Oral Dysesthesias
and Burning Mouth Syndrome: Taste is a Piece of the Puzzle
The published
version of this paper can be found in The Canadian Journal of Diagnosis, June,
2000, pp. 99-109.
Miriam Grushka,
MSc, DDS, PhD and Linda M. Bartoshuk, PhD
Despite numerous advances in our understanding of Burning Mouth Syndrome (BMS) diagnosis and management remain difficult. Part of the difficulty is the fact that patients often present with multiple oral complaints including burning, dryness, alterations of taste and taste phantoms. Non-taste, non-pain sensations also occur. Accurate epidemiological data are hard to collect because of the lack of universally accepted criteria. There are usually no clinical findings with BMS patients. When clinical findings do occur, treatment directed at correction of these factors is usually ineffective in reducing the oral burn and other dysesthesias and often serves to increase the frustration experienced both by the patients and their health care providers [1, 2] .
For most BMS patients, burning is usually reported on the tongue tip, lateral borders of the tongue, anterior palate and mucosal lips although it can occur at any intra-oral site [3] . Onset can be either gradual with no known precipitating factors. It can also be sudden and linked to a preceding dental procedure (including a tooth cleaning, filling or a new denture), upper respiratory infection or a course of antibiotics. Once started, the burning pain typically increases progressively over the day, reaching its maximum intensity by late evening. It is rarely present during the night and is often at its lowest intensity upon awakening but reappears ofter the first meal. The burning can last for many years with spontaneous partial remission occurring within 6 to 7 years after onset in about one-half to two- thirds of patients [4, 5] . No significant differences in age, sex, duration of disease or distribution of burning sites have been found among individuals who experience either partial or full remission compared to those individuals who report no remission [5] . There are few good data following the natural history of this disorder.
In most clinical populations, BMS patients are predominantly post-menopausal women. The usual time of onset ranges from several years before to approximately 12 years after menopause [3] . Hormone replacement therapy is rarely effective in reducing oral symptoms [6] .
Although many studies have searched for objective changes in BMS patients to explain the origin of the burning pain, these studies generally fail to identify causal factors. For example, denture wear, nutritional factors, systemic diseases, and estrogen levels have all been proposed as etiological agents; but treatment for each of these does not consistently reduce symptoms. One exception to this is oral burning secondary to the use of the angiotensin converting enzyme (ACE) inhibitors such as captopril, enalapril, and lisinopril [7] ; in these cases both the oral lesions (when present) and the pain have remitted following discontinuation of the medication.
A multitude of studies have demonstrated psychological changes in BMS subjects (including anxiety and depression) compared to age and sex matched control subjects (see [1] for a review). The presence of such psychological symptoms in combination with the absence of clinical findings has caused BMS to be viewed as a primarily psychological disorder associated with menopause. This belief has been fueled by the lack of responsiveness of BMS to most treatments, increasing the frustration of both patient and health-care provider and suggesting to some a lack of patient motivation in getting well.
A psychogenic basis for BMS has gained strength from a number of other sources as well. For example, in addition to the burning pain, many patients also complain of distressing oral dryness without any clinical evidence of mucosal alterations or increased tooth decay. Moreover, most salivary flow studies in BMS (see [1] for a review) have failed to demonstrate decreased salivary output although selective alterations in salivary levels of factors such as proteins, mucin and immunoglobulins have been found ( e.g. see [8, 9] ). Further, even in patients complaining of taste disturbances, there is rarely any evidence of weight changes [3] and patients rarely report difficulty eating as a result of the alterations in taste; in contrast, patients usually report increased comfort during eating with diminished dysgeusia and burning [3] .
Blood tests are usually normal. Allergies to dental materials and toxicity to mercury from silver amalgam fillings have not generally been supported by the literature (e.g. see [2] for a review). Attempts at dental solutions (e.g., replacement of silver fillings or dentures, implants, dentures made of hypoallergenic materials) are usually unsuccessful, sometimes even increasing the oral dysesthesias. These negative findings have previously been explained to be the result of neurotic or obsessive characteristics of patients. The finding in the 1980’s that low doses of tricyclic antidepressants or benzodiazepines (including amitriptyline or chlordiazepoxide) can reduce oral burning provided additional support for the psychogenic attributions [10, 11] .
