Introduction
Chronic daily headache comprises a heterogeneous group of disorders. Approximately 4 per cent of the population worldwide experience daily or near-daily headaches.Reference Dodick, Mauskop, Elkind, DeGryse, Brin and Silberstein1, Reference Pakalnis and Couch2 Headaches that occur more than 15 days per month and are unrelated to structural or systemic illness constitute chronic daily headache. Chronic daily headache is the most common problem seen in tertiary headache centres, and is associated with considerable disability.Reference Dodick, Mauskop, Elkind, DeGryse, Brin and Silberstein1, Reference Mathew, Frishberg, Gawel, Dimitrova, Gibson and Turkel3, Reference Silberstein, Stark, Lucas, Christie and DeGryse4 The term encompasses chronic migraine, chronic tension-type headache, new daily persistent headache, medication overuse headache and hemicrania continua. Chronic migraine is the most prevalent form of chronic daily headache.Reference Dodick, Mauskop, Elkind, DeGryse, Brin and Silberstein1, Reference Mathew, Frishberg, Gawel, Dimitrova, Gibson and Turkel3, Reference Silberstein, Stark, Lucas, Christie and DeGryse4 Prophylactic treatment for patients with chronic daily headache may consist of beta blockers, calcium channel blockers, serotonin antagonists, antidepressants, non-steroidal anti-inflammatory drugs or anti-epileptic drugs. However, no drug has proven ideal, due to inadequate efficacy and intolerable side effects.Reference Mathew, Frishberg, Gawel, Dimitrova, Gibson and Turkel3
Another common form of chronic daily headache is chronic tension-type headache. Population-based studies suggest a one-year prevalence of this disorder of 2.2 per cent.Reference Schwartz, Stewart, Simon and Lipton5, Reference Padberg, De Bruijn, De Haan and Tavy6 The precise pathogenesis is unknown. The most important clinical finding is increased tenderness of pericranial tissues upon palpation.Reference Rollnik, Tanneberger, Schubert, Schneider and Dengler7
According to the International Classification of Headache Disorders, 2nd edition (ICHD-II) classification of the International Headache Society, chronic tension-type headache is characterised by bilateral location, a pressing or tightening quality, and moderate intensity, and is not aggravated by routine physical activity.8 In clinical practice, a diagnosis of chronic tension-type headache is often made when patients do not meet the criteria for migraine, cluster headache or other well defined primary headache syndromes. Chronic tension-type headache patients tend to have a mixture of headache syndromes, a history of analgesic abuse and coexisting depression. The clinical and societal impact of tension-type headache is immense.Reference Rollnik, Tanneberger, Schubert, Schneider and Dengler7
Tension-type headache can be treated with simple analgesics, antidepressant drugs or physiotherapy. Although some patients might be treated effectively, a large proportion presents an ongoing challenge. Effective and tolerable treatments are clearly needed for both chronic daily headache and chronic tension-type headache.Reference Mathew, Frishberg, Gawel, Dimitrova, Gibson and Turkel3, Reference Padberg, De Bruijn, De Haan and Tavy6, Reference Binder, Brin, Blitzer, Schoenrock and Pogoda9 As stated for migraine, the goals of long-term treatment include reducing the frequency and/or severity of headaches, decreasing the use of pharmacotherapies, minimising the risk of exacerbation of headache, and reducing the potential for medication overuse.Reference Silberstein, Stark, Lucas, Christie and DeGryse4, Reference Barrientos and Chana10
Several therapeutic studies have investigated botulinum toxin type A as a treatment option for chronic daily headache.Reference Dodick, Mauskop, Elkind, DeGryse, Brin and Silberstein1, Reference Mathew, Frishberg, Gawel, Dimitrova, Gibson and Turkel3, Reference Silberstein, Stark, Lucas, Christie and DeGryse4, Reference Padberg, De Bruijn, De Haan and Tavy6, Reference Binder, Brin, Blitzer, Schoenrock and Pogoda9–Reference Bearden and Anderson14, Reference Dirnberger and Becker16–Reference Guyuron, Kriegler, Davis and Amini18 Botulinum toxin A is a focally administered neurotoxin which inhibits the release of acetylcholine at the neuromuscular junction. It is used therapeutically in disorders characterised by muscle hyperactivity.Reference Mathew, Frishberg, Gawel, Dimitrova, Gibson and Turkel3 The aforementioned studies have reported varying rates of success, depending on the injection site and the dose administered. While the results of open label studies have generally been positive,Reference Binder, Brin, Blitzer, Schoenrock and Pogoda9, Reference Eross, Gladstone, Lewis, Rogers and Dodick12 those of double-blind, placebo-controlled trials have not.Reference Padberg, De Bruijn, De Haan and Tavy6, Reference Rollnik, Tanneberger, Schubert, Schneider and Dengler7, Reference Schulte-Mattler and Krack11 There may be a small subset of patients who might benefit from this therapy, but presently we have no reliable means of identifying these individuals.Reference Pakalnis and Couch2, Reference Roach15
