Prophylactic treatment of migraine with botulinum toxin type A: a pharmacoeconomic analysis in a community setting

Summary

The purpose of this retrospective outpatient database analysis was to evaluate the impact of prophylactic botulinum toxin type A (BoNTA) treatment of migrainous headaches on the costs associated with triptan use and physician office visits.

The study was conducted in a community-based neurology practice. Consecutive patients diagnosed with episodic migraine (International Headache Society criteria 1.1, 1.2) or chronic migraine (criterion 1.5.1) who failed previous oral prophylactic headache treatments were treated with one BoNTA treatment (25–100 units).

No significant adverse events were reported. A single BoNTA treatment led to substantial reductions in triptan prescription use and in the frequency of office visits related to migraine symptoms, whilst also improving the condition of episodic and chronic migraine patients by decreasing the frequency of headache episodes by 53%. The cost of BoNTA treatment was offset by cost savings related to triptan use and physician office visits.

Keywords: :

• pharmacoeconomics
• prescription fees
• medical fees
• headache
• migraine
• tryptamines
• botulinum neurotoxin type A

Introduction

Approximately 18% of women and 7% of men suffer from migraine1, which is ranked as one of the world's most severely disabling disorders2. Some individuals with migraine may be at risk of developing a clinically progressive disorder as the frequency of migraine headaches increases even as the severity of episodes and the occurrence of associated symptoms such as phonophobia, nausea and vomiting, and photophobia decreases3–8. A pattern of daily or near-daily headaches emerges, characterised by the intermittent occurrence of severe migraine episodes9. The definition of chronic migraine has undergone revision and evolution in recent years10–12

Treatment of migrainous headaches consumes a large amount of healthcare resources. Billions of dollars attributed to migraine are spent annually for direct costs, including oral pharmacotherapy, physician visits and emergency department visits, in addition to indirect costs such as loss of productivity and missed work days13–15. Individuals with migraine use up to 2.5 times more prescription drugs than individuals without migraine16 and often overuse headache medications (>15 times/month and 2 days/week)17–19. Considerable numbers of individuals with migraine seeking relief of their symptoms overuse headache medications, which can exacerbate existing headache pain, increase the frequency of headache episodes and increase the risk of medication overuse headache (International Classification of Headache Disorders (ICHD) II criterion 8.2)8,18–25. Adding an effective prophylactic headache medication to a migraine treatment regimen is recommended to reduce the frequency of headache episodes, the use (and escalation) of acute headache pain medications, headache-related disability and visits to physician offices and emergency departments26,27.

Botulinum toxin type A (BoNTA; BOTOX®) is a focally administered purified protein that blocks the release of acetylcholine from pre-synaptic neurons28,29. In recently published in vivo and in vitro studies, BoNTA blocked the release of nociceptive mediators such as substance P, calcitonin gene-related peptide and glutamate from peripheral neurons, and reduced pain-related behaviours30–32. Data from clinical trials have shown that, compared with placebo, BoNTA treatment resulted in significant mean reductions from baseline in the frequency of headache episodes in patients with migraine26 and chronic daily headache33,34, in addition to significant mean reductions in the monthly use of acute headache pain medications34–36. BoNTA treatment of headache has been shown to be safe and well tolerated, with low discontinuation rates due to mostly mild, or moderate and transient treatment-related adverse events33,34,36.

The overall cost of migraine treatment is a paramount concern and represents a great financial burden to patients, employers, healthcare providers and society in general. It is desirable to identify cost-effective treatments that balance tolerability and efficacy to ease this burden. Pharmacoeconomic analyses of either acute or prophylactic migraine treatments have evaluated the effects of such treatments on several cost parameters, including: physician office visits or emergency department visits37–40; usage and associated costs of acute and/or preventive migraine treatment41–43; and lost productivity or missed work time37,38,43–49. The cost of treating patients for the side effects of acute and/or prophylactic migraine medications has also been evaluated and is an important consideration when analysing the cost effectiveness of various treatments37,46,48.

