11
Neuropathic Orofacial Pain
Olga A. Korczeniewska, PhD
Katherine France, DMD, MBE
Junad Khan, BDS, MPH, MSD, PhD
Martin S. Greenberg, DDS, FDS RCSEd
Rafael Benoliel BDS (Hons)
Eliav Eli, DMD, PhD
INTRODUCTION
Pain is a multifaceted experience involving physiological, cognitive, and emotional aspects. Reflecting this complexity, pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”1
Acute pain resulting from injury or a painful stimulus generally results in a withdrawal reaction, ensuring minimal or no damage to the organism. If tissue damage occurs, a local inflammatory response is initiated causing increased sensitivity in peripheral nociceptors (peripheral sensitization) and in dorsal horn neurons associated with pain transmission (central sensitization). Usually, the injured area becomes sensitive to light touch (allodynia) and hypersensitive to painful stimuli (hyperalgesia). The injured area is painful during the healing phase, in most cases the pain is resolved with no residual disability following healing.
Chronic pain, on the other hand, is not directly associated with injury; it continues beyond healing and has no value for the organism’s survival. It may be associated with primary or reactive changes in the nervous system that perpetuate the sensation of pain even in the absence of an active injury. Chronic pain is often not a symptom but a disease in itself that inflicts severe physical and emotional suffering on the individual. Chronic orofacial pain may be subdivided into three main symptomatic classes: musculoskeletal, neurovascular, and neuropathic.2
This chapter focuses on neuropathic orofacial pain (NOP); that is, painful neuropathies affecting oral and facial structures.
NEUROPATHIC PAIN
Neuropathic pain (NP) is defined as “pain arising as a direct consequence of any lesion or disease affecting the somatosensory system,”3,4 which induces chronic pain that may originate from a peripheral nerve, a ganglion, the dorsal root, or from the central nervous system (central NP).
The best estimate of NP prevalence is between 6.9–10% of population.5 The exact prevalence is unclear, in part due to inconsistent definitions and clinical criteria. The prevalence of syndromes involving NP is expected to increase together with life expectancy and disease survival rates. The relatively limited existing treatment options for NP, largely pharmacologic, may lead to impaired quality of life and extensive usage of health care facilities.6,7
The International Headache Society’s (IHS’s) classification and the International Classification of Headache Disorders (ICHD) can serve as the basis for the definitions and descriptions of the clinical NOP syndromes described in this chapter. 8 We review all the painful orofacial neuropathies except for the rarer pain conditions, such as optic neuritis, ischemic ocular motor nerve palsy, Tolosa–Hunt syndrome, paratrigeminal oculosympathetic (Raeder’s) syndrome, and recurrent painful opthalamoplegic neuropathy.
The quality of pain across many NPs is often described as burning, sharp, or electric. The pain may be evoked (stimulus‐dependent; e.g., mechanical, thermal) or spontaneous (stimulus‐independent)9 with hyperalgesia, allodynia (e.g., positive sensory sign) and/or numbness (e.g., negative sensory signs).10 Quantitative Sensory Testing (QST) can be used to evaluate the patients. In the absence of advanced QST tools, sensory function can be assessed using a simple pin, a blunt instrument, warmed and cooled implements, or cotton wool.11
Neuropathic Orofacial Pain
Neuropathic orofacial pain (NOP), sometimes termed as trigeminal neuropathic pain is an umbrella term that includes conditions related to painful lesions of the cranial nerves.12 The most common clinical entities are trigeminal neuralgia, painful post‐traumatic trigeminal neuropathies, and burning mouth syndrome.
NOP may be generally classified as peripheral or central, or based on the symptomology as episodic and continuous. Episodic neuropathies are characterized by short, sharp, or electrical like paroxysmal pain similar to trigeminal neuralgia, while post‐traumatic neuropathy or inflammation in nerve structures (neuritis) are commonly characterized by continuous burning pain.
NOP shares mechanisms and features with spinal neuropathic pain, yet it demonstrates inimitable characteristics. Conditions such as burning mouth syndrome or trigeminal neuralgia occur solely in this region, while other conditions such as painful diabetic neuropathy, one of the most common neuropathic conditions, rarely affects the orofacial region. This may be explained in part by trigeminal nerve injury studies that show divergent responses to physical and inflammatory insults compared to spinal nerves injury.13,14
There is no single, common, easy method to diagnose NOP. The diagnosis is based on self‐reports, symptoms, as well as physiological and behavioral methods. Occurrence of NOP may be spontaneous (stimulus‐independent) or touch‐evoked (stimulus‐dependent); these episodes may also be superimposed as a result of constant pain.
Some sensory signs and symptoms, particularly thermal or mechanical allodynia, are frequently associated with NOP. Evaluation of sensory changes is best performed by Quantitative Sensory Testing (QST), a method that utilizes noninvasive assessment and quantification of normal and abnormal responses of the nervous system to various stimuli.15 Typically, mechanical or thermal stimuli selectively activate different sensory nerve fibers (e.g., heat activates C‐fibers, cold stimuli and punctuate mechanical stimuli activate Aδ‐fibers and light touch activates Aβ fibers). Sensory evaluation can be performed using sophisticated equipment or using simple pin, blunt instruments, warmed and cooled implements, and cotton wool. Data obtained from QST can support treatment decisions; for example, when the pathology is mainly peripheral microsurgical repair or topical, treatment should be considered, while in cases where the pain has a strong central nervous system component, centrally acting drugs should be the treatment of choice.
Painful Trigeminal Neuropathies
The term “painful trigeminal neuropathy” (PTN) is an umbrella term bringing together a number of facial pains in the distribution(s) of one or more branches of the trigeminal nerve caused by a disorder associated with the trigeminal neuralgias and indicative of neural damage.8
The primary pain in PTN is continuous, and commonly described as burning, squeezing, or as pins and needles. Superimposed brief pain paroxysms can be present, but not as the main type of pain. Sensory changes within the trigeminal distribution—such as mechanical allodynia, cold hyperalgesia, and numbness—are prevalent findings in PTNs. Allodynic areas are different from trigeminal neuralgia’s trigger zones; they are generally much larger than the punctate trigger zones, and allodynic areas lack both the “latency” and “refractory period” associated with trigeminal neuralgia triggers.
Painful Trigeminal Neuropathy Attributed to Acute Herpes Zoster
Acute herpes zoster (HZ) or shingles is a reactivation of latent varicella virus infection that may occur even decades after the primary infection. The exact mechanisms leading to viral reactivation and the subsequent appearance of acute HZ are unknown. Clinical presentation of HZ includes a dermatomal vesicular eruption. The symptoms are more severe in immunocompromised patients and include a prolonged course, recurrent lesions mimicking a typical zoster infection, and involvement of multiple dermatomes.16
Diagnosis of HZ is based on the clinical presentation and laboratory testing.17 The clinical features important to the diagnosis include a painful prodrome, a unilateral dermatomal distribution, a vesicular or papular eruption, a history of a rash in the same distribution, and pain.16 Identification of viral DNA in vesicular or cerebrospinal (CSF) fluid provides a more definitive diagnosis.18 Additionally, identification of HZ DNA in saliva has been suggested as a possible and less invasive diagnostic test.18
HZ Etiology and Pathophysiology
Peripherally, viral replication induces epithelial cell degeneration and ballooning, followed by invasion of giant cells. In rare cases, necrosis and bleeding are observed. The vesicles rupture and release infectious contents.