In contrast to the above, since the late 1980’s, there has been a growing body of evidence that BMS is not psychological in origin. In fact, BMS may prove to be a model for other pain disorders both in the orofacial area and elsewhere. Studies carried out in the late 1980’s initially began to challenge the notion of causality (e.g., see [12] ) and suggested instead that the psychological factors found in BMS were the result and not the cause of the pain.
Burning pain, the main feature in BMS, is also a characteristic feature of some post-traumatic nerve injuries. In the latter conditions, however, additional sensory abnormalities are often present which manifest as changes in perception of touch, temperature, two-point discrimination and pain (e.g., see [13] ). Other than abnormalities in taste [14] psychophysical testing of many of these modalities in BMS subjects, however, failed to reveal abnormalities in perception at any of the intraoral and extraoral facial sites tested when compared to control subjects. The only exception was the finding that heat pain tolerance in BMS subjects was significantly reduced at the tongue tip [13] . These findings were extended by Lamey [15] who confirmed the absence of sensory abnormalities in perception of stimulus size in BMS subjects compared to controls. In contrast, more recent studies using argon laser stimulation have noted qualitative and quantitative differences in some sensory functions of BMS subjects [16] . Further, Lauritano et al [17] have demonstrated subclinical polyneuropathy in 50% of patients involving a loss of function in small diameter nerve fibres. Finally, Jaaskelainen et al [18] demonstrated abnormalities in the blink reflex of BMS patients which was associated with disease duration. These are consistent with the possibility of generalized modifications in the nervous system.
Taste phantoms (taste sensations in the absence of stimulation) are known to be associated with damage to the taste system. This results because the phantoms are related to inhibition in the taste system. For example, input via the chorda tympani taste nerve (branch of CN VII) travels to the cortex, crosses the midline and then descends, ultimately inhibiting the area of the brain receiving input from the glossopharyngeal nerve (CN IX). If the input from the chorda tympani is interrupted, the inhibition ceases, leading to intensified taste sensations from the area innervated by the glossopharyngeal nerve [19] as well as taste phantoms [20] . Topical anesthesia of the mouth has proved useful in the diagnosis of the origin of some of these phantoms [21-24] . For example, increases in taste intensity following topical anesthesia are characteristic of phantoms.
Anatomical associations between taste and oral pain support the idea that damage to taste might be associated with oral burn phantoms (i.e., BMS) as well as taste phantoms. Taste buds are found in some of the papillae that give the tongue its bumpy appearance. The fungiform papillae (shaped like button mushrooms, hence the name) are found on the anterior (mobile) portion of the tongue, foliate papillae are found on the edges of the rear of the tongue and circumvallate papillae are circular structures arranged in an inverted V across the rear of the tongue. Filiform papillae are the most numerous and are distributed across the tongue; they have no taste function. The fungiform papillae are easily visualized by swabbing blue food coloring on the tongue. The fungiform papillae do not stain as readily as the filiform papillae and so they remain pink against a blue background (see Figure 1). The pink fungiform papillae are easily counted with a magnifying glass and a flashlight. The number of fungiform papillae is related to genetic variation in the ability to taste.
This variation was discovered in 1931 when a chemist, Fox, found that some individuals could taste the bitter compound PTC (phenylthiocarbamide) while others could not [25] . Subsequent study (e.g., [26] ) has shown that individuals unable to taste PTC (and related chemicals) have the smallest number of fungiform papillae (as few as five in the area indicated in Figure 1). Individuals who taste PTC can be divided into medium and supertasters. The supertasters have the largest number of fungiform papillae (more than thirty in the area indicated in Figure 1). It is important to note that women are more likely than are men to be supertasters. Each fungiform papillae contains, on average, six taste buds. Of special importance for oral pain, each taste bud is surrounded by a basket-like collection of pain neurons [27, 28] . Thus a supertaster is a superperceiver of oral pain as well.
