BritishMedicalBulletin,2015,113:101–115 doi:10.1093/bmb/ldu040 AdvanceAccessPublicationDate:12January2015 Pharmacological interventions for the treatment of Achilles tendinopathy: a systematic review D o of randomized controlled trials w n lo a d NicolaMaffulli†,‡,*,RoccoPapalia§,StefanoD’Adamio§,LorenzoDiazBalzani§, ed andVincenzoDenaro§ from h †Centre for Sports and Exercise Medicine, Barts and The London School of Medicine and Dentistry, Mile ttps EndHospital,275BancroftRoad,LondonE14DG,UK,‡DepartmentofMusculoskeletalDisorders,Facultyof ://a c a Medicine and Surgery, University of Salerno, Via Salvador Allende, Baronissi, Salerno 84081, Italy, and de m §Department of Orthopaedic and Trauma Surgery, Campus Biomedico University of Rome, Via Alvaro del ic .o Portillo200,Rome,Italy u p .c *Correspondenceaddress.CentreforSportsandExerciseMedicine,BartsandTheLondonSchoolofMedicineandDentistry, om MileEndHospital,275BancroftRoad,LondonE14DG,UK.E-mail:[email protected] /b m b Accepted22November2014 /a rtic le Abstract -a b s Introduction: Several pharmacological interventions have been proposed for tra c the management of Achillestendinopathy, with no agreement on which isthe t/1 1 overallbestoptionavailable.Thissystematicreviewinvestigatestheefficacyand 3/1 safetyofdifferentlocalpharmacologicaltreatmentsforAchillestendinopathy. /10 1 /2 Sources of data: We included only randomized controlled studies (RCTs) 8 4 3 focusingonclinicalandfunctionaloutcomesoftherapiesconsistingininjec- 0 8 tion of a substance or local application. Assessment of the methodological by g quality was performed using a modified version of the Coleman method- u e s ologyscore(CMS)todeterminepossiblerisksofbias. t o n 1 Areasofagreement: ThirteenRCTswereincludedwithatotalof528studied 2 A pstautdieinests.exEalemviennedstuthdeieosurtecpoomrteesdothfepaotuietncotsmweshoofaipnpjelicetdiognlythceerryalpiterisn.itTrwatoe pril 20 1 patch.ThemeanmodifiedCMSwas70.6outof90. 9 Areas of controversy: There was no significant evidence of remarkable benefitsprovidedbyanyofthetherapiesstudied. Growing points: There is not univocal evidence to advise any particular pharmacological treatment as the best advisable non-operative option for Achillestendinopathyasequivalentalternative tothe mostcommonly used eccentric loading rehabilitation program. However, potential was shown by thecombinationofdifferentsubstancesadministeredwithphysicaltherapy. ©TheAuthor2015.PublishedbyOxfordUniversityPress.Allrightsreserved.Forpermissions,pleasee-mail:[email protected] 102 N.Maffullietal.,2015,Vol.113 Research: Thereisaneedformorelong-terminvestigations,studyinglarge enough cohort with standardized scores and evaluations shared by all the investigationstoconfirmthehealingpotential,andprovideastrongerstatis- ticalcomparisonoftheavailabletreatments. Keywords:Achilles,tendonpathology,tendinopathy,conservativetreatment,softtissuetherapy D o w n Introduction by ultrasound imaging or in an unguided blind loa d fashion.25 Along with this treatment, there is also a ed Tendinopathy,acommoncauseofpainanddisability, rolefortransdermaltopicalapplicationofdrugs,with fro isagenericcollectivetermthatindicatesacontinuum m topicalglyceryltrinitrate(GTN)26beingthesubstance h of localized pathological events usually caused by ttp mostlyusedfortreatmentofthiscondition. s sapnodrtgaecnteivriatliesfa,cretoprestit(iiv.ee.mhicorromtroanuemsaaonndthmeetteanbdoolinc There is a lack of comparative analysis of these ://aca disease).1–3 conservativetreatmentmodalitiestoallowtoestab- dem Tendinopathies produce tissue degeneration, lish which can be effectively and safely adopted to ic.o inflammation and functional weakness, and eventu- manage Achilles tendinopathy with the best pos- up ally,thetendonmayexperiencetraumaticruptureif