Activation of varicella zoster virus at the spinal root or cranial nerve neurons results in an inflammatory response that may also include the leptomeninges. Nerve damage following inflammation around the nerve trunk with lymphocytic infiltration of the nerve root contributes to pain in HZ. The ongoing inflammation may induce neuronal loss, fibrosis, and focal necrosis of nerve cells and satellite cell bodies.19 Infected DRG cells demonstrate cell degeneration and accumulation of glia cells. The distribution of sensory changes and development of hyperalgesia are associated with the spread within the spinal cord.
HZ Epidemiology
HZ does not generally appear in epidemics and does not follow a seasonal pattern. The annual incidence of HZ has been reduced significantly since the introduction of the first varicella vaccination in 1995.20
HZ incidence increases with age, approximately 0.3% of the population will develop HZ.20 More than 50% of patients over the age of 80 are at risk to develop HZ, and the overall lifetime risk to develop HZ is estimated as 30%.20 HZ is not common among young patients, and it remains to be determined when the presence of HZ in young patients should be interpreted as sign of underlying immunosuppressive disease.
Clinical Features of Acute HZ
Acute HZ is characterized by a unilateral, dermatomal, red macopapular rash that matures into vesicular eruptions over 3–5 days. The vesicles dry within another 7–10 days, but complete healing may take a month. HZ virus most commonly affects the thoracic nerves, followed by the lumbar region. The trigeminal nerves are affected in 8–28% of cases. Among the trigeminal cases, the ophthalmic branch involvement is most common, occurring in 80% of cases. Ophthalmic nerve involvement can result in keratitis, a vision‐threatening condition. When the maxillary or mandibular branches are affected, the vesicles may appear intraorally. Cervical nerves are affected in 13–23% of cases.
Pain in HZ is constant with superimposed piercing attacks. Evoked pain may be the prominent feature in some patients. The pain quality varies: burning (26%), stabbing (15%), shooting (15%), tingling (10%), and aching (9%) are common descriptors used.21 Its intensity is moderate to severe (VAS 6.2 average), but up to 25% of patients have no pain.22 High pain severity correlates with an increased incidence of Post Herpetic Neuralgia (PHN).22 In three‐quarters of the patients, acute HZ presents with prodromal pain, headache, itching, malaise, and fever.16,23–25 The pain develops 2–3 days (< 7) prior to acute HZ and may last with varying intensity up to 3–6 months after healing.24 Acute HZ patients may have mechanical allodynia and altered sensory thresholds that can spread to adjacent dermatomes, but is rarely bilaterally. Motor weakness may occur, but is usually transient.
Dermatomal pain with no rash, termed “zoster sine herpete,” is very rare and its diagnosis requires evidence of concurrent viral reactivation.26
HZ Management
Acute HZ treatment is focused on pain control, reducing the risk of complications such as spreading and local secondary infection, post herpetic neuralgia (PHN), as well as efforts to accelerate healing.24 Early initiation of antiviral treatment (less than 72 hours following rash onset), mainly in patients older than 50 years, shortens the rash duration and reduces pain severity and frequency.22,27 Meta‐analyses, however, did not find significant reductions in PHN incidence following oral acyclovir therapy28
Antiviral Medications
The antiviral medications used to treat acute HZ include valacyclovir (1000 mg x 3/d), acyclovir (800 mg x 5/d), and famciclovir (500 mg x 3/day). Valacyclovir is more efficacious than acyclovir in terms of pain resolution. Famciclovir is well‐tolerated therapy that has the advantage of reduced frequency of dosing.17 Brivudin is an antiviral medication that is available in some countries for the early treatment of HZ, mainly in immunocompetent adults. Overall, brivudin (125 mg daily) is superior to acyclovir (800 mg x 5/d), however it has a mixed efficacy profile.29 Brivudin and famciclovir (250 mg x 3/d) are comparable in effectiveness on pain and rash with similar tolerability. Severe drug interactions have been reported between brivudin and 5‐ fluorouracil (FU) and other 5‐fluoropyrimidines; therefore, brivudin should not be used along with 5‐FU or its derivatives, capecitabine, floxuridine, or flucytosine.29 Newer anti‐HZ drugs, such as the bicyclic nucleoside analogue FV‐100, the helicase‐primase inhibitor ASP2151, and valomaciclovir, have been evaluated in clinical trials and offer promising improved efficacy, reduced daily doses, and side effects.30
Systemic administration of corticosteroids in combination with antiviral medication offers clinically significant benefits for acute pain and quality of life outcomes when administered systemically within 72 hours of rash onset.29
Pain medications
Analgesics such as paracetamol or nonsteroidal anti‐inflammatory drugs (NSAIDs) should be used to control fever and pain. Stronger pain may require analgesic/NSAID combinations or short‐term opioid treatment, mainly for nonresponsive pain. Amitriptyline and gabapentin are centrally acting analgesics that can also provide some pain relief. Amitriptyline may be associated with cardiovascular effects, which limit its use in the elderly and medically complex patients.
Trigeminal Post‐Herpetic Neuralgia (PHN)
Post‐Herpetic Neuralgia (PHN) is a complication of acute HZ (shingles). It is a neuropathic pain syndrome that develops following herpes virus‐induced nerve injury. Affected nerve fibers induce burning pain that lasts long after the rash and blisters disappear.
Multiple risk factors contribute to the development of PHN, including age and severe symptoms such as pain and rash.25,31 Advanced age (> 50 years old) and intense pain independently predict PHN at 3 months after the acute infection.31,32 It is not clear when acute HZ transitions into PHN.33,34 HZ‐associated pain may be best classified into three phases: acute HZ (lasting less than 30 days); subacute HZ (more than 30 days but less than 120 days); and PHN (more than 120 days).16 This classification is in line with evidence suggesting that acute HZ and PHN have distinct pathophysiologies.35
Varicella vaccine may offer an effective method of preventing HZ and PHN in individuals at risk. The live attenuated zoster vaccine was shown to be effective in reducing the incidence of PHN among older adults36 as well as reducing the duration and severity of the acute disease.37 The vaccine has been shown to be 70% efficacious, safe, and effective. The efficacy of the vaccine appears to decrease with age; however, this can be overcome by vaccine modifications.30 Zoster vaccines are approved and recommended for individuals over the age of 50.38 The recombinant version was approved in the United States in 2017 and is safe and effective.39 A recent metanalysis concluded that the adjuvant recombinant subunit vaccine might be more effective39 at preventing herpes zoster than the live attenuated vaccine, but the recombinant vaccine also has a higher risk of local adverse events.