The purpose of this analysis was to evaluate the hypothesis that a single BoNTA treatment in individuals with migraine would be associated with pharmacoeconomic benefits, specifically in terms of costs associated with triptan treatment and the frequency of physician office visits.

Methods

Design and patients

This was a retrospective, open-label, outpatient analysis. Patients at a community-based general neurology practice who were diagnosed with episodic migraine (International Headache Society criteria 1.1, 1.2) or chronic migraine (criterion 1.5.1) with or without analgesic overuse, who were treated with triptans and BoNTA according to informed consent regulations, were considered eligible. For the purpose of this analysis, patients were considered as chronic migraine patients if they had ≥15 days of migraine per month regardless of whether they were overusing acute medications. Data from patients' records were collected from a database in November 2004 and included 75 consecutive individuals with migraine meeting the eligibility criteria who had received BoNTA treatment during the period from the 8th November 2001 to the 23rd November 2004 and had failed previous oral prophylactic headache treatments.

Treatment protocol

Patients were injected with 25–100 units (U) of BoNTA (2.5 U or 5.0 U per site) to the procerus, corrugator, frontalis, temporalis, occipitalis, trapezius, splenius capitis and/or levator scapulae muscles using a combination of the fixed-site and follow-the-pain approaches, according to the discretion of the physician50. Choice of dose and injection protocol was made according to the site and nature of the pain and the size of the muscle or muscles to be injected. Patients were instructed to use current acute treatments as needed.

Outcome measures

The primary outcome measure was the net cost of triptan medication use during the 3-month period after a single BoNTA headache treatment was administered. All seven types of triptans were used (Table 1); 66 patients used one triptan, 7 used two triptans and 2 used three triptans. The average triptan cost was determined to be $20.41/dose (specific triptan costs for this calculation were taken from the Redbook 2006 using the average wholesale price from the manufacturers). The average cost of BoNTA was determined to be $5.82/U (based on the average wholesale price from the manufacturer); triptan and BoNTA costs represent the average costs as of December 2006. Triptan cost was calculated by multiplying the number of doses used by $20.41. The net cost of triptan medication use over the 3-month period following administration of BoNTA was computed from the total cost of a single BoNTA treatment for 75 patients and the change in triptan costs calculated on the basis of usage.

Table 1. Unit cost of oral triptans (AWP in US$)*.

Drug	Dosage unit	Unit price	Average unit price of drug
Sumatriptan succinate (Imitrex®)	25 mg	21.33	20.37
	50 mg	19.89
	100 mg	19.89
Almotriptan malate (Axert®)	6.25 mg	19.12	19.50
	12.5 mg	19.88
Naratriptan hydrochloride (Amerge®)	1 mg	22.11	22.11
	2.5 mg	22.11
Frovatriptan succinate (Frova®)	2.5 mg	20.17	20.17
Eletriptan hydrobromide (Relpax®)	20 mg	18.32	18.32
	40 mg	18.32
Zolmitriptan (Zomig®)	2.5 mg	18.54	22.69
	5 mg	26.84
Rizatriptan benzoate (Maxalt®)	5 mg	19.69	19.69
	10 mg	19.69
Average unit triptan price			20.41

AWP: average wholesale price

* AWP as per the Redbook 2006.

A secondary endpoint was the effect of BoNTA treatment on the frequency and cost of office visits attributed to the need for headache treatment. The average cost of an office visit was determined to be $65, which was the average reimbursement rate for the study centre during the study period. The frequency of headache episodes per month and adverse events were also recorded.

All data were evaluated for the 3-month period preceding BoNTA treatment and compared with the 3-month period following treatment. Single-month values reported below were calculated from the 3-month totals. Only descriptive statistics were used in the analysis.

