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Keywords:

  • cluster headache;
  • case series;
  • kudzu

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. REPRESENTATIVE CASES (ALL OTHERS ARE INCLUDED IN APPENDIX A, AVAILABLE ONLINE ONLY)
  6. DISCUSSION
  7. CONCLUSION
  8. Acknowledgments
  9. REFERENCES
  10. Supporting Information

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.

Cluster headache is a rare disorder, generally considered to be the most painful of all types of headache.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 for periods interspersed with pain-free remissions, or chronic, in which the headaches occur constantly for more than a year with no remission longer than one month.2 Ten percent of episodic cluster headaches ultimately evolve into the chronic form, and these are termed secondary chronic. In standard descriptions of cluster headache, an “attack” refers to the actual paroxysm of pain, a “cluster period” to a period of time when attacks occur regularly, and a “remission period” to an interval during which no attacks occur.3 Cluster periods tend to recur at fixed intervals ranging from several months to several years, often occurring at the same time each year, and are marked by recurrent stabbing attacks that increase in intensity over 5 to 10 minutes, last 15 minutes to 3 hours, and then fade away. Attacks typically occur 1 to 3 times a day, usually at strikingly predictable times (often 2 hours after the patient falls asleep) but can sometimes occur as often as every 2 hours. The intensity of the pain is severe enough that patients have been known to commit suicide.4

Standard care for cluster headache includes acute treatments such as triptans or high-flow oxygen taken at the onset of an attack, supplemented with prophylactic treatments such as verapamil or lithium, which are taken on a continuous basis once a cluster period has begun, or before sleep in order to prevent nocturnal attacks in the case of ergotamine.1 Unfortunately, these treatments are rarely entirely effective and often have serious disadvantages. Triptans and ergot alkaloids often cannot be given frequently enough, and oxygen tanks are unwieldy and inconvenient. Many herbal remedies have been proposed to treat headache; of these, feverfew5 and cannabis6 have the most empirical support, but neither has been specifically evaluated for cluster headache.

Kudzu refers to any one of a number of vine species of the genus Pueraria that is indigenous to Asian countries, was imported to the USA in 1876, and has subsequently been used for green manure and fodder and as ground cover to prevent soil erosion.7 The use of Ge-gen (kudzu root) was described in the Chinese medical book Shang Han Lun–“Treatise on Fever”– 1800 years ago,8 and today its rhizome is a traditionally used component in Chinese medical polyprescriptions for liver diseases, strokes, and allergies. Kudzu contains antioxidants,9 has antipyretic and anesthetic effects,10 treats hypertension,11 dilates cerebral blood vessels, increases cerebral blood flow, and improves brain acetylcholine in a mouse Alzheimer model.12 Historically, it has had use in the treatment of alcohol-related problems since AD 600.13 Its use in the treatment of cluster headache has not previously been described.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. REPRESENTATIVE CASES (ALL OTHERS ARE INCLUDED IN APPENDIX A, AVAILABLE ONLINE ONLY)
  6. DISCUSSION
  7. CONCLUSION
  8. Acknowledgments
  9. REFERENCES
  10. Supporting Information

The study was approved by the McLean Hospital/Harvard Medical School IRB. A database of 235 cluster headache patients was surveyed via email on their use of a number of complementary and alternative remedies, including kudzu root. The subjects had been previously recruited for a study unrelated to kudzu14 and came from 3 sources – members of the Clusterbusters patient advocacy group (37), respondents to an online survey about quality of life issues affecting cluster headache patients who had checked a box agreeing to be contacted for future research studies (189), and people who had heard on the Internet that we were studying cluster headache and independently emailed us asking to participate (9). As of October 10, 2006, 159 (68%) had responded; of these, 22 (14%) endorsed using kudzu root or extract to self-treat their cluster headache. Questions were asked on a variety of complementary and alternative treatments for cluster headache and phrased in such a way that kudzu did not appear to be a topic of undue interest. We restricted our analysis to the 16 (73%) individuals who (1) agreed to be contacted for evaluation by telephone or email; (2) met International Classification of Headache Disorders, 2nd edition, criteria for cluster headache; (3) allowed us to obtain copies of medical records documenting a diagnosis of cluster headache by an MD or DO. If the medical records did not support the diagnosis, the subject was excluded from further analysis.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. REPRESENTATIVE CASES (ALL OTHERS ARE INCLUDED IN APPENDIX A, AVAILABLE ONLINE ONLY)
  6. DISCUSSION
  7. CONCLUSION
  8. Acknowledgments
  9. REFERENCES
  10. Supporting Information