In the past, we have obtained good short-term relief of chronic daily headache, lasting from several hours to several days, after administering a local anaesthetic nerve block to the supratrochlear nerve. Based on that experience and on the good results of other authors with resection of the corrugator supercilii muscle, we decided to investigate the effect of botulinum toxin, before deciding whether to resect this muscle.Reference Dirnberger and Becker16, Reference Bearden and Anderson17, Reference Guyuron, Varghai, Michelow, Thomas and Davis19, Reference Guyuron, Tucker and Davis20
Methods
All consecutive out-patients at our department with bilateral, frontally localised, daily headache, whose pain worsened with pressure on the orbital rim near the supratrochlearis nerve, were offered a local anaesthetic nerve block with Xylocaine at the orbital rim bilaterally. Patients were asked to grade their pain (verbally and non-independently) on a scale of zero (i.e. no pain) to 10 (i.e. severe pain) before and a few minutes after local anaesthetic injection by the first author (JAdR). If this injection stopped or reduced the pain (by at least half), patients were then offered an injection of botulinum toxin in the corrugator supercilii muscle.
All patients were classified as having chronic daily headache (including medication overuse headache); some cases were also classifiable as chronic tension-type headache according to ICHD criteria. No exclusion criteria were set. Patients were enrolled from May 2006 to November 2007; however, this was not a pre-planned period.
Intervention
Before botulinum toxin injection, each patient received a local nerve block with Xylocaine 2 per cent plus adrenaline 1:80 000 (Xylocaine; Dentsply Pharmaceutical, York, PA, USA), using a 27 gauge needle to ensure a pain-free injection. Botulinum toxin A was then injected into the corrugator supercilii muscle on each side, using a 25 gauge needle, in five steps of 0.1 ml, adding up to a total of 25 IU botulinum toxin A in 1 ml of NaCl 0.9 solution. This took about five minutes. Patients visited our out-patient clinic two months after the treatment to discuss the results.
Our ‘pilot’ patient received 20 IU (one side) at his initial treatment. The effect was good but lasted only about six weeks; therefore, we tried 40 IU (one side) at the next treatment. Because of severe eyebrow drooping, we reverted to the lower dose cited above for subsequent patients. Although this patient's eyebrow drooped for a month, his pain disappeared. One year later, he was still free of pain.
All other patients had bilateral pain and were injected bilaterally. We found no signs of sinus disease or other pathology as causes for patients' pain.
Patients
Our first patient was a 38-year-old woman. This patient had undergone nasal surgery five times because of congenital deformation and breathing difficulties. Her headache had commenced after the fourth operation. She had been treated with paracetamol, ibuprofen and pregabaline without significant improvement. Xylocaine injection lowered the pain score from eight to one. After botulinum toxin injection, the pain had an intensity of two for over two months. Interestingly, the remaining pain was localised at the site of the external nasal branch of the nasociliary nerve, not at the injection site. The patient requested re-treatment.
Our second patient was a 40-year-old woman. After four years of pain, she had undergone three courses of sinus, nasal septum and conchal surgery. The patient was allergic to pollen and dogs. Paracetamol and non-steroidal anti-inflammatory drugs had not improved her complaints. Xylocaine block and subsequent botulinum treatment lowered her pain score from seven to zero for two months.
Our third patient was a 55-year-old man. This patient had a long-term history of obstructive sleep apnoea syndrome and chronic obstructive pulmonary disease, and had undergone sinus surgery two times. He had been treated with bupivacaine and clonidine at the out-patient clinic of our anaesthetist's pain department. He was taking paracetamol, gabapentine and tramadol daily. After local Xylocaine injection, he was completely free of pain. After botulinum toxin injection, his pain score dropped from six to two, and he did not take any medication for two months. After his initial treatment, he asked for a second botulinum injection.
Our fourth patient was an 18-year-old man with a medical history of allergic disease who scored his pain as nine. He had taken sumatriptan and rizatriptan without any benefit. The patient had been missing some college classes every week because of his headache. Xylocaine injection made the pain disappear immediately; botulinum toxin injection brought relief for 10 weeks. After that period, the patient asked for a second treatment. Again, his pain score dropped (now from eight) to zero. The effect of another 25 IU lasted nine weeks. After this treatment, the patient requested a third injection, and was scheduled for resection of the corrugator supercilii muscle, using an endoscopic browlift procedure. At first follow up after surgery, he was pain-free.
