Management of Trigeminal Autonomic Cephalalgias in Children and Adolescents
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- Lambru, G. & Matharu, M. Curr Pain Headache Rep (2013) 17: 323. doi:10.1007/s11916-013-0323-1
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Primary headache disorders that are more frequently encountered in the paediatric population include migraine and tension-type headaches. The trigeminal autonomic cephalalgias (TACs), which includes cluster headache (CH), paroxysmal hemicrania (PH) and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), are rarely reported in the paediatric population. The 1-year prevalence of CH seems to be 0.03 %. The clinical features of childhood and adolescence onset CH seem to be similar to those of adult onset. Cranial autonomic features and restlessness seem to less prominent in children than in adults. When restlessness is present, it often manifests as thrashing around in children and can distract attention from the headache, thereby contributing to a delay in diagnosis. The frequency of cluster periods seems to be lower in childhood. Similarly, the duration of the single cluster period seems to be shorter. The temporal pattern shows a trend towards a gradual increase of frequency and duration of symptoms in adult life. In terms of management of paediatric CH, oxygen has been used successfully in several paediatric CH patients, and given its good side-effect profile, it is considered the abortive agent of choice for paediatric CH. Verapamil is the preventative drug of choice in both episodic and chronic CH, though paediatric patients should be started on lower doses and titrated according to age. Paediatric-onset PH and SUNCT are very rarely reported. The clinical phenotype and response to treatment seem to resemble the adult-onset form. Paediatric-onset TACs are poorly recognized and there is often a delay of several months or years before the diagnosis is made. Awareness of typical clinical pictures of these excruciating headaches is essential to allow prompt initiation of the appropriate management.
KeywordsChildhood onset headacheCluster headacheParoxysmal hemicraniaSUNCTPaediatric headacheTrigeminal autonomic cephalalgias
The trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders characterized by unilateral head pain that occurs in association with prominent ipsilateral cranial autonomic features. The TACs include cluster headache (CH), paroxysmal hemicrania (PH) and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). CH, PH and SUNCT are currently grouped into section 3 of the revised International Classification of Headache Disorders (ICHD-II).
The TACs are relatively rare in the adult population and are considered to be even more rare in the pediatric population. Childhood and adolescent onset TACs resemble the adult forms of the disorders with regard to the characteristics of the pain, the associated symptoms and response to treatments. Nonetheless, pediatric-onset TACs are poorly recognized and there is often a delay of several years before the diagnosis is made.
While the TACs can be recognized by distinctive short-lasting headaches with autonomic features, they differ in attack duration and frequency. The differentiation between the TACs is essential, since the treatments are very different. These syndromes are considered to be some of the most painful known to humankind, thereby underlining the importance of early recognition and initiation of the excellent but highly selective treatments.
CH is a strictly unilateral headache that occurs in association with cranial autonomic features and, in most patients, has a striking circannual and circadian periodicity. It is an excruciating syndrome, with female patients describing each attack as being worse than childbirth.
The prevalence of adult CH is estimated to be 0.1 % . CH can begin at any age, though the most common age of onset is the third or fourth decade of life. The first publications about cluster headache in childhood were in the early 1970s [2, 3]. In 1981, an interesting description of cluster headache symptoms in an infant was reported . At the beginning of the attack, the infant became irritable and unmanageable, touching and rubbing his forehead at the region of his right eye. The eye then began watering; the right eye demonstrated ptosis, and the skin in the region involved with pain was warm to the touch. The infant had one to two attacks daily, almost all of them occurring in the daytime, with spontaneous remission lasting no more than three days. When the child was three years of age, the attacks ceased spontaneously.
The onset of CH in the paediatric population is well reported, though the prevalence seems to be relatively low. A multicentre paediatric study in 27 Italian headache centres on 6,629 headache patients less than 18 years of age reported the 1-year prevalence of CH to be 0.03 % .
Childhood-onset CH shows a male preponderance with a ratio of 2.5:1 [6•], similar to that observed in the adult population . The mean age of onset of CH in childhood and adolescence is 11–14 years, with a wide range of 3–18 years .
Genetic factors appear to be involved in the same proportion of the paediatric population as in the adult population. In a recent review [6•], a positive family history for CH has been found in approximately 10 % of pediatric CH cases, whereas a positive family history for migraine was found in 25 %.