sibleresults.27Thismaybetheresultofthealready .com stresses that exceed the structure’s physiological growing wide range of drugs and substances cur- /bm resistanceareconstantlyappliedonthetissue.4–8 rentlyavailableforlocalapplication. b/a Major tendons such as the Achilles tendon are Wesystematicallyreviewthestudiesavailablewith rtic often subjected to overuse, especially in athletes the highest level of evidence and a randomized con- le-a b involvedinsportsthatrequirerunningorjumping.9–13 trolled design regarding pharmacological interven- stra Normal remodeling and repair of the damaged tions for the treatment of Achilles tendinopathy. ct/1 fibers acts to maintain the strength required by the Moreover, the assessment of the methodological 13 qualitywasperformedusingareliableand validated /1 utilizationofthetendon,but,ifthisprocessbecomes /1 deficient, over time it will cause the typical triad ttohoelp(oCsosilbelmeamnemtheotdhooldoogliocaglyflsacworseo,fCtMheSs)ettoriahlisg.hlight 01/28 found in most patients affected by Achillestendino- 4 3 pathy:pain,swellingandimpairedperformance.14–17 08 b Thepathologycanbeeitherinsertional,affectingthe Methods y gu portion of the tendon on its insertion to the calca- e s neus,oroccurwithinthebodyofthetendon3–6cm Searchstrategyandstudyselection t o n distaltotheinsertion.18–20 1 2 A Avarietyofconservativeinterventionshavebeen Wesetinclusioncriteriatoincludeonlyrandomized p proposedforthemanagementofthisAchillestendi- controlled trials (RCTs) focusing on any pharmaco- ril 2 0 nopathy, ranging from physiotherapy to pharmaco- logical modality for the management of Achilles 19 logicaltreatment.21–24 tendinopathy.Studieshadtobeconductedonhumans; Thislastclassofinterventionpresentswithnumer- theyhadtohaveclinicaland/orfunctionaloutcomesof ousoptions,withagrowingnumberofinjectablesub- thetherapyusedonthesymptomsofAchillestendino- stances (corticosteroids, high-volume saline solution, pathy.Thetherapyhadtobedeliveredlocally,andthe prolotherapy,autologousblood,platelet-richplasma, tendinopathy could have been located at the main aprotinin, botulinum toxin, sodium hyaluronate, bodyorattheinsertionoftheAchillestendon.Studies polysulphated glycosaminoglycan, polidocanol) wereincludedregardlessofthedurationofsymptoms. whichcanbesuppliedlocallybyguidanceprovided Weexcludedstudieswithcohortsof<20patients. PharmacologicalinterventionforAchillestendinopathy,2015,Vol.113 103 An Internet-based electronic search was carried notes, letters to editors and instructional courses. out adopting combination of different keywords Subsequently, the authors evaluated and discussed such as ‘conservative treatment’, ‘pharmacological thetopicanddesignoftheremaining62articles:45 intervention’, ‘nonoperative treatment’, ‘topical ofthemwereexcluded,becausetheirdesignwasnot application’ adding other terms that were ‘Achilles a randomized controlled trial or did not report the tendon’ and ‘tendinopathy’. The search, completed outcomesofinterest.Fourfurtherpublicationswere on May 1, 2014, was carried out analyzing online excluded,becausetheyincluded<20patients.Even- archives of PubMed, Google Scholar, CINAHL, tually, 13 publications presenting a randomized D Cochrane Central and Embase Biomedical to select comparison focusing on pharmacological interven- o w studiesmeetingtheaboveinclusioncriteria. tions for Achilles tendinopathy were considered n lo a Theliteraturepublishedinthelast25years(year eligibleandincludedinthisreview(Fig.1). d e d odfayp)uwblaicsastciorenenliemd,itawndaslafrnogmuag1e9s88acctoeptthede pforerstehnet Methodologicalqualityandriskofbias from articles were English, Italian and Spanish, given the assessment http s languagecapabilitiesoftheresearchteam.Thebibli- Each article was analyzed