TITLE: Botulinum Toxin A for Headaches in Adults: A Review of Clinical-Effectiveness and Safety

Transcription

1 TITLE: Botulinum Toxin A for Headaches in Adults: A Review of Clinical-Effectiveness and Safety DATE: 28 July 2009 CONTEXT AND POLICY ISSUES: Botulinum toxin is a neurotoxin that causes muscle paralysis by blocking the release of acetylcholine at neuromuscular junctions. 1 Although botulinum toxin subtypes A to G exist, only subtypes A and B are used in clinical practice. In Canada, botulinum toxin A (BTA) is marketed as Botox and Botox Cosmetic by Allergan Inc., 2 and as Xeomin by Merz Pharmaceuticals 3. Botox Cosmetic (Allergan Inc.) 4 and Dysport (Ipsen Biopharm Ltd) 5 are available in the United States. Approved indications include the treatment of focal spasticity, blepharospasm, strabismus, and cervical dystonia. 1 Treatment involves local intramuscular. Effects may last from several weeks to several months. 1,2 In Canada, BTA is not currently indicated for the management of headaches and governmentsponsored drug plans are receiving requests for coverage. To better guide off-label coverage decisions, information is required on the clinical benefits and harm of BTA when used for the management of headaches in adults, including chronic tension-type headache (CTTH), chronic daily headache (CDH), and cluster headache. RESEARCH QUESTIONS: What is the clinical benefit and harm of botulinum toxin A for the management of headaches in adults? METHODS: A limited literature search was conducted on key health technology assessment resources, including OVID Medline, The Cochrane Library (Issue 3, 2009), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international health technology Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 agencies, and a focused Internet search. The search was limited to English language articles published between 2004 and July Filters were applied to limit the retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), controlled clinical trials, and observational studies. HTIS reports are organized so that the higher quality evidence is presented first. Therefore, health technology assessment reports, systematic reviews and meta-analysis are presented first. These are followed by randomized controlled trials, controlled clinical trials, and observational studies. SUMMARY OF FINDINGS: One health technology assessment 6 (Table 1) and six systematic reviews 7-12 (Table 2) assessing BTA for the management of headaches were found. Nine RCTs and one subgroup analysis 22 were retrieved (Tables 3 and 4). Given the wealth of information, controlled clinical trials and observational studies were excluded. Health technology assessments A health technology assessment on the use of BTA for the management of primary chronic headache disorders, including migraines, chronic or episodic tension headaches, and cluster headaches, was published in 2004 (Table 1). 6 For the prophylaxis of tension headaches, the evidence (eight RCTs; n=348) was insufficient to support the use of BTA. No evidence was identified to support the use of BTA in the prevention of cluster headaches. Systematic reviews and meta-analysis Cluster headaches A systematic review (2008) on the various treatments used in cluster headaches found no evidence for the use of BTA in the prevention of cluster headaches (Table 2). 7 Chronic tension-type and chronic daily headaches A systematic review (2007) on the effects of treatments used in CTTH examined four RCTs (n=285) from a previous systematic review and a subsequent RCT (n=40), all published in or before 2004 (Table 2). 8 showed that compared to placebo, BTA may be no more effective for improving the symptoms of CTTH. Reported adverse events (AEs) included facial weakness, difficulty in swallowing, and disturbed local sensation. A systematic review (2008) published by the American Academy of Neurology evaluated the benefits and harm of BTA in the treatment of various autonomic and pain disorders, including CDH and CTTH (Table 2). 9 Based on four RCTs (total sample size not specified), there was insufficient evidence to support or refute a benefit in using BTA for the treatment of CDH. Four RCTs (total sample size not specified) indicated that BTA is ineffective and should not be considered for patients with CTTH. Transient and mild muscle weakness was the most commonly reported AE, occurring in 2.5% to 25% of patients. Two systematic reviews on the use of BTA in headache disorders were retrieved (Table 2). 10,11 The first (2008) 10 included three RCTs (n=1,117) on CDH and five RCTs (n=533) on CTTH. Findings did not support the clinical effectiveness of BTA when compared to placebo for CDH or Botulinum Toxin A for Headaches 2