The Cluster Attack
Cluster attacks are strictly unilateral, though the headache may alternate sides. It is centred around the orbital and temporal regions, though any part of the head can be affected. The pain is excruciatingly severe. The headache can range from 15 minutes to 3 hours. The signature feature of CH is the association with cranial autonomic symptoms . The autonomic features are transient, lasting only for the duration of the attack, with the exception of partial Horner’s syndrome.
The clinical features of childhood and adolescence onset CH attack seem to be similar to those of adult onset CH. Maytal et al. reviewed the phenotype of 35 paediatric-onset CH patients. Pain was felt in and around the eye in 31 patients (88 %). It commonly radiated to the temple (43 %), to the ipsilateral maxilla (40 %) and to the ipsilateral forehead (20 %). Common descriptions of the pain used were: burning, piercing, tearing, and boring. The majority of patients described their pain as severe . Although it has been suggested that cranial autonomic features may be less prominent in children than in adults [6•], the distribution of ocular, nasal and facial autonomic symptoms reflects the distribution in adult onset forms of CH. Lacrimation of the eye has been reported to be the most common symptom in childhood CH, followed by conjunctival injection and nasal discharge. Ptosis and nasal congestion were reported less frequently, whereas meiosis and flushing and sweating of the face and/or body were reported only in few patients . Restlessness during CH seems to be less frequently reported during CH attacks compared to adult onset CH . In a retrospective phenotyping study of paediatric onset CH patients, restlessness has been noted in nine out of 14 patients (64 %) [11•]. Subsequently, another three cases of paediatric CH, with a long follow-up, were described. The authors noted prominent cranial autonomic features in all of them, though only one patient was agitated during attacks . When present, restlessness often manifests as thrashing around in children and can distract attention from the headache, thereby contributing to a delay in diagnosis .
Other associated symptoms normally occurring in migraine, such as nausea, vomiting, photophobia and phonophobia have been reported in paediatric CH patients. In a retrospectively analysed series, seven out of 35 patients reported nausea during CH attacks (20 %) . Photophobia and phonophobia were also reported in another retrospective series of paediatric onset CH . Aura is now recognized as a clinical symptom of CH . Up to 20 % of CH patients can experience aura symptoms, a similar percentage of migraine sufferers who have aura. Awareness that focal transient neurological symptoms can accompany CH attacks and not only migraine is very helpful for the differential diagnosis of these two conditions in paediatric patients.
The cluster attack frequency varies between one every alternate day to three daily, although some have up to eight daily. In two series of pediatric onset CH, the majority of patients reported one or less than one attack a day [8, 11•]. Circadian rhythmicity, which is a cornerstone feature of CH, has been reported also in pediatric patients.
Alcohol, exercise, elevated environmental temperature and the smell of volatile agents are recognised precipitants of acute cluster attacks. Alcohol induces acute attacks, usually within an hour of intake, in the vast majority of sufferers, though in paediatric age this trigger is less helpful.
The Cluster Bout
CH is classified according to the duration of the bout. About 80–90 % of patients have episodic cluster headache (ECH), which is diagnosed when they experience recurrent bouts, each with a duration of more than a week and separated by remissions lasting more than four weeks. The bouts typically occur once or twice a year. Often, a striking circannual periodicity is seen with the cluster periods, with the bouts occurring in the same month of the year. The remaining 10–20 % of patients have chronic cluster headache (CCH), in which either no remission occurs within one year, or the remissions last less than one month .
The frequency of cluster periods seems to be lower in childhood. Similarly, the duration of the single cluster period seems to be shorter [6•]. It has also been observed that the temporal pattern shows a trend towards a gradual increase of frequency and duration of symptoms in adult life. In a series of 35 childhood onset CH patients, 13 (37 %) and 14 patients (40 %) reported an increase of frequency and duration of CH periods, respectively, in adulthood. Conversely, only four patients (11 %) reported a decrease in frequency and two patients (6 %) reported a decrease in duration of their cluster periods during their adulthood .
