucopolysaccharidoses. The Online Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill Medical."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1186\/s13023-015-0376-9","article-title":"Review and evaluation of the methodological quality of the existing guidelines and recommendations for inherited neurometabolic disorders","volume":"10","author":"Cassis","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1007\/s10545-005-0112-z","article-title":"Cumulative incidence rates of the mucopolysaccharidoses in Germany","volume":"28","author":"Baehner","year":"2005","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1002\/ajmg.a.20314","article-title":"Incidence of the mucopolysaccharidoses in Western Australia","volume":"123A","author":"Nelson","year":"2003","journal-title":"Am. J. Med. Genet."},{"key":"ref_5","first-page":"782","article-title":"Incidence of mucopolysaccharidoses in Tunisia","volume":"87","author":"Tebib","year":"2009","journal-title":"Tunis. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1002\/ajmg.a.32781","article-title":"Incidence of the mucopolysaccharidoses in Taiwan, 1984-2004","volume":"149A","author":"Lin","year":"2009","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1111\/j.1651-2227.2008.00965.x","article-title":"Mucopolysaccharidoses in the Scandinavian countries: Incidence and prevalence","volume":"97","author":"Malm","year":"2008","journal-title":"Acta Paediatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/ajmg.a.36833","article-title":"International guidelines for the management and treatment of Morquio A syndrome","volume":"167","author":"Hendriksz","year":"2015","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_9","first-page":"59","article-title":"Mortality in Patients with Morquio Syndrome A","volume":"15","author":"Lavery","year":"2015","journal-title":"JIMD Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/s10545-013-9587-1","article-title":"Diagnosing mucopolysaccharidosis IVA","volume":"36","author":"Wood","year":"2013","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/s10545-014-9737-0","article-title":"Pain: A prevalent feature in patients with mucopolysaccharidosis. Results of a cross-sectional national survey","volume":"38","author":"Brands","year":"2015","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1007\/s10545-014-9715-6","article-title":"Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): A phase 3 randomised placebo-controlled study","volume":"37","author":"Hendriksz","year":"2014","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.ymgme.2017.03.008","article-title":"MPS VI Study Group. The effect of galsulfase enzyme replacement therapy on the growth of patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome)","volume":"122","author":"Harmatz","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/1750-1172-6-55","article-title":"Enzyme Replacement Therapy and\/or Hematopoietic Stem Cell Transplantation at diagnosis in patients with Mucopolysaccharidosis type I: Results of a European consensus procedure","volume":"6","author":"Boelens","year":"2011","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e681","DOI":"10.1542\/peds.2004-1023","article-title":"Direct Comparison of Measures of Endurance, Mobility, and Joint Function During Enzyme-Replacement Therapy of Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome): Results After 48 Weeks in a Phase 2 Open-Label Clinical Study of Recombinant Human N-acetylgalactosamine 4-sulfatase","volume":"115","author":"Harmatz","year":"2005","journal-title":"Pediatrics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1542\/peds.2007-3847","article-title":"Long-term Efficacy and Safety of Laronidase in the Treatment of Mucopolysaccharidosis I","volume":"123","author":"Clarke","year":"2009","journal-title":"Pediatrics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s10024-005-0025-8","article-title":"Early Onset of Lysosomal Storage Disease in a Murine Model of Mucopolysaccharidosis Type VII: Undegraded Substrate Accumulates in Many Tissues in the Fetus and Very Young MPS VII Mouse","volume":"8","author":"Vogler","year":"2005","journal-title":"Pediatr. Dev. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14505","DOI":"10.1073\/pnas.96.25.14505","article-title":"Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the gene encoding alpha-N-acetylglucosaminidase","volume":"96","author":"Li","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1093\/glycob\/9.12.1389","article-title":"A mouse model for mucopolysaccharidosis type III A (Sanfilippo syndrome)","volume":"9","author":"Bhaumik","year":"1999","journal-title":"Glycobiology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/j.1399-0004.1998.tb02745.x","article-title":"Murine MPS I: Insights into the pathogenesis of Hurler syndrome","volume":"53","author":"Russell","year":"1998","journal-title":"Clin. