Trigeminal neuralgia

Case History

A 43-year-old woman, who had a thirteen-year history of severe right-sided facial pain associated with dysautonomia, presented for a dental evaluation of a complex, chronic orofacial pain disorder of long duration. The medical diagnosis was difficult because the combination of the conditions presented was rare in a single patient. The diagnostic process was made even more arduous by misleading and confounding factors in the patient's history. Further confusion resulted because the patient had had multiple, failed and often-invasive procedures that added postsurgical complaints and drug side effects to the milieu of symptoms.

The patient had a lengthy history of trigemino-autonomic cephalgia (TAC). Concomitant with dental procedures the patient experienced symptoms of unilateral, orbitotemporal headache associated with ipsilateral autonomie dysfunction. As her symptoms intensified, a variety of dental and medical remedies were attempted with only limited success. The diagnosis of chronic paroxysmal hemicrania-trigeminal neuralgia (CPH-tic syndrome) was ultimately determined by virtue of a meticulous history and responsiveness of symptoms to pharmacotherapies known to be effective for chronic paroxysmal hemicrania (CPH). This case illustrates a unique pharmacologic delivery system to facilitate the desensitization of intraoral trigger zones of trigeminal neuralgia (TN).

Chronic Paroxysmal Hemicrania

Chronic paroxysmal hemicrania is a condition for which the patient may seek a dental as well as a medical evaluation. Patients with paroxysmal hemicrania (PH) have the same pain characteristics as cluster-headache patients and may have the same associated signs and symptoms. The headaches associated with PH differ from cluster headaches in that they are of shorter duration, are much more frequent, and occur mainly in women. Like cluster headaches, the attacks are consistently unilateral, particularly involving the orbit and adjacent areas, and there may be one or more associated ipsilateral autonomie symptoms (eg, conjunctival injection, tearing, nasal congestion, rhinorrhea, [and less commonly] ptosis, miosis and eyelid edema).1 Headaches due to CPH resemble cluster headaches in character but are distinguishable by their dramatic response to indomethacin therapy.2

Chronic paroxysmal hemicrania belongs to a group of primary headache disorders that are characterized by brief, short-lived attacks of head pain that recur multiple times throughout the day and may occur during sleep, awakening the patient with pain. These syndromes are much less prevalent than other types of primary headaches (eg, migraine, tension-type) but are significantly more disabling.3 Pain is typically periorbital and retrobulbar in the midfacial region. Attacks of cluster headache may occur at a frequency of 4 to 8 per 24 hours and are described as severe or extremely severe. Attacks of CPH are more frequent-as many as 38 attacks per day have been reported-and are of shorter duration, approximately 15 to 20 minutes.4

Differential diagnosis of CPH includes myofascial pain, odontogenic pain (eg, dental abscess, atypical odontalgia) and TN. In some cases misdiagnoses of dental problems lead to unnecessary or inappropriate dental therapies.

Trigeminal Neuralgia

Trigeminal neuralgia is the most common form of paroxysmal facial pain. The incidence in the United States is 4:100,000/year and TN primarily affects patients over the age of 50.5 Trigeminal neuralgia is characterized by sudden bursts of electric-like, shooting pain which usually follows the unilateral distribution of the affected nerve. Unlike CPU, TN is not usually associated with secondary central excitatory or autonomic effects. There is no referred pain. Attacks of TN are also short-lived, as are those of CPH, but are often provoked by light touch or nonnoxious temperature stimulation of a specific area in the orofacial region. These specific areas are known as trigger zones and their presence helps to confirm the diagnosis. In addition to the brief, provoked, or spontaneous bursts of pain, a patient with TN may also report refractory periods during which, after several stimulated attacks of pain, no further stimulation is possible. Periods of remission lasting weeks, months or years may also be reported.

Trigeminal neuralgia may be classified as symptomatic or idiopathic. Symptomatic TN is more common in younger patients. Of symptomatic TN cases, 50% may be related to lesions with neurologic deficits such as tumor or vascular malformations, or demyelinating diseases such as multiple sclerosis or Lyme disease.6 Idiopathic TN is of unknown etiology,7 is more common than symptomatic and occurs more commonly in women than in men. While pain may last weeks or months and go into remission for months or years, with time there is a tendency for exacerbations and remissions, with an overall progressive increase in frequency, duration and severity of the attacks.

Differential diagnosis of TN includes acute dental pulpitis, temporomandibular disorders, atypical odontalgia, glossopharyngeal neuralgia, CPH and cluster headache.

