Efficacy of Bee Venom Acupuncture for Chronic Low Back Pain

14 Pages·2017·1.62 MB·English

toxins
Article
Efficacy of Bee Venom Acupuncture for Chronic Low
Back Pain: A Randomized, Double-Blinded,
Sham-Controlled Trial
Byung-KwanSeo1 ID,KyungsunHan2 ID,OjinKwon2,Dae-JeanJo3andJun-HwanLee2,4,* ID
1 DepartmentofAcupuncture&Moxibustion,KyungHeeUniversityHospitalatGangdong,892,
Dongnam-ro,Gangdong-gu,Seoul05278,Korea;[email protected]
2 ClinicalResearchDivision,KoreaInstituteofOrientalMedicine,Daejeon34054,Korea;
[email protected](K.H.);[email protected](O.K.)
3 DepartmentofNeurosurgery,KyungHeeUniversityHospitalatGangdong,892,Dongnam-ro,
Gangdong-gu,Seoul05278,Korea;[email protected]
4 KoreanMedicineLifeScience,UniversityofScience&Technology(UST),
CampusofKoreaInstituteofOrientalMedicine,Daejeon34113,Korea
* Correspondence:[email protected]
AcademicEditors:StuartM.BrierleyandIrinaVetter
Received:14October2017;Accepted:3November2017;Published:7November2017
Abstract: Beevenomacupuncture(BVA)isaneffectivetreatmentforchroniclowbackpain(CLBP)
throughthepharmacologicaleffectsofbeevenomandthesimultaneousstimulationofacupoints.
However, evidence of its efficacy and safety in humans remains unclear. Using a double-blind,
randomizedstudy,54patientswithnon-specificCLBPwereassignedtotheBVAandshamgroups.
AllparticipantsunderwentsixsessionsofrealorshamBVAfor3weeks,inadditiontoadministration
of180mgofloxoninperday. Theprimaryoutcome,thatis,“bothersomeness”derivedfromback
pain, was assessed using the visual analog scale. Secondary outcomes included pain intensity,
dysfunctionrelatedtobackpain(OswestryDisabilityIndex),qualityoflife(EuroQol5-Dimension),
anddepressivemood(Beck’sdepressioninventory). Outcomeswereevaluatedeveryweekduring
thetreatmentperiodandfollowedupatweeks4,8,and12. After3weeksofthetreatment,significant
improvementswereobservedinthebothersomeness,painintensity,andfunctionalstatusintheBVA
groupcomparedwiththeshamgroup. Althoughminimaladverseeventswereobservedinboth
groups,subsequentrecoverywasachievedwithouttreatment. Consequently,ourresultssuggestthat
itcanbeusedalongwithconventionalpharmacologicaltherapiesforthetreatmentofCLBP.
Keywords: beevenomacupuncture;pharmacopuncture;lowbackpain;chronicpain
1. Introduction
Chronic low back pain (CLBP) is one of the most common, expensive, and disabling
musculoskeletalconditionsthatlastlongerthan7to12weeks, anditischaracterizedbyfrequent
recurrence but without underlying pathological causes [1]. Research suggests that the chronic
progression of low back pain is associated with demographic factors, disease-related conditions
(multiplefunctionalsymptoms,paininthelegs,significantdisabilityatonset,multiplerecurrences
or in-hospital treatment), occupation, underlying spinal condition, and psychosocial state [2].
ThesocioeconomicburdenofCLBPisassociatedwithvariouscomorbidities,increasedprescriptions
of pain-relieving pharmacotherapy, and increased healthcare service utilization [3]. Research also
suggeststhatCLBPpatientswithassociatedsymptoms,includingdepression,anxiety,andinsomnia,
tend to obtain healthcare services more frequently. Among them, 36% of the patients received
combination therapy [3]. A cohort study demonstrated that more than 51% of patients with LBP
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receivedcomplementaryandalternativemedical(CAM)therapyduringtheirone-yearfollow-up[4].
Amongthealternativetherapies, acupunctureisconsideredapossibleoptionforthetreatmentof
CLBP [5,6]. A systematic review also proposed that acupuncture may have a favorable effect on
CLBP[7].
Pharmacopuncture is a new acupuncture technique that involves injecting herbal medicine
intoacupoints, thuscombiningthetherapeuticeffectofherbalmedicinewiththatofacupuncture.
Beevenomacupuncture(BVA)isarepresentativepharmacopuncturetherapythatoriginatedfrombee
stingtherapy.ItisalsoknownthatBVAcouldexertabetteranalgesiceffectthanneedleacupuncture[8].
PreviousresearchsuggeststhatBVAamelioratespainbyexertingthepharmacologicaleffectderived
from bee venom with the simultaneous stimulation of acupoints [9,10]. A study investigating the
useofpharmacopunctureinmusculoskeletalpatientsfromaKoreanmedicinehospitalreportedthat
98.6% of inpatients received pharmacopuncture treatment; among them 32.1% received BVA [11].
Onthebasisoftheclinicalexperienceswiththepain-relievingpropertiesofBVA,itismostfrequently
administeredforexperimentalandclinicalstudiesinvolvingmusculoskeletaldiseases[12]. Asan
acupuncture-relatedmodality,BVAhasbeenusedtorelievepainbyinjectingpurifiedanddilutedbee
venomintoacupoints[10]
Althoughthepain-reliefpropertyofBVAhasbeenreportedinanimalexperiments[9,13,14]and
clinicalrecommendations[10,15,16],thereisascarcityofevidencefromrigorousclinicaltrials[17].