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1097\/00005072-199710000-00010","article-title":"Human mucopolysaccharidosis IIID: Clinical, biochemical, morphological and immunohistochemical characteristics","volume":"56","author":"Jones","year":"1997","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1111\/j.1471-4159.1978.tb12388.x","article-title":"Neurochemistry of the mucopolysaccharidoses: Brain lipids and lysosomal enzymes in patients with four types of mucopolysaccharidosis and in normal controls","volume":"30","author":"Constantopoulos","year":"1978","journal-title":"J. Neurochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.semcdb.2004.03.002","article-title":"Secondary accumulation of gangliosides in lysosomal storage disorders","volume":"15","author":"Walkley","year":"2004","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1111\/j.1365-2990.2005.00675.x","article-title":"Abnormal neuronal metabolism and storage in mucopolysaccharidosis type VI (Maroteaux-Lamy) disease","volume":"31","author":"Walkley","year":"2005","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1097\/00005072-199802000-00006","article-title":"Caprine mucopolysaccharidosis-IIID: Clinical, biochemical, morphological and immunohistochemical characteristics","volume":"57","author":"Jones","year":"1998","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1002\/cne.20355","article-title":"Differential subcellular localization of cholesterol, gangliosides, and glycosaminoglycans in murine models of mucopolysaccharide storage disorders","volume":"480","author":"McGlynn","year":"2004","journal-title":"J. Comp. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.bbalip.2004.08.011","article-title":"Consequences of NPC1 and NPC2 loss of function in mammalian neurons","volume":"1685","author":"Walkley","year":"2004","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1034\/j.1600-0854.2000.011101.x","article-title":"Membrane traffic in sphingolipid storage diseases","volume":"1","author":"Pagano","year":"2000","journal-title":"Traffic"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1093\/brain\/awg089","article-title":"Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis","volume":"126","author":"Jeyakumar","year":"2003","journal-title":"Brain"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1073\/pnas.252784899","article-title":"Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB","volume":"100","author":"Ohmi","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1073\/pnas.0912937107","article-title":"Involvement of the Toll-like receptor 4 pathway and use of TNF antagonists for treatment of the mucopolysaccharidoses","volume":"107","author":"Simonaro","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"112","DOI":"10.2353\/ajpath.2008.070564","article-title":"Mechanism of glycosaminoglycan-mediated bone and joint disease: Implications for the mucopolysaccharidoses and other connective tissue diseases","volume":"172","author":"Simonaro","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.2353\/ajpath.2009.090211","article-title":"Glycosaminoglycan-Mediated Loss of Cathepsin K Collagenolytic Activity in MPS I Contributes to Osteoclast and Growth Plate Abnormalities","volume":"175","author":"Wilson","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_34","unstructured":"Kliegman, R.M., Stanton, B.F., St. Geme, J.W., and Schor, N.F. (2011). Pediatric Pain Management. Nelson Textbook of Pediatrics, Elsevier Saunders. [19th ed.]."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.rdc.2013.03.004","article-title":"Mucopolysaccharidoses and Other Lysosomal Storage Diseases","volume":"39","author":"Lampe","year":"2013","journal-title":"Rheum. Dis. Clin. N. Am."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1136\/ard.2008.095315","article-title":"Musculoskeletal manifestations of lysosomal storage disorders","volume":"68","author":"Aldenhoven","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1097\/01202412-199804000-00009","article-title":"Triggering in the mucopolysaccharidoses","volume":"7","author":"Haddad","year":"1998","journal-title":"J. Pediatr. Orthop. B"},{"key":"ref_38","unstructured":"Delfino, A. (2013). La Semeiotica Del Dolore, Weidmuller."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1002\/ca.22120","article-title":"The anatomy of osteoarthritic joint pain","volume":"27","author":"Witt","year":"2014","journal-title":"Clin. Anat."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1161\/01.CIR.46.6.1048","article-title":"Pathology of Angina Pectoris","volume":"46","author":"Vlodaver","year":"1972","journal-title":"Circulation"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1136\/hrt.12.1.17","article-title":"The cardiovascular system in gargoylism","volume":"12","author":"Lindsay","year":"1950","journal-title":"Br. Heart J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1111\/j.1651-2227.2005.tb02004.x","article-title":"Clinical presentation and follow-up of patients with the attenuated phenotype of mucopolysaccharidosis type I","volume":"94","author":"Vijay","year":"2005","journal-title":"Acta Paediatr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1111\/j.1464-5491.2004.01271.x","article-title":"Chronic painful peripheral neuropathy in an urban community: A controlled comparison of people with and without diabetes","volume":"21","author":"Daousi","year":"2004","journal-title":"Diabet. