Research Submission

Botulinum Toxin Type-A (BOTOX®) in the Treatment ofOccipital Neuralgia: A Pilot Study

Martin Taylor, DO, PhD; Sachin Silva, BS; Constance Cottrell, RN, PhD

Objective.—To determine the efficacy of occipital nerve blocks using reconstituted botulinum toxin type-A (BTX-A) inproviding significant and prolonged pain relief in chronic occipital neuralgia.

Background.—Occipital neuralgia is a unilateral or bilateral radiating pain with paresthesias commonly manifesting asparoxysmal episodes and involving the occipital and parietal regions. Common causes of occipital neuralgia include irritationor injury to the divisions of the occipital nerve, myofascial spasm, and focal entrapment of the occipital nerve. Treatment optionsinclude medication therapy, occipital nerve blocks, and surgical techniques. BTX-A, which has shown promise in relief of otherheadache types, may prove a viable therapeutic option for occipital neuralgia pain.

Methods.—Botulinum toxin type-A (reconstituted in 3 cc of saline) was injected into regions traversed by the greater andlesser occipital nerve in 6 subjects diagnosed with occipital neuralgia. Subjects were instructed to report their daily pain level(on a visual analog pain scale), their ability to perform daily activities (on several quality of life instruments) and their daily painmedication usage (based on a self-reported log), 2 weeks prior to the injection therapy and 12 weeks following injection therapy.Data were analyzed for significant variation from baseline values.

Results.—The dull/aching and pin/needles types of pain reported by the subjects did not show a statistically significantimprovement during the trial period. The sharp/shooting type of pain, however, showed improvement during most of the trialperiod except weeks 3-4 and 5-6. The quality of life measures exhibited some improvement. The headache-specific quality of lifemeasure showed significant improvement by 6 weeks which continued through week 12. The general health- and depression-related measures showed no statistical improvement. No significant reduction in pain medication usage was demonstrated.

Conclusions.—Our results indicate that BTX-A improved the sharp/shooting type of pain most commonly known to beassociated with occipital neuralgia. Additionally, the quality of life measures assessing burden and long-term impact of theheadaches, further corroborated improvement seen in daily head pain.

Key words: occipital neuralgia, Botox, headache, botulinum toxin

Abbreviations: IHS International Headache Society, HIT headache impact test, VAS visual analog scale

(Headache 2008;48:1476-1481)

Occipital neuralgia (ON) is a commonly anelement of chronic, refractory headaches. ON is char-acterized by paroxysmal sharp and/or throbbing pain

in the distribution of the greater and/or lesser occipi-tal nerves.1 The pain maybe unilateral or bilateral andis typically accompanied by paresthesias in the distri-bution of the occipital nerves.2 Causes of ON includeirritation of the occipital nerve due to degenerative ortraumatic changes of the cervical spine and surround-ing myofacial spasm.1 Common treatments thathave been employed in the past include, nonsteroi-dal anti-inflammatory drugs (NSAIDs), tri-cyclic

From the OrthoNeuro—Neurology, New Albany, OH, USA(M. Taylor and S. Silva); Headache Treatment and ResearchProject—Ohio University, Athens, OH, USA (C. Cottrell).

Address all correspondence to M. Taylor, 7277 Smith Mill Rd.,New Albany, OH 43054.

Accepted for publication January 19, 2008. Conflict of Interest: None

ISSN 0017-8748doi: 10.1111/j.1526-4610.2008.01089.xPublished by Wiley Periodicals, Inc.

Headache© 2008 the AuthorsJournal compilation © 2008 American Headache Society

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antidepressants, anti-epileptic medications, injectiontherapy using anesthetics and corticosteroids,3,4 neuro-surgical resection such as rhizotomy at C1-C3,5 atlan-toepistrophic ligament decompression of C2 dorsalroot ganglion,6 and electrical stimulation of sensorydistributions using subcutaneous surgical leads.7 Whilenerve blocks have been shown to provide short-termrelief, surgical methods report mixed results.8