A clinical trial comparing the use of BVA and sham BVA for the treatment of chronic back pain
showed that 4 weeks of BVA treatment leads to a decrease in the intensity of pain [17]. However,
clinicalevidencebasedonsubstantialtherapyisstilllacking. Asamatteroffact, tomaximizethe
therapeuticeffectofBVA,agradualincreaseinthedoseisessential. Clinically,doseincrementprotocol
hasbeenwidelyusedforvariousreasons. Byincreasingtheinjectionvolumeorbydecreasingthe
dilutionrate,theamountofbeevenominjectedintoeachacupointcanbeincreased. Adaptationto
low concentrations of bee venom can minimize side effects and by gradually increasing the dose,
thetherapeuticeffectcanbemaximizedatthesametime. Moreover,mostofthepatientswithCLBP
prefercombinationtherapyinsteadofBVAtreatmentalone. Inthiscontext,thecurrentstudywas
designedtoinvestigatewhetherthecombinedtreatmentofdoseincrementBVAandnon-steroidal
anti-inflammatorydrugs(NSAIDs)couldeffectivelytreatCLBP.
2. Results
2.1. StudyParticipants
We screened 54 patients and assessed them for eligibility. Ultimately, 54 CLBP patients were
enrolledintothestudy. (Figure1). Participantswererandomlyallocatedtoeitherthereal(n=27)or
shamBVAgroup(n=27). Nosignificantdifferenceswereobservedinthebaselinecharacteristicsand
clinicalfeaturesbetweenthetwogroups(Table1). Atotalof24participantsintheBVAgroupand
23participantsintheshamBVAgroupcompletedallthetreatmentsessionsandfollow-upevaluations.
ThreesubjectsfromtheBVAgroupandfoursubjectsfromtheshamBVAgroupwithdrewtheirconsent.
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FFiigguurree 11.. CCOONNSSOORRTT flflowow didaigargarmam. .BVABV: Ab:eeb eveenvoemno amcuapcuunpcutunrcet;u rNeS;ANIDSAs:I Dnos:n-sntoerno-isdtearlo aidnatil-
ainntfil-aimnflmaamtomryat dorryugdsr.u gs.
Table 1. Baseline characteristics of the participants from BVA and sham groups.
Table1.BaselinecharacteristicsoftheparticipantsfromBVAandshamgroups.
Characteristics BVA Group (n=27) Sham Group (n = 27) p-Value
Characteristics BVAGroup(n=27) ShamGroup(n=27) p-Value
Gender (Male/Female) † 9 (33.33%)/18 (66.67%) 4 (14.81%)/23 (85.19%) 0.1115
Gender(AMgaele (/yFeeamrsa)l e‡) † 9(33.33%4)/91.885(6 (61.467.4%4)) 4(14.81%5)0/.2037 ((8151.1.096%)) 0.01.1711575
Age(years)‡ 49.85(14.44) 50.07(11.06) 0.7175
Height (cm) § 162.03 (7.65) 160.35 (7.15) 0.4099
Height(cm)§ 162.03(7.65) 160.35(7.15) 0.4099
WeWigehitg(hktg )(k§g) § 64.0964(1.019.0 2(1)1.02) 61.6601(.6100. 2(61)0.26) 0.03.9329828
VitValitsaigl nsign
SBSPB(Pm m(mHmg)H§g) § 122.71822(1.728.6 3(1)2.63) 1201.2260(.2156. 3(41)5.34) 0.05.1531131
DBP(mmHg)§ 75.56(8.10) 72.93(10.48) 0.3071
DBP (mmHg) § 75.56 (8.10) 72.93 (10.48) 0.3071
Pulse(times/minute)‡ 75.81(9.85) 78.44(10.30) 0.3763
PulTseem (tpim(◦Ces)/‡minute) ‡ 36.1575(0.8.218 )(9.85) 36.7180.(404.2 (61)0.30) 0.04.6387163
SmokeT(eYmesp/ N(°oC))† †‡ 3(12.00%)3/62.21(58 8(0.0.02%8)) 0(0.00%)3/627.1(01 0(00..0206%) ) 0.01.0446181
DSrimnko(kYee s(/YNeso/)N†o) †† 10(430 .(0102%.0)/01%5)(/6202.0 (08%8).00%) 6(203 (.008.0%0)%/2)0/2(776 (.1920%0.)00%) 0.01.9120941
VASforboDthrienrsko (mYeense/sNso(m) m† )‡ 10 (54.109.0(01.%14))/15 (60.00%) 6 (253..1068(%1.0)/72)0 (76.92%) 0.09.0179329
VASforpain(mm)‡ 5.33(1.11) 5.28(1.02) 0.8745
VAS for bothersomeness (mm) ‡ 5.19 (1.14) 5.16 (1.07) 0.9073
BVA:bVeAevSe nfoomr paacuinp u(nmctmur)e ;‡ SBP:systolicblood5.p3r3e s(s1u.r1e1;)D BP:diastolicblood5.p2r8e s(s1u.r0e2;)V AS:visuala0n.8al7o4g5
scale.Datashownasmean(standarddeviation).†Chi-squaretest,‡Wilcoxonranksumtest,§Independentt-test,
†B†VFiAsh: erb’seeex avcetnteosmt. acupuncture; SBP: systolic blood pressure; DBP: diastolic blood pressure;
VAS: visual analog scale. Data shown as mean (standard deviation). † Chi-square test, ‡ Wilcoxon rank