Our fifth patient was a 43-year-old man. He had suffered nearly daily headache with a score of at least six if he did not use any medication, worsening during sports. He had been taking at least 1000 mg paracetamol every day. The patient was used to lifting heavy objects at work, where he installed heating systems. His frontally localised headache worsened on weekends when he had his first cup of coffee and paracetamol later than usual. He had a positive family history for migraine. At the time of his first injection, his pain scored only four (with paracetamol) but dropped to zero with Xylocaine. Botulinum toxin injection provided long-lasting relief. At follow up, the patient was taking only one 500 mg paracetamol dose every two weeks, and said no further treatment was needed.
Our sixth patient was a 45-year-old woman. She had a history of acromegaly and had recently undergone hypophysectomy. She had been taking 6000 mg paracetamol daily without benefit. Local anaesthetic immediately relieved the pain. Botulinum toxin provided relief for six weeks, with the pain score dropping from seven to two without paracetamol. The patient asked for a second treatment.
Our seventh patient was an 18-year-old woman whose recent history included endonasal frontal sinus surgery. She had previously undergone conchal surgery and antrostomy by the Claoué procedure. Her pain could be induced by exercise. Her nearly daily headache had a score of seven. She had been taking 2000 mg of paracetamol daily. Xylocaine reduced the pain immediately. After injection of botulinum toxin, the patient was pain-free on most days for about two months, although she still had migraine attacks every two weeks. At follow up, she requested a second treatment. The second treatment was also beneficial for about two months, after which time she asked for re-treatment. At the time of writing, she was to be scheduled for resection of the corrugator muscle.
Our eighth patient was a 46-year-old woman with a history of nasal surgery (of various types; seven operations in total). She had also undergone cataract surgery and suffered from chronic obstructive pulmonary disease. Her daily headache pain score dropped from seven to zero on local Xylocaine infiltration. Botulinum toxin relieved the pain for about six weeks. She asked for a second treatment, which helped for four weeks but only lowered the pain score to four. Nonetheless, because of the beneficial effect of the initial treatment, she requested another treatment. This third treatment, with 30 IU, provided full relief for three months. The patient was offered corrugator resection but refused, preferring a fourth injection of botulinum toxin.
Our ninth patient was a 28-year-old woman. She had a history of sinus surgery (three procedures), including an external approach to the frontal sinus on the left side. She had also undergone orbital decompression for Graves orbitopathy. Following Xylocaine injection, her daily pain score dropped from seven to zero on both sides. Unfortunately, the botulinum toxin injection brought relief only on the right side. The remaining left-sided pain may have been caused by iatrogenic neuropathy following sinus surgery. The patient asked for re-treatment after two months.
Our 10th patient was a 40-year-old woman with a history of chronic allergic sinusitis. She had suffered daily headache, frontally and on the left cheek. After local anaesthetic infiltration near the supratrochlearis and infraorbitalis nerves, her pain disappeared completely. Botulinum toxin injection gave two months of relief from the frontally localised pain. At the time of writing, we planned to treat the remaining, mild pain near the infraorbital region with amitriptyline. At follow up, the patient asked for a second treatment.
Results
Fourteen consecutive patients underwent Xylocaine infiltration, which immediately reduced their pain scores to two or less. Three of these fourteen patients refused treatment with botulinum toxin. (One patient did not believe it would be effective and asked for revision surgery of his polyposis nasi; in the other two, the Xylocaine injection was so effective that further treatment was unnecessary.)
The other 11 patients wanted to try botulinum toxin injection. All reported reduction of pain lasting about two months, during which time most (n = 7) were pain-free, and those who were not had a maximum pain score of two. Patients' mean pain scores were 7.1 (range six to nine) before botulinum toxin injection and 0.6 (range zero to two) afterwards. This low pain score lasted the whole period (as mentioned above) for every patient.
One patient received only one-sided relief; the remaining pain on the other side may have been due to neuropathy following an external approach to the frontal sinus on the still painful side. One patient who was pain-free in the frontal region still had pre-existing migraine attacks. Another frontally pain-free patient had pain localised in the region of the infraorbital nerve.
Although patients were allowed to continue taking their medications after botulinum toxin treatment, the amount taken was drastically reduced.
Adverse events
Two patients reported drooping of the eyebrow. This adverse effect was transient.