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0304-3959(02)00452-9","article-title":"A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury","volume":"103","author":"Siddall","year":"2003","journal-title":"Pain"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1142\/S0218810414500087","article-title":"Clinical characteristics of neuropathic pain in patients with carpal tunnel syndrome","volume":"19","author":"Sonohata","year":"2014","journal-title":"Hand Surg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1136\/bmj.39282.623553.AD","article-title":"Carpal tunnel syndrome","volume":"335","author":"Bland","year":"2007","journal-title":"BMJ"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/S0266-7681(96)80023-4","article-title":"Carpal tunnel syndrome in children and adolescents with no history of trauma","volume":"21","author":"Thomson","year":"1996","journal-title":"J. Hand Surg Br."},{"key":"ref_48","first-page":"141","article-title":"Morquio A syndrome: Diagnosis and current and future therapies","volume":"12","author":"Tomatsu","year":"2014","journal-title":"Pediatr. Endocrinol. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"S71","DOI":"10.1016\/j.pain.2012.12.007","article-title":"Pain in patients with spinal cord injury","volume":"154","author":"Finnerup","year":"2013","journal-title":"Pain"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.neulet.2016.02.005","article-title":"Neuropathic pain induced by spinal cord injury: Role of endothelin ETA and ETB receptors","volume":"617","author":"Forner","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0014-4886(02)00023-7","article-title":"Endothelin receptor expression in the normal and injured spinal cord: Potential involvement in injury-induced ischemia and gliosis","volume":"180","author":"Peters","year":"2003","journal-title":"Exp. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"f7656","DOI":"10.1136\/bmj.f7656","article-title":"Neuropathic pain: Mechanisms and their clinical implications","volume":"348","author":"Cohen","year":"2014","journal-title":"BMJ"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0304-3959(00)00269-4","article-title":"Pain in children and adolescents: A common experience","volume":"87","author":"Perquin","year":"2000","journal-title":"Pain"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1177\/0883073807300528","article-title":"Carpal Tunnel Syndrome in Children with Mucopolysaccaridoses","volume":"22","author":"Yuen","year":"2007","journal-title":"J. Child Neurol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"12","DOI":"10.5435\/JAAOS-21-01-12","article-title":"Mucopolysaccharide Disorders in Orthopaedic Surgery","volume":"21","author":"White","year":"2013","journal-title":"J. Am. Acad. Orthop. Surg."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"v13","DOI":"10.1093\/rheumatology\/ker395","article-title":"Pathogenesis of skeletal and connective tissue involvement in the mucopolysaccharidoses: Glycosaminoglycan storage is merely the instigator","volume":"50","author":"Clarke","year":"2011","journal-title":"Rheumatology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1750-1172-9-32","article-title":"Burden of disease in patients with Morquio A syndrome: Results from an international patient-reported outcomes survey","volume":"9","author":"Hendriksz","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2272","DOI":"10.1002\/ajmg.a.37172","article-title":"Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double-blind, pilot study","volume":"167","author":"Burton","year":"2015","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ymgme.2013.03.004","article-title":"High prevalence of femoral head necrosis in Mucopolysaccharidosis type III (Sanfilippo disease): A national, observational, cross-sectional study","volume":"109","author":"Maas","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1097\/BPO.0b013e31821f5ee9","article-title":"Musculoskeletal Manifestations of Sanfilippo Syndrome (Mucopolysaccharidosis Type III)","volume":"31","author":"White","year":"2011","journal-title":"J. Pediatr. Orthop."},{"key":"ref_61","first-page":"178","article-title":"Bony changes in common mucopolysaccharidoses","volume":"37","author":"Chen","year":"1996","journal-title":"Acta Paediatr. Sin."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1302\/0301-620X.79B4.0790576","article-title":"Carpal tunnel syndrome in the mucopolysaccharidoses and mucolipidoses","volume":"79","author":"Haddad","year":"1997","journal-title":"J. Bone Joint Surg. Br."