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Brief Communications
Response of Cluster Headache to Kudzu
R. Andrew Sewell, MD
Objective.—To describe the self-treatment of cluster headache with kudzu.Background.—Many cluster headache patients take over-the-counter (OTC) kudzu extract in the belief that it helps their
cluster attacks. Kudzu’s actual efficacy has not been studied.Methods.—A database of cluster headache patients was questioned about their use of various alternative remedies to treat
their cluster headache. Of 235 patients identified, 16 had used kudzu, consented to interviews, and provided medical records.Results.—In total, 11 (69%) experienced decreased intensity of attacks, 9 (56%) decreased frequency, and 5 (31%)
decreased duration, with minimal side effects.Conclusion.—Anecdotal evidence suggests that a component in OTC products labeled as kudzu may prove useful in
managing cluster headache. This hypothesis should be tested with a randomized clinical trial.
Key words: cluster headache, case series, kudzu
(Headache 2009;49:98-105)
Cluster headache is a rare disorder, generallyconsidered to be the most painful of all types of head-ache.1 It occurs predominantly in men (0.4% vs 0.08%of women), typically beginning in the third decade,and is categorized as either episodic, occurring forperiods interspersed with pain-free remissions, orchronic, in which the headaches occur constantly formore than a year with no remission longer than onemonth.2 Ten percent of episodic cluster headachesultimately evolve into the chronic form, and these aretermed secondary chronic. In standard descriptionsof cluster headache, an “attack” refers to the actualparoxysm of pain, a “cluster period” to a period oftime when attacks occur regularly, and a “remission
period” to an interval during which no attacks occur.3
Cluster periods tend to recur at fixed intervalsranging from several months to several years, oftenoccurring at the same time each year, and are markedby recurrent stabbing attacks that increase in inten-sity over 5 to 10 minutes, last 15 minutes to 3 hours,and then fade away. Attacks typically occur 1 to 3times a day, usually at strikingly predictable times(often 2 hours after the patient falls asleep) but cansometimes occur as often as every 2 hours. The inten-sity of the pain is severe enough that patients havebeen known to commit suicide.4
Standard care for cluster headache includes acutetreatments such as triptans or high-flow oxygen takenat the onset of an attack, supplemented with prophy-lactic treatments such as verapamil or lithium, whichare taken on a continuous basis once a cluster periodhas begun, or before sleep in order to prevent noctur-nal attacks in the case of ergotamine.1 Unfortunately,
From the VA Connecticut Healthcare/Yale University Schoolof Medicine—Psychiatry, West Haven, CT, USA.
Address all correspondence to R.A. Sewell, VA ConnecticutHealthcare/Yale University School of Medicine—Psychiatry,West Haven, CT 06516, USA.
Accepted for publication August 2, 2008. Conflict of Interest: None
ISSN 0017-8748doi: 10.1111/j.1526-4610.2008.01268.xPublished by Wiley Periodicals, Inc.
these treatments are rarely entirely effective andoften have serious disadvantages. Triptans and ergotalkaloids often cannot be given frequently enough,and oxygen tanks are unwieldy and inconvenient.Many herbal remedies have been proposed to treatheadache; of these, feverfew5 and cannabis6 have themost empirical support, but neither has been specifi-cally evaluated for cluster headache.
Kudzu refers to any one of a number of vinespecies of the genus Pueraria that is indigenous toAsian countries, was imported to the USA in 1876,and has subsequently been used for green manureand fodder and as ground cover to prevent soil ero-sion.7 The use of Ge-gen (kudzu root) was describedin the Chinese medical book Shang Han Lun – “Trea-tise on Fever” – 1800 years ago,8 and today its rhizomeis a traditionally used component in Chinese medicalpolyprescriptions for liver diseases, strokes, and aller-gies. Kudzu contains antioxidants,9 has antipyreticand anesthetic effects,10 treats hypertension,11 dilatescerebral blood vessels, increases cerebral blood flow,and improves brain acetylcholine in a mouse Al-zheimer model.12 Historically, it has had use in thetreatment of alcohol-related problems since AD600.13 Its use in the treatment of cluster headache hasnot previously been described.
