INTRODUCTION — By definition, "central pain" is neuropathic pain caused by a lesion or dysfunction in the central nervous system. The clinical presentation can be quite variable among patients [1]. The International Classification of Headache Disorders recognizes two entities that are central causes of facial pain [2]:
●Central neuropathic pain attributed to multiple sclerosis
●Central post-stroke pain
This topic will discuss these conditions. Other causes of facial pain are reviewed elsewhere. (See "Overview of craniofacial pain".)
ANATOMY — A lesion at any level of the central nervous system from the spinal trigeminal nucleus or spinal dorsal horn to the cerebral cortex has the potential for causing central neuropathic facial pain. There may be a higher risk for developing central pain when the spinothalamic and quintothalamic pathways are affected, compared with suprathalamic lesions [1].
PATHOPHYSIOLOGY — Although the mechanisms are poorly understood [3], two general hypothetic processes have in the past been implicated. In the first one, an "irritative lesion" affecting somatosensory pathways may lead to increased activity in otherwise normal nociceptive pathways. In the second one, neurons, remote from the lesion site, become hyperactive and hypersensitive after losing normal synaptic inputs through "denervation" [1]. The result of the central nervous system lesion is an abnormal, sensitized state of central structures leading to persistent pain in the absence of ongoing tissue injury [4]. An abundance of different mechanisms extending from the peripheral to the central nervous system (brain, spinal cord, and descending modulating systems) have now been implicated in neuropathic pain pathophysiology [5].
GENERAL CHARACTERISTICS OF CENTRAL PAIN — Clinically, the presentation of central neuropathic facial pain can vary significantly in severity, character, and location. Pain can be constant or intermittent, and pain intensity can range from mild to excruciating [1]. Characteristic symptoms, alone or combined, include [6]:
●Muscle pain, felt as cramping, constriction, or crushing.
●Dysesthesia, most commonly with a burning character. Dysesthesia may be poorly localized and may be constant or intermittent in response to a stimulus (pain may be delayed after the stimulus in central pain).
●Hyperpathia (a heightened response to noxious stimuli).
●Allodynia (interpretation of nonpainful stimuli as painful).
●Shooting/lancinating intermittent pain.
●Circulatory-like pain (pins and needles, stings, jabs).
Internal and external stimuli, including cold, movement, light touch, and emotional distress, often exacerbate central pain [1]. Steady and evoked pain (allodynia and hyperpathia) is most commonly encountered in central pain caused by brain lesions, while neuralgic pain due to brain lesions is rare [3,7], although it can occur such as in trigeminal neuralgia from pontine ischemic infarction [8,9]. Nevertheless, central pain can be difficult to describe, and most patients experience more than one pain quality [1]. Bizarre, vague terms might be utilized by patients attempting to explain what they are feeling [6].
Central pain results from central nervous system lesions. Hence, it should occur in association with neurologic symptoms and/or signs such as impaired somatic sensibility. The onset of central pain often coincides with, or shortly follows, the return of transiently lost or impaired sensation related to a lesion affecting somatosensory pathways. However, the onset of the pain may be delayed for years after the insult [1]. In addition, central pain can occur even after a brain lesion that left no permanent, clinically detectable sensory loss [3].
The diagnosis of central craniofacial pain is made when clinical evidence supports a disease process in the central nervous system and the pain characteristics are consistent with central pain.
The following are suggested general diagnostic criteria for central pain [1]:
●History of disease in the brain or spinal cord
●Laboratory/radiologic support of central nervous system disease
●Pain starting after the onset of central nervous system disease, with the onset of pain often delayed
●Pain with a regional distribution, rather than corresponding to individual nerves
●Pain quality compatible with central pain
●Sensory abnormality is present
●Non-sensory symptoms and signs may or may not be present
CENTRAL NEUROPATHIC PAIN ATTRIBUTED TO MULTIPLE SCLEROSIS — Central neuropathic pain attributed to multiple sclerosis is described as unilateral or bilateral craniocervical pain of varying presentation, with or without sensory changes, attributed to a demyelinating lesion of the central connections of the trigeminal nerve in an individual with multiple sclerosis [2].
Diagnostic criteria, according to the International Classification of Headache Disorders, 3rd edition (ICHD-3) require all of the following [2]:
●Facial and/or head pain
●Multiple sclerosis has been diagnosed with magnetic resonance imaging (MRI) demonstration of a demyelinating lesion in the brain stem or ascending projections of the trigeminal nuclei
●Pain has developed in temporal relation to the demyelinating lesion or led to its discovery
●Not better accounted for by another ICHD-3 diagnosis
The pain may be continuous or paroxysmal. Other associated sensory disturbances may include dysesthesia, hypoesthesia, anesthesia, hypoalgesia, and paresthesia [2].