Botulinum toxin type-A (BTX-A; Botox®, Aller-gan, Irvine, CA, USA) has been reported to showfavorable efficacy and safety in the treatment ofseveral refractory headache types.9 Volcy et al haveshown BTX-A to be effective in reducing frequency ofepisodic migraines and controlling associated occipitalpain in a case report.10 Kapural et al showed a superioreffect of BTX-A occipital nerve blocks compared tothoseperformed with bupivacaine in a retrospective caseseries.11 However, no evidence to date has demon-strated improvement after BTX-A injections in thetreatment of head pain primarily from ON in a pro-spective study. The mechanism of BTX-A lies inits anti-spasmodic and anti-nociceptive effects. Wehypothesized that the anti-spasmodic effect of BTX-Amay help to partially relieve pain associated with ONby reducing spasticity around the occipital nerves.Furthermore, BTX-A’s anti-nociceptive effects, whichhave been linked to release-inhibition of Substance P,calcitonin gene-related protein, and glutamate,12-14

may reduce nerve hypersensitivity and referred pain inON.

MATERIALS AND METHODSSubjects.—Six subjects, 2 men and 4 women,

between the ages of 24 and 53 years, participated inthis study. Of the 6 subjects, 5 suffered from bilateralhead pain with a frequency of 5 or more headachesper week and a persistence of over one year. Thestudy was conducted from January 26, 2005 to Febru-ary 1, 2006 at the clinics of the investigators. The

protocol for this study was approved by the OhioUniversity Institutional Review Board with oversightthroughout the entire trial. The subjects were diag-nosed with chronic ON per the criteria established bythe International Headache Society. Subjects suffer-ing from Myasthenia Gravis, who had hypersensitiv-ity to botulinum toxin, or were on concomitant usageof aminoglycoside, were excluded from the study. Pre-viously prescribed prophylactic and abortive treat-ment was allowed during the study but the usage ofnew medications was prohibited.

Procedure.—The primary outcome measure of thestudy was the efficacy of BTX-A occipital nerveblocks in reducing ON-associated pain and parethe-sias. This measure was assessed based on a self-reported rating of the subjects’ daily headache types(dull aching pain, sharp shooting pain, pins andneedles pain) on a Visual Analog Pain and Medica-tion Use Diary (VPAM). The VPAM was maintainedfor 2 weeks prior to the initial treatment to establish abaseline. After treatment, the VPAM was maintainedfor an additional 12 weeks and mean scores were cal-culated based on each 2-week period and comparedto baseline (Fig. 1).

The secondary outcome measures of the studyincluded efficacy of BTX-A occipital nerve blocks inpromoting headache-free days and reducing medica-tion use (assessed based on VPAM scores), and inimproving overall quality of life assessed based onMOS-SF36, Beck Depression Index (BDI), HeadacheDisability Index (HDI), and Headache SpecificQuality of Life (HSQL) outcome assessment ques-tionnaires. The inventories and questionnaires werereported during the initial 2-week baseline periodand during weeks 6 and 12, following treatment. Thescores were analyzed per the guidelines set forth foreach questionnaire/inventory, based on each 2-weekperiod.

Treatment.—A 27-guage needle was inserted in-ferolateral to the occipital protuberance, along the

Screened

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quality of life

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of life measures

Weeks 7-8-Records VPAM

Weeks 9-10-Records VPAM

Weeks 11-12-Records VPAM

-Records quality

of life measures

Fig 1.—Flow of participants through the study. BTX = botulinum toxin; VPAM = Visual Analog Pain and Medication Use Diary.

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superior nuchal line at an angle of 90° towardthe occiput until a bony endpoint was reached. Theneedle was then withdrawn and the areas of thegreater and lesser branches of the occipital nervewere traversed. These areas were bathed in a total of50 units of BTX-A reconstituted in 3 cc of normalsaline at each symptomatic side.15

Statistical Analysis.—Data were analyzed usingthe GraphPad Prism Statistical Analysis Software(version 4.03). Mean values of VPAM scores werecompared to scores reported after treatment, usinga paired t-test at the alpha (a) = 0.05 leveling. TheVPAM mean scores were also used to assess the pro-portion of subjects (responder rate) reporting �30%and a �50% reduction from baseline in average dailypain intensity. A chi-square test was used to test thestatistical validity of the responder rate. The overallquality of life measures (BDI, HSQL,16 MOS-SF36,HDI17) were summarized using both initial and lastobservations carried forward scores and analyzedat the alpha (a) = 0.05 leveling using a paired t-test.All statistical analyses were conducted at a 95%confidence interval and a P value less than .05 wasconsidered statistically significant.