separately using the ://a ographiesofallthearticlesidentifiedforinclusionin Coleman Methodology Score, a 10-criteria reliable ca d thefirstplacewerescreenedbyhandtoincludeany and validated scoring system (CMS) assessing the em other related studies that might have met the inclu- impact of methodologyon the reported outcomesof ic.o u sioncriteriabutweremissedattheelectronicsearch. trials.28 Since this tool was originally intended to p.c A total of 500 published articles, found using the evaluatetheoutcomesofsurgicalinterventionforten- om above-mentionedsteps,werethencollectedtoevalu- dinopathy, we partially adapted it to be suited for /bm b atetheirpossibleinclusioninthisreview. evaluation of the methodology in studies regarding /a The abstract of all papers were analyzed separ- therapiesotherthansurgery.Wethereforemodifiedit rticle atelybytwoinvestigators(R.P.andL.D.B)excluding intoa9-criteriaassessment,insteadoftheoriginal10, -ab s biomechanicalreports,studiesonanimals,cadavers, withaneventualmaximumscoreof90,whichidenti- tra in vitro, case reports, literature reviews, technical fiesclinicalstudiesideallywithoutanybias(Table1). ct/1 1 3 /1 /1 0 1 /2 8 4 3 0 8 b y g u e s t o n 1 2 A p ril 2 0 1 9 Fig.1Selectionprocessofthestudies. 104 N.Maffullietal.,2015,Vol.113 Investigators independently rated each study calculating the Pearson correlation coefficient (r) among those included, then they met and discussed betweenthetwovariables. aboutthosewhereadifferenceofmorethan2point was found comparing the ratings of all observers, Results untilconsensuswasreached. Samplefeaturesandfollow-up Statisticalanalysis Based on the available data, a total of 528 patients WeanalyzedthecorrelationbetweentheCMSscore wereadministeredlocaldrugtreatmentontheAchil- D o of the articles and their yearof publication by plot- lestendontotreatadiagnosedtendinopathy(males: w n ting data on a diagram and then by digitally 187;females:144;asfortheremainingpatients,no loa d e d Table1ModifiedColemanmethodologyscore fro m Section Numberorfactor Score http s PartA:onlyonescoretobegivenforeachsection ://a c Studysize >60 10 ad 41–60 7 em 20–40 4 ic.o u <20,notstated 0 p .c Meanfollow-up(months) >24 5 o m 12–24 2 /b m <12,notstatedorunclear 0 b /a Numberofintervention Oneexclusiveintervention 10 rtic Morethanoneintervention,but>90%ofsubjectsundergoingthesameone 7 le Notstated,unclearor<90%ofthesubjectsundergoingthesameintervention 0 -ab s Typeofstudy Randomizedcontrolledtrial 15 tra c Prospectivecohortstudy 10 t/1 Retrospectivecohortstudy 0 13 Diagnosticcertainty Inall 5 /1/1 0 In>80% 3 1 /2 In<80% 0 8 4 PartB:scoresmaybegivenforeachoptionineachofthethreesectionsifapplicable 30 8 Descriptionofproduct/ Adequate(productstatedandnecessarydetailsofapplicationgiven) 5 b y application Fair(materialsonlystatedwithoutelaboration) 3 g u Inadequate,notstatedorunclear 0 e s Outcomecriteria Outcomemeasuresclearlydefined 2 t o n Timingofoutcomeassessmentclearlystated 2 1 2 Useofoutcomecriteriathathavereportedgoodreliability 3 A p Useofoutcomecriteriawithgoodsensibility 3 ril 2 Outcomeassessment Subjectsrecruited(resultsnottakenfromsurgeons’files) 5 0 1 9 Investigatorindependentofsurgeon 4 Writtenassessment 3 Minimalinvestigatorassistanceonassessmentcompletionbysubjects 3 Descriptionofsubjectselection Selectioncriteriareportedandunbiased 5 Recruitmentratereported: >80% 5 <80% 3 Eligiblesubjectsnotincludedinthestudysatisfactorilyaccountedfor 5 or100%recruitment PharmacologicalinterventionforAchillestendinopathy,2015,Vol.113 105 specific information was presented). The mean age quantityoftheproductdispensedandtheassociation ofpatientsatthetimeoftreatmentrangedfrom2829 withothertreatmentarefullydescribedinTable4. to50,30,31foranaverageof46.3years. The mean follow-up time was 7.3 