Patients with multiple sclerosis who have unilateral pain with the characteristics of classic trigeminal neuralgia due to a multiple sclerosis plaque affecting the trigeminal nerve root are classified by the ICHD-3 as having trigeminal neuralgia attributed to multiple sclerosis [2]. Trigeminal neuralgia occurs in 1 to 2 percent of patients with multiple sclerosis, about 20 times the prevalence in the general population [10]. Conversely, multiple sclerosis is the cause of trigeminal neuralgia in about 2 percent of patients with trigeminal neuralgia [10]. (See "Trigeminal neuralgia", section on 'Mechanisms'.)
CENTRAL POST-STROKE PAIN — Central post-stroke pain is described as usually unilateral facial and/or head pain, with variable presentation, involving part or the whole of the craniocervical region and associated with impaired sensation that is caused by stroke [2]. It is not caused by a lesion of the peripheral trigeminal nerve or other cranial or cervical nerves. The pain is attributed to a lesion involving the ascending projections of the trigeminal nuclei, with possible involvement of the cervical spinothalamic pathways and cortical processing. Depending on the specific site of the lesion, the ipsilateral trunk and/or limbs may be affected. The disorder affects 0.5 to 8 percent of patients following stroke [11-14].
Diagnostic criteria for central post-stroke pain according to the International Classification of Headache Disorders, 3rd edition (ICHD-3) require all of the following [2]:
●Facial and/or head pain
●Ischemic or hemorrhagic stroke has occurred
●Evidence of causation demonstrated by both of the following:
•Pain has developed within six months after the stroke
•Imaging (usually MRI) has demonstrated a vascular lesion in an appropriate site
●Not better accounted for by another ICHD-3 diagnosis
The pain is usually persistent but can also be paroxysmal [15]. In contradistinction to the ICHD-3 diagnostic criteria [2], its onset may be delayed months or even years after the stroke [1]. In a systematic review of 16 studies that reported the incidence of central post-stroke pain, symptoms occurred with stroke onset in 26 percent of patients, within 1 month in 31 percent, between 1 month and 1 year in 41 percent, and more than 12 months after the stroke in 5 percent of patients [16]. The intensity of the pain may vary, may increase by physical/emotional stress, and may be alleviated by relaxation. The pain can be a great burden in some patients, leading to severe depression and even suicide [15].
PHARMACOLOGIC TREATMENT — Therapy for central pain can be challenging. Most treatment options fit into the following categories [1]:
●Drugs that reduce central nervous system activity (anticonvulsants, benzodiazepines, baclofen).
●Drugs that enhance the reuptake of serotonin and noradrenaline (antidepressants).
●Drugs that influence adrenoceptors (clonidine) and direct opiate receptor agonists. Of note, these agents are typically prescribed by a pain specialist. We do not commonly use them.
●Peripheral and central electrical stimulation. (See 'Neuromodulation and surgery' below.)
Limited scientific evidence is available regarding pharmacotherapy for most types of central pain [7]. Except for a few drugs, such as amitriptyline and lamotrigine, treatment is based on anecdotal observations and consensus opinions [1]. Furthermore, it is unknown whether a treatment that is effective in one central pain syndrome can be beneficial in another [17]. It is therefore difficult to apply available guidelines for neuropathic or central pain management to facial pain specifically [18].
A treatment algorithm for neuropathic pain has been proposed based upon a systematic review of randomized clinical trials in various central and peripheral neuropathic pain conditions [17]. European Federation of Neurological Societies (EFNS) guidelines from 2010 have similar recommendations [18]. The following recommendations can be made for central neuropathic pain:
●Tricyclic antidepressants are first-line agents.
●Gabapentin/pregabalin are second choices. However, these agents are first choices in older adults or when tricyclics are contraindicated.
●Lamotrigine and opioids are third-line agents, the latter due to the risk of dependency, addiction, and overdose [19].
A 2014 consensus statement from the Canadian Pain Society for neuropathic pain recommended gabapentin, pregabalin, tricyclic antidepressants, and serotonin noradrenaline reuptake inhibitors (duloxetine, venlafaxine) as first-line treatments [20]. Tramadol and controlled-release opioids were considered second-line for moderate to severe pain, cannabinoids were third-line treatments, and methadone, anticonvulsants with lesser evidence of efficacy (eg, lacosamide, lamotrigine), tapentadol, and botulinum toxin were fourth-line treatments.