2.2. Psruimma treystO, §u Itncdomepeendent t-test, †† Fisher’s exact test.
Our primary outcome measure was “bothersomeness,” measured by the visual analog scale
2.2. Primary Outcome
(VAS)[18]. BoththeBVAandshamgroupsshowedasignificantdecreaseinbothersomeness(Figure2
andTOabulre p2r)i.mOauryr roeustuclotsmseh moweaesdutrhe awtaths r“ebeowtheeerksosmofenBeVsAs,”tr meaetamsuenretdw bays tshuep veirsiuoarl taonsahloagm sctraelea t(mVAenSt)
w[1i8th]. aBnotohb stherev BeVdAle aasntds qsuhaamres gmroeuapnsd sihffoewreendc eas soigfn−if1i.c0a9n[t9 d5e%crCeaIs−e 1in.9 8b,o−th0e.2rs1o]m(pe=ne0s.0s 1(6F4ig).uAres 2th aenred
wTaasblneo 2s).i gOnuifir craensuceltsin shinotwereadc ttihoant ethffreecet (wpe=ek0s.1 o9f4 B2)V,Ath itsrecaatnmbeenitn wtearsp sruetpeedritohra ttog srhoaump etrffeeacttmaenndt twimiteh
eafnfe octbsinedrveepde nledaesnt tslqyuaafrfeesc tmedeathne drieffseurletn.cGerso oufp −1e.f0fe9c [t9,5w%h iCchI −i1s.d98if,f −er0e.2n1c]e (spb =e t0w.0e1e6n4)g. rAous pthsedreu ewtaos
snuob jseicgtns’ifiincdanivcied iuna lindtieffrearcetniocne sedffiedctn o(pt a=f f0e.c1t9t4h2e), “tbhoisth cearnso bme einnetessrp”rmeteeads uthreast (gpr=ou0p.1 6ef9f3e)c.tH aonwd etvimere,
teimffeecte fifnedcte,pienncdluednitnlyg atrfefeacttmede ntthpe erreisoudlta. nGdrofoulplo ewff-eucpt, pwehriiocdh ,iws dasiffaesreignnciefisc baenttwfaecetno rgraoffuepctsi ndgueth teo
subjects’ individual differences did not affect the “bothersomeness” measures (p = 0.1693). However,
time effect, including treatment period and follow-up period, was a significant factor affecting the
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Toxins 2017, 9, 361 4 of 14
outcome measure (p <0.0001). Decreased bothersomeness persisted after treatment in both the groups;
outcomemeasure(p<0.0001). Decreasedbothersomenesspersistedaftertreatmentinboththegroups;
however, there was no difference between the two groups.
however,therewasnodifferencebetweenthetwogroups.
Toxins 2017, 9, 361 4 of 14
outcome measure (p <0.0001). Decreased bothersomeness persisted after treatment in both the groups;
however, there was no difference between the two groups.

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(aBcVuApu)nocrtusrhea m(BVtrAea)t more nsth.am(A )trCehatamngenest. in(Av) isCuhaalnagneasl oign svcaisleua(lV AanSa)loscgo rsecsalfeo r(VbAotSh)e rsscoomreesn efsosr
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TTaabbllee 22.. ComCopmarpisaornis oonf troefatmtreeanttm anendt foalnlodw-fuopll orwes-puopnsree aspftoern s3e waefetkesr o3f bweee evkesnoomf abceuepuvnecntoumre
aincutepruvenncttuiorne. intervention.
BVA Group (n = 27) Sham Group (n=27)
Outcome Time BVAGroup(n=27) ShamGroup(n=27) Within (BG) † Within (PG) † p-Value ‡
Outcome Time Mean SD Mean SD Within(BG)† Within(PG)† p-Value‡

VAS score Mean SD Mean SD
Figure 2. Reduced symptoms as a result from chronic back pain after 3 weeks of bee venom
VABSostchoerresomeness
acupuncture (BVA) or sham treatment. (A) Changes in visual analog scale (VAS) scores for
Baseline 5.19 1.14 5.16 1.07
bothersomeness (B) Changes in VAS scBooretsh eforrs opmaine ninetsesnsity. * Significant difference of pre-post
comparison within groups. † Significant difference betBwaeseenlw itnweeoe kgr 3o ups5 a.1t 9e2a.c5h2 t ime p1o.i1n14t .(8p9 < 0.05). 5.136.59 1.10.767 <0.0001 * <0.0001 * 0.0164 *
weekw3eek 4 2.522.63 1.819.74 3.539.56 1.26.708 <<00.0.0000011 ** <<00..00000011 ** 00.0.0514684 *
Table 2. Comparison of treatment and follow-up respwoneseek waf4eteerk 3 8w ee2ks.6 o3f3 b.6e3e venom1. 7a24cu.4p2u ncture3 .536.70 2.10.896 <00..00000611 ** <00.0.0000021 * * 0.088.02534 8