Results are summarized in the Table. Of the 11 subjects with episodic cluster headache, 8 (73%) experienced a decrease in the intensity of their attacks, 7 (64%) experienced a decrease in frequency, 4 (36%) experienced decreased attack length, and 2 (18%) experienced a truncated cluster period. One subject experienced increased attack intensity, frequency, and duration. Of the 5 subjects with chronic cluster headache, 3 (60%) experienced decreased attack intensity, 2 (40%) decreased frequency, and 1 (20%) decreased attack duration, while 1 (20%) had increased attack intensity.

Table Table.—. Effect of Kudzu on Cluster Headache
No.Age (years)SexHeadache typeKudzu brandDose (mg)Freq.Trial lengthEffect on attackPeriod lengthSide effects
Intens.Freq.Dur.
  1. Ø = no effect; CNS = central nervous system; Dur. = duration; F = female; Freq. = frequency; GI = gastrointestinal; Intens. = intensity; M = male; MS = musculoskeletal; N/A = chronic cluster headache therefore no cluster periods; NSI = Neutraceuticals Science Institute; NW = Nature's Way; PF = Planetary Formula; SW = StarWest Botanicals; NH = Nature's Herb; 1° = primary; 2° = secondary.

 159F2° chronicNW613Tid2 monthsØØØN/AØ
 236MEpisodicroot?Bid6 weeks[DOWNWARDS ARROW][DOWNWARDS ARROW]ØØCNS
 335MEpisodicPF1500Tid7 weeks[DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW]Ø
 447F2° chronicPF1500Tid12 months[DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW]N/AGI
 536F2° chronicNW1226Qd2 weeks[UPWARDS ARROW]ØØN/AØ
 657MEpisodicPF1500Qhs1 day[DOWNWARDS ARROW][DOWNWARDS ARROW]Ø?GI
 757FEpisodicNW1226Tid12 months[DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW]ØØ
 832MEpisodicPF1500Tid12 monthsØØØØGI
 948MEpisodicPF1500Tid8 months[DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW]ØGI, MS
1048M2° chronicPF1500Tid2 months[DOWNWARDS ARROW]ØØN/AØ
1143FEpisodicNW613Bid3 weeks[UPWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW]?Ø
1242MEpisodicNW1226Tid12 months[DOWNWARDS ARROW][DOWNWARDS ARROW]?ØØ
12   PF1500Bid3 weeks[DOWNWARDS ARROW][DOWNWARDS ARROW][DOWNWARDS ARROW]ØØ
1340F1° chronicNW1226Tid13 weeks[DOWNWARDS ARROW][DOWNWARDS ARROW]?N/AØ
1431FEpisodicNSI650Qd-tid5 weeks[DOWNWARDS ARROW][DOWNWARDS ARROW]ØØØ
1549MEpisodicSW800Qhs3 weeksØØØ[DOWNWARDS ARROW]Ø
1632FEpisodicNH100Qd ØØØØØ

Efficacy for cluster attack in this group showed a clear dose–response relationship: 3 of the 4 treatment nonresponders were taking less than 1000 mg a day (total pill weight; actual dose of kudzu is substantially less), and only 3 of 7 (43%) patients taking kudzu less than 3 times a day showed benefit. Of the 6 who reported no effects or worse effects from kudzu, all were 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, the most common being gastrointestinal effects experienced by 4 (25%). Measured by total dose per day, the effect of kudzu on cluster attack intensity, frequency, and duration also showed a dose–response relationship, whereas its effect on cluster period length did not.

image

Figure 1.—. Percent of patients reporting improvement in cluster attack intensity, frequency, and duration and cluster period length, stratified by total daily dose of unstandardized extract consumed. A dose–response relationship is apparent in kudzu's effects on cluster attacks, but not on cluster period length.