3 CTTH. 10 The second systematic review (2009) 11 included three RCTs (n=1,115) on CDH and six RCTs (n=651) on CTTH. The study results did not support the use of BTA for CDH. In CTTH, the studies suggested that BTA is ineffective, regardless of injection site, dosage or injection regimen. 11 Harm The safety of BTA when used for various conditions (not limited to headaches) was examined in a systematic review (2004) that included a meta-analysis of the number and the frequency of adverse events (AEs) (Table 2). 12 Thirty-six studies with 2,309 participants, of which 1,425 received BTA (Botox ), met the inclusion criteria. There were no severe AEs reported. Mild-tomoderate AEs were reported at a rate of 24.8% (353/1,425) in the BTA group compared to 15.0% (133/884) in the control group (p<0.001). The adjusted, weighted-risk difference was 9% and the number-needed-to-harm was 11. Focal weakness was reported with significantly greater frequency in BTA-treated patients when compared with patients in the control group (p< ). There were no significant differences between groups in other AEs including pain or reaction at injection the site, headache, back pain, neck pain, or ptosis. Randomized controlled trials Chronic tension-type headaches Six randomized, placebo controlled studies were identified, of which five were double-blinded 13-16,18 and one was single-blinded 17 (Table 3). With the exception of the single-blinded study that showed a statistically significant improvement in two end-points, all studies were negative for their primary end-point. Chronic daily headaches Three randomized, double-blind, placebo controlled studies were identified (Table 4) One sub-group analysis 22 of a larger trial 20 was also retrieved. All RCTs reported negative results. The sub-group analysis showed a significant improvement in patients not taking concurrent prophylactic medications. 22 Limitations The RCTs on CTTH used different products (Botox or Dysport ), doses, and injection sites (follow the pain approach versus fixed injection sites) making comparisons difficult. With the exception of one study, 15 CTTH studies did not include enough study participants to detect a clinically important difference between the treatment and control group. CDH consists of different types of primary headaches, which may have different pathophysiological profiles. 11 A clear definition for CDH has not been established by the International Headache Society. 23 The RCTs on CDH included patients with a diagnosis of chronic migraine, CTTH, new daily persistent headache, and hemicrania continua. 20 Furthermore, a sub-group analysis 22 of patients not receiving prophylactic medications showed positive results in favor of BTA. The heterogeneous nature of the included patients may affect the results. It is possible that BTA may be effective in more homogenous groups of patients; but this has yet to be determined in RCTs. Botulinum Toxin A for Headaches 3

4 CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: Compared to placebo, there is evidence that BTA is not effective in the management of CTTH or CDH. These results need to be interpreted in light of the fact that CDH includes different types of primary headaches. In addition, one RCT showed significant improvement in a subgroup of patients not receiving concurrent prophylactic medications. 22 There may be sub-groups of patients that benefit from BTA who have not yet been identified in RCTs. In CTTH, all, but one study, 15 were underpowered to detect a clinical difference. No information about the clinical effectiveness of BTA for the management of cluster headaches was found. In summary, evidence from systematic reviews and RCTs indicates that BTA may not be effective for the treatment of CTTH or CDH when compared with placebo. Furthermore, BTA may be associated with adverse effects including focal weakness. PREPARED BY: Christine Perras, B.Sc. Phm., MPH, Research Officer Michelle Clark, B.Sc., Research Assistant Jessie Cunningham, M.I.St., Information Specialist Health Technology Inquiry Service htis@cadth.ca Tel: Botulinum Toxin A for Headaches 4