Varicella vaccine is contraindicated in immunosuppressed individuals, a group that is at high risk of infection. Instead, passive immunity with an immune globulin preparation should be considered for these patients following exposure to varicella.17,30
PHN Etiology and Pathogenesis
Some of the characteristics commonly found in PHN patients include scarring of sensory ganglia and peripheral nerve damage (often bilateral) with loss of large myelinated nerve fibers.19 Both peripherally and centrally generated mechanisms are involved in PHN and the extent to which each of the processes contributes to PHN will affect the clinical presentation.40 Patients with the least residual epidermal neurites following acute HZ more often develop PHN, suggesting mechanisms secondary to nerve damage.19 In trigeminal PHN patients, neurophysiological abnormalities in the A‐delta and C fibers were associated with the intensity of the constant burning pain, while dysfunctions of A‐beta fibers were associated with paroxysmal pain.41,42
PHN patients do not usually present with an active viral infection. PHN patients develop spinal dorsal horn atrophy, which does not exist in acute HZ patients that do not progress to PHN.19 Postmortem examination has revealed bilateral, severe, peripheral nerve pathology in an ophthalmic PHN patient;43 while the trigeminal ganglion and trigeminal root were unaffected, suggesting that PHN progresses from peripheral to central structures. It is assumed that ongoing activity in peripheral nociceptors plays an important role in the early PHN stages (< 1 yr) while central mechanisms have more prominent role in later stages.44
PHN Epidemiology
The specific incidence of PHN in the trigeminal region is not known; however, the overall PHN incidence is estimated at 3.9–42.0/100,000 person per year.5 The frequency of persistent pain 3 months following acute HZ increases with age, ranging from 0.3% in patients under 44 years old to 9% in those 75 and older.19 Between 5–40% of acute HZ patients will report pain 6 months following initial onset,16,36 and it has been estimated that after 1 year, 5–10% of the patients will report persistent pain.16,36 There is some variability in the reported durations of pain following acute HZ.
PHN Clinical Features
The ophthalmic division of the trigeminal nerve is most commonly involved in trigeminal PHN.45 The quality of pain associated has been described as burning, throbbing, stabbing, sharp, or shooting. Most PHN patients will report a constant, deep, burning or aching pain. However, variable temporal patterns of pain have been reported, with some PHN patients presenting with constant pain and others with paroxysmal pain as the leading symptom.41
Between 30–50% of PHN patients report itching of the affected area, termed post‐herpetic itch (PHI).46 Although PHI is usually mild to moderate, in some cases it may be extremely bothersome and is often subjectively graded as worse than pain.19 PHI may be accompanied by anesthesia and may result in self‐injury from persistent scratching.46 PHN pain is typically severe with VAS ratings of 8. When present, background pain fluctuates from moderate to excruciating.
The affected areas are usually hypoesthetic or anesthetic, with pale or red/purple scars. These “anesthetic” scars often exhibit allodynia and hyperalgesia. No different from other neuropathic pain conditions, a heterogeneous mix of sensory signs and symptoms are observed in PHN.41 Most patients with PHN develop allodynia and diminished responses to temperature and pinprick.
PHN Treatment
Several evidence‐based treatment options are available for PHN. It appears that early treatment improves treatment effectiveness.47,48 TCAs present an effective treatment option for PHN with an overall Number Needed to Treat (NNT) of 2.6. Amitriptyline is the most extensively studied Tricyclic Antidepressant (TCA); however, other available TCAs such as nortriptyline or desipramine may also be used. Gabapentin (NNT of 4.4) and pregabalin (NNT 3.3–4.93) have been proven to be efficacious and are relatively safe in elderly patients.47,48 Opioids (NNT ~ 2.7) and tramadol (NNT of 4.8) are a treatment option; however, the risk of Opioid Abuse Disorder (OAD) should be considered.47,48 In the presence of allodynia, lidocaine patches (NNT ~4) are useful, with significantly fewer side effects compared to systemic drugs.49–51 High concentrations of topical capsaicin (8%) (NNT of 8.8) was shown52 as a safe treatment option.52 For trigeminal PHN, however, capsaicin patches are not recommended and extreme care should be taken when applying treatments around the eyes.53 Post‐herpetic itch (PHI) is extremely difficult to treat; local anesthetics provide some temporary relief, but it does not usually respond to antihistamines.
More invasive PHN treatment options include epidural and intrathecal steroids, sympathetic and sensory nerve blocks, spinal cord stimulation, and neurosurgical techniques with dorsal root entry zone (DREZ) lesion.54,55
Painful Post Traumatic Trigeminal Neuropathy (PTTN)
Neuropathy (sensory change) is a disease resulting from damage to or malfunctioning of the somatosensory nervous system. When accompanied by pain it is termed as painful neuropathy.
Neuropathies can be divided into: peripheral neuropathy, when pain originates in peripheral nerve; ganglionopathy, when the ganglion is involved; radiculopathy, when affecting the dorsal root; or central neuropathic pain, when this originates from the central nervous system. Often there are overlapping conditions. This section focuses on Painful Traumatic Trigeminal Neuropathy (PTTN): pain resulting from damage to the trigeminal nerve. PTTN has been previously termed in the literature as: phantom tooth pain, atypical odontalgia, and atypical facial pain.
Craniofacial or oral trauma are probably the most common PTTN etiologies;56,57 however, minor dental interventions such as nerve blocks, root canal treatment, and third molar extractions may also result in PTTN.58–62 Other causes include infection (i.e., AIDS), metabolic abnormalities (i.e., diabetes), malnutrition, vascular abnormalities (i.e., trigeminal neuralgia), infarction (i.e., central post stroke pain), neurotoxins, radiation, and autoimmune diseases. In most cases, occurrence of iatrogenic PTTN or other post‐traumatic neuropathies does not reflect on the quality of the surgical intervention.63
PTTN Etiology and Pathogenesis
The pathophysiology of painful traumatic neuropathies involves a series of events in the nervous system, involving changes in functional, biochemical, and physical characteristics of neuronal and glial cells. These changes are time dependent and progress from the peripheral to the central nervous system.64–71 Selected aspects of these events are discussed in the subsequent section.
Peripheral Sensitization
Peripheral sensitization is usually initiated in response to a variety of stimuli or types of tissue damage. Inflammatory mediators that are released at the damaged area directly activate or indirectly sensitize nociceptors. Development of sensory changes such as hyperalgesia and/or allodynia are characteristic of peripheral sensitization.
It has been shown that perineural inflammation along the nerve trunk (not necessarily in the nociceptor area) can induce ectopic activity and spontaneous pain at the target organ supplied by the nerve.72,73 Inflammation can affect nerve function either by secretion of mediators such as cytokines or by local pressure induced by edema.74 The inflammatory process and the peripheral sensitization progress rapidly; however, the condition is reversible. Nevertheless, if inflammation persists, it may induce nerve damage.75
Nerve Injury and Ectopic Activity
Trauma or severe inflammation may result in neuronal tissue injury leading to subsequent cell death. However, if the proximal stump survives, healing may occur, which often involves disorganized sprouting of nerve fibers that form a neuroma. Neuroma formation may be dependent on the degree of nerve damage and usually occurs when the perineurium is damaged. Milder injuries, such as nerve constriction or compression, may induce focal demyelination and regions of neuroma formation, which are characterized by ectopic neural activity partially caused by upregulation of specific sodium and calcium channels and downregulation of potassium channels. Mechanical and chemical stimulation of the neuroma can induce ectopic activity, resulting in pain when the injured area (and the neuroma) is touched. Ectopic activity is also seen in the cell bodies of injured nerves in the dorsal root or trigeminal ganglia; this may in part explain spontaneous neuropathic pain. Experimentally, trigeminal nerve neuromas are less active than those in sciatic nerve, suggesting relative resistance of the trigeminal nerve to trauma‐induced hyperactivity.
