Timothy C. Hain, MD Page last modified: March 28, 2013
Botox (Botulinum toxin injections) have recently been FDA approved for prevention of migraine. The mechanism is thought to be a blocking of sensory nerves in the head, not through paralysis of muscles in the head. A recent review of Botox for Migraine, published in JAMA, is that of Jackson et al (2012).
There has recently been a large number of papers supporting the use of Botox for migraine, all referencing the same study called the "PREEMPT" study. The PREEMPT study was funded by the company that sells Botox -- Allergan. Of course, studies funded by groups that have a vested interest in the results should be viewed with skepticism, as investigators may be reluctant to "bite the hand that feeds them". Others have also noted in print that the authors of headache studies often seem to be heavily funded by the manufacturors of the drugs that they are studying, which should lead one to question the headache literature in general, as well as the Botox literature in particular.
We are also unsure why so many authors have published similar articles about the same study and group of subjects. One would think that one paper would be enough. Instead, there has been large cluster of repetitive papers. This is a situation where while there are many papers claiming a benefit, they are all about the same group, an in reality, should be viewed as a single paper.
At any rate, evidence so far suggests that Botox reduces migraines to a small to modest extent, and has few side effects. Placebo injections also reduce migraine, but to a lesser extent, but of course, with less side effects.
Additionally, the cost of Botox is high. It is particularly suitable for persons who cannot tolerate conventional approaches, and persons who have very good insurance or considerable financial resources. Botox is a "boutique" migraine treatment.
Lets look at some papers.
The PREEMPT study, funded by Allergan, is the study that the FDA based its decision to approve Botox for chronic migraine. It was a large study, involving more than 1000 patients. As the retail price of Botox would be roughly $5000/patient, and there are also many other costs, this study must have cost many millions.
The figure above is from Lipton et al (2011). The HIT-6 score is a "headache impact" score, derived from answers to a 6 question survey. Scores ranged from 36 to 78. Lets assume the average was 50. Then, a change in score of about 5 reflects roughly a 10% drop in headache impact. The difference in score between placebo and active treatment was about 2.5, thus advantage over placebo is roughly 5%. We are not against placebo -- improvement is improvement.
Aurora et al (2010), reported that there was no difference between the number of migraines in treated patients vs placebo, but there was reduction in intensity and duration. Diener et al, 2010 also supported use of this Botox for chronic migraine. Lipton et al (2011), again reporting PREEMPT data, concluded that treatment with Botox is associated with significant and clinically meaningful reductions in headache impact. Of course, a significant reduction may not be very large, when one is studying 1000+ patients, as with larger numbers of patients, smaller changes can be detected as significant.
Delstanche et al (2010) felt that the PREEMPT trial showed only a modest gain (about 11%) over placebo. Evidently Delstanche went through a similar analysis as above.
Cody and Schreiber (2011) and Mathew et al (2009), similarly reported that Botox was equivalent to another anticonvulsant migraine prophylactic (topiramate -- Topamax), but again has fewer side effects. Jackson et al (2012), in a metanalysis reported that Botox is no better than valproate, topamax, or amitriptyline. Of course, this does not say that it is worse either. Topiramate is a moderately effective treatment for migraine prevention. We find it hard to see how Botox, with a small to modest effect, could be as effective as valproate, topiramate or amitriptyline, which all are associated with about 50% reduction in headache impact. In other words, we think that the studies suggesting Botox has a 50% improvement (e.g. topiramate) rather than a 10% improvement, were flawed.
Farinelli et al (2006) reported that best results are found after 12 full months of treatment. Oterino et al (2011) found ER visits went from an average of 3 to 0.4 per "trimester" (?). This is impressive.
We would be interested in seeing a study that compares some other method of numbing up the head (perhaps a sunburn treatment incorporating a local anesthetic), applied every day, to Botox. We would predict that there might be similar effectiveness to Botox.
We would also be interested in seeing a study that looked at combinations of other migraine prevention medications -- such as venlafaxine, with Botox. One would think that their effect would be at least additive. Contrary to this general idea, a recent trial in which topiramate and inderal were combined for chronic migraine, was stopped because of lack of evidence that there was any benefit (Silberstein et al, 2012). Of course, this does not mean that the combination is also ineffective in episodic migraine, which comprises about 97% of all migraine. Also, note that this combination competes with an extremely expensive treatment for chronic migraine, Botox. In our opinion, it still is prudent to exhaust inexpensive combinations for chronic migraine, before turning to Botox.