months, Outcomemeasures rangingfrom330,31to1432months.Adetailedover- Different scores were used to evaluate the outcomes. viewofdemographicdataisgiveninTable2. ThemostfrequentlyusedscorewastheVISA-Ascore (Victorian Institute of Sports Assessment- Achilles Qualityofmethodology tendon).31–36,38,40 D o The CMS version adopted for this study offered w n ratingsrangingfrom6131to8033,35outof90,witha Outcomedata loa d e mtheisanshvoawluseaofg7o0o.d6gaennderaalstmanedthaorddodleovgiya.tioTnheofco6m.3-; We included 13 published articles. Eleven studies d fro reportedtheoutcomesofdifferentdrugsadministered m pletescoringforeachstudyisavailableinTable3. h locally through injections: in particular, three studies ttp s investigatedtheuseofplatelet-richplasma(PRP),two ://a Publicationdate studies illustrated the role of autologous blood injec- ca d The Pearson correlation coefficient did not show a tions and two studies reported the results obtained em strong enough association between CMS data and injecting polidocanol. Corticosteroids, skin-derived ic.o fibroblasts,prolotherapyandaprotinininjectionswere up theyearofpublication(r:0.26);morerecentstudies .c werenotconductedwithbetterdesignsandmethod- reportedinonestudyeach.Twostudiesexaminedthe om outcomesofpatientswhoappliedGTNonthesiteof /b ologythanolderones. m b tendernesssiteusingapatch(Table4,Fig.2). /a rtic Subjectselectionandproductapplication le PRPinjections -a b The selection criteria of patients were described in de Jonge et al.35in2011 were not able toshowany stra detailinallthepapersreviewed.Thepreciseclassand superiority of PRP injections over a placebo (saline) ct/1 1 3 Table2Demographicdata /1 /1 0 1 Study Year Patientsrecruited M F Meanfollow-up Meanage /2 8 Tot=528 Tot=187 Tot=144 (months) attreatment 430 8 Av=40.6 Av=23.4 Av=18.0 Av=7.3 Av=46.3 b y SD=14.5 SD=10.5 SD=7.6 SD=3.8 SD=6.1 g u e s AlfredsonandÖhberg30 2005 20 9 11 3 50 t o n Belletal.33 2013 53 27 26 6 49 1 2 Brownetal.34 2006 26 17 9 12 46 A p DdeajCornugzeeettaall..2395 12908181 2584 1N8/A 1N0/A 312 2489.7 ril 20 1 deVosetal.36 2010 54 26 28 6 49.5 9 Kaneetal.37 2008 40 N/A N/A 6 40.5 Kearneyetal.38 2013 20 N/A N/A 6 49 Paolonietal.26 2004 65 40 25 6 49 Obaidetal.39 2012 40 N/A N/A 6 45.2 Pearsonetal.31 2011 33 15 18 3 50 Willbergetal.32 2008 52 35 17 14 49.6 Yellandetal.40 2011 43 N/A N/A 12 46.6 N/A,Notavailable;M,Male;F,Female;Tot,Total;Av,Average;SD,Standarddeviation. 106 N.Maffullietal.,2015,Vol.113 Table3Colemanmethodologyscoresforeachstudy patientswhounderwentautologousbloodinjections, reviewed but the length of follow-up (3 months) suggeststhat this may be only a short-term expectable result. In Study Year FinalColemanscore fact, a more recent study by Bell et al.33 failed to AlfredsonandÖhberg30 2005 71 confirmthesamebenefitofperitendinousautologous Belletal.33 2013 80 bloodinjectionsinadditiontoastandardizedtraining Brownetal.34 2006 77 program over a longer time span (6 months DaCruzetal.29 1988 64 follow-up).ThedifferenceinVISA-Ascoresachieved dejongeetal.35 2011 80 D between the two randomized groups was only 1.2 o deVosetal.36 2010 69 points, with no significant difference of the experi- wn Kaneetal.37 2008 63 lo a Kearneyetal.38 2013 70 mented treatment (P=0.689). No difference was de d Paolonietal.26 2004 70 found for the ability to return to sporting activity fro Pearsonetal.31 2011 61 (P=0.679)either. m h Obaidetal.39 2012 66 ttp WYeillllabnedrgeettaal.l4.302 22000181 7707 PTohleidroacnadnoomliiznejdec,tdioonusble-blindtrialbyAlfredsonand s://aca d Öhberg30focusedonthepotentialbenefitofthescler- em injectioncombinedwiththetypicaleccentricloading osing substance polidocanol on chronic tendinopa- ic.o u exercise program in terms of clinical outcomes and thies. Twenty patients were randomized