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"307","DOI":"10.3928\/00904481-20140723-05","article-title":"An 8-Year-Old Girl with a History of Stiff and Painful Joints","volume":"43","author":"Raiman","year":"2014","journal-title":"Pediatr. Ann."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.pediatrneurol.2012.08.010","article-title":"Enzyme replacement therapy in an attenuated case of mucopolysaccharidosis type I (Scheie syndrome): A 6.5-year detailed follow-up","volume":"47","author":"Jurecka","year":"2012","journal-title":"Pediatr. Neurol."},{"key":"ref_65","first-page":"387","article-title":"Carpal tunnel syndrome in children","volume":"69","year":"2003","journal-title":"Acta Orthop. Belg."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1302\/0301-620X.78B2.0780307","article-title":"Occipito-atlanto-axial fusion in Morquio-Brailsford syndrome. A ten-year experience","volume":"78","author":"Ransford","year":"1996","journal-title":"J. Bone Joint Surg. Br."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1750-1172-5-5","article-title":"Mucopolysaccharidosis VI","volume":"5","author":"Valayannopoulos","year":"2010","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1136\/archdischild-2012-303482","article-title":"Pain in young people aged 13 to 17 years with cerebral palsy: Cross-sectional, multicentre European study","volume":"98","author":"Parkinson","year":"2013","journal-title":"Arch. Dis. Child."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1111\/j.1651-2227.2009.01626.x","article-title":"Pain in children with cerebral palsy: A cross-sectional multicentre European study","volume":"99","author":"Parkinson","year":"2010","journal-title":"Acta Paediatr."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e407","DOI":"10.1542\/peds.2013-0224","article-title":"Characteristics of Pain in Children and Youth With Cerebral Palsy","volume":"132","author":"Penner","year":"2013","journal-title":"Pediatrics"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1001\/archpedi.157.12.1219","article-title":"The Incidence of Pain in Children with Severe Cognitive Impairments","volume":"157","author":"Breau","year":"2003","journal-title":"Arch. Pediatr. Adolesc. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/j.1460-9592.2005.01773.x","article-title":"The Revised Flacc Observational Pain Tool: Improved reliability and validity for pain assessment in children with cognitive impairment","volume":"16","author":"Malviya","year":"2006","journal-title":"Pediatr. Anesth."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.pedn.2012.03.023","article-title":"Optimizing the Assessment of Pain in Children Who Are Cognitively Impaired Through the Quality Improvement Process","volume":"27","author":"Zarnowsky","year":"2012","journal-title":"J. Pediatr. Nurs."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1097\/00004703-200608000-00002","article-title":"Long-term outcomes of adaptive functions for children with mucopolysaccharidosis I (Hurler syndrome) treated with hematopoietic stem cell transplantation","volume":"27","author":"Bjoraker","year":"2006","journal-title":"J. Dev. Behav. Pediatr."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/8904_2015_521","article-title":"Long-Term Cognitive and Functional Outcomes in Children with Mucopolysaccharidosis (MPS)-IH (Hurler Syndrome) Treated with Hematopoietic Cell Transplantation","volume":"29","author":"Shapiro","year":"2015","journal-title":"JIMD Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1002\/ajmg.a.38014","article-title":"Impact of elosulfase alfa in patients with morquio A syndrome who have limited ambulation: An open-label, phase 2 study","volume":"173","author":"Harmatz","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s10545-010-9059-9","article-title":"Efficacy of recombinant human \u03b1-L-iduronidase (laronidase) on restricted range of motion of upper extremities in mucopolysaccharidosis type I patients","volume":"33","author":"Marucha","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.jpeds.2004.01.046","article-title":"Enzyme replacement therapy for mucopolysaccharidosis I: A randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase)","volume":"144","author":"Wraith","year":"2004","journal-title":"J. Pediatr."},{"key":"ref_79","unstructured":"U.S, Food and Drug Administration (2018, October 06). Center for drug Evakuation and Research, Available online: www.accessdata.fda.gov\/scripts\/cder\/drugsatfda."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.jpeds.2004.03.018","article-title":"Enzyme replacement therapy in mucopolisaccaridosis VI","volume":"144","author":"Harmatz","year":"2004","journal-title":"J. Pediatr."