Botox is probably useful for episodic migraine, although not everyone agrees (e.g. Schurks et al, 2008; Relja et al, 2007; Jackson et al, 2012). As Botox works for a more severe chronic migraine, it should also work for episodic migraine. It would also seem likely that lower doses of Botox might work in the less severe episodic migraine.
Botox is also reported useful for occipital neuralgia (Taylor et al, 2008). We find this conclusion a bit dubious as we would not expect that a weak agent like Botox would be able to do much for a very noxious pain such as occipital neuralgia.
Practically, most insurances will not pay for Botox for episodic migraine, and the cost of the drug is very high. This makes it a drug most useful for persons with episodic migraine who have considerable financial means.
The cost of Botox treatment for migraine is very high due to the very high cost of the drug (distributed by Allergan). In the US, Botox is covered under some insurance policies, including Medicare, for chronic migraine. To qualify requires good documentation of more than 50% "duty cycle" for migraine. Oddly enough, continued approval of Botox for migraine usually requires reduction in headache days -- which the PREEMPT study suggested doesn't happen - -what is reduced is headache impact, not days.
Botox, as used as suggested by the PREEMPT study, is expensive. The recommended dose is 155 units of Botox. The final cost will depend on insurance and the amount of Botox used for the procedure. +
The diagnosis code for Chronic Migraine is 346.70. Botox is billed under the code 64612 or 64613, and there is also a J-code, J0585.
Use of Botox is fraught with financial peril for Neurology doctor's offices because of the games medical insurance companies play. This outside link talks about this in more detail.
Botox is extremely expensive, and if insurance does not reimburse for the drug, the office gets "stiffed" for a very large bill. Additionally, some insurances "approve" the drug, but then pay the bill in a very delayed fashion (i.e. we hope they eventually pay for the drug). By delayed, I mean more than a year. For this reason, it is best to only treat patients whose insurance uses "specialty pharmacies", that ship the drug to the office. This eliminates the risk of insurance not paying for the drug.
Additionally, some insurances such as Medicare don't use specialty pharmacies and also do not fully pay for the drug itself. For some reason, Medicare's fee schedule does not cover the drug itself. Thus, the Medicare payment schedule has been adjusted so that the entire process is a loss for the practice, when one includes the cost of the doctor's time, staff time, equipment cost, rent ... In other words, Medicare has "gamed" the system so that it "covers" Botox for migraine, but have managed to make "coverage" mean something other than pay for the treatment.
We have observed several of our migraine patients who have paid out of pocket to have a less expensive Botox treatment done by their dermatologists. The cost of this treatment, in the US, is generally about $400. We call this "Botox lite". We have not formally collected data, or compared it to to more expensive Botox procedures, but it seems to us from anecdotal reports that the Botox lite procedure is helpful for migraine. The data referenced above would also support the general idea that Botox reduces migraine severity. We do not know of any studies that have looked at the added benefit of injections in the neck and back of head (generally not favored by dermatologists), compared to the front and side. According to Jackson et al (2012), there "does not appear to be a difference in outcomes when .. injected in a fixed schedule, when certain muscle groups are injected, or when toxin is injected using a follow the pain protocol. In other words, the large dose PREEMPT protocol results are no better than the lower dose "follow the pain" protocols.
The main benefit of making the effort to qualify for the insurance route, to us, seems to be that more Botox is used. Typically about 150 units of Botox are used for a "migraine protocol" Botox, while only 30-40 units are used for the "Botox lite" procedure.
For the PREEMPT protocol, with a tiny needle, the doctor makes 10 to 30 injections of a very small amount of liquid (0.1 cc). The injections are done just under the skin, in forehead, temples and back of neck. The total amount of injection, about 150 units, is less than used for many other conditions. The procedure takes about 30 minutes (1 hour for first time).
For the "follow the pain" protocol (Botox Lite), a smaller number of injections are given where the headache pain commonly occurs.