Clinical features of the trigeminal autonomic cephalalgias
1/alternate day −8/day
1–40/day (> 5/day for more than half the time)
Duration of attack
Restless or agitated
Sumatriptan or Zolmitriptan nasal spray
Differentiating between migraine and CH can be difficult in some cases, as unilaterality of pain and presence of migrainous and autonomic symptoms are features common to both. The features that can be useful in distinguishing CH from migraine include: relatively short duration of headache, rapid onset and cessation, circadian periodicity, precipitation within an hour by alcohol, restlessness or agitation during the attack and clustering of attacks with intervening remissions in ECH.
The diagnosis of CH is made entirely on the basis of a good clinical history and a detailed neurological examination. Any atypical features in the history or abnormalities on neurological examination (with the exception of partial Horner’s syndrome) warrant further investigations to search for organic causes. It remains unclear whether every TAC patient requires neuroimaging; if it is considered, then magnetic resonance imaging (MRI) is the preferred modality. Given the rarity of CH in childhood and adolescence, it seems reasonable to offer neuroimaging to all paediatric patients to exclude a symptomatic cause.
Management of paediatric CH (and other TACs) is not well substantiated by appropriate studies and is derived almost exclusively from experience in adult patients. Currently, there are both medical and surgical interventions available for these patients. Medical management falls into one of three categories; acute, preventive or transitional therapies. Acute or abortive treatment is given at the onset of an attack and is aimed at aborting the attack itself, whilst the aim of preventive medication is to produce a rapid suppression of attacks and maintain that remission while the patient is still in a bout. However, preventive treatments generally need to be titrated to an optimum dose, and therefore there can be a delay of a few days to weeks before their beneficial effect emerges. Transitional treatments are therapies that can be used to rapidly suppress the attacks, but are only effective for a few days to weeks and can therefore be very helpful while waiting for the preventive treatments to work. Surgical treatments are generally avoided until the medical treatments are exhausted.
Because the pain of CH builds up so rapidly, the most efficacious agents are those that involve parenteral or pulmonary administration.
Inhalation of 100 % oxygen, at 7–12L/min, is rapidly effective in relieving pain in the majority of sufferers . It should be inhaled continuously for 15–30 minutes via a non-rebreathing facial mask. Oxygen has been used successfully in several paediatric CH patients [6•], and given its good side-effect profile, it is the abortive agent of choice for paediatric CH.
Subcutaneous and Intranasal Triptans.
Subcutaneous sumatriptan is the most effective abortive treatment for cluster headache . In CH, unlike in migraine, subcutaneous sumatriptan can be prescribed at a frequency of twice daily, on a long-term basis if necessary, without risk of tachyphylaxis or rebound [19, 20]. Sumatriptan and zolmitriptan nasal spray are both more effective than placebo [21, 22]. While experience with the use of subcutaneous sumatriptan in the pediatric population is limited, Sumatriptan nasal spray has been shown to be well tolerated in children between 12 and 17 years old at the dose of 20 mg, in randomized, placebo-controlled studies in migraine .
Corticosteroids are highly efficacious and the most rapid acting of the preventative agents . Caution has to be exercised in their use because of the potential for serious side effects. Treatment is usually limited to a short intensive course of 2–3 weeks in tapering doses because of the potential for side effects . Unfortunately, relapse almost invariably occurs as the dose is tapered. For this reason, steroids are used as an initial therapy in conjunction with preventives, until the latter are effective.
In adolescence, a marked relief of cluster headache in 59 (77 %) of 77 ECH patients, and a partial relief in another 12 % of patients treated with prednisone was reported . A report of sustained efficacy of intravenous (IV) prednisolone in a 7-year-old female has been reported. In this case, prednisolone was started at 50 mg IV and reduced every fourth day (50 mg IV for 3 days, 25 mg for the next 3 days, 15 mg IV for the following 3 days, and 5 mg for the last 3 days of the therapy), leading to the termination of attacks on the third day of the treatment and allowing a subsequent pain-free period for several months .
Greater Occipital Nerve (GON) Block.
Injection of local anaesthetic and corticosteroid around the GON on the affected side can abort a bout of cluster headache . Though there are no reports on the use of GON blocks in paediatric CH, it is an excellent short-term strategy, with only very modest, infrequent side effects.