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.ymgme.2016.01.012","article-title":"Elevated TNF-\u03b1 is associated with pain and physical disability in mucopolysaccharidosis types I, II, and VI","volume":"117","author":"Polgreen","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e519","DOI":"10.1542\/peds.2006-1609","article-title":"Gabapentin successfully manages chronic unexplained irritabily in children with severe neurologi impairment","volume":"119","author":"Hauer","year":"2007","journal-title":"Pediatrics"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"198","DOI":"10.3928\/00904481-20100318-04","article-title":"Identifying and managing sources of pain and distress in children with neurological impairment","volume":"39","author":"Hauer","year":"2010","journal-title":"Pediatr. Ann."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1111\/j.1365-2125.2011.03970.x","article-title":"Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials","volume":"72","author":"Lynch","year":"2011","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.nurt.2009.08.002","article-title":"Cannabinoids as pharmacotherapies for neuropathic pain: From the bench to the bedside","volume":"6","author":"Rahn","year":"2009","journal-title":"Neurotherapeutics"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.bbr.2008.07.028","article-title":"Delta 9-tetrahydrocannabinol suppresses vomiting behavior and Fos expression in both acute and delayed phases of cisplatin-induced emesis in the least shrew","volume":"196","author":"Ray","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_87","first-page":"847","article-title":"Cannabinoids in the management of spasticity associated with multiple sclerosis","volume":"4","author":"Malfitano","year":"2008","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1212\/01.wnl.0000253187.66183.9c","article-title":"Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial","volume":"68","author":"Abrams","year":"2007","journal-title":"Neurology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.mayocp.2013.04.018","article-title":"Marijuana and chronic nonmalignant pain in adolescents","volume":"88","author":"Harrison","year":"2013","journal-title":"Mayo Clin. Proc."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1016\/j.jpain.2015.07.014","article-title":"Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). COMPASS study team","volume":"16","author":"Ware","year":"2015","journal-title":"J. Pain"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1093\/bja\/83.4.637","article-title":"Adverse effects of cannabis and cannabinoids","volume":"83","author":"Asthon","year":"1999","journal-title":"Br. J. Anaesth."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1747-597X-4-7","article-title":"Relief-oriented use of marijuana by teens","volume":"4","author":"Bottorff","year":"2009","journal-title":"Subst. Abuse Treat. Prev. Policy"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/j.jpain.2009.09.009","article-title":"The impact of adolescent chronic pain on functioning: Disentangling the complex role of anxiety","volume":"11","author":"Cohen","year":"2010","journal-title":"J. Pain"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.pain.2006.12.021","article-title":"Disability in adolescents with chronic pain: Patterns and predictors across different domains of functioning","volume":"131","author":"Eccleston","year":"2007","journal-title":"Pain"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1093\/jpepsy\/jsr024","article-title":"Anxiety, coping, and disability: A test of mediation in a pediatric chronic pain sample","volume":"36","author":"Kaczynski","year":"2011","journal-title":"J. Pediatr. Psychol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.jad.2013.05.042","article-title":"Complementary and alternative therapies as add-on to pharmacotherapy for mood and anxiety disorders: A systematic review","volume":"150","author":"Ravindran","year":"2013","journal-title":"J. Affect. Disord."},{"key":"ref_97","first-page":"21","article-title":"Chronic pain management: Nonpharmacological therapies for chronic pain","volume":"432","author":"Chang","year":"2015","journal-title":"FP Essent."},{"key":"ref_98","first-page":"CD003968","article-title":"Psychological therapies for the management of chronic and recurrent pain in children and adolescents","volume":"2","author":"Eccleston","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Oliveira, N.C. (2016). Audiovisual distraction for pain relief in paediatric inpatients: A crossover study. Eur. J. Pain.","DOI":"10.1002\/ejp.915"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1177\/0095798499025003003","article-title":"The social and cultural context of coping with sickle cell disease: II. The role of financial hardship in adjustment to sickle cell disease","volume":"25","author":"Barbarin","year":"1999","journal-title":"J. Black Psychol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"151","DOI":"10.2190\/QQKG-EPFA-A2FN-GHVL","article-title":"Overcoming Barriers to Access and Utilization of Hospice and Palliative Care Services in African-American Communities","volume":"50","author":"Winston","year":"2004","journal-title":"Omega J. Death Dying."