Results

Patients

A total of 75 consecutive migraine patients (50/75 (66.7%) chronic migraine; 71 (94.7%) female; mean age 46 years, age range 18–65 years) were administered one BoNTA treatment (7,230 U of BoNTA; mean per patient, 96.4 U) at a total cost of $42,078.60 for the entire cohort, or a mean cost of $561.05 per patient.

Triptan usage and costs

In the 3 months prior to BoNTA treatment, patients were prescribed 3,774 triptan doses (1,258 per month) at a cost of $77,027 ($25,676 per month) for the entire cohort, or a mean cost of $1,027.03 per patient ($342.34 per patient per month) (Figure 1). The subgroup of 50 chronic migraine patients was prescribed 3,003 triptan doses (1,001 per month) at a cost of $61,291 ($20,430 per month) in the 3 months preceding BoNTA treatment, representing a cost of $1,225.82 per patient ($408.61 per patient per month) (Figure 2).

Figure 1. Total triptan costs for the entire cohort before and after BoNTA treatment. Triptan costs decreased by $ 42,003 after treatment.

Figure 2. Total triptan costs for the 50 CM patients before and after BoNTA treatment. Triptan costs decreased by $ 35,146 in CM patients after treatment.

In the 3 months following BoNTA treatment, patients were prescribed 1,716 triptan doses (572 per month, a 55% decrease). Total triptan costs declined to $35,024 ($11,675 per month and $155.66 per patient per month), a saving of $42,003 ($14,001 per month and $186.68 per patient per month) post BoNTA treatment (Figure 1). Chronic migraine patients were prescribed 1,281 triptan doses (427 per month, a 57% decrease) at a cost of $26,145 ($8,715.07 per month) in the 3 months post BoNTA treatment, representing a saving of $35,146 ($11,715 per month and $234.31 per patient per month) (Figure 2). Subtracting the decreased triptan cost from the cost of BoNTA treatment ($42,078.60) for the entire cohort, the net change in drug cost resulting from decreased triptan use during the 3-month period following BoNTA treatment was $75.60 (or approximately $1 per patient) for the entire group. Subtracting the cost of BoNTA treatment ($28,256.10) from the decreased triptan cost for the chronic migraine patients, the net savings in drug cost resulting from decreased triptan use during the 3-month period following BoNTA treatment was $6,889.92 (or $137.80 per patient) for the subgroup of patients with chronic migraine.

Office visit frequency and costs

In the 3-month period prior to BoNTA treatment, patients had a total of 128 office visits attributed to migraine symptoms, costing $8,320 in office visits pre BoNTA treatment. In the 3 months following BoNTA treatment, the frequency of office visits was reduced to 80 visits costing $5,200 in office visits post BoNTA treatment, a medical savings of $3,120 for the entire group in office visits alone (Figure 3).

Figure 3. Office visit costs before and after BoNTA treatment for the entire cohort. BoNTA, botulinum toxin type A.

Net savings after BoNTA treatment

The net drug and medical savings for the entire cohort after a single BoNTA treatment cycle resulting from decreased triptan use and decreased office visits was $3,044.40 ($40.59 per patient).

Frequency of headache episodes per month

The total frequency of migraine episodes per month, as indicated in patient headache diaries, before BoNTA treatment was 1,547 episodes per month for the entire group (mean per patient, 20.63 episodes per month; range 4–30 episodes per month). After BoNTA treatment, the frequency of migraine episodes per month declined by 53% to 731 episodes for the entire group (mean per patient, 9.75 episodes per month; range 0–30 episodes per month) (Figure 4). In the subgroup of individuals with chronic migraine, headache frequency decreased by 55% from 1,320 per month (mean per patient, 26.40 headaches per month; range 15–30 headaches per month) to 589 per month (mean per patient, 11.78 headaches per month; range 0–30 headaches per month) (Figure 5).

Figure 4. Mean frequency of migraines/month per patient for the entire cohort before and after BoNTA treatment.

Figure 5. Mean frequency of migraines/month per patient, individuals with chronic migraine.