Preventive treatments of cluster headache
Level of evidence (EFNS)(19)
Level of evidence (AAN)(20)
Common side effects
ECG monitoring for cardiac arrhythmias
Hypotension, constipation, peripheral oedema
Lithium levels, renal function, thyroid function
Diarrhoea, tremor, polyuria
Paraesthesias, weight loss, cognitive dysfunction, fatigue, dizziness, taste alteration
Annual visceral fibrosis screening: Echocardiogram, Chest x-ray Abdominal and pelvis MRI scan Relevant blood tests
Nausea/vomiting Muscle cramps, Abdominal pain, Peripheral oedema, Retroperitoneal fibrosis (rare)
Somnolence, fatigue, dizziness, weight gain, peripheral oedema, ataxia
Full blood count, liver function
Weight gain, fatigue, tremor, hair loss, nausea
Verapamil is the preventative drug of choice in both episodic and chronic CH . There are reports of efficacy of verapamil in children at doses between 120 mg and 240 mg, though this agent is often used at doses of up to 960 mg daily in adults. Verapamil can cause heart block by slowing conduction in the atrioventricular node. Observing for PR interval prolongation on ECG can monitor potential development of heart block. There is only one formal guideline in the literature for the titration of the verapamil dose in adults , which recommends starting patients on 240 mg daily and incrementing the dose in steps of 80 mg every 2 weeks under ECG guidance. The dose is increased until the cluster attacks are suppressed, side effects intervene or the maximum dose of 960 mg daily is achieved. In the paediatric population, we recommend starting at a lower dose of 40–80 mg daily and titrating the dose in steps of 40 mg, up to 360 mg a day in total.
In adults, medically intractable CCH is a rare but highly disabling disorder, and it is therefore appropriate to consider surgical interventions in these patients. There are no reports of surgical intervention for the management of pediatric CH, though medically refractory CCH cases are described [6•]. Surgery is a last-resort measure in treatment–resistant patients, and should only be considered when the pharmacological options have been exploited to the fullest. Historically, destructive procedures involving the trigeminal nerve have been tried in CH. However, they are associated with considerable morbidity and therefore have largely been abandoned. Most recently, neurostimulation therapies with either hypothalamic deep brain stimulation or occipital nerve stimulation (ONS) have emerged. These approaches are very promising, and ONS especially offers a more acceptable side effect profile than destructive and invasive approaches [32•].
PH, like CH, is characterized by strictly unilateral, brief headaches that occur in association with cranial autonomic features. PH differs from CH mainly in the higher frequency and shorter duration of individual attacks, though there is a considerable overlap in these characteristics. However, unlike CH, PH responds in a dramatic and absolute fashion to indometacin , thereby underlining the importance of distinguishing it from CH.
PH is a very rare syndrome. The prevalence of PH is not known, but the relationship compared to CH is reported to be approximately 1–3 %. The most common age of onset is the second or third decade of life, though there is a wide range of age of onset (1–68 years), with several case reports of onset before the age of 18 years [33–40]. PH seems to be equally prevalent in females and males .
The clinical phenotype of PH is highly characteristic [33, 41]. The pain is strictly unilateral and centred around the orbital and temporal regions, though any part of the head can be affected. It is excruciatingly severe. The headache usually lasts 2–30 minutes. Attacks of PH invariably occur in association with ipsilateral cranial autonomic features. Up to 85 % of patients report at least one migrainous feature of photophobia, nausea or vomiting during an attack. Similar to CH, patients are often restless or agitated during an attack. The attacks occur at a high frequency. Typically, patients have more than five attacks daily, though the frequency of attacks shows a considerable fluctuation, ranging between one and 40 daily. The attacks occur randomly throughout the 24-hour period, without a preponderance of nocturnal attacks as in cluster headache. While the majority of attacks are spontaneous, common triggers include stress, release from stress, exercise, alcohol ingestion and neck movement .
PH is classified depending on the presence of a remission period. About 35 % of patients have episodic paroxysmal hemicrania (EPH), which is diagnosed when there are clear remission periods between bouts of attacks. The remaining 65 % of patients have chronic paroxysmal hemicrania (CPH) (26), which is diagnosed when patients have either no remission within one year, or the remissions last less than one month .