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.annemergmed.2003.11.019","article-title":"Inadequate analgesia in emergency medicine","volume":"43","author":"Rupp","year":"2004","journal-title":"Ann. Emerg. Med."},{"key":"ref_103","unstructured":"World Health Organization (2003). Acupuncture Review and Analysis of Reports on Controlled Clinical Trials, World Health Organization."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/0304-3959(87)90011-X","article-title":"Involvement of endogenous opioid peptides in acupuncture analgesia","volume":"31","author":"He","year":"1987","journal-title":"Pain"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"134","DOI":"10.3390\/children1020134","article-title":"Acupuncture for pediatric pain","volume":"1","author":"Golianu","year":"2014","journal-title":"Children"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S0885-3924(02)00506-7","article-title":"A phase I study on the feasibility and acceptability of an acupuncture\/hypnosis intervention for chronic pediatric pain","volume":"24","author":"Zeltzer","year":"2002","journal-title":"J. Pain Symptom Manag."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0168-0102(01)00207-3","article-title":"Influence of serotonin receptor antagonists on substance P and serotonin release evoked by tooth pulp stimulation with electro-acupuncture in the trigeminal nucleus cudalis of the rabbit","volume":"40","author":"Yonehara","year":"2001","journal-title":"Neurosci. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.expneurol.2005.06.018","article-title":"Effects of electroacupuncture on cold allodynia in a rat model of neuropathic pain: Mediation by spinal adrenergic and serotonergic receptors","volume":"195","author":"Sun","year":"2005","journal-title":"Exp. Neurol."},{"key":"ref_109","first-page":"823","article-title":"Exercise in warm water decreases pain and improves cognitive function in middle-aged women with fibromyalgia","volume":"25","year":"2007","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S0025-6196(11)62384-7","article-title":"Effectiveness of resistive heating compared with passive warming in treating hypothermia associated with minor trauma: A randomized trial","volume":"76","author":"Kober","year":"2001","journal-title":"Mayo Clin. Proc."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1093\/ecam\/nel068","article-title":"Randomized controlled trials of pediatric massage: A review","volume":"4","author":"Beider","year":"2007","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1067\/mmt.2003.11","article-title":"Evaluation of chiropractic management of pediatric patients with low back pain: A prospective cohort study","volume":"26","author":"Hayden","year":"2003","journal-title":"J. Manip. Physiol. Ther."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1093\/jmt\/41.3.241","article-title":"The impact of group singing on mood, coping, and perceived pain in chronic pain patients attending a multidisciplinary pain clinic","volume":"41","author":"Kenny","year":"2004","journal-title":"J. Music Ther."},{"key":"ref_114","unstructured":"Jeffery, M.M., Butler, M., Stark, A., and Kane, R.L. (2011). Multidisciplinary Pain Programs for Chronic Noncancer Pain [Internet]."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.ctcp.2009.02.008","article-title":"Animal-assisted therapy as a pain relief intervention for children","volume":"15","author":"Braun","year":"2009","journal-title":"Complement. Ther. Clin. Pract."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1177\/0898010105280112","article-title":"Canine visitation (pet) therapy: Pilot data on decreases in child pain perception","volume":"24","author":"Sobo","year":"2006","journal-title":"J. Holist. Nurs."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.jor.2018.01.036","article-title":"Total hip arthroplasty in Hurler syndrome\u20148 years follow up\u2014A case report with review of literature","volume":"15","author":"Gautam","year":"2018","journal-title":"J. Orthop."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/s10545-011-9304-x","article-title":"Orthopaedic management of Hurler\u2019s disease after hematopoietic stem cell transplantation: A systematic review","volume":"34","author":"Kruyt","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1302\/1863-2548.11.170042","article-title":"Does orthopaedic surgery improve quality of life and function in patients with mucopolysaccharidoses?","volume":"11","author":"Williams","year":"2017","journal-title":"J. Child Orthop."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/10\/3063\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:24:20Z","timestamp":1760196260000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/10\/3063"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,8]]},"references-count":119,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,10]]}},"alternative-id":["ijms19103063"],"URL":"https:\/\/doi.org\/10.3390\/ijms19103063","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,8]]}}}