However, we do not use opioids to treat central neuropathic facial pain. Importantly, a position statement from the American Academy of Neurology (AAN) regarding opioid use for chronic noncancer pain stated that "there is no substantial evidence for maintenance of pain relief or improved function over long periods of time without incurring serious risk of overdose, dependence, or addiction" [21]. While there is evidence for short-term pain relief using opioids, these (if used) should only be part of the pain management strategy. The risks of chronic opioid therapy for chronic conditions such as headache, fibromyalgia, and chronic low back pain likely outweigh the benefits [21]. It is unclear if the same applies to chronic central neuropathic face pain, but the possibility exists, warranting judicious opioid use if at all.
When medications of choice fail, a trial-and-error approach can be attempted with other drugs that have been used for neuropathic pain, including but not limited to phenytoin, carbamazepine, clonazepam, valproate, phenothiazines, mexiletine, and baclofen [7].
In studies evaluating treatment of specific clinical syndromes recognized as central causes of facial pain, the following observations have been made:
●For central post-stroke pain, amitriptyline (titrated to 75 mg daily) and lamotrigine (titrated to 200 mg daily) are the only medications shown to be effective in small randomized controlled trials [15,22,23]. Of these, amitriptyline has been considered first-line treatment for central post-stroke pain. In contrast, a different conclusion was reached by a later systematic review and meta-analysis of eight small randomized trials involving 459 patients with central post-stroke pain that evaluated amitriptyline, anticonvulsants, opioids, transcranial magnetic stimulation, and acupuncture [24]. The results suggested that these treatments had no benefit for improving pain or other patient-important outcomes, based upon low- or very low-certainty evidence.
●For paroxysmal or neuralgic pain associated with multiple sclerosis, carbamazepine is the drug of choice [1,25]. The evidence supporting this is consensus opinion and clinical experience only.
Choice of therapy — We suggest carbamazepine as initial therapy for treatment of neuralgic facial pain attributed to multiple sclerosis or stroke (eg, trigeminal neuralgia secondary to pontine ischemic infarction).
For treatment of non-neuralgic central post-stroke pain or non-neuralgic pain from multiple sclerosis, we suggest tricyclic antidepressants as initial pharmacologic therapy. Amitriptyline is the most effective tricyclic for central pain. When tricyclic medications are contraindicated or poorly tolerated, gabapentin or pregabalin are preferred alternative choices. Lamotrigine is another alternative.
Some patients who have both neuralgic and non-neuralgic (steady) neuropathic pain may benefit from combining carbamazepine (for neuralgic pain) with amitriptyline or gabapentin/pregabalin (for steady, non-neuralgic pain).
Referral for specialty care should be pursued if the diagnosis is uncertain or if the patient fails to respond to usual management.
Carbamazepine — For patients with neuralgic facial pain attributed to multiple sclerosis, carbamazepine may be started at 100 to 200 mg daily; the dose can be increased slowly over several days as needed for pain relief to a maximum total dose of 1200 mg per day in divided doses.
Carbamazepine is associated with rare but serious side effects, including agranulocytosis and aplastic anemia. The Stevens-Johnson syndrome and toxic epidermal necrolysis are additional rare complications, particularly during the first eight weeks of therapy, and are significantly more common (estimated incidence of 5 percent) among patients with the HLA-B*1502 allele [26]. This allele occurs almost exclusively in patients of South Asian ancestry. Screening for this allele is recommended in patients of these ethnic groups prior to starting carbamazepine. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Genetic factors'.)
Amitriptyline — Amitriptyline can be started at 10 to 25 mg nightly and titrated up in 10 to 25 mg steps every one to three weeks as tolerated and as needed for pain relief or until a maximum dose of 100 to 125 mg nightly is reached. Amitriptyline and most other tricyclics are sedating. Additional side effects of tricyclics include dry mouth, constipation, tachycardia, palpitations, orthostatic hypotension, weight gain, blurred vision, and urinary retention. Confusion can occur, particularly in older adults.
Gabapentin — Gabapentin can be started at 300 mg daily and titrated up as needed for pain relief. In patients who are poorly tolerant of side effects, the titration can be as low as 100 mg daily. Adequate relief is typically achieved with gabapentin doses ranging from 900 to 2400 mg daily, given in three divided doses [27]. Doses as high as 3600 mg daily are tolerated by most patients. The most common adverse effects include somnolence, diarrhea, mood swings, ataxia, fatigue, nausea, and dizziness.