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In comparison, of the 36 (13%) respondents from the cohort of 285 in the database who endorsed using acupuncture, 4 (11%) felt it made their cluster headache worse, 7 (20%) felt it improved their cluster headache, and 21 (58%) reported no effect. Of the 58 (20%) respondents who endorsed using the “water method”– drinking a glass of water every half an hour during the cluster period – 3 (5%) felt it made their cluster headache worse, 16 (28%) felt it improved their cluster headache, and 37 (64%) reported no effect (Fig. 2). These data should not be construed as evidence of lack of efficacy of these 2 methods; rather, assuming that the effects of acupuncture and polydipsia on cluster headache are no different than placebo, then the reported efficacy of kudzu in this cohort is more than twice as great as would be expected from chance alone.

image

Figure 2.—. Subjective global effect of different “alternative” treatment modalities on cluster headache symptoms. There is no evidence to suggest that either acupuncture or polydipsia is more effective for cluster headache than placebo.

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REPRESENTATIVE CASES (ALL OTHERS ARE INCLUDED IN APPENDIX A, AVAILABLE ONLINE ONLY)

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. REPRESENTATIVE CASES (ALL OTHERS ARE INCLUDED IN APPENDIX A, AVAILABLE ONLINE ONLY)
  6. DISCUSSION
  7. CONCLUSION
  8. Acknowledgments
  9. REFERENCES
  10. Supporting Information

Case No. 2.— A 36-year-old man with no other medical conditions had suffered from episodic cluster headache since age 16 years, characterized by 6 weeks of one or two 2-hour attacks per day separated by a 4- or 5-month remission period. The attacks consisted of a boring pain in his temple and a knot in his neck, along with lacrimation, ptosis, meiosis, conjunctival injection, flushing, diaphoresis, and restlessness. Frequent absences caused problems at work, and the secondary depression and fatigue caused strain in his interpersonal relationships.

He finds oxygen and sumatriptan to be effective abortive medications, and as prophylactic medication, he has tried propanolol and amitriptyline, which are ineffective, verapamil and psilocybin, which decrease the frequency and intensity of attacks, and prednisone, which stops the attacks only while he is taking it.

When his last cluster period began, in June of 2005, he read on an Internet forum that kudzu treated cluster headache, so he decided to boil 1.5 ounces of dried kudzu root and drink it as a tea twice a day. Even though he was using no other medication, he suffered only 4 attacks during the entire 6-week cluster period, all mild. The cluster period was unchanged in length. He also had approximately 10 “phantom attacks,” a phenomenon he had experienced previously on verapamil. He was able to avoid taking all conventional prophylactic medication, and suffered no side effects from the kudzu other than vivid dreams. He does not smoke or use illicit drugs, but drinks 3 or 4 glasses of wine a week and 2 cups of green tea a day.

Case No. 3.— A 36-year-old man with no significant medical conditions except for a history of benign familial infantile convulsions, which he had outgrown by age 3 years, started to have episodic cluster headaches at age 28 years and was correctly diagnosed at age 33 years. Each cluster period lasted 8 to 10 weeks separated by a remission period of 7 or 8 months, occurred usually in autumn or late February, and consisted of as many as 6 cluster attacks a day, at all times of day and night. Each attack was characterized by a right-sided sharp boring pain radiating into his jaw and neck, sweating, ptosis and eyelid edema, conjunctival injection, rhinorrhea, phono- and osmophobia lasting 45 to 90 minutes. He coped well, suffering no job or relationship difficulties as a result, but grappled with persistent fears that there was “something deeply wrong” with his brain.

For 5 years he remained untreated, assuming that he had a sinus problem or simply trying not to think about it, and then started medication. Verapamil 120 mg a day decreased his attack frequency to once or twice daily, but did not decrease the attack intensity and caused him memory and coordination difficulties. Valproate triggered 2 of the most painful and prolonged attacks he had ever experienced, so he discontinued it. Sumatriptan was an effective abortive, but side effects that included intensification and prolongation of subsequent attacks as well as a dull persistent ache at the site of the attacks the next day prompted him to discontinue it.

In February 2005, he started to experience “twinges” in his right eye, heralding the beginning of a cluster period, and with his first full-blown attack, he started on Planetary Formulas kudzu extract 1500 mg 3 times a day as well as a twice-daily multivitamin. To his surprise, he found that he experienced only 8 attacks for the remainder of the cluster period, which was half its usual length (only 7 weeks), no attack lasting longer than 30 minutes. The attacks differed from the usual – although they still caused agitation and pacing, there were no associated autonomic symptoms, only pain, and the intensity of the pain was attenuated – and these occurred only when he decreased the dose of kudzu to twice a day, forgot, or delayed a dose. He experienced no side effects.