METHODSThe study was approved by the McLean Hospital/
Harvard Medical School IRB. A database of 235cluster headache patients was surveyed via email ontheir use of a number of complementary and alterna-tive remedies, including kudzu root. The subjects hadbeen previously recruited for a study unrelated tokudzu14 and came from 3 sources – members of theClusterbusters patient advocacy group (37), respon-dents to an online survey about quality of life issuesaffecting cluster headache patients who had checkeda box agreeing to be contacted for future researchstudies (189), and people who had heard on the Inter-net that we were studying cluster headache and inde-pendently emailed us asking to participate (9). As ofOctober 10, 2006, 159 (68%) had responded; of these,22 (14%) endorsed using kudzu root or extract toself-treat their cluster headache. Questions wereasked on a variety of complementary and alternative
treatments for cluster headache and phrased in such away that kudzu did not appear to be a topic of undueinterest. We restricted our analysis to the 16 (73%)individuals who (1) agreed to be contacted for evalu-ation by telephone or email; (2) met InternationalClassification of Headache Disorders, 2nd edition, cri-teria for cluster headache; (3) allowed us to obtaincopies of medical records documenting a diagnosis ofcluster headache by an MD or DO. If the medicalrecords did not support the diagnosis, the subject wasexcluded from further analysis.
RESULTSResults are summarized in the Table. Of the
11 subjects with episodic cluster headache, 8 (73%)experienced a decrease in the intensity of theirattacks, 7 (64%) experienced a decrease in frequency,4 (36%) experienced decreased attack length, and 2(18%) experienced a truncated cluster period. Onesubject experienced increased attack intensity, fre-quency, and duration. Of the 5 subjects with chroniccluster headache, 3 (60%) experienced decreasedattack intensity, 2 (40%) decreased frequency, and 1(20%) decreased attack duration, while 1 (20%) hadincreased attack intensity.
Efficacy for cluster attack in this group showed aclear dose–response relationship: 3 of the 4 treatmentnonresponders were taking less than 1000 mg a day(total pill weight; actual dose of kudzu is substantiallyless), and only 3 of 7 (43%) patients taking kudzu lessthan 3 times a day showed benefit. Of the 6 whoreported no effects or worse effects from kudzu, allwere taking it less than 3 times a day, whereas 8 of 10(80%) taking the more frequent dose benefitted(Fig. 1). Side effects were mild and infrequent, themost common being gastrointestinal effects experi-enced by 4 (25%). Measured by total dose per day, theeffect of kudzu on cluster attack intensity, frequency,and duration also showed a dose–response relation-ship, whereas its effect on cluster period length didnot.
In comparison, of the 36 (13%) respondents fromthe cohort of 285 in the database who endorsed usingacupuncture, 4 (11%) felt it made their cluster head-ache worse, 7 (20%) felt it improved their clusterheadache, and 21 (58%) reported no effect. Of the 58
Headache 99
Tabl
e.—
Eff
ect
ofK
udzu
onC
lust
erH
eada
che
No.
Age
(yea
rs)
Sex
Hea
dach
ety
peK
udzu
bran
dD
ose
(mg)
Freq
.Tr
iall
engt
h
Eff
ect
onat
tack
Peri
odle
ngth
Side
effe
cts
Inte
ns.
Freq
.D
ur.
159
F2°
chro
nic
NW
613
Tid
2m
onth
sØ
ØØ
N/A
Ø2
36M
Epi
sodi
cro
ot?
Bid
6w
eeks
!!
ØØ
CN
S3
35M
Epi
sodi
cPF
1500
Tid
7w
eeks
!!
!!
Ø4
47F
2°ch
roni
cPF
1500
Tid
12m
onth
s!
!!
N/A
GI
536
F2°
chro
nic
NW
1226
Qd
2w
eeks
"Ø
ØN
/AØ
657
ME
piso
dic
PF15
00Q
hs1
day
!!
Ø?
GI
757
FE
piso
dic
NW
1226
Tid
12m
onth
s!
!!
ØØ
832
ME
piso
dic
PF15
00Ti
d12
mon
ths
ØØ
ØØ
GI
948
ME
piso
dic
PF15
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d8
mon
ths
!!
!Ø
GI,
MS
1048
M2°
chro
nic
PF15
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mon
ths
!Ø
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/AØ
1143
FE
piso
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NW
613
Bid
3w
eeks
""
"?
Ø12
42M
Epi
sodi
cN
W12
26Ti
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mon
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id3
wee
ks!
!!