Phenotypic Changes
Nerve injury results in altered expression of neuropeptides in trigeminal ganglion, suggesting functional modifications. For example, under normal circumstances, Aβ fibers transmit innocuous stimuli; however, in the presence of persistent inflammation or injury there is a phenotypic change and they begin to express substance P.67 Aβ fibers thus acquire the ability to induce painful sensations in response to peripheral stimulation, partially explaining the phenomenon of allodynia.
Sensitivity to Catecholamines
During periods of stress or anxiety, which are accompanied by increased sympathetic activity, patients may report increased pain in the injured area. This may be due to upregulation of α‐adrenoreceptors in the dorsal root ganglion and the site of injury that induce sensitivity to circulating catecholamines. Additionally, sensory‐sympathetic interactions can be amplified by basket‐like sprouting of sympathetic fibers around large neuronal cell bodies within the dorsal root ganglion. This phenomenon has not been detected in the trigeminal ganglion and may explain the relative rarity of sympathetically maintained craniofacial pain.13
Central Sensitization
Ongoing or bursts of activity from primary afferents transmitted to the dorsal horn neurons (DHN) may trigger changes in the central nervous system. Repeated input from primary nociceptive afferents increasingly depolarizes DHNs leading to augmented responses (“wind up”). Prolonged DHN depolarization results in activation of the NMDA receptor (NMDAr), a calcium channel normally blocked by a magnesium ion. Upon activation, the magnesium ion blocking the NMDAr is removed, allowing calcium ion influx to the DHN and initiating a variety of intracellular events. Activation of NMDAr is thought to contribute to central sensitization by enhancing neuronal activity. Repeated nociceptive afferent input also leads to activation of other calcium channels (L‐, P‐, and N‐type) resulting in increases in intracellular calcium and DHN hypersensitivity, which manifests as hyperalgesia and/or allodynia.
Prolonged hypersensitivity may activate adjacent DHNs, probably by diffusion of neurotransmitters or by unmasking of silent inter‐DHN connections. Activation of adjacent DHNs expands the receptive field area, leading to perception of pain in areas not normally innervated by the involved peripheral nerve. The increase in receptive field can be detected clinically as sensitivity in the uninjured areas in the vicinity of the injury, named secondary hyperalgesia. The phenomenon of central sensitization accounts for increased pain and spread of pain to adjacent structures in patients with severe facial pain. The early neuronal excitability responds well to treatment as it is activity dependent. However, prolonged stimulation and long‐term changes originating in the DRG and DHNs involve modified gene expression and downregulation of repressor mechanisms that lead to further excitability. It is important to note that central sensitization characterized by hyperalgesia, temporal summation, and abnormal sensation may also develop following a minor injury such as third molar extraction or root canal treatment.76,77
Some months after nerve injury, neuronal death occurs (mainly C‐fibers) and sprouting of Aß fibers from deeper lamina follows as injured C‐fiber terminals withdraw from lamina I/II. The sprouting of Aß fibers results in increased pain induced by light touch.78
Glial and Satellite Glial Cells
Spinal cord glial cells have been shown to play an important role in the normal development, connectivity, and plasticity of the central nervous system.64 They also have a role in the initiation and maintenance of chronic pain and pain modulation. Glia cells express receptors and transporter proteins for many neurotransmitters and are able to release excitatory molecules, such as pro‐inflammatory cytokines, glutamate, nitric oxide, and prostaglandins, in response to neuronal signals. This leads to the enhancement of DHN hyperexcitability and neurotransmitter release from primary afferents.64,79 Glial cells may be an attractive therapeutic target because they participate in pathological pain and not in acute nociceptive responses.80,81
PTTN Epidemiology
Traumatic injuries to the trigeminal nerve largely result in either no residual deficit or in a nonpainful neuropathy; only a small proportion develop a painful neuropathy. There is wide interindividual variability in the onset and features of PTTN following identical injuries.
Macro trauma
Mild hypoesthesia of the infraorbital nerve is frequently observed following zygomatic complex fractures; however, neuropathic pain develops in only 3.3% of patients followed up for 6 months56 compared to around 5–17% in other body regions.82,83
Dental Implants
Neuropathy secondary to direct or indirect neuronal trauma may develop following implant placement. Between 0.6–36% of patients will experience neurosensory disturbances following implant placement84–89 as a result of damage to adjacent nerves that may also lead to pain.90–92 The large incidence range for neurosensory disturbances may imply that both transient and permanent changes were included. However, the exact incidence of postimplant PTTN is unclear. Direct damage may occur during site preparation and/or implant insertion, and indirect damage may result from bleeding and pressure buildup around the nerve or a perineural inflammatory response.
In some cases a major nerve trunk, usually the inferior alveolar nerve, may be impinged to a variable degree,93,94 especially when the implant is over inserted. In these cases, significant sensory dysfunction is immediately present postoperatively and the neuropathy is believed to result from inflammation and direct physical damage caused by the preparation and/or the implant.95
A small group of patients develop pain in spite of normal healing and in the absence of apparent complications. Pain and “sensitivity” to mechanical (chewing, brushing) and often thermal stimuli develop in these patients following implant loading. In some cases, the pain resolves when the implant is unloaded. The underlying mechanism for this pain is unclear; however, it is believed to be neuropathic.96
Mandibular and Third Molar Extraction
Between 0.3–1% of third molar extractions may be associated with altered sensation in the lingual or inferior alveolar nerve that persists for varying periods.97,98 Lingual nerve damage is observed less frequently than inferior alveolar nerve injuries99–101 but may reach 4% in extraction techniques involving nerve retraction.102
Nonpainful neuropathies that may develop following dental interventions have a reasonably good prognosis and most patients report improvement.103
Root Canal Treatment
Multiple factors, including apical infection or inflammation104,105 accidental injection or leakage of hypochlorite rinsing solution106–108, and extrusion of filling materials109,110 have been reported to cause chemical/physical injury that may contribute to nerve damage following endodontic therapy. Between 3–13% of cases report persistent pain following successful endodontics58,111–114, and 5% of surgical endodontics cases will develop chronic neuropathic pain.115 Multiple factors have been associated with persistent pain following endodontic treatment, including: long duration of preoperative pain, marked symptomatology from the tooth, previous chronic pain problems, and history of painful treatment in the orofacial region.113,114 Patients with persistent pain following endodontic treatment may have a deficient endogenous inhibitory system.77 The importance of preoperative pain parameters implies that some sensitization may have occurred, predisposing to chronic pain.
