Onabotulinumtoxin A ( B otox)

At least 2% of the population suffers from chronic migraine, a disorder that can be very disabling in terms of pain, quality of life, missed workdays, and interruption of usual activities throughout the month. In October 2010, Onabotulinumtoxin A (onabot) brand name Botox (Allergan, Irvine, CA, USA) was approved by the US Food and Drug Administration (FDA) as a preventive strategy for patients having headaches most days of the month, lasting at least 4 hours per day. This approval was based upon 2 randomized, placebo-controlled trials conducted at 122 sites across North America and Europe that demonstrated decreased number of headache days, decreased hours of headache, and improved function with administration of onabot. Chronic migraine, per the latest edition of the International Classification of Headache Disorders (ICHD-3 beta), is defined as headache at least 15 days per month, with a least 8 of those days meeting criteria for migraine, in this pattern for more than 3 months. This means that for at least 8 headache days, light sensitivity and noise sensitivity, or nausea, must be present, and the pain should be moderate to severe in intensity. However, the prescribing information for onabot approved by the FDA did not put all these criteria in place. Instead, chronic migraine, for the purposes of approved use of onabot, is described simply as headache (with any characteristics) at least 15 days per month lasting 4 hours per day. Onabot is not approved, nor has it been proven to work, in individuals with headaches fewer than 15 days per month. Onabot is an injectable protein produced by a bacterium (Clostridium botulinum) that paralyzes muscles into which it is injected. The precise location and quantity of each injection has been tested extensively for safety and effectiveness in treating a wide variety of disorders. Onabot is believed to work for migraine by blocking pain-signaling transmission between the head and neck and the central brain where migraine is generated. Onabot is not a cure for migraine. In fact, in the trials leading to its approval, there were only about 2 fewer headache days per month in those who received it compared with those who received placebo, although the number of hours of headache per month was decreased by about 1/3. However, people who had received onabot in the studies were found to be better able to function and perform their usual activities even when they did have headache. The 2 clinical trials that led to FDA approval used a standardized set of injections called the PHASE III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) protocol. With this protocol, developed and tested extensively, 31 small injections of 5 units each are placed at prescribed locations over the forehead, sides of the head, and back of the head and neck. The injections are just under the skin, creating a small bubble or wheal at the site that is usually not visible beyond a few hours. The PREEMPT injection sites are illustrated in the Figure. The amount of medicine approved by the FDA for chronic migraine prevention, and administered in the PREEMPT protocol, is 155 units. However, onabot only comes in vials of 100 or 200 units. Rather than throw out the remaining 45 units in the bottle, many practitioners will offer to administer the remainder in areas in which patients particularly have pain. This additional treatment strategy is called “follow the pain,” and it was also used by many of the PREEMPT testing sites before FDA approval. Unfortunately, although “follow the pain” injections are frequently administered, it is not fully established whether they provide additional benefit. The PREEMPT protocol for onabot injections is the only FDA-approved injection pattern for chronic migraine, and practitioners are specially trained in its administration. Although