His next cluster period began with 4 times daily attacks in late November 2005, but he delayed taking kudzu until the intensity of the attacks became excruciating, in the second week of December, for fear that he would develop tachyphylaxis. Restarting a dose of Planetary Formulas 1500 mg 3 times a day, he found that his attacks diminished in both frequency and intensity to zero over the next 2 weeks, and the remainder of the cluster period passed asymptomatically until it ended in January.

He smokes a pack of cigarettes every day, drinks one drink of alcohol every few months, and smokes cannabis roughly twice a year. He uses no other illicit drugs but drinks 4 to 5 cups of coffee a day.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. REPRESENTATIVE CASES (ALL OTHERS ARE INCLUDED IN APPENDIX A, AVAILABLE ONLINE ONLY)
  6. DISCUSSION
  7. CONCLUSION
  8. Acknowledgments
  9. REFERENCES
  10. Supporting Information

The putative mechanism of action by which kudzu might affect cluster headache should these results be verified is unclear. It is thought that the other therapeutic benefits of kudzu are due to phytoestrogens, particularly isoflavones, which possess both estrogenic and antiestrogenic properties, can act as selective estrogen receptor modulators,15 and have a long pedigree in the treatment of a number of disorders.16 Flavonoids are phenolic compounds widely distributed in plants, with over 4000 currently known.17 Their astringency probably repels insects, making isoflavonoids the most important group of plant-protective phytoalexins.18 The isoflavone puerarin, which is the principal component in kudzu,19 has hypoglycemic properties and increases coronary blood flow, reducing the frequency of acute angina events20 and normalizing endothelin, renin, angiotensin II post-myocardial infarction in 3 days.21 Puerarin attenuates mecamylamine-induced deficits in inhibitory avoidance performance in rats, presumably through nicotinic-receptor agonism and N-methyl-D-aspartic acid (NMDA) agonism and serotonin decrease.22 It does not act as a beta-blocker or calcium antagonist, however.23 The 3 times daily dosing of kudzu that appears necessary to ameliorate cluster headache is consistent with puerarin's pharmacokinetic profile.24 Daidzein is a metabolite of puerarin and daidzin, another isoflavone in kudzu. Unlike daidzin and puerarin, daidzein scavenges free radicals25 and is estrogenic,26 albeit thousands of times less potent than the synthetic estrogen diethylstilbestrol.

Estrogen and progesterone levels are normal in cluster headache, but the dramatically higher prevalence of the disorder in males, the increase in incidence around menopause,27 and the tendency of cluster headache to remit during pregnancy28 argue for a protective effect of female reproductive hormones that may be replicated by the phytoestrogens in kudzu.

Kudzu has been reported to decrease alcohol intake in both preclinical29 and clinical trials. Investigators found that over-the-counter (OTC) preparations of kudzu that contain less than 1% or 2% isoflavones are not effective in limiting alcohol intake, but a concentrated (25% isoflavone) form of kudzu was effective in reducing alcohol intake by binge drinkers.30 The rate of alcoholism is high in cluster headache patients,31 which is surprising as alcohol is a reliable trigger of a cluster attack during a cluster period, although it may be consumed without consequence during a remission period. In one sample, 91% of cluster headache patients drank alcohol, with 61% falling into the category of moderate to excessive drinkers,32 and in another, more than 90% drank alcohol, with a significant proportion being “heavy drinkers.”31 Levi found that 67% of his sample assessed with the Mm-MAST (Michigan Alcoholism Screening Test) had scores indicative of alcoholism.33 Other studies have found lower rates of alcohol consumption, but still far higher than those of noncluster headache controls – 61% vs 41% in one sample,34 with daily use reported by 36% of cluster headache patients vs 14% of controls. However, as alcohol triggers cluster attacks, 79% of cluster headache patients dramatically decrease their alcohol consumption during a cluster period,33 in contrast with smoking, the rate of which does not change. It is thus conceivable that the isoflavones in kudzu are treating a common factor underlying both alcoholism and cluster attacks.