Paroxysmal Hemicrania-Tic Syndrome

Paroxysmal hemicrania may coexist with TN and is referred to as PH-tic syndrome.8 A review of the medical literature nnds that CPH and TN occurring in the same patient has been reported on only four previous occasions.9-12

Recognition of the syndrome is important for therapeutic reasons. The tic-like pains often respond to medications that are used for TN (eg, carbamazepine), while the cluster or CPH headache responds to agents that are used specifically for that diagnosis.1

Symptoms

The patient reported that the pain was strictly unilateral, involving the nose, right eye, temple and maxillary teeth. She described the pain as being like lightning bolts in her sinuses and eyes. Attacks were moderate to severe and lasted as little as 3 to 5 minutes, with longer attacks having a duration of up to 45 minutes. Pain was not continuous but occurred in a series of attacks that lasted for months at a time. Periods of remission from these attacks also lasted for months. At the time of the initial evaluation, orofacial pain had been fairly constant. Dysautonomia was present during the severe attacks of longer duration. This included copious ipsilateral sweating, facial flushing, nasal discharge and lacrimation. Pain was exacerbated by stress. A review of the patient's history showed that the prolonged attacks seemed to worsen in February of each year and the pain continued until March or April. Her history showed that the duration of the pain was prolonging, with pain persistent through May. Remissions occurred during the summer. Attacks sometimes occurred in winter but were not as severe.

In addition to the symptoms noted above, the patient also described brief paroxysmal pain that usually occurred during attacks. This pain radiated from the ipsilateral maxillary buccal mucosa. Paroxysmal pain could be stimulated by light touch (cotton-tip applicator) of the right maxillary buccal mucosa and along the right upper lip. There were no other trigger zones on the face or intraorally, although the patient did report difficulty wearing makeup. Repeated provocation of the trigger zones of the buccal mucosa led to a refractory period of 15 to 20 minutes, after which the trigger zones became susceptible to further stimulation. Mild allodynia was present on the ipsilateral cheek, as well as an occasional warming/burning dysesthesia between attacks. The patient had experienced these symptoms since onset at age 33. She related the onset of her orofacial pain to the placement of a crown restoration on a maxillary right molar.

Clinical Examination

There was no significant sensory loss. The patient felt hyperalgesia, perhaps bordering on allodynia, in the second division of the ipsilateral trigeminal nerve (CN V2), but she was symmetrical regarding light touch, point discrimination and pinprick. She reported increased burning pain of her cheek at the start of her menstrual cycle. She explained that the burning pain began and brief paroxysm of periorbital pain broke through approximately 1 day into her cycle.

Brain imaging was negative for intracranial lesions or plaque. Magnetic resonance imagery with contrast of the cavernous sinus was also negative. Earlier diagnostic evaluations had included a negative lumbar puncture. All serology was consistently within normal limits.

Prior Treatment

The patient had been examined/treated by 16 separate healthcare providers with only marginal success. Prior treatments ranged over multiple endodontic procedures, including apicoectomy, temporomandibular joint therapy, and nasal septum and sinus surgery. Pain control was attempted through pharmacology and acupuncture.

Past Medications

Past medications included analgesics, antihistaminics, antimigraine medications, birth control, nonsteroidal anti-inflammatory drugs (NSAIDs) and antidepressants. At one point indomethacin was prescribed, 25 mg three times per day, which provided dramatic but not total relief and was, therefore, abandoned as ineffective. Carbamazepine 1200 mg/day was prescribed for a one-month trial. It was ineffective, as were amitriptyline and a variety of opiates that provided only a marginal reduction of symptoms.

Medications taken by the patient at the time of the initial examination were:

* Gabapentin 1200 mg/day

* Nortriptyline 50 mg/day

* Occasional NSAIDs

All of the patient's past neurologic examinations were reportedly negative.

Diagnostic Conclusion

Based on the location, duration, quality, frequency and temporal behavior of the attacks, and the precipitating factors that were present for at least one component of the patient's complaints, it was concluded that the patient suffered with two distinct pain disorders.

The unilateral, orbitotemporal headaches associated with ipsilateral autonomic dysfunction that usually lasted not longer than 45 minutes and recurred three or more times daily were best described as a TAG. At one point this component of the patient's orofacial pain resolved when she was prescribed indomethacin. Based on the history and on her positive response to indomethacin, it was determined likely that one facial pain disorder suffered by this patient was CPH, although a cluster variant may have been possible. She also suffered with frequent, episodic neuralgic pain in the distribution of the second and third divisions of the trigeminal nerve (CN V2-V3), which met the diagnostic criteria for TN (ie, trigger zones in the buccal mucosa and ipsilateral upper lip which, when lightly stimulated, provoked paroxysmal pain). She was given carbamazepine and gabapentin. Her response was unclear. It was concluded that she was symptomatic of cluster-tic syndrome and, although various medications provided marginal relief from some of her overall symptoms, she was never treated for both conditions simultaneously. She may have had relief from one complaint while the other was active.