The differential diagnoses that need to be considered are: secondary causes of PH, other TACs and hemicrania continua (HC). A large number of symptomatic cases of PH, caused by diverse pathological processes at various intracranial sites, have been described, though a causal relationship is difficult to ascertain in most of these cases . PH can be differentiated from CH and SUNCT with a trial of indometacin. HC is a strictly unilateral headache that is continuous and associated with ipsilateral cranial autonomic symptoms. Both PH and HC are exquisitely responsive to indomethacin, and can be differentiated on the basis of the clinical phenotype .
As a relatively high number of symptomatic cases have been reported, an MRI brain scan should be routinely performed in all PH patients.
The treatment of PH is entirely preventive, as attacks are too short and intense for any acute oral treatment to be effective.
Indometacin is the treatment of choice and, in fact, has been deemed the sine qua non for establishing the diagnosis . Complete resolution of the headache is prompt, usually occurring within 1–2 days of initiating the effective dose. The typical maintenance dose ranges from 25 to 100 mg daily, but doses up to 300 mg daily are occasionally required . In children from 1 month to 18 years of age, the dose of 0.5–1 mg/kg twice daily should be used. Talvik et al. described a 3-year-old female with a year history of CPH who responded dramatically to 50 mg of indometacin, becoming pain-free. Interestingly, although the symptoms were typical for PH, she has been diagnosed 10 months after the onset of the symptoms . This case highlights the importance of recognising the possible childhood onset of this disorder.
For patients who cannot tolerate indomethacin, one faces a difficult challenge. No other drug is consistently effective in PH. Other drug therapies that have been reported to be effective in PH include cyclooxygenase-2 inhibitors, calcium channel antagonists (verapamil, Flunarizine), topiramate or greater occipital nerve blocks .
Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), as its name implies, is a disorder characterised by strictly unilateral, severe, neuralgic attacks centred on the ophthalmic trigeminal distribution that are brief in duration and occur in association with both conjunctival injection and lacrimation .
SUNCT is relatively rare, with a recent study showing a prevalence of 6.6 per 100,000 population . SUNCT has a slight male predominance, with a sex ratio of 1.5:1 . The typical age of onset is between 40 and 70 years, with a mean age of onset of 48 years and a range between 2 and 77 years. Pediatric-onset SUNCT is very rare, with only five case reports in the literature [46–50].
The attacks are strictly unilateral, though may alternate sides. The pain is usually maximal in the ophthalmic distribution of the trigeminal nerve, but can radiate to any part of the head. The pain has an excruciating intensity and a neuralgic quality. The individual attacks are relatively brief, lasting between 5 and 240 seconds. Three different types of pain have been described in SUNCT syndrome: single stabs; groups of stabs and a saw-tooth pattern in which repetitive spike-like paroxysms occur without reaching the pain-free baseline between the individual spikes. By definition, all SUNCT patients had both ipsilateral conjunctival injection and lacrimation associated with their attacks . Patients are often restless or agitated during the attacks . The attack frequency during the symptomatic phase varies immensely between sufferers and within an individual sufferer. Attacks may be as infrequent as once a day, or less to more than 60 per hour.
The majority of patients can precipitate attacks by touching certain trigger zones within trigeminal innervated distribution and, occasionally, even from an extra-trigeminal territory. Precipitants include touching the face or scalp, washing, shaving, eating, chewing, brushing teeth, talking and coughing. Unlike in trigeminal neuralgia, most patients have no refractory period.
The temporal pattern is quite variable, with the symptomatic periods alternating with remissions in an erratic manner. Symptomatic periods generally last from a few days to several months and occur once or twice annually. Remissions typically last a few months, yet can range from 1 week to 7 years. Symptomatic periods appear to increase in frequency and duration over time .
Paediatric onset SUNCT syndrome has been reported only in four children (three idiopathic and one secondary), aged from 5 to 11 years [46–50]. In all of them, the clinical phenotype of the headache resembled the adult-onset form. The first case was reported by D’Andrea and Granella. They described a 10-year-old female with very short-lasting, spontaneous, strictly unilateral but alternating side attacks, associated with lacrimation and conjunctival injection. The patient did not require any treatment, since the headache disappeared spontaneously a few months after the onset . Subsequently, a second case of young onset SUNCT was reported in a 5-year-old male. His bout lasted five months and no relapses were reported after a year of follow-up . More recently, a 6-year-old male with idiopathic SUNCT was described. Compared to the previous cases, the headache lasted for 4 years and responded to lamotrigine .