RESULTSOf the 6 subjects who participated in this study,

2 were men (mean age 43.16 � 3.78 years) and 4were women (mean age 38.94 � 12.59 years), withmean ages of 40.33 � 10.14 years. The headachehistory ranged from 1 to 3 years (mean 2.1 � 0.62).Two subjects reported a prior history of depressionand anxiety while 4 reported a prior history of car-diovascular, gastrointestinal, or renal disease. Onesubject did not complete the full 14-week durationof the study but instead participated through week4. His or her data have been included in the analysis.One subject failed to report daily headache scoresduring the 2-week period following treatment.His or her data have also been included. Nodemographic, phenotypic, or gender-related factorswere taken into consideration when administeringtreatment. Subject profiles are summarized in theTable.

Four of the subjects reported daily VPAM scoresof 5 or higher for 2 of the 3 types of pain evaluated.

The baseline daily rescue medication intake was1.22 � 0.04 pills daily. Five of the 6 subjects reportedtemporary relief of symptoms from previous occipitalnerve blocks supporting a clinical diagnosis of ON.Previous medications used for pain included narcoticsin all subjects, muscle relaxants and antidepressants in5 subjects, and anti-epileptics and non-steroidals in 4subjects. No new medications were started for painduring the study in any patient. No significant changein the amount of daily rescue medication was seencompared to baseline.

A statistically significant reduction in VPAMheadache rating from baseline served as the primaryefficacy point for this study. The dull aching painscores, while exhibiting a reduced mean from baseline(4.83 � 1.41), did not show a statistically significantimprovement during any evaluation interval (Fig. 2a).The pins/needles pain scores showed a general trendtoward improvement with statistical significance atweeks 3-4 and weeks 5-6 (Fig. 2b).The sharp/shootingpain scores, on the other hand, showed a statisticallysignificant improvement from baseline (5.75 � 2.37)during most evaluation periods except weeks 3-4 andweeks 5-6 (Fig. 2c).

The secondary outcome measures of this studyincluded the number of headache-free days, thereduction in pain medication usage, and the improve-ment in overall quality of life measures (MOS-SF36,BDI, HSQL, and HDI). None of the subjects reportedheadache-free days on the VPAM, upon treatment.Several subjects did, however, report zero scores for aparticular pain type but did not report such a score forall 3 pain types, on the same day. Most commonly, theheadache type that was reported with a zero scorewas the pins/needles type of pain.

The BDI did not show a statistically significantreduction from baseline (25.0 � 14.21) (Fig. 3a). Thebaseline mean score, which reflected moderate

Table.—Demographic and Health History Data ofStudy Participants

Number of subjects (N) 6Age 40.38 � 10.13Gender 2 male; 4 femaleUnilateral/bilateral 1 unilateral; 5 bilateral

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depression (17-29) leveled to 21.50 � 17.62 duringweeks 5-6 (moderate depression) and 17.20 � 5.215during weeks 11-12 (moderate depression). At least2 subjects did not report BDI scores during at leastone evaluation period. Their remaining scores wereincluded in the statistical analysis. Though the scoresdid not show a statistically significant improvement,they did exhibit a trend toward improvement.

The HDI did not demonstrate a statistically sig-nificant improvement (Fig. 3b), even though themean scores showed a trend toward improvement.

The HDI scores reduced from 68.33 � 20.88 to a61.00 � 22.01 during week 6 and 57.60 � 13.96 duringweek 12. A decrease in the total HDI of 29 points isconsidered significant improvement.16

The HSQL17 measure showed a statistically sig-nificant reduction from baseline (61.00 � 13.91)during both evaluation periods (week 6, P = .0211 andweek 12, P = .0315) (Fig. 3c). One subject failed toreport scores during the third evaluation period whileanother provided partial ratings during the secondevaluation period. Both subjects’ scores were in-cluded in the analysis.