The third problem was her symptoms, which were described in terms of secondary hyperalgesia. The burning, spreading second-division trigeminalnerve (CN V2) pain was only present during attacks. It was not clear if this was a manifestation of secondary hyperalgesia from past dental surgeries or sinus procedures. It was possible that this hyperalgesia or sensitivity of the skin overlying the affected region was related to resolving symptoms of CPH attacks.13

Treatment

Over the course of several months there were several trials of various medications that seemed to offer relief from the symptoms of CPH. Seasonal use of indomethacin was uniformly successful in controlling the severe, prolonged midfacial pain attacks. However, management of the TN was more difficult, as the paroxysmal episodes were refractory to most medications and the attacks often seemed to blend into, or were perhaps initiated by, the symptoms associated with CPH. On some occasions the paroxysmal pain would occur in repeated volleys that made the distinction between CPH and TN even more difficult to discern.

Following a neurologic/headache evaluation, the patient was given an intravenous load of valproate sodium followed by oral valproex sodium; valproex sodium has been shown to have good success in the treatment of both TAG and TN. The valproex sodium was increased and the gabapentin tapered. It was felt that if her pain responded to the valproex sodium then a cluster-tic variant was likely. If, on the other hand, the pain was due to CPH-tic syndrome then indomethacin would be required. Serology studies were performed throughout this regimen to monitor platelets and liver function.

In addition to the medications initially provided, desensitization of peripheral trigger zones associated with the TN was also attempted by use of topical transdermal/transmucosal preparations.

Transdermal Medications

The transdermal delivery of medications to a treatment target represented a unique and effective means by which to accomplish this and other forms of pharmacotherapy with a minimal, if not negligible, systemic effect.

A compounded liposomal base that contained penetration enhancers was used to carry the medications transdermally and transmucosally. Two distinct transdermal formulations were used: (1) an external liposome transdermal gel containing ketamine, ketoprofen and guaifenesin; and (2) an intraoral liposonial Orabase containing carbamazepine, lidocaine, capsaicin, ketoprofen, ketamine, gabapentin and clonidine. The use of several medications was considered in order to address the complex nature of the patient's pain syndrome, which included the neuropathic component. The receptors of the various medications used in this case were documented as resident in the local tissues.14

Based on the key role that the N-Methyl-D-Aspartate (NMDA) receptor performed in causing pain and suffering in this patient, the authors suggested (1) an NMDA antagonist, (2) a glutamate/alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist, and (3) either an alpha-2 agonist or a [gamma]-aminobutyric acid (GABA-[beta]) agonist. The regimen of low-close, multiple, concomitant, complementary therapy starts with at least these three medications incorporated into either external or internal transdermal bases, normally applied at 6-hour intervals on a regular basis and as often as every 2 hours as needed for breakthrough pain. Dose escalation can occur daily or every other day until pain is relieved or, although they are rare, until side effects occur. If needed, additional medication from a different mode of action should be added within 1 or 2 weeks after the start of therapy. Implementing this treatment algorithm involves a process of thoughtful consideration for the specific patient.14

The uniqueness of chronic neuropathic pain is that its multiple etiologies share a common pathway. The key mechanism involved in the modulation of afferent signals in the central nervous system (CNS) is the NMDA receptor.15 Located throughout the CNS, the NMDA receptors play a crucial role in the modulation of pain signals, the maintenance of chronic neuropathic pain and the development of hyperalgesia and allodynia.16-17 This development is the result of activation of the NMDA receptor by glutamate, which in turn affects other ionic receptors. Non-NMDA receptors are also referred to as AMPA, substance P, alpha agonists and antagonists, GABA agonists and the free radical system. Since AMPA receptors are known to be located in close proximity to NMDA receptors, antagonists of these receptors should be used together.18

Mechanisms of Transdermal Delivery

The skin is a barrier that protects the body from invasion by extracorporal foreign bodies or infectious organisms. Certain compounds have the ability to cross the layers of the skin and mucosa for local effects and to obtain access to blood vessels and the general circulation.

Transdermal compounds are designed to transport medications through the skin or mucosa; the medication is delivered transdermally as an alternative to oral or patenterai administration. This is useful when systemic administration is contraindicated or when effective levels of medications would result in unacceptable side effects. This method of drugdelivery is especially suited to localized neuropathic conditions when a variety of systemic neuropathic medications have been tried with suboptimal results.

