Botulinum toxin for the treatment of headache

PICHON RIVIERE, A.; AUGUSTOVSKI, F.; GARCIA MARTI, S.; GLUJOVSKY, D.; ALCARAZ, A.; LOPEZ, A.; BARDACH, A.; CIAPPONI, A; ROMANO, M

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2012 p. 1 - 27

1668-2793

This paper will evaluate the use of botulinum toxin (BT) in episodic migraine, chronic tension headache and chronic migraine. Episodic migraine (EM) refers to headaches which occur less than 15 times a month for a period of 3 months. An estimated 10 to 15% of Western populations suffer from episodic migraine. This disorder is more common in women by a ratio of 3 to 1, particularly in the age group of 15 to 45 years. The chronic headaches can be chronic migraines (MC) or chronic tension headaches (CTH) which are characterized by feeling pain in more than 15 days a month for three months. Chronic migraine (CM) is a disabling neurological disorder affecting approximately 2% of the general population. Pharmacological agents are used for acute and prophylactic treatment for most types of headache. Beta-blockers, antidepressants, anticonvulsants and calcium channel blockers are used as prophylactic treatment, mainly in those who have 6 to 8 episodes a month. Despite all this available medication in many patients with chronic daily headaches, some headaches are refractory to these treatments and persist up to 20 days per month leading to drug abuse, worsening quality of life and limiting their everyday activities. It is in this group the use of TB as a potential therapeutic agent is recommended. Technology Botulinum toxin type A (BTA) is a neurotoxin that inhibits the calcium-mediated release in presynaptic vesicles of acetylcholine at the neuromuscular junction. The exact mechanism of BTA for antinociception is unknown. The procedure is performed on an outpatient basis. Intramuscular injections are carried out at approximately 35 points around the head and neck. Repeating the treatment after 12 weeks is recommended. The exact number and frequency of injections is unknown and it must agree with each patient\´s needs. The dose used varies but is generally between 100 and 200 IU of TBA. This technology is approved by FDA (October 2010) and ANMAT (April 2011) solely for the treatment of chronic migraine. Objective Evaluate the available evidence about the effectiveness, safety and insurance policy related to the use of TBA in patients with ME. MC, CST. Methods A search was conducted in the major bibliographic databases DARE, NHS EED and generic Internet search engines, as well as health technology assessment agencies and health funders. Priority was given to systematic reviews, randomized controlled trials (RCTs), health and economic technology assessments, clinical practice guidelines and insurance policies of other health systems. Results The results are categorised according to the different types of headache. For episodic migraine we found a meta-analysis and two studies published thereafter, for the CTH we get an RCT and for the CM we get 3 RCT. In relation to episodic migraine we found a meta-analysis carried out in 2009 by Shuhendler that included 8 RCTs, double-blind, placebo-controlled to study the effectiveness of TBA vs placebo, in which 1601 patients were included. Follow-up time of the studies was 90 days. No significant difference was found in the incidence of migraine frequency between the TBA and placebo at 30, 60 and 90 days, with both at 42%. There was no significant difference between the two doses of toxin used (low doses of <100 IU and high doses of > 100 IU). An RCT was published in 2009 which included 127 patients with episodic migraine, comparing the TBA vs placebo. This study aimed to evaluate reduction in the frequency and intensity of migraine episodes. There was a mean reduction of 0.54 and 0.94 attacks/ month, but this was not statistically significant. Another RCT was published by Chankrachang et al. in 2010 which included 128 patients to evaluate the effectiveness of BTA as a prophylactic treatment for migraine vs placebo. No changes were observed in the frequency of migraine episodes. With regard to the CTH , an RCT was published in 2006 which included 300 patients. Again, this showed no statistically significant difference between placebo groups and groups given different doses of TBA in the number of days per month with no headaches. There was a statistically significant difference, but probably clinically irrelevant, in favor of TBA at a dose of 150U for a secondary outcome (4.5 vs 2.8 days without headaches per month, p = 0.007). For the treatment ofCM two RCTs PREEMPT 1 and 2 (n = 679 n = 705) were found, comparing placebo vs. TBA. Both studies lasted 24 weeks with an open stage at 32 weeks. For both studies the primary outcome was the change in frequency of headache episodes. The first study found no significant differences between the placebo group and TBA for the primary outcome (-5.2 episodes/month versus -5.3 episode /month, p = 0.344). Statistically significant differences in secondary outcomes were found (reduction of headache or migraine days per month). These results ranged around -1.5 days of pain per month. The second study (PREEMPT II) showed a decrease in the average frequency of headache days for the TBA group at week 24, -9.0 vs -6.7. For secondary outcomes, reduction in the basal frequency of days with migraine, there was a difference in favour of TBA, -8.7 vs -6.3. In the evaluation of reduction in consumption of specific medication there was a slight decrease for the placebo group. Based on these results (PREEMPT I and II) treatment with TB was approved by the FDA for the treatment of chronic migraine. The third RCT carried out by Magalhaes in 2010 compared the effects of BTA (Botox) vs amitriptyline in the treatment of chronic migraines. They were evaluated for a reduction of at least 50% in the number of pain episodes. No differences were found for any of the outcomes assessed. There is some uniformity between the various health agencies to endorse the use of TBA for chronic migraine, but not for episodic migraine or chronic headache tension. The average dose used in studies for a treatment session is 160 IU (corresponding to two vials). The cost per application is approximately 6,000 pesos (TBA + application fee). 4 applications per year are used. Conclusions TBA has not been proved to be superior to placebo for the prophylaxis treatment of chronic headache tension or episodic migraine. In general, its use is endorsed among patients who meet the criteria for chronic migraine set by the International Headache Society and who have failed or have intolerance of contraindications to other prophylactic agents. It should be noted that the benefit seen in studies in patients with CM , who promoted its adoption by the FDA and the various regulatory agencies was of low magnitude. These benefits include a reduction of -2.3 headache episodes per month compared to a baseline of 12, or in secondary outcomes (reduction in the number of headache days per month) -1.5 with a baseline of 20 days. These results, more than being statistically significant, are clinically irrelevant, implying a significant cost.