Figure 1. Line drawings of the distribution of fungiform papillae in a nontaster (right side) and a supertaster (left side). The large circles (6 mm in diameter) are the templates used to count fungiform papillae. This is equivalent to the size of the hole produced by most paper punches.
There are connections between taste and oral pain in the central nervous system as well. This was demonstrated by anesthetizing the chorda tympani nerve on one side. The intensity of oral pain produced by capsaicin (the compound that makes chilis burn) intensified on the side contralateral to the anesthesia; however, this occurred in supertasters, not nontasters [29] .
New
Model of BMS
We propose that BMS represents an oral pain phantom induced in susceptible individuals by damage to the taste system. We suggest that normally, taste input inhibits the area of the brain receiving input from the trigeminal nerve. Damage to the chorda tympani releases that inhibition leading to intensification of normal trigeminal sensations as well as phantom trigeminal sensations. Trigeminal sensations include oral pain as well as sensations of touch and oral dryness.
Figure 2. Perceived intensity of the peak pain experienced with burning mouth syndrome plotted against the number of fungiform papillae in the 6 mm template indicated in Figure 1. The peak pain was assessed with Green’s labeled magnitude scale [43] as modified by Bartoshuk et al [44] .
There are several lines of evidence that support this model and explain why BMS is found predominantly (but not exclusively) in postmenopausal women. First, the ability to taste bitter is reduced following menopause [30, 31] ; this reduction acts like taste damage in that it reduces taste input to the CNS. With that reduction, there is an increase in the perceived intensity of oral burn to supertasters [32] . Second, topical anesthesia of the mouth intensifies the oral burn of many BMS patients [1, 33] . Just as with the anesthetic effects on taste phantoms, the intensification of a phantom with anesthesia suggests that the phantom results from release of inhibition. Third, the intensity of the peak oral pain experienced in BMS correlates with density of fungiform papillae [34, 35] ; that is, individuals with BMS are supertasters (see Figure 2). Fourth, preliminary spatial taste testing in BMS subjects shows damage to the anterior tongue (chorda tympani nerve); in particular, the ability to taste bitter is reduced, or in some cases, abolished completely [35] .
Related evidence for the interaction of pain, taste and perhaps oral dryness/wetness are provided by studies following injury during third molar extraction or other dental procedures. For instance, there have been reports of taste loss, burning pain of the tongue and lips, tingling and drooling following dental treatment excluding extraction ( e.g. [36] ). Similarly, parasthesias, pain, abnormal tastes, and drooling have been reported to follow damage to the inferior alveolar nerve and lingual nerve during mandibular third molar extraction [37] . Moreover, Sandsedt et al [37] have also demonstrated that although the male/female ratio was 30:70 in patients who have suffered injury to the trigeminal nerve during lower third molar extraction, women and older patients tended to have the most severe complaints. The association of symptomatology similar to the types of complaints reported in BMS suggests a relationship between symptoms that cannot be totally explained by the actual degree of nerve injury alone. Other mechanisms, including damage to some nerve fibers and release of inhibition of others, appear to provide a better model for the understanding of the totality of the complaints following nerve injury.
If this model fits, it changes the underpinnings of our understanding of orofacial pain. It implies that previously difficult to understand disorders such as atypical odontalgia, may have a logical explanation. Atypical odontalgia can follow a dental procedure and result in constant tooth pain in the absence of any pathology. Based on the model proposed above, minor injury to the chorda typmpani, from whatever cause, may be able to release inhibition on the trigeminal nerve, resulting in oral pain and increased activity in the muscles of mastication ( since the masticatory muscles are innervated by CN V). In fact, preliminary observations (Grushka and Bartoshuk, unpublished data) support the finding of selective taste loss at the fungiform papillae in atypical odontalgia patients. Preliminary evidence suggests the possibility that patients susceptible to this type of damage may be supertasters which might put them at greater risk from dental interventions. Evaluation of this model and its associated risk factors may be helpful in understanding which patients are at risk and in devising ways to protect them from injury and/or reinjury.