The differential diagnosis of very brief headaches includes: SUNCT (primary and secondary forms), trigeminal neuralgia, primary stabbing headache and PH.
Secondary SUNCT is typically seen with either posterior fossa or pituitary gland lesions . A case of secondary SUNCT in an 11-year-old girl, due to an astrocytoma of the ipsilateral pontocerebellar angle was reported. After the partial removal, the pain attacks persisted, but were shorter and less intense . The case emphasizes the need for brain MRI, even in patients presenting with typical SUNCT and without neurologic deficits, as in the aforementioned case.
In addition, a recent study systematically looked for trigeminal neurovascular conflict with dedicated trigeminal MRI scans, and found a high proportion of ipsilateral vascular loops in contact with the trigeminal nerve in SUNCT .
Differentiating Features of SUNCT and trigeminal neuralgia
Male: female ratio
Site of pain
Sparse or none
The association of secondary SUNCT with pituitary disorders, posterior fossa abnormalities and trigemino-vascular conflict emphasizes the need for a cranial MRI, including an adequate view of the pituitary and the trigeminal nerves.
Management of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)
Local blocks (including greater occipital nerve block)
Microvascular decompression of the trigeminal nerve
Occipital nerve stimulation
Hypothalamic deep brain stimulation
Any pathophysiological construct for TACs must account for the three major clinical features characteristic of the various conditions that comprise this group: trigeminal distribution pain, ipsilateral autonomic features, and the circadian periodicity of the attacks. The pain-producing innervation of the cranium projects through branches of the trigeminal and upper cervical nerves to the trigeminocervical complex, from whence nociceptive pathways project to higher centers. This implies an integral role for the ipsilateral trigeminal nociceptive pathways in TACs. The ipsilateral autonomic features suggest cranial parasympathetic activation (lacrimation, rhinorrhoea, nasal congestion and eyelid oedema) and sympathetic hypofunction (ptosis and meiosis). It has been suggested that the pathophysiology of the TACs revolves around the trigeminal-autonomic reflex . There is considerable experimental animal literature to document that stimulation of trigeminal afferents can result in cranial autonomic outflow, the trigeminal-autonomic reflex . In fact, some degree of cranial autonomic symptomatology is a normal physiologic response to cranial nociceptive input, and patients with other headache syndromes often report these symptoms. The distinction between the TACs and other headache syndromes is the degree of cranial autonomic activation, not its presence [54, 55].
The cranial autonomic symptoms may be prominent in the TACs due to a central disinhibition of the trigeminal-autonomic reflex . Supporting evidence is emerging from functional imaging studies: positron emission tomography studies in CH  and PH , and functional MRI studies in SUNCT syndrome  have demonstrated hypothalamic activation. Importantly, the involvement of posterior hypothalamic structures may account for the rhythmicity or periodicity that is such a hallmark of these conditions. Hypothalamic activation is not seen in experimental trigeminal distribution head pain . Furthermore, there is abundant evidence for a role of the hypothalamus in mediating anti-nociceptive  and autonomic responses . In view of the presence of direct hypothalamic-trigeminal connections , the TACs may be due to an abnormality in the hypothalamus with subsequent trigeminovascular and cranial autonomic activation.
The TACs are a group of primary headache disorders characterized by unilateral head pain that occurs in association with ipsilateral cranial autonomic features. Childhood and adolescent onset TACs are even more rare than the adult-onset forms, but resemble them with regard to the characteristics of the pain, the associated symptoms and response to treatments. Nonetheless, pediatric-onset TACs are poorly recognized and there is often a delay of several months or years before the diagnosis is made. Awareness of typical clinical pictures of these excruciating headaches expedites the diagnosis and allows prompt initiation of the appropriate management.
Conflict of interest
Dr. Giorgio Lambru declares that he has no conflict of interest.
Dr. Manjit Matharu is a section editor for Current Pain and Headache Reports. He is a board member for Allergan Ltd. He has received a grant from St. Jude Medical and honoraria from Merck Sharpe Dohme. He has also received payment for development of educational presentations including service on speakers’ bureaus from St. Jude Medical and Allergan Ltd.