5 PREFERENCES: 1. Taylor P. Agents acting at the neuromuscular junction and automomic ganglia. In: Brunton LL, editor. Goodman and Gilman's the pharmacological basis of therapeutics. 11th ed. New York (NY): McGraw-Hill; p Botox. In: e-theraputics+. [database online]. Ottawa (ON): Canadian Pharmacists Association; Available: (accessed 2009 Jul 15). 3. Xeomin. In: e-theraputics+. [database online]. Ottawa (ON): Canadian Pharmacists Association; Available: (accessed 2009 Jul 15). 4. Botox cosmetic. In: [database online]. Bethesda (MD): Food and Drug Administration; Available: gdetails (accessed 2009 Jul 15). 5. Dysport. In: [database online]. Bethesda (MD): Food and Drug Administration; Available: gdetails (accessed 2009 Jul 15). 6. Samson D. Botulinum toxin for treatment of primary chronic headache disorders. Technol Eval Cent Asses Program Exec Summ 2004;19(10): Matharu M, Silver N. Cluster headache. BMJ Clin Evid (Online) 2008;2: Available: (accessed 2009 Jul 28). 8. Krishnan A, Silver N. Headache (chronic tension-type). BMJ Clin Evid (Online) 2009;7: Available: (accessed 2009 Jul 28). 9. Naumann M, So Y, Argoff CE, Childers MK, Dykstra DD, Gronseth GS, et al. Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008;70(19): Schulte-Mattler WJ, Leinisch E. Evidence based medicine on the use of botulinum toxin for headache disorders. J Neural Transm 2008;115(4): Obermann M, Diener HC. Is botulinum toxin useful in treating headache? No. Curr Treat Options Neurol 2009;11(1): Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin 2004;20(7): Schulte-Mattler WJ, Krack P, BoNTTH Study Group. Treatment of chronic tension-type headache with botulinum toxin A: a randomized, double-blind, placebo-controlled multicenter study. Pain 2004;109(1-2): Botulinum Toxin A for Headaches 5

6 14. Padberg M, de Bruijn SF, de Haan RJ, Tavy DL. Treatment of chronic tension-type headache with botulinum toxin: a double-blind, placebo-controlled clinical trial. Cephalalgia 2004;24(8): Silberstein SD, Göbel H, Jensen R, Elkind AH, DeGryse R, Walcott JM, et al. Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study. Cephalalgia 2006;26(7): Straube A, Empl M, Ceballos-Baumann A, Tölle T, Stefenelli U, Pfaffenrath V, et al. Pericranial injection of botulinum toxin type A (Dysport) for tension-type headache - a multicentre, double-blind, randomized, placebo-controlled study. Eur J Neurol 2008;15(3): Hamdy SM, Samir H, El-Sayed M, Adel N, Hasan R. Botulinum toxin: could it be an effective treatment for chronic tension-type headache? J Headache Pain 2009;10(1): Harden RN, Cottrill J, Gagnon CM, Smitherman TA, Weinland SR, Tann B, et al. Botulinum toxin a in the treatment of chronic tension-type headache with cervical myofascial trigger points: a randomized, double-blind, placebo-controlled pilot study. Headache 2009;49(5): Ondo WG, Vuong KD, Derman HS. Botulinum toxin A for chronic daily headache: a randomized, placebo-controlled, parallel design study. Cephalalgia 2004;24(1): Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C, et al. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache 2005;45(4): Silberstein SD, Stark SR, Lucas SM, Christie SN, Degryse RE, Turkel CC, et al. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc 2005;80(9): Dodick DW, Mauskop A, Elkind AH, DeGryse R, Brin MF, Silberstein SD, et al. Botulinum toxin type a for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medications: a randomized double-blind, placebo-controlled study. Headache 2005;45(4): Olesen J, Bousser M, Diener H, Dodick D, First M, Goadsby PJ, et al. The international classification of headache disorders. 2nd ed. Oxford (UK): International Headache Society; Available: (accessed 2009 Jul 15). Botulinum Toxin A for Headaches 6

7 APPENDIX: Table 1: Health Technology Assessment on Botulinum Toxin A in the Management of Primary Chronic Headache Disorders Reference Search methods Samson Update to an HTA published in Medline 2002 to 2004 and handsearching. Study selection and indications RCT, DB, PC. Migraines; chronic or episodic tension-type headaches; cluster headaches. Health outcomes Headache frequency, severity and duration; disability; AEs. 4 studies from the original 2002 HTA and 4 additional studies found with new search; n= studies rated fair quality; 6 studies rated poor quality. The 2 better-rated studies did not find significant differences between placebo and BTA in the prevention of tension headaches. No information found on cluster headaches. Minor AEs include ptosis, acute headache, neck weakness, nausea, pain at injection site and diplopia. AEs=adverse events; BTA=botulinum toxin A; DB=double-blind; PC=placebo-controlled; RCT=randomized controlled trial Botulinum Toxin A for Headaches 7