The general health-related quality of life,reflectedin the MOS-36 item short form (SF-36), showed noimprovement upon treatment in its cumulative ormental health components (Fig. 3d). However, thephysical health component showed improvementduring weeks 11-12 (P = .0300) (Fig. 3e).

COMMENTSWe describe the first prospective study for the

treatment of ON with BTX-A. ON is commonlymanifested as a sharp/shooting type of pain.18 In thisregard, the VPAM results appear to be consistent inthat the sharp/shooting pain was the only pain typethat showed a consistent improvement and hadthe most significant reduction upon treatment. Thepatient’s perception of improvement, reflected in thequality of life measures, further corroborated such aconclusion. The HSQL measures showed consistentimprovement upon treatment, while measures thatassessed symptoms of depression and generalhealth did not show such improvement. Though thereduction in headache burden (HDI) was notconsidered clinically significant (reduction of �29points), the HSQL did show a clinically significantreduction.

The dull/aching pain score showed a consistentand progressive decrease in mean until a minimumvalue (at weeks 7-8) and then showed a progressiveincrease and leveling (at weeks 11-12). The lowestP-value (.056) coincided with the most significantscore reduction (at weeks 7-8). The pins/needles painscore showed a similar trend, reaching a minimumat weeks 5-6 and then progressively increasing andleveling at weeks 11-12. Again the lowest P-value

Baseline Weeks 3-4 Weeks 7-8 Weeks 11-120.00.51.01.52.02.53.03.54.04.55.05.5

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Fig 2.—(a) Evolution of Dull/Aching Pain Score. (b) Evolutionof Pins/Needles Pain Score. *Weeks 3-4 (mean � SD =1.171 � 1.088; P = .217). **Weeks 5-6 (mean � SD = 0.8318 �

0.9875; P = .0295). (c) Evolution of Sharp/Shooting PainScore. **Weeks 1-2 (mean � SD = 3.651 � 2.896; P = .0453);***Weeks 7-8 (mean � SD = 2.7 � 1.751; P = .0019);****Weeks 9-10 (mean � SD = 3.341 � 0.895; P = .0307);*****Weeks 11-12 (mean � SD = 3.418 � 1.40; P = .0417).

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coincided with the minimum during weeks 5-6. In thecase of the quality of life measures, this trend waseven more pronounced. The BDI scores showed aconsistent decrease in both the mean score and theP-value. A similar trend was evident in the HDI andthe MOS-SF36 scores. Based on such a trend, and thestandard deviations associated with each mean, itcould be speculated that the scores may have shown astatistically significant reduction had the sample sizebeen larger and the standard deviations lower.

The results of this study are consistent with theindependent retrospective trial performed by Kapuralet al11 in which a 50-unit dose of BTX-A was alsoinjected at each symptomatic side for the treatment

of ON. This is the only other study to our knowledgeusing botulinum toxin A or B to specifically treat ON.

Finally, several limitations in our study areworth mention. Purely subjective outcome measuresare an intrinsic weakness of all headache studiesinvolving self-reporting. We have attempted tocounter such biases with secondary measures ofglobal impressions, which closely paralleled head-ache diary predictors. Injection of normal saline hasbeen associated with improvement in headache.19

Thus, a placebo response is perhaps inevitable.Finally, the small sample size limited the power ofthe outcomes. The results of this trial suggest thatfurther large placebo-controlled trials are warranted

Baseline Weeks 5-6 Weeks 11-120

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Fig 3.—(a) Evolution of Beck Depression Index Score. (b) Evolution of Headache Disability Index (HDI) Score. (c) Evolution ofHeadache Specific Quality of Life Score. *Evaluation Period I (mean � SD = 41.50 � 10.45; P = .0211); **Evaluation Period II(mean � SD = 42.00 � 10.89; P = .0315). (d) Evolution of MOS-SF36 Scores. (e) Evolution of MOS-SF36 Score (Physical HealthComponent). **Evaluation Period II (mean � SD = 33.80 � 8.58; P = .0300).

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using 50 units of BTX-A at each occiput for thetreatment of ON.

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