Adverse events

No serious adverse events were reported in this study. However, two events (mild injection-site bruising and blepharoptosis) were each reported in approximately 5% of patients.

Discussion

Migraine places a substantial financial burden on societies across the world, with billions of dollars consumed annually in direct and indirect costs13–15,51. Individuals with migraine having a more severe chronic disorder use significantly greater healthcare resources and place a greater financial burden on society than those with mild or moderate migraine52,53. Physician office visits (including consultations) and pharmacotherapy combined constitute the greatest proportion of the direct costs associated with migraine treatment14,15,52,53.

In this analysis, BoNTA treatment reduced the financial burden of triptan treatment and physician office visits for a group of 75 consecutive patients with episodic or chronic migraine. Following a single BoNTA treatment, triptan use declined by 55%, representing a $42,003 saving over a 3-month period for the entire cohort. This represents a saving of $186.68 per patient per month in triptan costs. Interestingly, the frequency of migraine episodes per month was reduced by almost the same proportion (53%). The net drug and medical savings was $3,044.40 for the entire group of 75 individuals with migraine in a 3-month period (net savings of $40.59 per patient). Greater cost savings were observed in the subgroup of patients with chronic migraine. As practice remained consistent and no behavioural or educational changes were implemented during the course of the study, the authors believe that these savings were attributable to BoNTA treatment; however, it is possible that unrecognised individual patient adaptations influenced these results.

A pharmacoeconomic analysis conducted by Brown et al estimated that approximately two-thirds of the monthly cost of topiramate treatment for migraine would be offset by a reduction in the cost of acute medication use and reduced work loss if treatment reduced the frequency of migraine episodes43. The cost effectiveness of prophylactic migraine treatment may also be influenced by the baseline frequency of migraine episodes. An analysis by Adelman et al found that antiepileptic drugs used as prophylactic treatment for migraine would be cost effective only for those patients experiencing 10 migraine episodes or more per month in the case of divalproex sodium or considerably more than 10 migraine episodes per month for topiramate and gabapentin54. In addition, numerous pharmacoeconomic analyses of acute or prophylactic migraine treatments have shown that the medication costs of such treatment can be offset by reductions in healthcare utilisation and savings from increased productivity37–39,44,46,48,55.

In this analysis, a single BoNTA treatment was associated with net savings from reduced triptan use and office visits. The effectiveness of BoNTA in reducing the financial burden of migraine in this episodic and chronic migraine population may be due to its efficacy in treating the symptoms of migraine. Data from controlled clinical trials have demonstrated that BoNTA treatment significantly reduced the mean frequency of headache episodes compared with placebo in episodic migraine patients and in individuals with migraine having chronic daily headache33–36. In many of those same patients, BoNTA treatment significantly reduced the monthly use of acute headache pain medications33,34,36.

Although the retrospective, open-label nature of this analysis limits the interpretation of these results, the data were collected in a community-based neurology practice rather than in a large headache centre or university hospital setting, which may give a more accurate portrayal of typical migraine patients seen in community practice. The present analysis was limited by the lack of a historical control group and the non-inclusion of other important dependent variables potentially related to the 53% decline in headache frequency per month, such as the costs associated with emergency department visits, hospitalisations, other medical treatments and the use of prophylactic and other types of acute medications. This analysis was further limited by excluding consideration of indirect costs, such as time lost from work, family and social activities as well as administration costs.

The results of this analysis indicate that BoNTA treatment of migraine can reduce the financial burden of migraine by reducing medication use and physician office visits, perhaps as a result of efficacy in treating migraine symptoms. On the basis of these preliminary results, and the results of other controlled trials of BoNTA treatment of migraine and chronic daily headache, a large, randomised, double-blind study with a control group to evaluate the effect of multiple BoNTA treatment cycles on direct and indirect costs of migraine treatment, particularly in chronic migraine patients, would be of great interest.

Notes