8 Table 2: Systematic Reviews on the Benefits and Harm of Botulinum Toxin A versus Placebo in the Management of Cluster, Chronic Tension-Type, and Chronic Daily Headaches Reference Search methods Cluster headache Matharu Medline to September 2006; Embase 1980 to September 2006; Cochrane library; various websites. Study selection SRs and RCTs in any language. Health outcomes Headache relief measured by headache frequency, severity, and duration. No studies identified on the effects of BTA for the prevention of cluster headaches. Chronic tension-type headache Silver Medline 1966 to March 2006; Embase 1980 to March 2006; Cochrane library; various websites. SRs and RCTs in any language. Headache frequency, severity, and duration. One SR (search date 2004; includes 4 RCTs; n=285) and one RCT; n=40 were found. 3 of the 4 RCTs included in the SR found no significant difference between BTA and placebo in headache frequency, while 1 RCT reported a significant reduction from baseline in headache intensity and days without pain after BTA treatment (p value not reported and no between group comparison). One subsequent RCT reported no significant difference between BTA and placebo. BTA may be no more effective than placebo at improving the symptoms of CTTH and has been associated with AEs. AEs=facial weakness, difficulty in swallowing, and disturbed local sensation. Botulinum Toxin A for Headaches 8

9 Reference Search methods Naumann Not described. Health outcomes VAS; area under the headache curve, proportion of severe headaches posttreatment. Schulte- Mattler Medline (search timeframe not specified). Obermann Medline (search timeframe not specified). Study selection Not described. 4 RCTs (total sample size not specified), 2 of which were of higher quality. Based on these 2 studies, the authors concluded that BTA is probably ineffective for CTTH. AEs=transient weakness of neck muscle, local skin tension, ptosis, flulike reaction. RCT, PC. Not reported. 5 RCTs; n=533. No significant difference between BTA and placebo. No serious AEs reported. RCT, PC. Not reported. 6 RCTs; n=651. The authors concluded that BTA is probably ineffective for CTTH. AEs not reported. Chronic daily headache Naumann Not described. Not described. Change in headachefree days. 4 RCTs (sample size not specified), all of lower quality. A large number of patients had a diagnosis of transformed migraines. The authors concluded that, based on inconsistent results, there is insufficient evidence to support or refute a benefit of BTA in CDH. AEs=ptosis, weakness of neck, flu-like reaction. Schulte- Mattler Medline (search timeframe not specified). Obermann Medline (search timeframe not specified). RCT, PC. Not reported. 3 RCTs; n=1,117. Primary outcome criteria not met. No serious AEs reported. RCT, PC. Not reported. 3 RCTs; n=1,115. The authors concluded that BTA is probably ineffective for CDH. AEs not reported. Botulinum Toxin A for Headaches 9

10 Reference Search Study Health methods selection outcomes Harm (Botox used in various conditions and not limited to headaches) Naumann Medline, Embase, Cochrane library for the years 1966 to RCT, PC, other active comparators, DB. Number and frequency of AEs and complications. 36 RCTs; n=2,309. (1,425 participants received Botox ). 24.8% (353/1,425) AEs for BTA vs. 15.0% (133/884) for control group (p<0.001). Adjusted, weighted-risk difference=9%. Number-needed-to-harm=11. AEs= focal weakness, pain or reaction at injection site, headache, back pain, neck pain, and ptosis. AEs=adverse events; BTA=botulinum toxin A; CDH=chronic daily headache; CTTH=chronic tension-type headache; DB=double-blind; PC=placebo-controlled; RCT=randomized controlled trial; SR=systematic review; VAS=visual analogue scale Botulinum Toxin A for Headaches 10