intervention. weewke8ek 12 3.632.70 2.422.00 3.730.15 1.19.677 0<.00.0060101* * <00..00000021 ** 0.305.80822 3
Pain intewnesietky 12 2.70 2.00 3.15 1.77 <0.00 01* <0.00 01* 0. 3502
BVA Group (n = 27) Sham Group (n=27)
Outcome Time Within (BG) † Within (PG) † p-Value ‡
Mean SD PaMineainnt ensitSyDBaseline 5.33 1.11 5.28 1.02
VAS score Ba selwineeek 3 5.332.59 1.111.82 5.238.52 1.10.270 <0.0001 * <0.0001 * 0.0486 *
Bothersomeness
weekw3eek 4 2.592.56 1.812.80 3.532.70 1.27.003 <<00.0.0000011 ** <00.0.0000051 * * 00.0.0247836 *
Baseline 5.19 1.14 5.16 1.07
week 3 2.52 1.89 3.59 w1.6e7e kw4eek< 08.0 0012 *.5 63.63 <0.00011 .*8 20.42 0.0164 *3 .730.70 2.10.396 <00..00000813 ** 00..00000025 ** 0.900.06297 3
week 4 2.63 1.74 3.56 w2.0e8e wke8ek <102.0 0013 *.6 32.63 <0.00021 .*4 22.06 0.0548 3.730.22 1.19.676 0<.00.0080301* * <00..00000021 ** 0.204.97086 9
week 8 3.63 2.42 O3.7D0 I scorwe1. e96e k12 0.00612 *. 63 0.00022 *. 06 0.8823 3.22 1.76 <0.00 01* <0.00 01* 0. 2478
week 12 2.70 2.00 3.15 1.77 <0.0001 * <0.0001 * 0.3502
Pain intensity Baseline 30.14 9.17 32.07 12.48
Baseline 5.33 1.11 5.28 1.02 week 3 18.25 11.16 26.76 11.28 <0.0001 * 0.0100 * 0.0085 *
week 3 2.59 1.82 3.52 1.70 <0.0001 * <0.0001 * 0.0486 *
week 4 16.15 10.71 26.96 13.01 <0.0001 * 0.0259 * 0.0018 *
week 4 2.56 1.80 3.70 2.03 <0.0001 * 0.0005 * 0.0273
week 8 3.63 2.42 3.70 1.96 0.0083 * 0.0002 * 0.9069

week 12 2.63 2.06 3.22 1.76 <0.0001 * <0.0001 * 0.2478
ODI score
Baseline 30.14 9.17 32.07 12.48
week 3 18.25 11.16 26.76 11.28 <0.0001 * 0.0100 * 0.0085 *
week 4 16.15 10.71 26.96 13.01 <0.0001 * 0.0259 * 0.0018 *
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Table2.Cont.
BVAGroup(n=27) ShamGroup(n=27)
Outcome Time Within(BG)† Within(PG)† p-Value‡
Mean SD Mean SD
ODIscore
Baseline 30.14 9.17 32.07 12.48
week3 18.25 11.16 26.76 11.28 <0.0001* 0.0100* 0.0085*
week4 16.15 10.71 26.96 13.01 <0.0001* 0.0259* 0.0018*
week8 19.06 10.60 26.40 12.84 <0.0001* 0.0955 0.0349*
week12 16.81 9.34 24.54 12.51 <0.0001* 0.0407* 0.0171*
BDIscore
Baseline 10.52 7.99 14.44 9.66
week3 7.00 6.72 14.22 12.59 0.0026* 0.0719 0.0429*
week4 8.15 7.23 13.11 10.32 0.0002* 0.0677 0.1670
week8 8.78 7.76 13.74 11.37 0.1963 0.1337 0.2525
week12 7.30 7.12 13.26 10.78 0.0064* 0.2018 0.0765
EQ-5Dscore
Baseline 0.778 0.097 0.738 0.115
week3 0.843 0.102 0.774 0.106 0.0009* 0.1567 0.0511
week4 0.845 0.095 0.773 0.100 0.0005* 0.1793 0.0278*
week8 0.816 0.141 0.777 0.128 0.0997 0.1978 0.5776
week12 0.812 0.155 0.790 0.110 0.1317 0.0961 0.9381
BVA:beevenomacupuncture;VAS:VisualAnalogScale;ODI:OswestryDisabilityIndex;BDI:Beck’sDepression
Inventory;EQ-5D:EuroQol5-Dimension;†p-valuebyWilcoxonsignedranktestorpairedt-test(ODIandBDIof
BVAgroupandEQ-5Doftotalgroup);‡p-valuebyAnalysisofcovariance(ANCOVA),adjustingforbaselinescores;
*p<0.05.
2.3. SecondaryOutcomes
Secondaryresultswerethepainintensity,disability,qualityoflife,anddepressionasmeasured
bytheVAS,OswestryDisabilityIndex(ODI),EuroQol5-Dimension(EQ-5D),andBeck’sDepression
Inventory(BDI),respectively. AfterthreeweeksofBVAorshamtreatment,painintensityandback
pain-related dysfunction decreased significantly in both groups (Table 2 and Figure 2). However,
thesubjectstreatedwithBVAshowedgreaterimprovementsinpainintensityandbackpain-related
dysfunctionthanthesubjectsintheshamgroup. Atourprimaryendpoint, whichwasafterthree
weeksofintervention,painintensity,representedbytheVASscore,significantlydecreasedintheBVA
group when compared to that in the sham group (least squares mean difference of −0.95 [95% CI
−1.89,−0.01],p=0.0486)andthedifferencepersistedforaweek.