Discussion
Our study was not a double-blind trial, so the effect of botulinum toxin treatment may have been influenced by many biases. However, the effect of botulinum toxin A on nearby skin wrinkles makes it impossible to conduct a truly blinded study.Reference Roach15 A high placebo response is an established confounder in evaluating the treatment of painful conditions.Reference Padberg, De Bruijn, De Haan and Tavy6, Reference Schwedt, Hentz and Dodick21 Moreover, some authors state that botulinum toxin A is an unproven and expensive treatment which potentially may have negative side effects.Reference Evers and Olesen22 However, the results of our study were overwhelmingly favourable. Even if the benefits were due to a placebo effect, the treatment would still be worthwhile. In our study, all consecutive patients experienced pain reduction in the frontal region for nearly two months, and all opted for re-treatment as soon as pain returned.
The literature includes some placebo-controlled, double-blind trials conducted to evaluate the effectiveness of headache treatment with botulinum toxin A. Most authors conclude that botulinum toxin A is not highly effective, or not effective at all.Reference Pakalnis and Couch2, Reference Roach15 However, these trials mix headache types and/or injection sites and doses.Reference Mathew, Frishberg, Gawel, Dimitrova, Gibson and Turkel3, Reference Silberstein, Stark, Lucas, Christie and DeGryse4, Reference Padberg, De Bruijn, De Haan and Tavy6, Reference Rollnik, Tanneberger, Schubert, Schneider and Dengler7, Reference Schmitt, Slowey, Fravi, Weber and Burgunder23 Furthermore, these studies do not mention the corrugator supercilii muscle as a specific site. Most importantly, there is no convincing rationale for this therapy.Reference Roach15 Some authors do consider the effects of botulinum toxin A injection into the corrugator muscle and of resection of this muscle, but mainly for the treatment of migraine.Reference Dirnberger and Becker16, Reference Bearden and Anderson17, Reference Guyuron, Kriegler, Davis and Amini18, Reference Guyuron, Tucker and Davis20, Reference Behmand, Tucker and Guyuron24, Reference Smuts, Schultz and Barnard25
The observation that patients with migraine exhibit considerable hypertrophy of the corrugator muscles has already been mentioned, and it has been postulated that the trigeminal nerves are stimulated by strong contraction of the corrugators.Reference Smuts, Schultz and Barnard25 The supraorbital region has been mentioned as a trigger point for migraine.Reference Mosser, Guyuron, Janis and Rohrich26 It has been proposed that the nerves are stimulated by strong contraction of the corrugator supercilii.Reference Guyuron, Tucker and Davis20
Our results contribute to the discussion on the effectiveness of treating headache with botulinum toxin A. We believe it is important to discriminate between the types of pain treated. Only then will it be possible to differentiate the types of headache that can effectively be treated from those that cannot.
If this treatment is indeed as effective as we claim, this begs the question of why. Botulinum toxin A does not have a known positive effect on sensory nerve fibres. However, some suggest that it inhibits the release of nociceptive mediators.Reference Mathew, Frishberg, Gawel, Dimitrova, Gibson and Turkel3 To explain its effect, we would need to review the prevailing theories and then refine our hypothesis.
It has been postulated that increased pericranial tenderness may be due to an increased sensitivity in either the peripheral or the central nervous system. This theory states that the muscle pain is produced mainly by noxious stimuli which lead to increased synthesis and release of endogenous algogenic substances such as serotonin, bradykinin, histamine and prostaglandins. The liberation of algogenic substances would lower tissue pH and then activate the arachidonic acid cascade, producing a number of unsaturated lipid products. Next, sensitisation of nociceptors would cause spontaneous neuronal discharge. This process would lower the threshold for stimuli that normally provoke pain, and cause increased neuronal firing in response to stimuli not ordinarily perceived as painful. Central sensitisation can be generated by prolonged nociceptive inputs from the periphery.Reference Fernández de las Peñas, Cuadrado, Arendt Nielsen, Simons and Pareja27, Reference Bendtsen28
Trigger points are primary hyperalgesic zones (the hypersensitive spot is a taut band in a skeletal muscle, with both local and referred pain). They are responsible for the development of central sensitisation.Reference Fernández de las Peñas, Cuadrado, Arendt Nielsen, Simons and Pareja27 So-called ‘tenderpoints’ have increased tenderness, with local but not referred pain.Reference Fernández de las Peñas, Cuadrado, Arendt Nielsen, Simons and Pareja27 In all our patients, pain could be provoked by exerting pressure on the orbital rim at the site of the supratrochlear nerve. However, according to the above two definitions, we believe this site to be neither a trigger point nor a tenderpoint. We reason as follows: there were no taut bands; the corrugator supercilii muscle is a mimic and not a skeletal muscle; and the patients did not recognise this point as the primary hyperalgesic zone, but felt pain or tenderness in the entire frontal region. Nonetheless, we still prefer to speak of a trigger point for the pain.