into two p .c healing ofthe tendon, withno significant intergroup groups:GroupAunderwentinjectiontreatmentwith om differences for VISA-A scores (P=0.292) and ultra- polidocanol and Group B with local anesthetic sub- /bm sonographic assessments (P=0.647) over a 1-year stances.TheVASpainandthepatient’ssatisfactionat b/a follow-up. In agreement with these findings, a 3monthsofthosewhowereinjected,comparedwith rtic le follow-up study to this RCT36 confirmed that injec- thoseofwhomreceivedinjectionsoflocalanesthetics -a b tiontherapyusingPRPdoesnotproduceasignificant only, supported the superiority of the tested treat- stra improvement in patients with Achilles tendinopathy ment, with significant differences in the values ct/1 comparedwithsaline.Theauthorsenrolledandran- recorded (P<0.005). The results were further con- 13 domizedatotalof54patients,andtheVISA-Ascores firmedbythefactthat,whenpatientsinGroupBwho /1/1 0 over24weeksfollow-upshowednosignificantdiffer- didnotexperiencebenefitfrominjectionoflocalanes- 1/2 8 encesbetweenthetwogroups. theticsubstanceswerecrossedovertoreceiveaninjec- 4 3 Kearney et al.38 published a pilot study for a tion of polidocanol, they experienced improvements 08 largerRCTontheefficacyofPRPinjectionsforten- ofthesamemagnitudeasinthepatientsinGroupA, by g dinopathyof the main bodyof the Achillestendon. whohadoriginallyreceivedaninjectionofpolidoca- ue s Theyexplicitlynotethatthestudyisunderpowered, nol.Fromtheseencouragingresults,thesamegroup32 t o n and, in 20 patients, they failed to find a statistically performed a further trial investigating whether a 1 2 significant difference between the outcome scores higherconcentrationofpolidocanol(10mg/ml)leads Ap (VISA-A)recordedforbothgroupsatfinalfollow-up to better results with a lesser number of injections. ril 2 0 (P=0.171). Thefinalclinicalevaluationat14monthsshowedno 19 significant differences regarding patient’s satisfaction Autologousbloodinjections between the group with more injections and the one InthestudyconductedbyPearsonetal.,3133patients withless,butgreaterquantityofthedrug,injections. previously treated with standard eccentric loading exercisewithouttheexpectedbenefitweretoundergo Injectionsofothersubstances oneautologousbloodinjectioninadditiontoastan- DaCruz et al.29 carried out a prospective, rando- dardized rehabilitation protocol. Clinical evaluation mized,double-blindstudyonapharmacologicalinter- showed a slight improvement of symptoms in the ventiononpatientsaffectedbyAchillestendinopathy, P h Table4Typeofinterventionandproductusedineachtrialincluded a r m D a o Studyname Year tTeynpdeinopathy Siteoftendinopathy Intervention Product Placebo/Control Sharedtreatment colo wnlo g a ica de AlfrÖedhsboenrga3n0d 2005 Chronica Mid(-2p–o7rtcimonfrom Maxinimjecutmionosf(t3w–o6 5mg/mlofpolidocanol Lidoacdareinnea5linmeg5/mµgl/+ml N.S. linter d from Belletal.33 2013 Chronica Midsin-ppseoecrritfitiioeodnn))(not Twowmeeoknstahplyaritn)jections 3mlofautologouswholeblood Needlingonly Eccerenhtraibcilloitaadtiionng ventionfo https://ac program rA ade Brownetal.34 2006 Chronica Mid-portion(not Threeweeklyinjections 3ml(30000kiu)ofaprotinin 3mlofsalineand Eccentricloading ch m specified) and1mlxylocaine1% 1mlxylocaine1% rehabilitation ille ic.o s u DaCetruazl.29 1988 N.S. N.S. Singleinjection 40macgetoaftemienth1ymlplroedfnmisaorlcoaninee 1m0pl.lo2afi5nm%arcaine Iceinupglrtor+galrsoaocmuanld tendino p.com/b p m 0.25% application ath b/a dejoetnagle.35 2011 Chronica Mid7-pcomrtfiroonm(2– Singleinjection 4mlofPRP 4mlofsaline Eccerenhtraibcilloitaadtiionng y,20 rticle 15 -a insertion) program , b V s deVosetal.36 2010 Chronica Mid-portion(2– Singleinjection 4mlofPRP 4mlofsalinesolution Eccentricloading ol. trac 7cmfrom rehabilitation 11 t/1 3 1 