TherewereclinicallymeaningfulchangesintheODIscore(Table2andFigure3). Atbaseline,
therewerenosignificantdifferencesbetweenthegroups. Asthestudytreatmentcontinued,theODI
scorestartedtoimprovesignificantlyduringthefirstweekofthetrial(leastsquaresmeandifferenceof
−7.67[95%CI−13.29,−2.05],p=0.0085),althoughintheBVAgroupafterthefirstweekitdecreased
continuously throughout the 12 weeks of study. The difference between the groups maximized
(10.81points)atweek4.
TheBDIscorealsodecreasedsignificantlyintheBVAgroupduringweeks2,3,and4(p=0.0026,
0.0002, and 0.0162, respectively), but no significant difference was observed in the sham group
throughoutthestudy. Thedifferencebetweenthetwogroupswasthegreatest(leastsquaresmean
differenceof−4.86[95%CI−9.70, −0.02],p=0.0492)bytheendofthetreatmentperiod(week3).
However,groupeffect,whichisthedifferencebetweentwogroupsfromthebaselineaffectedtheresult.
The overall quality of life of both groups improved as shown by an increase in the EQ-5D
scores. However, only the real BVA group showed significant improvement at weeks 2, 3, and 4
(p=0.0029, 0.0009, and 0.0005, respectively), while the only the EQ-5D score of the sham group
changedsignificantlyatweek4(leastsquaresmeandifferenceof0.056[95%CI0.000,0.103],p=0.0278),
whichwasoneweekafterthecompletionoftreatment.
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Toxins 2017, 9, 361 4 of 14
outcome measure (p <0.0001). Decreased bothersomeness persisted after treatment in both the groups;
however, there was no difference between the two groups.

Figure 3. Bee venom acupuncture (BVA) improved the functional and psychological status related to
Figure3.Beevenomacupuncture(BVA)improvedthefunctionalandpsychologicalstatusrelatedto
cchhrroonniicc bbaacckk ppaaiinn.. ((AA)) CChhaannggeess iinn bbaacckk ppaaiinn rreellaatteedd ddyyssffuunnccttiioonn.. ((BB)) CChhaannggeess iinn bbaacckk ppaaiinn rreellaatteedd
ddeepprreessssiivvee ssyymmppttoommss ((CC)) CChhaannggeess inin babcakc kpapiani nrerlaetleadte dquqauliatyli toyf oliffel.i f*e S.ig*nSifigicnainfitc daniftfedreifnfecree onfc peroef-
post comparison within groups. † Significant difference between two groups at each time point (p <
pre-postcomparisonwithingroups. Significantdifferencebetweentwogroupsateachtimepoint
0.05).
(p<0.05).
2.4. Credibility Analysis
2.4. CredibilityAnalysis
Both the BVA and sham groups showed high credibility in all four categories of the credibility
BoththeBVAandshamgroupsshowedhighcredibilityinallfourcategoriesofthecredibility
test (Table 3). There was no significant difference among the groups. Moreover, no significant change
test(Table3). Therewasnosignificantdifferenceamongthegroup s. Moreover,nosignificantchange
was observed within both groups after the treatment period.
wFiagsuroe b2s. eRrevduecded wsyimthptionmsb oast ha grersuolut fprosma fchterornitch beactkr epaaitnm aeftenr t3p weereikos do.f bee venom

acupuncture (BVA) or sham treatment. (A) Changes in visual analog scale (VAS) scores for
bothersomeness (B) Changes in VAS scores for pain intensity. * Significant difference of pre-post
comparison within groups. † Significant difference between two groups at each time point (p < 0.05).
Table 2. Comparison of treatment and follow-up response after 3 weeks of bee venom acupuncture
intervention.
BVA Group (n = 27) Sham Group (n=27)
Outcome Time Within (BG) † Within (PG) † p-Value ‡
Mean SD Mean SD
VAS score
Bothersomeness
Baseline 5.19 1.14 5.16 1.07
week 3 2.52 1.89 3.59 1.67 <0.0001 * <0.0001 * 0.0164 *
week 4 2.63 1.74 3.56 2.08 <0.0001 * <0.0001 * 0.0548
week 8 3.63 2.42 3.70 1.96 0.0061 * 0.0002 * 0.8823
week 12 2.70 2.00 3.15 1.77 <0.0001 * <0.0001 * 0.3502
Pain intensity
Baseline 5.33 1.11 5.28 1.02
week 3 2.59 1.82 3.52 1.70 <0.0001 * <0.0001 * 0.0486 *
week 4 2.56 1.80 3.70 2.03 <0.0001 * 0.0005 * 0.0273
week 8 3.63 2.42 3.70 1.96 0.0083 * 0.0002 * 0.9069
week 12 2.63 2.06 3.22 1.76 <0.0001 * <0.0001 * 0.2478
ODI score
Baseline 30.14 9.17 32.07 12.48
week 3 18.25 11.16 26.76 11.28 <0.0001 * 0.0100 * 0.0085 *
week 4 16.15 10.71 26.96 13.01 <0.0001 * 0.0259 * 0.0018 *
Toxins2017,9,361 7of14
Table3.Comparisonsoftreatmentcredibilitybeforeandafterthetreatmentperiod.