Antidepressants: For many years, low dose tricyclic antidepressants ( TCA’s) including amitriptyline, desipramine, nortriptyline, imipramine and clomipramine remained the treatment of choice in the management of BMS. The choice of these medications was based on the effectiveness of the tricyclic antidepressants as analgesics. Controlled trials demonstrated the effectiveness of amitriptyline in alleviating oral burning in some BMS patients [10] . However, despite the evidence of efficacy of the tricyclics, many patients choose to discontinue their use due to incomplete relief together with side effects including weight gain, constipation, and increased mouth dryness. Studies with selective serotonin reuptake inhibitors (SSRI’s) other than trazadone have not yet been reported. Controlled trials have failed to demonstrate efficacy of trazadone in BMS [38] . Anecdotal reports of the use of SSRI’s in BMS also provide little evidence of their efficacy in BMS. No controlled trials are available for MAO inhibitors.
Benzodiazepines: There are several published reports that both chlordiazepoxide and clonazepam, GABA (gamma-amino butyric acid) receptor agonists, may be effective for some orofacial pain conditions including BMS [11, 39, 40] . These drugs are believed to facilitate the inhibitory actions of GABA. In one study, [11] chlordiezepoxide reduced the pain in BMS in approximately two-thirds of subjects at daily doses of 15 to 30 mg daily. More recent studies [39, 40] have suggested that only low doses of clonazepam are required to reduce the oral burning - and in some cases the taste dysgeusias as well -in up to 70% of patients at very low doses. Woda et al [40] additionally demonstrated the possibility of a topical effect of clonazepam in reducing oral burning in approximately 2/3 of their BMS patients when this medication was used in a dissolve and spit technique. Although it is possible that these medications may be exerting their effect through their sedative-hypnotic activity, their efficacy at very low doses suggests the possibility of a selective action at some point in the taste-pain pathways.
These studies also suggest no particular benefit to increasing doses of clonazepam beyond what appears to be its “window” of activity in BMS. Anecdotally, it appears that some patients with only a partial response to clonazepam may do better on a combination of medications ( e.g. clonazepam and low dose gabapentin-50 to 300 mg ) rather than on higher doses of either medication. Interestingly, some preliminary evidence suggests that other associated oral dysesthesias including taste disturbances and subjective oral dryness may remit along with the burning pain in successfully treated individuals. There is currently no data to explain the variability of clonazepam in BMS (1/3 almost complete remission;1/3 with partial effect; 1/3 with no effect replicated in two studies [39, 40] .
Capsaicin: Capsaicin desensitization is an effective oral anlygesia when lesions are present [41] . According to our hypothetical model, capsaicin would not be expected to be effective in reducing BMS since the burn is a central and not a peripheral phenomenon.
This is in contrast to atypical odontalgia, in which peripheral triggers in the periodontal membranes of the affected teeth do appear to respond to capsaicin desensitization and/or topical anesthetic with temporary relief of pain [42] . Current anecdotal treatment for these teeth suggests a combination of topical anesthetic and/or capsaicin on the peripheral trigger to decrease excitation together with a systemic agent (e.g., a tricyclic antidepressant and/or gabapentin and/or other anticonvulsant).
Figure 3 presents a hypothetical model of the multi-factorial nature of BMS. This includes burning pain as either the result of increased excitatory output of the trigeminal nerve either from direct injury to the nerve ( e.g. from infection or vesiculo-bullous lesions) leading to increased output, or else to decreased inhibition at the central projection field of the trigeminal nerve secondary to damage of the chorda tympani. Understanding the mechanism of injury is helpful in directing both investigation and treatment.
Figure 3. Proposed model of pathogenesis of burning mouth.
Figure 4 presents a flow chart of the diagnostic process. This approach seeks to find evidence of peripheral nerve damage using clinical examination, hematology, and investigation for objective signs of decreased salivary flow and taste disturbance. In addition, the effects of topical anesthesia on both burning and other dysesthetic sensations can help determine if the pain is of peripheral or central origin.
Figure 4. Flow chart of diagnosis of burning mouth and other oral dysesthesias.
This model provides a working blueprint for future investigation of BMS and other oral dysesthesias. We believe that this model will assist in the unraveling of complex oral dysesthesias. Understanding these dysesthesias will facilitate treatment.
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