Multiple factors, including apical infection or inflammation104,105 accidental injection or leakage of hypochlorite rinsing solution106–108, and extrusion of filling materials109,110 have been reported to cause chemical/physical injury that may contribute to nerve damage following endodontic therapy. Between 3–13% of cases report persistent pain following successful endodontics58,111–114, and 5% of surgical endodontics cases will develop chronic neuropathic pain.115 Multiple factors have been associated with persistent pain following endodontic treatment, including: long duration of preoperative pain, marked symptomatology from the tooth, previous chronic pain problems, and history of painful treatment in the orofacial region.113,114 Patients with persistent pain following endodontic treatment may have a deficient endogenous inhibitory system.77 The importance of preoperative pain parameters implies that some sensitization may have occurred, predisposing to chronic pain.
Local Anesthetic Injections
Nerve injury may occur following local anesthetic injection secondary to physical trauma by the needle or by chemical insult from the anesthetic solution.116–119 Injuries more commonly occur during blocks to the inferior alveolar and lingual nerves, with lingual nerve injuries being more permanent.62 Lingual nerve injury is more likely during repeated injections and when the injection was reported as painful.62 The signs associated with injury due to local anesthetic injection are similar to other PTTNs and include burning pain, paraesthesia, allodynia, or hyperalgesia. It has been suggested that the degree of injury may be dependent on the type and toxicity of anesthetic agent used.120,121 Articaine 4%, when used as an inferior alveolar nerve block, was shown to be significantly associated with nerve injury and clinical symptoms.122 Therefore, its use for nerve blocks should be limited.
PTTN Diagnosis
Trauma cases should be carefully assessed to detect fractures, other injuries, and extent. Depending on the case, plain radiography or cone beam computerized tomography (CBCT) may be used.
Sensory testing is recommended, preferably with quantitative dynamic assessment,11,123 to evaluate the degree of injury.124,125 When advanced quantitative sensory testing (QST) equipment is not available, dental instruments may be adapted to assess gross sensory changes associated with PTTN. For example, pin‐prick sensation can be tested with a dental probe, thermal sensation with warm/cool instruments, and mechanosensation with cotton wool. The affected areas should be carefully mapped, marked, and photographed to become part of the patient’s documentation, evaluation, and follow‐up.
PTTN Clinical Features
PTTN is more prevalent in females and commonly occurs around 45–50 years of age.61,126–128 The pain is in the injured area and the affected nerve dermatome accompanied by evident sensory dysfunction.126 The pain may spread across dermatomes, but rarely crosses the midline. However, in more extensive injuries, where multiple nerves are affected, bilateral pain may occur. The pain is usually burning or shooting, with a moderate to severe intensity (VAS 5‐8)59,60,126,127,129 continuous, and long lasting.126 Paroxysmal spontaneous pain and pain triggered by touch or function has also been reported.59 Unlike trigeminal neuralgia, triggering areas are usually not accompanied by a latency or refractory period.126 Allodynia or a positive Tinel’s sign occurs more frequently in PTTN than in trigeminal neuralgia.59
Painful neuropathies may be associated with positive (e.g., dysesthesia) and negative symptoms (e.g., numbness).123,126,127 The sensory symptoms frequently associated with PTTN include thermal and mechanical allodynia.130 Extensive changes in the central nervous system somatosensory processing may induce additional sensory changes.11,131,132 The sensory changes may be described by the patients as swelling, a foreign body, numbness, hot or cold, local redness, or flushing, but these are not always demonstrable.59,126
Patients with PTTN may present with elevated levels of depression and pain catastrophizing and reduced quality of life. Quality of life and emotional problems, but not anxiety, can by predicted based on the intensity of the pain.127,133
PTTN Management
PTTN is characterized by a poor prognosis, improvement is observed in less than one‐third of patients and only 10–20% will report a significant improvement.103,127 Approximately half of the patients reported no improvement or worsened pain. Some degree of pain was experienced by most cases even at an average of 13 years after onset.127 Prevention is obviously preferable; however, it is not always possible.
Approaches for Preventing PTTN
It is unclear why some patients develop persistent postinjury (or postsurgical) pain and others do not. The factors contributing to the development of persistent pain may be grouped into three phases:134 (1) the preoperative phase includes risk factors specific to each patient, such as psychosocial parameters, genetically controlled pain modulatory mechanisms, the presence of related preoperative pain (i.e., painful surgical site), and comorbidities such as other pain disorders, obesity, and sleep disorders;135 (2) the intraoperative phase includes surgery dependent factors, such as technique, associated nerve and tissue injury, as well as the analgesic regimens; (3) the postoperative phase involves the patient’s coping ability, postoperative pain intensity, healing with scar formation, as well as possible additional confounding factors such as chemotherapy or other unrelated treatments.134,136
Preventive analgesia (pre‐emptive analgesia) is often recommended to avert the development of persistent postsurgical pain. Preventive intervention may involve various modalities and the recommended protocol varies with pre‐, intra‐ and postoperative components. Currently there is not enough evidence supporting a routine implementation or a unified protocol,137 yet a preventive strategy should be employed in selected cases. This may include selection of an alternative surgical approach that can minimize tissue damage and nerve involvement, preoperative anti‐inflammatory and analgesic treatments, deep local or regional anesthesia, and adequate postoperative analgesics to ensure no perioperative pain. Gabapentin employed 2 hours preoperatively and continued for 1–5 days postoperatively may reduce the incidence of persistent postsurgical pain.136 Preoperative anesthetic blocks have been suggested to reduce postoperative pain, but no protocol has been broadly accepted.138,139 The use of local anesthetic blocks during surgery (under general anesthesia) to prevent the injury‐associated afferent barrage and resultant central sensitization has been proposed; however, results are inconsistent. Local anesthetics have been shown to suppress postoperative pain and reduce analgesic consumption, but the effect on preventing chronic pain is unknown.140
A less efficient pain modulatory capacity has been shown to be indicative of patients’ risk to develop postoperative chronic pain.141–143 This could eventually translate to a chairside screening test to identify at patients at risk.
Factors contributing to lack of success in preventive strategies include inadequate management of the injury related sensory barrage and inadequate pain treatment duration.139 Preventive programs for selected patients (at risk) should include preoperative and perioperative analgesics, deep local or regional anesthesia, and excellent postoperative analgesics.
Approaches for Established Painful Traumatic Trigeminal Neuropathies
Pharmacotherapy
Anti‐inflammatory therapy is indicated for the treatment of postoperative clinically symptomatic temporary perineural inflammation (neuritis), as inflammation and neuritis has been shown to have a significant role in the pathophysiology of NP. Standard NSAIDs (for example, naproxen 500 mg b.i.d., ibuprofen 400 mg t.i.d.) are recommended to treat mild cases. The use of steroids such as prednisone, 40–60 mg initially then tapered over 7–10 days, or dexamethasone, 12–16 mg initially then similarly tapered, may be warranted in severe cases with sensory alterations or significant pain. Animal studies show that early dexamethasone may reduce neuropathic pain144 but there is no support for this concept from rigorous clinical studies. Treatment with steroids should be as short as possible and tapered to reduce side effects from consistently high dosages. If treatment is successful, patients may be transferred to a NSAID with an antacid treatment for a further 7–10 days.