The use of transdermal or transmucosal preparations allows the medications to treat a target tissue with effective levels of medications while avoiding systemic uptake or side effects. The mechanism of delivery of transdermal and transmucosal preparations is a carrier that will transport the medications through the skin or mucosa to the target tissue. For this patient, a topical preparation was prescribed to target the intraoral trigger zones in an attempt to reduce the episodes of attacks of the TN.

A matrix is formed within a Pluronic lecithin organogel (PLO), into which the drug is absorbed. The epidermis is lipid in nature, and PLO is a hydrophilic/lipophilic liposomal delivery system. This transdermal lecithin-based gel enhances the transportation of many drugs through the epidermis and mucosa.

The molecules of the chosen medications are compounded into micellessmall, spherical structures composed of a few dozen to a few thousand molecules that attract one another to reduce surface tension within the membrane of a cell (Figure 1). The head of the molecules composing the micelle is hydrophilic (water soluble) and the interior is hydrophobic (lipid soluble). Due to the manner in which the individual units composing the micelle are arranged, water does not penetrate into the core of the aggregate sphere. Under proper conditions, micelles form lipid bilayers called liposomes. These lipid bilayers are fundamental to the structure of all biologic membranes. The liposome can penetrate the lipid-solublc epidermis layer.

PLO is a transdermal gel base that acts as a carrier for the liposome and enclosed medication and moves it across the skin where it can have local effects or be taken up by the bloodstream. Many drugs, regardless of lipophilicity, size or polarity, can be enclosed in PLO. The result is that the liposome packets (micelle) filled with the chosen medication pass through the skin or mucosa and into the underlying soft tissue. Once through the skin or mucosa, the micelle breaks down, releases the enclosed medication and generates its effects on the target nerve endings, muscle, and so on. This system is compatible with a wide variety of drugs. Table 1 lists the advantages and disadvantages of transdermal application and supplies a list of some of the currently available medications for transdermal application.

Attempts to reduce the symptoms of this patient's TN component of her complex orofacial pain disorder were not successful with the use of orally administered medications. The application of topical anesthetic agents was successful in ameliorating the symptoms; therefore, it was felt that this patient was a good candidate for treatment with topical medications for management of the neuropathic portion of her pain complaints.

This compounded medication was delivered intraorally to the target area in the right maxillary buccal fold by way of a neurosensory stent (Figure 2), which is a laboratory-processed acrylic shield similar to a denture base that is custom-fitted to the soft tissue in the region (Figure 3). This stent acted as a mechanism to carry the transmucosal compound to the target area and protected the trigger zones of TN from stimulation. A thin coating of the medication was placed in the shell of acrylic and was applied to the target area, where it was held in place by adding Orabase to the PLO. Orabase is typically applied intraorally to protect mucosal injuries and intraoral ulcers. Mixing this material into the compound gives it an adhesive quality, initially the compound was changed every 4 to 6 hours.

Within approximately 10 days the activity of the trigger zones was diminished and remained so after 2 weeks. The frequency of use of the compound was reduced slowly to twice daily and then discontinued after 8 weeks. The patient was advised to use the compound as needed if she began to feel sensitive in the region.

Oral doses of verapamil 480 mg/day and gabapentin 4000 mg/day were added in conjunction with the topical therapies, which resulted in an additional reduction of pain by 50% and amelioration of the TN trigger zones. Indomethacin controls the CPH-related symptoms, with the occasional use of a methylprednisolonc in a quick tapering dose for severe attacks of CPU/TAC.

Conclusion

This presentation describes a rare occurrence of CPH-tic syndrome. Orofacial pain can manifest in many ways, some of which may mimic dental pain. The patient presented with severe CN and idiopathic vascular facial pain; she had submitted to multiple and nonproductive medical and dental treatments, many of which were invasive. With the realization that her facial pain was not of odontogenic or otolaryngologic origin, more viable diagnoses were achieved, appropriate treatment was implemented, and relief followed. The recognition of two or more comorbid conditions suggested combined and unique therapies, which offered success where singular therapies had not been efficacious.

References

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18. Salt TE. NMDA receptors and their interactions with other excitatory amino acid receptors in synaptic transmission in the mammalian central nervous system. In: Collingridge GL, Watkins JC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed. New York: McGraw-Hill; 1996:276-294.

Gary M. Heir, DMD

University of Medicine and Dentistry of New Jersey

Division of Diagnostic Sciences

New Jersey Dental School

Newark, New Jersey

Bernard Covalesky, RPh

Scott Karolchyk, RPh, MS

Pharmacy Creations

Randolph, New Jersey

Address correspondence to: Gary M. Heir, DMD, 718 Broadway, Bayonne, NJ 07002. E-mail: heirgm@umdnj.edu

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