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1340
F1°
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1431
FE
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650
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1549
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1632
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piso
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NH
100
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noef
fect
;C
NS=
cent
ral
nerv
ous
syst
em;
Dur
.=du
ratio
n;F=
fem
ale;
Freq
.=fr
eque
ncy;
GI=
gast
roin
test
inal
;In
tens
.=in
tens
ity;
M=
mal
e;M
S=
mus
culo
skel
etal
;N
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terh
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ther
efor
eno
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terp
erio
ds;N
SI=
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trac
eutic
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ceIn
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te;N
W=
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ure’
sWay
;PF=
Plan
etar
yFo
rmul
a;SW
=St
arW
estB
otan
ical
s;N
H=
Nat
ure’
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erb;
1°=
prim
ary;
2°=
seco
ndar
y.
100 January 2009
(20%) respondents who endorsed using the “watermethod” – drinking a glass of water every half an hourduring the cluster period – 3 (5%) felt it made theircluster headache worse, 16 (28%) felt it improvedtheir cluster headache, and 37 (64%) reported noeffect (Fig. 2). These data should not be construed asevidence of lack of efficacy of these 2 methods; rather,assuming that the effects of acupuncture and polydip-sia on cluster headache are no different than placebo,then the reported efficacy of kudzu in this cohort ismore than twice as great as would be expected fromchance alone.
REPRESENTATIVE CASES (ALL OTHERSARE INCLUDED IN APPENDIX A,AVAILABLE ONLINE ONLY)
Case No. 2.—A 36-year-old man with no othermedical conditions had suffered from episodic clusterheadache since age 16 years, characterized by 6 weeksof one or two 2-hour attacks per day separated by a 4-or 5-month remission period.The attacks consisted ofa boring pain in his temple and a knot in his neck,along with lacrimation, ptosis, meiosis, conjunctivalinjection, flushing, diaphoresis, and restlessness. Fre-quent absences caused problems at work, and thesecondary depression and fatigue caused strain in hisinterpersonal relationships.
He finds oxygen and sumatriptan to be effectiveabortive medications, and as prophylactic medication,he has tried propanolol and amitriptyline, which areineffective, verapamil and psilocybin, which decreasethe frequency and intensity of attacks, and pred-nisone, which stops the attacks only while he is takingit.
When his last cluster period began, in June of2005, he read on an Internet forum that kudzu treatedcluster headache, so he decided to boil 1.5 ounces ofdried kudzu root and drink it as a tea twice a day.Even though he was using no other medication, hesuffered only 4 attacks during the entire 6-weekcluster period, all mild. The cluster period wasunchanged in length. He also had approximately 10“phantom attacks,” a phenomenon he had experi-enced previously on verapamil. He was able to avoidtaking all conventional prophylactic medication, andsuffered no side effects from the kudzu other thanvivid dreams. He does not smoke or use illicit drugs,but drinks 3 or 4 glasses of wine a week and 2 cups ofgreen tea a day.
Case No. 3.—A 36-year-old man with no significantmedical conditions except for a history of benignfamilial infantile convulsions, which he had outgrownby age 3 years, started to have episodic cluster head-aches at age 28 years and was correctly diagnosed atage 33 years. Each cluster period lasted 8 to 10 weeksseparated by a remission period of 7 or 8 months,occurred usually in autumn or late February, and con-sisted of as many as 6 cluster attacks a day, at all timesof day and night. Each attack was characterized by a
Fig 1.—Percent of patients reporting improvement in clusterattack intensity, frequency, and duration and cluster periodlength, stratified by total daily dose of unstandardized extractconsumed. A dose–response relationship is apparent in kudzu’seffects on cluster attacks, but not on cluster period length.
Fig 2.—Subjective global effect of different “alternative” treat-ment modalities on cluster headache symptoms. There is noevidence to suggest that either acupuncture or polydipsia ismore effective for cluster headache than placebo.
Headache 101
right-sided sharp boring pain radiating into his jawand neck, sweating, ptosis and eyelid edema, conjunc-tival injection, rhinorrhea, phono- and osmophobialasting 45 to 90 minutes. He coped well, suffering nojob or relationship difficulties as a result, but grappledwith persistent fears that there was “somethingdeeply wrong” with his brain.
For 5 years he remained untreated, assuming thathe had a sinus problem or simply trying not to thinkabout it, and then started medication. Verapamil120 mg a day decreased his attack frequency to onceor twice daily, but did not decrease the attack inten-sity and caused him memory and coordination diffi-culties. Valproate triggered 2 of the most painful andprolonged attacks he had ever experienced, so hediscontinued it. Sumatriptan was an effective abor-tive, but side effects that included intensification andprolongation of subsequent attacks as well as a dullpersistent ache at the site of the attacks the next dayprompted him to discontinue it.