PTTNs are extremely difficult to manage.145 Estimation of the Number Needed to Treat (NNT) for neuropathic pain induced by peripheral nerve injury is challenging due to the insufficient number of controlled trails. However, traumatic neuropathies are the most recalcitrant to treatment.145,146 Antiepileptic drugs (AEDs) and tricyclic antidepressants (TCAs) remain the mainstays of NP treatment.47,48,147
The available pharmacotherapies (antidepressants, anticonvulsants, opioids) may provide improved quality of life, sleep, and mood, but usually require high doses for NP, resulting in significant side effects. In NP patients, a 30–50% reduction in pain is considered significant pain relief, and only 20–40% of patients attain this.148–152
Drugs with mixed serotonin/noradrenaline (e.g., amitriptyline and nortriptyline) or serotonin and noradrenaline reuptake inhibitors (e.g., venlaflaxine and duloxetine) have been shown to be superior to the selective serotonin reuptake inhibitors.153,154 The NNTs for TCAs such as amitriptyline in painful polyneuropathies is relatively good and estimated to be 2.1.147 The more novel antidepressant drugs, the serotonin and noradrenaline reuptake inhibitors (SNRIs) demonstrated less efficacious pain relief (NNT = 5) for NP; however, they have significantly fewer side effects and therefore may be considered as an alternatives for the treatment of painful polyneuropathy.147
As a group, anticonvulsant drugs (ACD) are inferior to the antidepressants in the management of painful polyneuropathies. However, ACDs are heterogeneous in their efficacy for painful neuropathies.155,156 Carbamazepine or oxcarbazepine are efficacious in painful polyneuropathies (NNT = 3.7), but have more side effects than pregabalin (NNT = 4.5) or gabapentin (NNT = 6.4).147 Based on the efficacy of pregabalin and gabapentin in other peripheral neuropathies, they are theoretically good options for managing PTTN.
Opioids are not considered an effective treatment for traumatic neuropathies (NNT = 5).147 Combinations of drugs with different modes and sites of action may offer improved efficacy with reduced side effects. In diabetic polyneuropathy or postherpetic neuralgia, combinations of nortriptyline and gabapentin, or nortriptyline and morphine, have been shown to be more efficacious than monotherapy.157,158 Similarly, patients with painful diabetic neuropathy who did not respond to gabapentin monotherapy showed significant pain improvement when treated with the combination of gabapentin and venlafaxine.159 An oxycodone–gabapentin mix was shown to be more efficacious than gabapentin alone in diabetic neuropathy patients.160 Lower doses of gabapentin and morphine may also be combined to achieve significant analgesia in patients with PHN and diabetic neuropathy .161 Combining gabapentin and an opioid was shown to be superior to gabapentin alone in the treatment of neuropathic pain in adults, but this combination increases the risk of side effects.162 On the other hand, a combination of duloxetine and pregabalin was reported to provide no significant advantage over high‐dose monotherapy in the treatment of diabetic peripheral neuropathy.163 To date, there is a lack of clear evidence supporting recommendation of any one specific drug combination for neuropathic pain.162
Based on the available evidence, TCAs/SNRIs or gabapentin/pregabalin are the first drugs indicated in painful peripheral neuropathy.47,48,147 In patients initiated on amitriptyline that develop severe side effects, imipramine, desipramine, duloxetine, or venlafaxine should be considered. If these fail or are contraindicated, gabapentin or pregabalin offer the best chances for success. Similarly, in patients on gabapentin/pregabalin, treatment failure is an indication for a trial of TCAs or SNRIs. Combination therapy of SNRI or TCA with gabapentin or pregabalin should be considered if the above treatment options are partly successful.147 Opioids or tramadol may be used only as third line monotherapy or add on therapy. It is important to keep in mind that opioid treatments pose a risk of addiction and abuse potential. Therefore, screening, preventive measures, and careful monitoring should be in place in all clinics prescribing opioids. Cannabinoids are increasingly being tested147 and have NNTs of 3–5 in peripheral and central neuropathic pain.164,165
When applying a widely accepted pharmacotherapy protocol for neuropathic pain in a cohort of PTTN patients, unfortunately only 11% of patients achieved a ≥ 50% reduction in pain intensity, and patients with higher pain intensity scores were less likely to benefit from the therapy.145 Comparable response rates have been reported in other painful neuropathies,147 emphasizing the need for new drugs and treatment options for chronic neuropathic pain.
Topical treatments offer the benefit of minimal side effects, fewer drug–drug interactions, and improved patient tolerance; however, the affected areas are not always amenable to treatment.166,167 Evidence‐based topicals include lidocaine or capsaicin (low and high concentrations) patches and locally injected onabotulinum toxin A.168 Individually prescribed topical formulations are also in use.166
Cognitive behavioral therapy (CBT)
CBT does not have significant effects on pain intensity and quality of life measures in neuropathic pain patients.169 Nonetheless, NP patients should be offered psychosocial therapy as anxiety and depression are frequently comorbid.
Surgical Options
Surgery is recommended to improve sensation in injured patients with nonpainful neuropathies.170–172 Roughly 50% of repaired cases will recover complete sensory function within 7 months173 if treated within 1 year of injury.171,174–177 Inferior alveolar nerve injuries have a marginally better prognosis with surgical treatment compared to lingual nerve injuries178,179 and the presence of a neuroma is a negative prognostic factor.173,177
The role of surgery for painful trigeminal neuropathies is not clear. Often, patients with painful traumatic trigeminal neuropathy end up with more pain following peripheral surgical procedures (exploration, further apicoectomies). Therefore, patients with painful traumatic neuropathies should not undergo further surgery unless there are specific indications.180 Surgical intervention for PTTN patients may be indicated for the release of scar tissue, decompression, and neuroma excision, all of which have been shown to have good success rates.180
Decompression of an injured nerve by shortening or removing the implant completely may promote healing and prevent neuropathy. Each situation needs to be weighed individually according to the time elapsed since insertion, type, and degree of the nerve injury. Early removal or replacement of the implants (< 24–48 hours after placement) has been suggested to reduce incidence of neuropathy and pain.180,181 Microsurgical repairs may be considered for total resections of nerve bundles such as the inferior alveolar. Pharmacotherapy may be considered in management of early nerve injury and evidence of neuritis.
Osseointegrated implant removal may induce substantial collateral damage; therefore, implant removal must be weighed against the potential tissue damage and loss of function.
Central Surgery
In refractory cases, central nervous system procedures may be considered.182,183 Trigeminal dorsal root entry zone (DREZ) surgery may be performed.183 However, the primary choice of surgery should be minimally invasive, such as computed tomography (CT)‐guided percutaneous trigeminal tractotomy‐nucleotomy (surgical division of the descending fibers of the trigeminal tract in the medulla) aimed to ablate pathways that carry sensation from the face.