BVAGroup(n=27) ShamGroup(n=27)
Outcome Time Within(BG)† Within(PG)† p-Value‡
Mean SD Mean SD
Credibilitytest
Improvementexpected
Baseline 5.15 0.60 4.89 0.58
week3 5.15 0.66 4.85 0.66 0.9999 0.9999 0.3211
Recommendationtoothers
Baseline 4.67 0.78 4.56 1.01
week3 4.74 0.66 4.67 0.83 0.9999 0.8359 0.8491
Treatmentlogical
Baseline 4.89 0.80 4.41 0.84
week3 4.89 0.58 4.67 0.78 0.9999 0.1826 0.9938
Effectivealsoforotherdiseases
Baseline 4.48 1.09 4.56 0.93
week3 4.70 0.82 4.52 1.16 0.2500 0.9648 0.2349
†p-ValuebyWilcoxonsignedranktest;‡p-ValuebyAnalysisofcovariance(ANCOVA)adjustingforbaselinescores.
2.5. AdverseEvents
SixpatientsfromtheBVAgroup(22.2%)andfourpatientsfromtheshamgroup(14.8%)reported
adverse events. Four patients from the real BVA group experienced a minimal itching sensation,
butrecoveredcompletelywithoutanytreatment. TwopatientsfromtherealBVAgroupandfour
patientsfromtheshamgroupexperiencednon-specificcomplaints,includingheadache(twoinsham
BVAandoneinrealBVA),generalizedmyalgia(oneinrealBVA),anddizziness(twoinshamBVA).
Therewasnosignificantdifferenceamongthegroups(p=0.484).
3. Discussion
Tothebestofourknowledge,thisisthefirstrandomizedcontrolledtrial(RCT)thathascompared
increasingdosesofBVAandshamtreatmentasanadjuncttoNSAIDsforCLBPpatients. Ourresults
showedthatthreeweeksofpragmaticBVAtreatmentsusingtheprotocolfordoseincrementscouldbe
effectiveforthereliefofbothersomeness,painintensity,functionalstatusrelatedtoCLBP,andquality
oflife. Thesesuperioreffectswereobservedduringthetreatmentperiodandseemedtolastduring
thenineweeksoffollow-up,withoutanyharmfulreactions. BVAexertsitspharmacologicalactions
throughthebioactivecompoundsisolatedfrombeevenom[15].
Despite the clinical favorability and broad utilization for pain management [12], evidence
from rigorous RCTs to investigate the effectiveness of BVA in CLBP is limited [10]. A prospective
observationalstudyreportedthatCAMtreatmentwithBVAhadabettereffectonpainreliefandthe
ODI score than conventional treatment in patients with lumbar intervertebral disc herniation [19].
TherewerefewRCTsregardingtheefficacyofBVAforlowbackpain. Kimetal. reportedthatfive
sessionsofBVAimprovedlowbackpainwhencomparedwithshamBVA(normalsalineinjection)[20].
In a randomized, sham-controlled, triple-blind, two-group parallel clinical trial, Shin et al. [17]
demonstratedthateightsessionsofBVAatsixacupoints(0.1mLBVAforeachacupoint)over4weeks
improvedpainintensity,function,andthequalityoflife;however,atthetimeoftheeighthtreatment
thepainintensitywasnotsignificantlydifferentbetweenthetwogroups.
We attempted to reproduce the actual clinical environment by using an adjunctive BVA with
NSAIDsprotocolandincrementalbeevenomprotocol. Alongwithrigorousblindingmeasuresamong
theparticipants,assessor,practitioner,andstatistician,ourcredibilityanalysisshowedthatparticipants
in both the groups expected a logical treatment and believed that both treatments were effective.
Tominimizethenon-specificandplaceboeffectstheparticipantsfrombothgroupsweretreatedusing
thesameprotocol. Basedonpreviousstudies, clinicalexperience, andthroughaconsensusofthe
Toxins2017,9,361 8of14
experts,alltreatmentprocedures,includingtheBVAprotocolandacupoints,wererigorouslydesigned
sothattheycouldnotbediscriminated.
OurstudyyieldedsurprisingresultsintherecoveryoftheoverallsymptomsofCLBP.Asopposed
totheresultsfromtheshamgroup,theprimaryoutcome(bothersomeness)significantlydecreased
after3weeks(sixsessions)ofBVAtreatment. VASscoresforpainintensityshowedananalogical
tendency. Thefollow-upobservationaftertreatmentrevealedthatthedecreasedbothersomenessand
painlastedforaweek. However,5weeksafterthetreatmentwascompleted,thesymptomswerenot
statisticallydifferentbetweenthegroups. Nonetheless,inbothgroups,theimprovementinsymptoms
frombaselinepersisted.
There are several probable reasons why both groups showed significant improvement. First,
allthesubjectsinourstudytookananalgesicduringthetreatmentperiod. Onobservationduring
the follow-up (without any treatment), we found that the therapeutic effect of the BVA treatment
persistedandwassuperiortothatintheshamgroup. Second,theshamBVAtreatmentmayhave
stimulatedacupointswhenthenormalsalinewasinjected,possiblyyieldinganeffectsimilartothat
ofacupuncture.