Pregabalin — Pregabalin is started at as little as 25 mg once daily to as much as 50 mg three times a day (total 150 mg/day) and is then slowly increased to 100 mg three times a day (total 300 mg/day) over a week or more. Higher doses may be effective if tolerated but should not exceed a total dose of 600 mg daily. When stopping the drug, it should be tapered over a week, as withdrawal symptoms may occur. Common side effects of pregabalin are dizziness, somnolence, dry mouth, peripheral edema, and weight gain. Pregabalin can also cause sedation and confusion. It is designated as a schedule V controlled substance in the United States because it has been reported to cause euphoria.
Lamotrigine — Lamotrigine is started at 25 mg daily for the first two weeks of therapy. The dose can then be increased to 50 mg daily for weeks 3 and 4, 100 mg daily for week 5, and 200 mg daily beginning week 6. Rash is the most common side effect associated with lamotrigine treatment and requires discontinuation of the drug since a hypersensitivity reaction may result and lead to life-threatening complications such as Stevens-Johnson syndrome and toxic epidermal necrolysis.
NEUROMODULATION AND SURGERY — Neuromodulation and invasive procedures to treat central neuropathic facial pain are reserved for patients with significant disability who have failed noninvasive measures [7,28]. Transcutaneous electrical nerve stimulation has been recommended as an initial option by some authors [1].
Encouraging results have been obtained since the 1990s with chronic motor cortex stimulation. However, 2016 guidelines from the European Academy of Neurology found only poor to moderate quality of evidence that motor cortex stimulation is efficacious for neuropathic pain [29]. The relief after motor cortex stimulation may subside with time [7].
Deep brain stimulation and destructive lesions, such as medial thalamotomy, are last-resort procedures, only considered after other alternatives have failed and only in specialized centers [1].
Neuromodulatory and interventional options for neuropathic pain are discussed in greater detail separately. (See "Approach to the management of chronic non-cancer pain in adults", section on 'Physical modalities' and "Approach to the management of chronic non-cancer pain in adults", section on 'Interventional therapy for chronic pain'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathic pain".)
SUMMARY AND RECOMMENDATIONS
●Anatomy – A lesion at any level of the central nervous system, from the spinal trigeminal nucleus or spinal dorsal horn to the cerebral cortex, has the potential for causing central neuropathic facial pain. (See 'Anatomy' above.)
●Clinical features of central facial pain – Central craniofacial pain occurs after the onset of a disease process in the central nervous system. The pain can be constant or intermittent, and pain intensity can range from mild to excruciating. Sensory abnormalities such as dysesthesias, hyperpathia, and/or allodynia may be present. The pain is typically in a regional distribution, rather than corresponding to individual nerves.
●Etiologies
•Facial pain attributed to multiple sclerosis is characterized by unilateral or bilateral facial pain, with or without dysesthesia, attributed to a demyelinating lesion of the central connections of the trigeminal nerve. (See 'Central neuropathic pain attributed to multiple sclerosis' above.)
•Central post-stroke pain is characterized by unilateral pain and dysesthesia associated with impaired sensation involving part or the whole of the face, attributed to stroke and not explicable by a lesion of the trigeminal nerve. (See 'Central post-stroke pain' above.)
●Pharmacologic treatment options – Limited scientific evidence is available regarding pharmacotherapy for most types of central pain. Except for a few drugs, treatment is based on anecdotal observations and consensus opinions. (See 'Pharmacologic treatment' above.)
•For patients with neuralgic central neuropathic pain attributed to multiple sclerosis or stroke, we suggest treatment with carbamazepine (Grade 2C). (See 'Pharmacologic treatment' above and 'Carbamazepine' above.)
•For patients with non-neuralgic central post-stroke pain or non-neuralgic pain from multiple sclerosis, we suggest initial therapy with tricyclic antidepressants (Grade 2C). Amitriptyline is the preferred tricyclic. For patients intolerant of or unresponsive to tricyclics, gabapentin, pregabalin, and lamotrigine are alternatives. (See 'Pharmacologic treatment' above and 'Amitriptyline' above and 'Gabapentin' above and 'Pregabalin' above and 'Lamotrigine' above.)
●Treatment for refractory cases – Neuromodulation or surgical therapy is considered only in specialized centers and reserved for patients with central craniofacial pain who have significant disability, have failed noninvasive measures, and have no contraindications. (See 'Neuromodulation and surgery' above.)