insertion) program 3 Kaneetal.37 2008 N.S. Mid-portion(4– Onedailytransdermal 2.5mg/24hofglyceryl None Eccentricloading /1/1 0 6cmfrom patch trinitrate rehabilitation 1 /2 insertion) program 8 4 Kearney 2013 N.S. Mid-portion(2– Singleinjection 3–5mlofPRP Eccentricloading None 30 8 etal.38 6cmfrom rehabilitation b y insertion) program g u Obaidetal.39 2012 Chronica N.S. Singleinjection Skin-derivedfibroblast 5mlofbupivacaine 5mlbupivacaine es suspendedinautologous t o n plasma 12 Paoloni 2004 Chronica Mid-portion Onedailytransdermal 1.25mg/24hofglyceryl Inertpatch Eccentricloading A p etal.26 (2–6cmfrom patch trinitrate rehabilitation ril 2 insertion) program 01 9 Tablecontinues 1 0 7 1 0 8 D o w n lo a d e d fro m h ttp s ://a c a Table4 Continued d e m Studyname Year Type Siteoftendinopathy Intervention Product Placebo/Control Sharedtreatment ic.o u tendinopathy p .c o m Pearson 2011 Chronica Mid-portion Oneortwoinjections 3mlofautologousblood Needlingonly Eccentricloading /b etal.31 (2–7cmfrom (timingN.S.) rehabilitation m b Willberg 2008 Chronica Midin-psoerrttiioonn) Maximumofthree 10mg/mlofpolidocanol 5mg/mlof N.Sp.rogram /article etal.32 (2–7cmfrom injections(6–8 polidocanol -a b s insertion) weeksinbetween) tra Yelleatnadl.40 2011 Chronica Mid(-2p–o7rtcimonfrom 4–12weeklyinjections Prol0o.t1h%eralipgyn:o2c0a%ineg/0lu.1c%ose/ Eccerenhtraibcilloitaadtiionng Eccerenhtraibcilloitaadtiionng ct/11 3 insertion) ropivacaine program program /1 /1 0 1 aChronictendinopathy≥3months. /2 N.S.,Notspecifiedwithinthestudydata. 84 3 0 8 N b .M y g a u ffu es lli t o en ,tal. 12 A 2 p 015 ril 2 , 0 V 1 o 9 l. 1 1 3 PharmacologicalinterventionforAchillestendinopathy,2015,Vol.113 109 D o w n lo a d e d fro m h ttp s ://a c a d e m ic .o u p .c o m /b m b /a rtic le -a b s tra c t/1 1 3 /1 /1 0 1 /2 8 4 3 0 Fig.2Networkofcomparisonsincludedintheanalysis.Studies(numberofpatients). 8 b y g u investigating the role of corticosteroid injections controls (VISA-A, P=0.946; return to sport, P= e s (methylprednisolone acetate). The controls received 0.364).Theyacknowledgedthatthestudywasunder- t o n local anesthetic only in the same fashion. At final powered, and therefore, the statistically negative 1 2 follow-up (12 weeks), they were not able to find a results should be considered in the light of the fact Ap significant higher improvement within the interven- thattherewasaneasilydetectabletrendforimprove- ril 2 0 tiongroupinanyoftheprimaryoutcomesmeasured mentoverplacebo. 19 (painscore,tendernessandactivitylevels). Yellandetal.40evaluated43patientswithpainful Brown et al.34 investigated whether aprotinin mid-portion Achilles tendinopathy. Patients were could achieve better improvement than the usual randomizedintothreegroups:eccentricloadingexer- rehabilitationprotocoladoptedtotreatAchillestendi- cise (n=15), prolotherapy injections, consisting of a nopathyintheirRCT.TheyrecordedVISA-Ascores, solutionof20%glucose/0.1%lignocaine/0.1%ropi- tenderness, satisfaction and otherclinical parameters vacaine,andcombinedtreatment.Patientswereevalu- overaperiodof52weeksin26patientsanddemon- atedclinicallyusingtheVISA-Ascore,consideringas strated no statistical differences compared with primary outcome a minimum clinically important 110 N.Maffullietal.,2015,Vol.113 change(MCIC)of20points.Follow-uptimeswereat Moreover, histological examination did not show 3,6and12months.Clinicalevaluationshowedasig- any difference in neovascularization, collagen syn- nificant improvement for all groups compared with thesis or stimulated fibroblasts in patients from the thebaselineforallfollow-uptimepointsconsidered. two groups who were operated, and finally demon- However,theincreaseinoutcomesfrombaselinefor strated no evidence of modulation of nitric oxide patients who underwent