A similar clinical study with BVA (0.1 mL BVA for each acupoint) and sham BVA for back
painshowedasignificantdecreaseinthepainintensityinthetwogroups,althoughnosignificant
differenceswereobservedbetweenthegroups[17]. Thiscorrespondstoourstudyresultsthatsham
BVAcanalsocontributetopainrelief. However,ourstudyisuniqueasweusedincrementaldosesof
BVA,insteadofusingasingledoseofbeevenomthroughoutthestudy. Wegraduallyincreasedthe
injectionvolumeeveryweek. ThisimpliesthattheincrementaldosesofBVAwerethedominantfactor
fortheoverallimprovementobservedinourstudy.
StudieshaverevealedthattheanalgesiceffectofBVAispartiallymediatedbythedescendingpain
inhibitorysystem,includingtheactivationoftheα2-adrenergicreceptor[21],aswellasthemodulation
ofimmuneresponsesincludingthereductionofc-Fosexpression[22]. Theanti-inflammatoryactivity
ofBVAisrelatedtotheinhibitionofCOX-2activityandtheproductionofpro-inflammatorycytokines
(TNF-αandIL-1β)[23],aswellastheinductionofapoptosisthroughtheactivationofcaspase-3[24].
Other than the analgesic effect of BVA, we also found several other noteworthy results. BVA
treatmentnotonlyreducedtheintensityofpainbutalsodecreasedthedegreeofdisabilityrelatedto
CLBP.“Bothersomeness”wasdevelopedasasymptom-basedhealthoutcomemeasureforchronic
disease[25]andhas beenusedasa severitymeasurein primarycare, withsuitabilityfor patients
withLBPaswellasphysicians[18,26,27]. Thebothersomenessoflowbackpainmeasurestheseverity
ofsymptomscorrelatedwithpainanddisabilityamongprimarycarepatientswithnonspecificlow
backpainandcanbeapredictorofoutcome[18]. Bothersomenessisameasureofpain,functional
status,workabsence,psychologichealth,andotherLBPfactors[18,28,29]. Itsreliabilityandsuitability
is validated in LBP studies [30]. The decreased VAS for bothersomeness in our study indicates
improvementintheperceptionofclinicalseverityanditsimpactondailylifeofpatientswithCLBP.
Surprisingly,unlikethepreviousstudyofShinetal.[17],outstandingimprovementwasobserved
intheODIscore. Asignificantreductioninbackpain-relateddysfunction,asassessedbytheODI
score, persisted throughout the 12 weeks of follow-up. Quality of life as assessed by EQ-5D was
significantlyreducedbytheBVAfromthetreatmentsessionsuntilthe1-weekfollow-up. Furthermore,
depressivesymptoms,asassessedbyBDI,weresignificantlyreducedonlyintheBVAgroup,butnot
intheshamgroup.
Asystematicreviewregardingbeevenom(BV)demonstratesthatadverseeventsrelatedtoBV
arefrequentandpractitionersshouldbecautiouswithitsconcentration,especiallywhenincreasing
thedose[31]. TheBV-specificresponses,suchaspain,swelling,redness,anditchingofskin,could
bedetectedbypatientsanddoctors. Astudywith130casesofBVAtreatmentinaKoreanmedicine
hospital reported that 28.5% of patients suffered from an itching sensation [32]. A meta-analysis
comparingBVAandnormalsalineshoweda3.61-timesashighariskofadverseeventsinBVA[31].
Studiesemphasizedthataskintestforhypersensitivityreactionisneededtopreventadverseevents.
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Ourclinicalstudydemonstratedseveralminoradverseevents,whichwerelessthanweexpected.
Despitetheincrementaldoseprotocol,skintestsperformedpriortothestudypreventedtheincidence
ofcriticaladverseevents.
Ourstudyhasafewlimitationswhichshouldbetakenintoconsiderationwheninterpretingthe
results. AlthoughwesuccessfullyblindedtheBVAandshamtreatmentgroups,incorporatinganother
shamgroupwithanon-invasivetreatmentmayhavedemonstratedpronouncedresults. Moreover,
tofindthemaximumtolerableinjectiondoseinhumans,groupswithdifferentconcentrationsofBVA
shouldbeconsideredinfutureexperiments.
In conclusion, our results have established clinical evidence that BVA could improve
bothersomeness, pain intensity, functional status, and the quality of life of patients with
CLBP. This suggests that BVA treatment may be a potential candidate along with conventional
pharmacologicaltherapiesforthetreatmentofCLBP.
4. MaterialsandMethods
4.1. StudyDesign
This was a balanced-randomized, double-blinded, placebo-controlled, parallel-group study
conductedattheKyungHeeUniversityHospitalatGangdong(KHUHGD)fromApril2011toAugust
2013. WeenrolledpatientswithCLBPtoreceiveeitheroneofthefollowingtworegimens: sixsessions
ofBVAwithNSAIDsorshaminjectionwithNSAIDsoverthreeweeks. Thisstudywasconducted
following the rules of the Declaration of Helsinki. According to the delegation of responsibilities
log, each study step, suchas treatment preparation, acupuncture practice, outcomemeasurement,
study coordination, data management, and statistical analyses, were performed by independent
researchers. ThestudywasapprovedbytheInstitutionalReviewBoard(IRB)ofKHUHGD(approval
number: KHNMC-OH-IRB2011-006),andregisteredatClinicalTrials.gov(numberNCT01491321).
Afulldetailofthetrialprotocolwasdisclosedinapreviouspublication[33].