The use of kudzu to treat cluster headache was unknown before December 2005, when reports of its therapeutic effects appeared on the Internet and propagated rapidly through the cluster headache patient population. A number of studies have found that approximately 50% of patients use the Internet to obtain medical information, and 60% in one study reported that they felt that information on the Internet was the “same as” or “better than” information from their doctors.35 Although Internet medical advice is frequently characterized as inaccurate, incomplete, or inconsistent,36 the rapid and widespread dissemination of unverified medical information also permits the trial-and-error discovery of new treatments by enthusiastic patient groups.

Caution should be applied in interpreting these findings, as case series are by their very nature subject to selection bias, recall bias, and the placebo response. However, several factors mitigate these limitations in this case series. Recruitment over the Internet selects for younger, more educated, and more motivated subjects,37 likely leading to increased reported efficacy. This group was not, however, otherwise selected for positive response to kudzu or alternative medications, and this group did not report a comparable positive response to acupuncture and other alternative medications. Although it has not been established that acupuncture and polydipsia are ineffective in treating cluster headache, if these methods are actually effective, then that would strengthen, not weaken, our conclusions.

Although there was no placebo arm, cluster headache is known to respond poorly to placebo; controlled trials have shown a placebo response of 0% to prophylactic medications such as verapamil,38 capsaicin,39 and melatonin.40 As cluster attacks typically wax and wane over the course of a cluster period, improvement in symptoms can be difficult to attribute to medication effect. However, each cluster period is generally very similar in pattern and length for a given patient, making differences noticeable, and 2 patients (no. 4 and no. 12, see supplemental cases) used a challenge–rechallenge test to verify that the kudzu was having an effect on their headaches. Furthermore, 6 (38%) of the subjects had maintained detailed headache diaries corroborating their retrospective recall of efficacy.

Finally, the concentration of isoflavones in OTC kudzu preparations is unstandardized, and varies from 0.5% to 3% (Lukas, personal communication), making it difficult to quantify the actual amount of active ingredient ingested by the subjects. However, this variability should attenuate rather than exaggerate any dose–response relationship, and the fact that such a relationship was still identifiable despite the variable concentrations of isoflavones present, further argues for therapeutic effect.

CONCLUSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. REPRESENTATIVE CASES (ALL OTHERS ARE INCLUDED IN APPENDIX A, AVAILABLE ONLINE ONLY)
  6. DISCUSSION
  7. CONCLUSION
  8. Acknowledgments
  9. REFERENCES
  10. Supporting Information

Although few subjects were able to completely discontinue conventional medications, a substantial proportion found that kudzu extract in a variety of low-concentration OTC preparations ameliorated the intensity, frequency, and duration of their cluster attacks, with minimal side effects, although kudzu had no effect on the length of the cluster period. Should these results be confirmed with a randomized clinical trial of standardized extracts, kudzu may prove to have a role in the management of cluster headache.

Acknowledgments

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. REPRESENTATIVE CASES (ALL OTHERS ARE INCLUDED IN APPENDIX A, AVAILABLE ONLINE ONLY)
  6. DISCUSSION
  7. CONCLUSION
  8. Acknowledgments
  9. REFERENCES
  10. Supporting Information

Acknowledgments: The author thanks Earth and Fire Erowid, Robert Wold and the Clusterbusters, for assistance with data collection; Harrison Pope, Scott Lukas, Mehmet Sofuoglu, and Bruce Price for their comments on an earlier draft of this article, and Jonathan Byron for bringing kudzu to the attention of the cluster headache community. Funding was provided by NIDA, NIH T32-DA07252. No funding source had any role in study design, collection, analysis, or interpretation of data, writing of the report, or submission of the manuscript.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. REPRESENTATIVE CASES (ALL OTHERS ARE INCLUDED IN APPENDIX A, AVAILABLE ONLINE ONLY)
  6. DISCUSSION
  7. CONCLUSION
  8. Acknowledgments
  9. REFERENCES
  10. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. REPRESENTATIVE CASES (ALL OTHERS ARE INCLUDED IN APPENDIX A, AVAILABLE ONLINE ONLY)
  6. DISCUSSION
  7. CONCLUSION
  8. Acknowledgments
  9. REFERENCES
  10. Supporting Information

SUPPLEMENTAL CASE REPORTS FOR “Response of Cluster Headache to Kudzu” (Case no. 1, 4-16).

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HEAD_1268_sm_Suppl_Case.pdf160KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.