In February 2005, he started to experience“twinges” in his right eye, heralding the beginning ofa cluster period, and with his first full-blown attack,he started on Planetary Formulas kudzu extract1500 mg 3 times a day as well as a twice-daily mul-tivitamin. To his surprise, he found that he experi-enced only 8 attacks for the remainder of the clusterperiod, which was half its usual length (only 7weeks), no attack lasting longer than 30 minutes. Theattacks differed from the usual – although they stillcaused agitation and pacing, there were no associ-ated autonomic symptoms, only pain, and the inten-sity of the pain was attenuated – and these occurredonly when he decreased the dose of kudzu to twicea day, forgot, or delayed a dose. He experienced noside effects.
His next cluster period began with 4 times dailyattacks in late November 2005, but he delayed takingkudzu until the intensity of the attacks became excru-ciating, in the second week of December, for fear thathe would develop tachyphylaxis. Restarting a dose ofPlanetary Formulas 1500 mg 3 times a day, he foundthat his attacks diminished in both frequency andintensity to zero over the next 2 weeks, and theremainder of the cluster period passed asymptomati-cally until it ended in January.
He smokes a pack of cigarettes every day, drinksone drink of alcohol every few months, and smokescannabis roughly twice a year. He uses no other illicitdrugs but drinks 4 to 5 cups of coffee a day.
DISCUSSIONThe putative mechanism of action by which
kudzu might affect cluster headache should theseresults be verified is unclear. It is thought that theother therapeutic benefits of kudzu are due to phy-toestrogens, particularly isoflavones, which possessboth estrogenic and antiestrogenic properties, can actas selective estrogen receptor modulators,15 and havea long pedigree in the treatment of a number of dis-orders.16 Flavonoids are phenolic compounds widelydistributed in plants, with over 4000 currentlyknown.17 Their astringency probably repels insects,making isoflavonoids the most important group ofplant-protective phytoalexins.18 The isoflavone puer-arin, which is the principal component in kudzu,19
has hypoglycemic properties and increases coronaryblood flow, reducing the frequency of acute anginaevents20 and normalizing endothelin, renin, angio-tensin II post-myocardial infarction in 3 days.21 Puer-arin attenuates mecamylamine-induced deficits ininhibitory avoidance performance in rats, presumablythrough nicotinic-receptor agonism and N-methyl-D-aspartic acid (NMDA) agonism and serotonindecrease.22 It does not act as a beta-blocker or calciumantagonist, however.23 The 3 times daily dosing ofkudzu that appears necessary to ameliorate clusterheadache is consistent with puerarin’s pharmacoki-netic profile.24 Daidzein is a metabolite of puerarinand daidzin, another isoflavone in kudzu. Unlikedaidzin and puerarin, daidzein scavenges free radi-cals25 and is estrogenic,26 albeit thousands of times lesspotent than the synthetic estrogen diethylstilbestrol.
Estrogen and progesterone levels are normal incluster headache, but the dramatically higher preva-lence of the disorder in males, the increase in inci-dence around menopause,27 and the tendency ofcluster headache to remit during pregnancy28 arguefor a protective effect of female reproductive hor-mones that may be replicated by the phytoestrogensin kudzu.
102 January 2009
Kudzu has been reported to decrease alcoholintake in both preclinical29 and clinical trials. Inves-tigators found that over-the-counter (OTC) prepara-tions of kudzu that contain less than 1% or 2%isoflavones are not effective in limiting alcoholintake, but a concentrated (25% isoflavone) form ofkudzu was effective in reducing alcohol intake bybinge drinkers.30 The rate of alcoholism is high incluster headache patients,31 which is surprising asalcohol is a reliable trigger of a cluster attack duringa cluster period, although it may be consumedwithout consequence during a remission period. Inone sample, 91% of cluster headache patients drankalcohol, with 61% falling into the category of mod-erate to excessive drinkers,32 and in another, morethan 90% drank alcohol, with a significant propor-tion being “heavy drinkers.”31 Levi found that 67%of his sample assessed with the Mm-MAST (Michi-gan Alcoholism Screening Test) had scores indica-tive of alcoholism.33 Other studies have found lowerrates of alcohol consumption, but still far higherthan those of noncluster headache controls – 61% vs41% in one sample,34 with daily use reported by36% of cluster headache patients vs 14% of con-trols. However, as alcohol triggers cluster attacks,79% of cluster headache patients dramaticallydecrease their alcohol consumption during a clusterperiod,33 in contrast with smoking, the rate of whichdoes not change. It is thus conceivable that theisoflavones in kudzu are treating a common factorunderlying both alcoholism and cluster attacks.