4.2. SampleSizeCalculation
ThesamplesizewasestimatedbasedonaprioracupuncturestudyonCLBPthatuseda10cm
VASpainscoreasameasureoftheprimaryeffectiveness. Themeandifferenceandcommonstandard
deviationof10cmintheVASpainscore(meandifference=1.5,SD=2.73)wereusedtodetermine
thesamplesize[34]. Assumingatwo-samplet-testmodelfortwo-armedstudy,27patientspergroup
werenecessarywithpowertobe80%,levelofsignificance5%(two-sided),andananticipateddropout
rateof20%. Interimanalysiswasnotconsideredinthisstudy.
4.3. EligibilityCriteria
Patientswererecruitedthroughadvertisementsinlocalnewspapers,onhospitalwebsites,and
bulletinboards. Eligibilitywasdeterminedusingtheinclusionandexclusioncriteria(Table4)[33].
Written informed consent was obtained from the participants after receiving an explanation of
the study protocol. Participants were educated about the possible adverse events, including
itching, local swelling, erythematous change, and a hypersensitivity reaction. The participants
werealsoinformedthattheycouldstoptheirparticipationatanystagewithoutanydisadvantages.
Theparticipantswereexcludedfromthestudyiftheyrefusedtocontinue,withdrewtheirconsent,
violated enrollment criteria or trial protocol, or participated in less than four treatment sessions.
Participantswerealsoinformedthatthetrialcouldbestoppedincaseofunacceptablerisksofserious
adverseeventsorsevereclinicaldeteriorationbytheprincipalinvestigator;theywouldbetreatedand
compensatedbasedonthereimbursementagreement.
Thisstudyincludedbothmenandwomenintheagegroupof18to65yearswithnon-specific,
uncomplicatedLBPforatleastthreemonths,scoring≥4pointsona10cmVASforbothersomeness
from LBP, and without any abnormalities on neurological examination (e.g., lumbosacral nerve
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function,deeptendonreflexes,plantarresponse,voluntarymuscleactivation,andsensoryfunction).
Asapartofthescreeningprocedure,askinhypersensitivitytestwasperformedonallthepatients[33].
The exclusion criteria of the study were as follows: subjects with radicular pain, serious spinal
disorders,chronicdiseasesthatcouldaffectorinterferewiththetherapeuticoutcomes,previousspinal
surgery,painfulconditionsinducedbytrafficaccidents,apparentmusculoskeletalpainotherthanback
pain,conditionssuchasclottingdisorders,administrationofananticoagulantagent,pregnancyand
seizuredisorderswhereBVAmightnotbesafe;patientswithdocumentedhypersensitivereactions
topreviousBVAtreatments,beestingsorinsectbites;severepsychiatricorpsychologicaldisorders;
patientswhowereusingcorticosteroids,narcotics,musclerelaxantsorherbalmedicinestotreatlow
backpain,oranymedicationsconsideredinappropriatebytheinvestigatoratthetimeofthestudy
wereexcludedfromthestudy. Furthermore,subjectswithpendinglawsuits/receiptofcompensation
duetoLBP,thosewhorefusedtoparticipateinthetrialorprovideconsentandunabletoreadand
writeintheKoreanlanguage,wereexcludedfromthestudy.
Table4.Inclusionandexclusioncriteriaofthestudy.
InclusionCriteria
Agebetween18to65yearsold
Experiencedlowbackpainforthepreviousthreemonthsormore.
Scoringmorethan4pointsona10cmVisualAnalogScale(VAS)forbothersomenessoflowbackpain
Exhibitingnoabnormalitiesonneurologicalexamination(forexample,lumbosacralnervefunction,
deeptendonreflexes,plantarresponse,voluntarymuscleactivation,andsensoryfunction)
Havingnon-specific,uncomplicatedlowbackpainthatqualifiesasthefollowingInternational
ClassificationofDiseases10codes:
M513 Otherspecifiedintervertebraldiscdegeneration
M545 Lowbackpain
M548 Otherdorsalgia
M549 Dorsalgia,unspecified
S335 Sprainandstrainoflumbarspine
S336 Sprainandstrainofsacroiliacjoint
S337 Sprainandstrainofotherandunspecifiedpartsofthelumbarspineandpelvis
Participantswhoagreedandsignedtheinformedconsent
Exclusioncriteria
Backpainwithradicularpain
Seriousspinaldisorders,includingmalignancy,vertebralfracture,spinalinfection,andinflammatory
spondylitis
Otherchronicdiseasesthatcouldaffectorinterferewiththetherapeuticoutcomes,including
cardiovasculardisease,diabeticneuropathy,activehepatitis,fibromyalgia,rheumatoidarthritis,dementia,
andepilepsy
Historyofspinalsurgeryorsubjectsscheduledforspinalsurgeryduringthestudy
Paininducedbytrafficaccidents
Musculoskeletalpainotherthanbackpain
Conditionsthatcanbeaggravatedbybeevenomtreatment,including:clottingdisorders,administration
ofanticoagulantagents,pregnancy,andseizuredisorders
Hypersensitivereactionstopreviousbeevenomtreatments,beestringsorinsectbites
Severepsychiatricorpsychologicaldisorders
Currentuseofcorticosteroids,musclerelaxants,narcotics,orherbalmedicines.Useofanymedication
consideredinappropriatebytheinvestigator
Pendinglawsuitorreceiptofcompensationbecauseoflowbackpain
Subjectswhorefusedtoparticipateinthetrialorprovideinformedconsent
SubjectsunabletoreadandwriteinKoreanlanguage