The most credible aetiological suggestion regarding trigger points is the hypothesis that abnormal depolarisation of motor endplates and sustained muscular contraction give rise to a localised ‘adenosine triphosphate energy crisis’.Reference McPartland and Simons29 According to a recent systematic review, current evidence does not support the use of botulinum toxin A injection at trigger points for myofascial pain.Reference Ho and Tan30
• This small case study investigated the use of botulinum toxin A injection for localised frontal pain
• The authors speculate that such pain may be due to entrapment of the supratrochlear nerve in the corrugator supercilii muscle
• Xylocaine injection appeared to be a very good predictor of the effectiveness of botulinum toxin injection into the corrugator supercilii muscle, as treatment of frontally localised chronic tension-type headache and chronic daily headache
• The authors note the difficulty of conducting a randomised, placebo-controlled study to assess the effects of botulinum toxin
We suggest that this type of pain is caused by entrapment of the supratrochlear nerve in the corrugator supercilii muscle. Fibres of the nerve are known to course through this muscle.Reference Guyuron, Tucker and Davis20, Reference Smuts, Schultz and Barnard25, Reference Muehlberger, Fisher and Lehnhardt31 This might also explain the effect of our therapy. Contraction of the muscle (leading to aggravation of the pain during exercise, as experienced by three patients) would cause more pain to develop. Decreased contractility following botulinum toxin A would lower the pain. Atrophy of the muscle, mentioned as a negative side effect, would thus not always be a negative effect according to this hypothesis.Reference Evers and Olesen22 On the contrary, it might explain the long-term effect of the second treatment in our pilot patient. We suggest that a reduction in afferent sensory activity from this nerve when entrapment is halted may represent the potential mechanism by which botulinum toxin injection exerts its therapeutic effect.
Our study group consisted of patients referred to our department. According to their former physicians or ENT surgeons, they were referred for sinus headache. Seven out of 11 patients (including the pilot patient) had been operated upon before receiving botulinum toxin A. Two patients had been operated upon for other medical problems. This raises the question of whether (iatrogenic) injury or neuropathy after infection might play a role in the pathogenesis of chronic daily headache or chronic tension-type headache. However, it might also indicate that a primarily incorrect diagnosis was often established in these patients, since most were probably operated upon because of their headache.
Furthermore, this study shows that a local anaesthetic block can be very helpful when deciding whether or not to use botulinum toxin A injection. We would advise performing such anaesthesia, on the grounds of our experience. In our small study group, such an injection seemed to be an effective outcome predictor. The effect of botulinum toxin A, in turn, might be helpful in predicting which patients could benefit from surgical excision or transection. Excision of the corrugator supercilii muscle has been proven effective in the treatment of tension-type headaches and possibly also migraine.Reference Dirnberger and Becker16, Reference Bearden and Anderson17, Reference Guyuron, Varghai, Michelow, Thomas and Davis19, Reference Guyuron, Tucker and Davis20
If its effectiveness can be demonstrated, botulinum toxin A injection would be a valuable treatment option for headache sufferers. A medication that has few adverse systemic effects, a long duration of action and the benefit of anti-ageing cosmetic effects would be a popular therapeutic option.Reference Pakalnis and Couch2 The promising results in our carefully selected patient group suggest that there might be a large population which could benefit from this therapy, if selection procedures were followed correctly. The adverse effects observed in our study, and in the published literature, were mild to moderate.Reference Dodick, Mauskop, Elkind, DeGryse, Brin and Silberstein1, Reference Ashkenazi and Silberstein13, Reference Dutton and Fowler32 Therefore, no contraindication to the use of botulinum toxin in such patients seems to exist at present. The use of botulinum toxin could potentially offset substantial costs in terms of healthcare and lost labour.Reference Barrientos and Chana10
Conclusion
Xylocaine injection seems to be a very good predictor of the effectiveness of botulinum toxin A injection into the corrugator supercilii muscle as treatment of frontally localised chronic daily headache and frontally localised chronic tension-type headache. We hypothesise that this pain is caused by neuronal entrapment of the supratrochlearis nerve in this muscle. Furthermore, we found botulinum toxin to be a safe and very effective treatment allowing pain relief in this patient group.