onlyeccentric loading exer- synthaseintendonstreatedwithGTN. cises was significantly less compared with the two othergroups(P=0.005)withregardstostiffnessand limitation of activity. These benefits occurred earlier Discussion Do w in those patients who underwent prolotherapyalone Achilles tendinopathy is acommon and debilitating n lo a orcombinedcomparedwithothersassignedtophys- conditionaffectingespeciallyathletes,withanoccur- d e icalOrebhaaidbiliettatiaoln.3o9nlpye.rformed a randomized con- raelsnoceafrfaetcetionfg∼se5d0e%ntainryminidddivleidduiasltsa.n41c,e42ruItninsears,dibfufi-t d from trolled trial to assess the clinical efficacy of autolo- cult condition to manage, since its etiology is still http s gous,skin-derived,collagen-producingcells.Twenty unclear. Repeated overloading, down-regulation of ://a patients were randomized and assigned in the treat- MMPs, increase in oxidase enzymes and a hypoxic ca d ment arm, while 20 more and control arm. The microenvironment have all been recently linked to em VISA-A and VAS pain scores were used as outcome favoraninflammationprocesswithinthetissuewith ic.o measures. At the second visit, at 3 and 6 months consequentdegeneration.16,43–47 up .c follow-up, the authors found a significant improve- Conservative treatment is generally the first line om ment (respectively, P=0.02, P=0.07, P<0.001) in option, but the available modalities are ineffective /bm thestudygroupcomparedwithcontrolgroup. in 25–45% of cases, mostly eventually requiring b/a surgery.14,48Despite allthis, there is anoveralllack rtic le GTNtransdermalpatch intheliteratureofsolidrandomizedcontrolledtrials -a b Paolonietal.26publishedaRCTinvolvingtheuseof aboutthevariousoptionspresentedforthemanage- stra GTN transdermal patches application for the treat- mentofthistendinopathy.49–51 ct/1 1 mentofthistendinopathy.Theyenrolled65patients, In the last few years, several conservative treat- 3 /1 who were randomized to analyze the effects of this ments modalities have been proposed for Achilles /1 0 intervention combined with physiotherapy com- tendinopathy with an increasingly relevant role 1/2 pared with rehabilitation alone. They reported a taken by either local drug administration25 such 84 3 clearsuperiorityofthetestedintervention,withsig- as blood products,52 hyaluronic acid,53 botulin 08 b nificantly reduced pain with activity and at night, toxin,54polidocanol,32proteinaseinhibitors,34corti- y g improved functional measures and improved out- costeroids,25 high-volume image guided injections ue s comesinpatientswithAchillestendinopathy,witha (HVIGI),55etc. t o n conclusivemeaneffectsizeforalloutcomemeasures This review collected the evidence drawn only 1 2 of 0.14. Theysuggest to exercise caution in indicat- from the highest quality studies identified in the Ap ing this treatment to patients suffering from symp- current literature, and we included 13 randomized ril 2 0 toms linked to hypotension, because these could be controlledtrials,all ratedlevel1 ofevidence.56Only 19 enhancedbysupplyofGTN. few of them were able to produce promising results Kaneetal.,37ontheotherhand,didnotfindany worth advising the use of the tested substance for significantsuperiorityintheoutcomesofthepatients routineuseinthetreatmentofAchillestendinopathy. who underwent application of the patch compared A positive effectiveness was demonstrated in both withcontrols.Following6monthsoftreatment,they randomized studies investigating polidocanol,30,32 a didnotfindsignificantdifferenceamongthegroups sclerosing agent causing thrombosis of the intima inAOSsubscores,evaluatingbothpainanddisabil- layerof the local vessels which results in decrease of ity (3.0 vs. 3.1, P=0.42; 2.15 vs. 2.25, P=0.38). tissue inflammation. Ultrasound guided injections of