Side effects are common but rarely significant. Some people have mild drooping of one eyelid for several weeks. There may be some flattening of the skin around the injection site (this is why Botox works for wrinkles in plastic surgery). There is just no risk at all of total body paralysis or an effect on lung function.
Rare cases have been reported of an allergic reaction to Botox.
One can resume normal activities immediately after the injection. There is no tiredness.
The headaches should lessen in frequency and severity over one to two weeks, with the effect lasting up to 4 months. The success rate can be as high as 65% in certain populations. In general though, for all comers, there is a small to modest effect. The procedure can be repeated every 3 to 4 months. If the first trial does not help, it may be worthwhile to repeat it.
Botox seems to work by reducing pain transmission locally. Somewhat like a 3 month local anesthetic.
Bohluli et al (2011), reported that Botox works for trigeminal neuralgia. We find this surprising as it is hard to see how a local agent could reduce pain due to increased excitability in the trigeminal ganglion, as well as work for the extremely severe pain of trigeminal neuralgia. In our practice, we do not use Botox for trigeminal neuralgia. Gazerani et al (2006), found that Botox reduces the pain from locally applied capsaicin (hot pepper) as early as one week. This makes sense to us.
Perhaps Botox is similar to a "semi-permanent acupuncture". In other words, we suspect that acupuncture for migraine and Botox work through similar mechanisms, but that acupuncture has a more substantial medication/counseling/placebo component than Botox. Of course, the effect of most types of acupuncture is temporary, while the effect of Botox lasts for roughly 3 months.
The author's clinical practice, Chicago Dizziness and Hearing, offers Botox treatment for chronic migraine headache, that has failed to respond to a vigorous trial of conventional medications. It is generally available through neurology practices that treat migraine.
Dr. Hain, the author of this article, has eaten lunch on several occasions paid for by Allergan. Additionally, Dr. Hain and his partner, were trained by Allergan in the technique of treating migraine with Botox. Dr. Hain is not on the Allergan speaker's bureau, and he has never been paid by Allergan to write or speak about his opinions on Botox.
Aurora, S. K., D. W. Dodick, et al. (2010). "OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial." Cephalalgia : an international journal of headache 30(7): 793-803.
Aurora, S. K., M. Gawel, et al. (2007). "Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study." Headache 47(4): 486-499.
Bohluli, B., M. H. Motamedi, et al. (2011). "Use of botulinum toxin A for drug-refractory trigeminal neuralgia: preliminary report." Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 111(1): 47-50.
Cady, R. and C. Schreiber (2008). "Botulinum toxin type A as migraine preventive treatment in patients previously failing oral prophylactic treatment due to compliance issues." Headache 48(6): 900-913.
Cady, R. K., C. P. Schreiber, et al. (2011). "A multi-center double-blind pilot comparison of onabotulinumtoxinA and topiramate for the prophylactic treatment of chronic migraine." Headache 51(1): 21-32.
Diener, H. C., D. W. Dodick, et al. (2010). "OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial." Cephalalgia : an international journal of headache 30(7): 804-814.
Dodick, D. W., C. C. Turkel, et al. (2010). "OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program." Headache 50(6): 921-936.
Elkind, A. H., P. O'Carroll, et al. (2006). "A series of three sequential, randomized, controlled studies of repeated treatments with botulinum toxin type A for migraine prophylaxis." The journal of pain : official journal of the American Pain Society 7(10): 688-696.
Farinelli, I., G. Coloprisco, et al. (2006). "Long-term benefits of botulinum toxin type A (BOTOX) in chronic daily headache: a five-year long experience." The journal of headache and pain 7(6): 407-412.
Gazerani, P., C. Staahl, et al. (2006). "The effects of Botulinum Toxin type A on capsaicin-evoked pain, flare, and secondary hyperalgesia in an experimental human model of trigeminal sensitization." Pain 122(3): 315-325.
Mathew, N. T. and S. F. Jaffri (2009). "A double-blind comparison of onabotulinumtoxina (BOTOX) and topiramate (TOPAMAX) for the prophylactic treatment of chronic migraine: a pilot study." Headache 49(10): 1466-1478.
Relja, M., A. C. Poole, et al. (2007). "A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches." Cephalalgia : an international journal of headache 27(6): 492-503.
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