11 Table 3: Randomized, placebo-controlled studies* of botulinum toxin A in the management of chronic tension-type headache (one injection session and final evaluation at week-12) Reference Administration (brand, dose, injection site) Schulte-Mattler Dysport U fixed site Padberg Botox U per kg; maximum 100 U follow the pain approach for Silberstein Botox up to 150 U fixed site Number of participants Primary end-points 112 Headache diary used to calculate the area under the headache curve at 6 weeks before and 12 weeks after treatment. 40 Headache intensity on VAS at 12 weeks; mean number of headache days; headache hours per day. 300 Mean change from baseline in the number of headache-free days per month, for 3 months. No statistically significant difference. AE=transient weakness of the eyelids, neck or both. No statistically significant difference. 8 minor AEs in BTA group: pain at injection site, muscle weakness, numbness in the neck, and nausea. Placebo more effective than 150 U (p=0.007). No statistically significant difference for other doses. Straube Dysport 210 U or 420 U fixed site 125 (118 evaluated) Change in the number of headache-free days at weeks after treatment compared to 4 weeks before treatment. AEs were mild and transient and included muscle weakness, neck pain or rigidity, hypertonia, pain or burning at injection site. No statistically significant difference. Significantly more AEs in BTA group at week 12 (p=0.02). AEs=muscle weakness and dysphagia. Botulinum Toxin A for Headaches 11

12 Reference Hamdy Administration (brand, dose, injection site) Botox 2 to 12 U injected into tender points (mean total dose=50 U) fixed site and follow the pain approach Number of participants Primary end-points 28 Number of headache days per month, headache severity assessed by VAS and HDI at 30 and 90 days compared to baseline. Changes from baseline at 90 days: 37.5% reduction in headache days (treatment group) vs % reduction (placebo) p=0.000; 43.68% decrease in headache severity assessed by VAS (treatment group) vs % (placebo) p=0.001; 40.74% decrease in HDI (treatment group) vs. 6.60% (placebo) p= Harden Botox 25 U per trigger points, up to 4 trigger points (maximum dose of 100 U) follow the pain approach for 23 Headache frequency; headache intensity and range of motion at baseline and at 12 weeks. 3 types of AEs reported in BTA group: hematoma at injection site, blepharoptosis, and itching and pain at the site of injection. No statistically significant difference. One mild and transient AE reported in BTA group (head extensor weakness). AEs=adverse events; BTA= botulinum toxin A; HDI=headache disability inventory; U=unit; VAS=visual analog scale * all trials were double-blinded except for a single-blinded study 17 Botulinum Toxin A for Headaches 12

13 Table 4: Randomized, Double-Blind, Placebo-Controlled Studies on Botulinum Toxin A in the Management of Chronic Daily Headache Reference Ondo Dodick Administration (brand, dose, injection site) Botox 200 U single injection session follow the pain approach for Botox every 90 days for 9 months (mean dose=190 U) follow the pain approach for Matthew Botox every 90 days for 9 months (mean dose=190 U) follow the pain approach for Number of Participants Primary end-point 60 Number of headache-free days as assessed by diary for 12 weeks. 228 sub-group analysis of patients not taking concurrent prophylactic medications (see Matthew ) Change from baseline in the frequency of headache-free days per 30-day period. 355 Change from baseline in the frequency of headache-free days in a 30-day period at day 180. No statistically significant difference. AEs were mild with no significant differences between groups (33 AEs with BTA vs. 39 with placebo). One patient in BTA group experienced ptosis. Statistically significant difference in favor BTA (p=0.032 at 6 months and p=0.023 at 9 months). Four patients in the BTA group discontinued study due to AEs. Most frequently reported AEs with BTA=muscle weakness, neck pain, headache, and blepharoptosis. No statistically significant difference. Significantly more AEs in BTA group (76.1% vs. 63.1% in placebo group; p=0.033): muscle weakness, neck pain, blepharoptosis, and skin tightness. Botulinum Toxin A for Headaches 13

14 Reference Administration (brand, dose, injection site) Silberstein Botox U, 150 U or 225 U every 90 days for 9 months fixed site Number of Participants AEs=adverse events; BTA= botulinum toxin A; U=unit Primary end-point 702 Mean change from baseline in the frequency of headache-free days in a 30-day period at day 180. No statistically significant difference. 27 patients in the BTA group withdrew from the study due to AEs. Most frequently reported AEs=muscle weakness, neck pain or rigidity, pain at injection site, hypertonia, headache, shoulder and arm pain, and hypersthesia. Botulinum Toxin A for Headaches 14