The use of kudzu to treat cluster headache wasunknown before December 2005, when reports of itstherapeutic effects appeared on the Internet andpropagated rapidly through the cluster headachepatient population. A number of studies have foundthat approximately 50% of patients use the Internetto obtain medical information, and 60% in one studyreported that they felt that information on the Inter-net was the “same as” or “better than” informationfrom their doctors.35 Although Internet medicaladvice is frequently characterized as inaccurate,incomplete, or inconsistent,36 the rapid and wide-spread dissemination of unverified medical informa-tion also permits the trial-and-error discovery of newtreatments by enthusiastic patient groups.
Caution should be applied in interpreting thesefindings, as case series are by their very nature subjectto selection bias, recall bias, and the placebo response.However, several factors mitigate these limitations inthis case series. Recruitment over the Internet selectsfor younger, more educated, and more motivated sub-jects,37 likely leading to increased reported efficacy.This group was not, however, otherwise selected forpositive response to kudzu or alternative medica-tions, and this group did not report a comparablepositive response to acupuncture and other alterna-tive medications.Although it has not been establishedthat acupuncture and polydipsia are ineffective intreating cluster headache, if these methods are actu-ally effective, then that would strengthen, not weaken,our conclusions.
Although there was no placebo arm, clusterheadache is known to respond poorly to placebo; con-trolled trials have shown a placebo response of 0% toprophylactic medications such as verapamil,38 capsai-cin,39 and melatonin.40 As cluster attacks typicallywax and wane over the course of a cluster period,improvement in symptoms can be difficult to attributeto medication effect. However, each cluster period isgenerally very similar in pattern and length for agiven patient, making differences noticeable, and 2patients (no. 4 and no. 12, see supplemental cases)used a challenge–rechallenge test to verify that thekudzu was having an effect on their headaches. Fur-thermore, 6 (38%) of the subjects had maintaineddetailed headache diaries corroborating their retro-spective recall of efficacy.
Finally, the concentration of isoflavones in OTCkudzu preparations is unstandardized, and variesfrom 0.5% to 3% (Lukas, personal communication),making it difficult to quantify the actual amount ofactive ingredient ingested by the subjects. However,this variability should attenuate rather than exag-gerate any dose–response relationship, and the factthat such a relationship was still identifiable despitethe variable concentrations of isoflavones present,further argues for therapeutic effect.
CONCLUSIONAlthough few subjects were able to completely
discontinue conventional medications, a substantial
Headache 103
proportion found that kudzu extract in a variety oflow-concentration OTC preparations ameliorated theintensity, frequency, and duration of their clusterattacks, with minimal side effects, although kudzu hadno effect on the length of the cluster period. Shouldthese results be confirmed with a randomized clinicaltrial of standardized extracts, kudzu may prove tohave a role in the management of cluster headache.
Acknowledgments: The author thanks Earth andFire Erowid, Robert Wold and the Clusterbusters, forassistance with data collection; Harrison Pope, ScottLukas, Mehmet Sofuoglu, and Bruce Price for their com-ments on an earlier draft of this article, and JonathanByron for bringing kudzu to the attention of the clusterheadache community. Funding was provided by NIDA,NIH T32-DA07252. No funding source had any role instudy design, collection, analysis, or interpretation of data,writing of the report, or submission of the manuscript.
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SUPPORTING INFORMATION
Additional Supporting Information may be found inthe online version of this article:
SUPPLEMENTAL CASE REPORTS FOR“Response of Cluster Headache to Kudzu” (Case no. 1,4-16).
Please note: Blackwell Publishing is not responsiblefor the content or functionality of any supporting mate-rials supplied by the authors. Any queries (other thanmissing material) should be directed to the correspond-ing author for the article.
Headache 105
Headache ISSN 0017-8748
! 2008 the Author doi: 10.111/j.1526-4610.2008.01268.x
Journal compilation ! 2008 American Headache Society Published by Wiley Periodicals, Inc.
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SUPPLEMENTAL CASE REPORTS FOR
Response of Cluster Headache to Kudzu (Case no. 1, 4-16)
CASE #1
A 60-year old woman with no other medical
conditions was diagnosed with episodic chronic
cluster headaches at age 42 that became chronic at
age 43. She usually suffered three but could have as
many as eight attacks per day lasting 90 minutes
each, following no pattern that she could discern. The