Orofacial Complex Regional Pain Syndrome (CRPS)
Complex Regional Pain Syndrome (CRPS) is a category of chronic, painful neuropathic disorders resulting from injury.184 Three types of CRPS have been defined: CRPS I (reflex sympathetic dystrophy); CRPS II (causalgia); and CRPS‐NOS (not otherwise specified) to allow inclusion of patients not meeting all the criteria.185 CRPS’s clinical presentation includes spontaneous pain, allodynia, and hyperalgesia not limited to dermatomal regions.186
The specific signs that differentiate CRPS from non‐CRPS neuropathic pain include regional changes in skin color, temperature, and motor function, sweating, edema, and thermal allodynia.187 CRPS I may develop as a result of relatively minor local trauma with surgery, fractures, crush injuries, and sprains being the most common causes.188 Injections, local infection, and burns resulting in minor or not identifiable nerve lesions with disproportionate pain have also been associated.189 CRPS II occurs less frequently and results from substantial injury to a major nerve, most often following high velocity trauma or surgery. The major distinguishing characteristic of CRPS is the disproportionate severity of the syndrome relative to the injury and nondermatomal spread of pain over time.184 Pain is commonly felt in the most distal part of the affected limb. CRPS I and CRPS II are often difficult to differentiate.189
It is not clear if CRPS occurs in the craniofacial region. The cases reported justify the diagnosis only on interventions aimed at interfering with sympathetic input,190 although sympathetic involvement is not always essential for CRPS diagnosis.191 With the exception of trophic and motor changes, CRPS criteria are similar to PTTN and other neuropathic pain conditions.
Classic Facial Neuralgias
The classic neuralgias that affect the craniofacial region are a unique group of neurologic disorders involving the cranial nerves and are characterized by: (1) brief episodes of shooting, often electric shock‐like pain along the course of the affected nerve branch; (2) trigger zones on the skin or mucosa that precipitate painful attacks when touched; and (3) pain‐free periods between attacks and refractory periods immediately after an attack, during which a new episode cannot be triggered. These clinical characteristics differ from other neuropathic pain disorders, which tend to be constant and have a burning quality without the presence of trigger zones.
Neuropathic pain involving the spinal nerves tends to be constant, whereas involvement of the cranial nerves may result in either constant pain or the classic brief episodes of shooting pain depending upon both the nature of the underlying disorder and the position of the lesion along the course of the nerve. For example, tumors involving the trigeminal nerve between the pontine angle in the posterior cranial fossa and the ganglion in the middle cranial fossa will usually result in the lancinating electric shock pain of classic TN, whereas more peripheral lesions will usually result in more constant pain. The classic craniofacial neuralgias include trigeminal neuralgia, glossopharyngeal neuralgia, occipital neuralgia, and geniculate neuralgia.
Trigeminal Neuralgia (TN)
TN, once also called tic douloureux, is the most common of the cranial neuralgias and chiefly affects individuals older than 50 years of age. The ICHD‐3 subdivides TN into three subtypes that may only be diagnosed following imaging. Classical trigeminal neuralgia (CTN) occurs with “demonstration on MRI or during surgery of neurovascular compression (not simply contact), with morphological changes in the trigeminal nerve root.” Compression is typically associated with nerve atrophy or displacement. Secondary trigeminal neuralgia is reserved for a typical TN phenotype associated with a local or systemic disease. Finally, idiopathic trigeminal neuralgia has been introduced for patients with typical TN not associated with nerve compression, local or systemic disease. Both classical and idiopathic trigeminal neuralgia are subdivided into purely paroxysmal and those with concomitant persistent pain.
TN Etiology and Pathogenesis
Approximately 10% of TN cases are symptomatic and have detectable underlying pathology, such as a tumor of the cerebellopontine angle, a demyelinating plaque of multiple sclerosis, or a vascular malformation. The most common tumor associated with TN is a meningioma of the posterior cranial fossa.
The most widely accepted theory is that a majority of cases of classic TN are caused by an atherosclerotic blood vessel (usually the superior cerebellar artery) pressing on and grooving the root of the trigeminal nerve. This pressure results in focal demyelinization and hyperexcitability of nerve fibers, which will then fire in response to light touch, resulting in brief episodes of intense pain.192 Evidence for this theory includes the observation that neurosurgical decompression of the nerve root from the vessel eliminates the pain in a majority of cases.193 Additional evidence for this theory was obtained from a study using tomographic magnetic resonance imaging, which showed that contact between a blood vessel and the trigeminal nerve root was significantly more frequent on the affected side.
Evidence against this theory explaining all cases of classic TN includes the observation by neurosurgeons that vascular compression is not always detected and manipulation of the area of the nerve root may eliminate the painful episodes even when an atherosclerotic vessel is not pressing on the nerve root. Neurovascular compression (NVC) is not identifiable in a significant number of CTN patients. For example, in a series of 219 patients with paroxysmal TN, 28.3% had no imaging evidence of NVC194 and up to 17% of patients undergoing surgery for TN had no NVC.195,196 Moreover, NVC is prevalent both on the symptomatic and asymptomatic side (89% versus 78%) in TN patients, but severe NVC is more prevalent on the symptomatic side (53% versus 13%).197 Interestingly, pain recurrence after initially successful MVD is often not accompanied by renewed nerve compression.198
Furthermore, 17% of age‐matched TN‐free controls have imaging evidence of NVC.199–203 Moreover, 14% of cadavers with no history of CTN demonstrate vascular contacts, although these had minimal grooving.199,200 Classifying CTN and ITN separately allows further study of these groups. TN patients with no NVC are typically younger and three times more likely to be female,204 supporting the clinical value of the new classification.
Observing neurovascular contact of itself, therefore, has low predictive value in establishing a diagnosis of CTN. The presence of anatomical changes associated with the neurovascular contact increases specificity and positive predictive value.203 Although NVC clearly plays a role in individual patients, at a population level, the high prevalence of NVC and the rarity of CTN suggest that a finding of NVC in CTN may often be insignificant. Current evidence postulates that TN is a far more complex disease (or cluster of diseases) than previously appreciated.
The pathophysiology of TN seems complex. Around 2% of all TN cases may be familial, and family clusters of TN indicate that it may have a genetic origin.205 Some of the suggested causes include: inherited anatomical changes affecting the base of the skull, which would promote compression of the trigeminal nerve by vascular structures; mutations in the gene encoding calcium channels resulting in hyperexcitability;205 as well as mutations in the serotonin transporter gene (5‐HTTLPR).206 Therefore, certain individuals may be prone to develop pain following neurovascular compression while others may be resistant, as in traumatic neuropathies.
TN Clinical Features
The majority of patients with TN present with characteristic clinical features, which include episodes of intense shooting, stabbing pain that lasts for a few seconds and then completely disappears. The pain characteristically has an electric shock‐like quality and is unilateral except in a small percentage of cases. The maxillary branch of the trigeminal nerve is the branch that is most commonly affected, followed by the mandibular branch, and, rarely, the ophthalmic branch. Involvement of more than one branch occurs in some cases.
Pain in TN is precipitated by a light touch on a “trigger zone” present on the skin or mucosa within the distribution of the involved nerve branch. Common sites for trigger zones include the nasolabial fold and the corner of the lip. Shaving, showering, eating, speaking, or even exposure to wind can trigger a painful episode, and patients often protect the trigger zone with their hand or an article of clothing. Intraoral trigger zones can confuse the diagnosis by suggesting a dental disorder, and TN patients often first consult a dentist for evaluation. The stabbing pain can mimic the pain of a cracked tooth, but the two disorders can be distinguished by determining whether placing food in the mouth without chewing or whether gently touching the soft tissue around the trigger zone will precipitate pain. TN pain will be triggered by touching the soft tissue, whereas pressure on the tooth is required to cause pain from a cracked tooth. Just after an attack, there is a refractory period when touching the trigger zone will not precipitate pain. The number of attacks may vary from one or two per day to several per minute. Patients with severe TN may be severely disabled by attacks that are triggered by speaking or other mouth movements and in severe cases there can be significant weight loss due to inability to eat without severe pain.
In some patients, a dull continuous pain called pretrigeminal neuralgia precedes the typical shooting pain by weeks or months. In this stage, trigeminal neuralgia is more difficult to diagnose and is more often confused with dental pathology.
TN Diagnosis
The diagnosis of TN is based on the history of shooting, electric shock‐like pain along a branch of the trigeminal nerve, the presence of trigger zones and refractory periods. A routine cranial nerve examination will be normal in patients with idiopathic TN, but sensory and/or motor changes may be evident in patients with underlying tumors or other CNS pathology. A clinical examination alone may be insufficient to distinguish symptomatic from classic TN; in some cases, electrophysiological testing of trigeminal reflexes is more accurate. Local anesthetic nerve blocks, which temporarily eliminate the trigger zone, and painful episodes are also good diagnostic tools.
Since approximately 10% of TN cases are caused by detectable underlying pathology, enhanced MRI of the brain is indicated to rule out tumors, multiple sclerosis, and vascular malformations.207 Magnetic resonance angiography may also be needed to detect difficult to visualize vascular abnormalities.
TN Management
Initial therapy for TN should consist of trials of drugs that are effective in eliminating the painful attacks. Anticonvulsant drugs are most frequently used and are most effective. Carbamazepine is the most commonly prescribed drug and is an effective therapy for greater than 85% of newly diagnosed cases of TN. The drug is administered in slowly increasing doses until pain relief has been achieved. Skin reactions, including severe cases of erythema multiforme and toxic epidermal necrolysis, are serious side effects. Patients receiving carbamazepine must have periodic hematologic laboratory evaluations because serious life‐ threatening blood dyscrasias occur in rare cases. Monitoring of hepatic and renal function is also recommended. Patients who do not respond to carbamazepine alone may obtain relief by combining carbamazepine with baclofen or gabapentin. Oxcarbazepine is the 10‐ketoanalogue of carbamazepine with a similar mode of action and is often better tolerated than carbamazepine. Routine serial testing for blood dyscrasias is not required, but hyponatremia may be a problem for elderly patients, especially those with cardiovascular disease such as an atrioventricular heart block.
Gabapentin, another anticonvulsant with fewer serious side effects than carbamazepine, may be effective in milder cases, but does not appear to be as reliable as carbamazepine or oxcarbazepine.
Other drugs that are effective for some patients include phenytoin, lamotrigine, baclofen, topiramate, and pimozide. Since TN may have temporary or permanent spontaneous remissions, drug therapy should be slowly withdrawn after a patient remains pain free for 3 months.
In cases where drug therapy is ineffective or when the patient is unable to tolerate the side effects of drugs after trials of several agents, surgical therapy is indicated. A number of surgical procedures that result in temporary or permanent remission of the painful attacks have been described, these include: procedures performed on the peripheral portion of the nerve, where it exits the jaw; at the gasserian ganglion; and at the brainstem, at the posterior cranial fossa.
Peripheral surgery includes cryosurgery on the trigeminal nerve branch that triggers the painful attacks. This procedure is most frequently performed at the mental nerve for cases involving the third division and at the infraorbital nerve for cases involving the second division. The potential effectiveness of this procedure can be evaluated prior to surgery by determining whether a long‐acting local anesthetic eliminates the pain during the duration of anesthesia. This procedure is usually effective for 12 to 18 months, at which time it must be repeated, or another form of therapy must be instituted.
One procedure performed at the level of the gasserian ganglion is percutaneous radiofrequency thermocoagulation, although some clinicians continue to advocate glycerol block at the ganglion or compression of the ganglion by balloon microcompression. A severe complication of peripheral procedures is severe neuropathic pain including anesthesia dolorosa, which is numbness combined with severe intractable pain.
The most extensively studied and most successful surgical procedure is microvascular decompression of the nerve root at the brainstem where the artery is separated from the nerve root. Over 70% of patients experience long‐term relief of symptoms.193 It should be noted that 30% of the patients experienced a recurrence of symptoms and required a second procedure or alternative therapy. Complications are rare but include stroke, facial numbness, and facial weakness.
Gamma knife stereotactic radiosurgery is a minimally invasive technique for the treatment of TN.208 The technique uses multiple beams of radiation, converging in three dimensions to focus precisely on a small volume of brain tissue. The method relies on precise MRI sequencing that helps localization of the beam and allows a higher dose of radiation to be given to targets inside the skull (for TN treatment: the trigeminal nerve where it enters the brainstem) with more sparing of normal tissue. This technique is not as effective as microvascular decompression, but is particularly helpful for elderly patients with a high risk of complications from surgery.
In summary, therapy for TN presently includes a variety of both medical and surgical approaches, each of which is effective for some patients. Drug therapy, including trials of several drugs or combinations of drugs, should be attempted before surgery is recommended. When surgery is necessary, the patient should be carefully counseled regarding the advantages and disadvantages of the available surgical procedures. Clinicians should also remember that since spontaneous remissions are a feature of TN, procedures resulting in temporary relief might be all that is necessary in some cases.
Glossopharyngeal Neuralgia (GN)
Glossopharyngeal neuralgia is a rare condition that is associated with paroxysmal pain that is similar to, although usually less intense than, the pain of TN. The location of the trigger zone and pain sensation follows the distribution of the glossopharyngeal nerve, namely, the pharynx, the base of the tongue, external ear canal, and infra‐auricular retromandibular region.209 Pain is triggered by stimulating the pharyngeal mucosa during talking or swallowing. The pain may be confused with geniculate neuralgia because of the common ear symptoms or with a temporomandibular disorder since pain may be associated with mandibular movements.
Glossopharyngeal neuralgia may occur with TN and, when this occurs, a search for a common central lesion is essential. Glossopharyngeal neuralgia also may be associated with vagus nerve involvement, which may cause syncope, asystole, bradycardia, hypotension, and cardiac arrest. Insertion of a pacemaker may be required to prevent syncopal episodes. The application of a topical anesthetic to the pharyngeal mucosa eliminates glossopharyngeal nerve pain, which can aid in distinguishing GPN from other cranial neuralgias.
The most common causes of glossopharyngeal neuralgia are intracranial or extracranial tumors and vascular abnormalities that compress the ninth cranial nerve. Treatment is similar to that for TN, with a good response to carbamazepine and oxcarbazepine. Refractory cases are treated surgically with microvascular decompression, percutaneous radiofrequency thermocoagulation, or gamma knife radiosurgery.210,211
Nervus Intermedius (Geniculate) Neuralgia
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