Today’s health care professional is faced with the stark reality that the most common reason patients seek medical or dental care in the United States is due to pain or dysfunction. Recent studies reveal that the head and neck region is the most common site of the human body to be involved in a chronic pain condition . The orofacial region is plagued by a number of acute, chronic, and recurrent painful maladies. A population-based survey of 45,711 households revealed that 22% of the United States population experienced orofacial pain on more than one occasion in a 6-month period . Pain involving the teeth and the periodontium is the most common presenting concern in dental practice. Non-odontogenic pain conditions also occur frequently. Recent scientific investigation has provided an explosion of knowledge regarding pain mechanisms and pathways and an enhanced understanding of the complexities of the many ramifications of the total pain experience. Therefore, it is mandatory for the dental professional to develop the necessary clinical and scientific expertise on which he/she may base diagnostic and management approaches. Optimum management can be achieved only by determining an accurate and complete diagnosis and identifying all of the factors associated with the underlying pathosis on a case-specific basis. A thorough understanding of the epidemiologic and etiologic aspects of dental, musculoskeletal, neurovascular, and neuropathic orofacial pain conditions is essential to the practice of evidence-based dentistry/medicine.
Pain has been characterized as nociceptive, neuropathic, and mixed. Nociceptive pain is defined as pain transmitted by normal physiologic pathways via peripheral nerves to the central nervous system in response to potentially tissue-damaging stimuli . Examples include frank dental pain, myofascial pain, and degenerative joint disease. It is typically described as diffuse aching, stiffness, or tenderness. Neuropathic pain refers to pain initiated or caused by a primary lesion or dysfunction in the nervous system . Conditions representative of neuropathic pain are postherpetic neuralgia, trigeminal neuralgia, trauma-induced neuropathy, atypical odontalgia /non-odontogenic toothache, idiopathic oral burning, and complex regional pain syndrome. Neuropathic pain conditions are frequently associated with qualities with which the patient is not familiar. This may make it difficult for the patient to communicate their pain experience. Typical descriptors used by patients include stabbing, burning, electric-like, or sharp, with numbness or tingling projected to a cutaneous area . Aching pain does not preclude the possibility of a neuropathic basis for the patient’s pain . Mixed pain is caused by a combination of primary injury or secondary effects. It is described by a myriad of terms that may be diagnostically confusing to the practitioner. Each of these types of pain is associated with variable mechanisms that must be targeted to optimize treatment outcomes.
Neuropathic orofacial pain
Neuropathic orofacial pain is relatively common. It is diagnosed in approximately 25 to 30% of patients presenting in a tertiary care University-based Facial Pain Center (H.A. Gremillion, unpublished data, 2006). It is associated with significant interpatient variability regarding presentation and response to treatment. Current scientific evidence supports a complex pathophysiology.
Chronic neuropathic pain may result from nerve injury or damage. In the vast majority of cases, chronic neuropathic pain cannot be satisfactorily treated with conventional analgesics and is generally resistant to opioids . It is characterized by spontaneous pain that is often unprovoked. Box 1 lists relevant clinical features that are associated with neuropathic orofacial pain.
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Precipitating factors, such as trauma or disease, can typically be identified.
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There may be a delay in onset after initial injury/insult (days to months).
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Typical patient complaints of pain may include burning, paroxysmal lancinating, or sharp episodes.
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Additional complaints may be related to paresthesia or dysesthesia. Paresthesia is expressed as abnormal, not necessarily unpleasant, sensations such as heaviness, tingling, or numbness. Dysesthesia is regarded as abnormal or unpleasant sensations such as burning, stinging, or stabbing.
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The area in which pain is experienced may exhibit sensory deficit.
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Physical examination may reveal allodynia, hyperalgesia, or sympathetic hyperfunction. Allodynia is defined as pain resulting from a stimulus that does not normally cause pain. Hyperalgesia is an increased or exaggerated response to painful stimuli.
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Local pathophysiology is associated with an abnormal nerve healing (eg, sprouting, neuroma formation).
Pathophysiology
The pathophysiology of neuropathic orofacial pain has not been fully elucidated, but a number of mechanisms have been suggested. Change in excitability of primary nociceptive afferents may be the single most important factor in generation and maintenance of acute chemogenic pain or chronic neuropathic pain in humans .
Deafferentation is defined as a continuous pain after complete or partial damage to a nerve. It may occur after facial trauma, dental extraction, placement of dental implants, endodontic therapy (surgical and nonsurgical), crown preparation, periodontal therapy, and bleaching of teeth. It may develop after the most perfect procedure if there is a predisposition or if peripheral or central neural sensitization occurs.
Deafferentation pain is associated with the following clinical characteristics: pain in the structure before amputation, persistent pain after the injured tissue has healed, discrete trigger areas in the affected region, and pain that is refractory to usually effective treatments. The estimated incidence of deafferentation pain postendodontic treatment has been reported to be 3 to 6% . Pulpal extirpation is followed by a degenerative process of primary trigeminal axons and neurons in the spinal trigeminal nucleus, specifically in subnucleus caudalis. This finding suggests that a central mechanism plays a role in the ongoing pain condition .
Demyelination is a degenerative process that is associated with a loss of integrity of the myelin sheath that normally protects nerve fibers. This may result in an aberration in nerve impulse generation and conduction. Demyelination can occur peripherally or centrally. Multiple sclerosis is the most well known example of a central demyelinating disease. When the disease affects the trigeminal ganglion, it can present as trigeminal neuralgia. The peripheral nervous system neurons can undergo pathologic damage from numerous sources, such as vascular compression, radiation, inflammation, trauma, infection, and exposure to neurotoxins . This damage occurs in two primary ways: demyelination and axotomy (deafferentation with severance of the axon). It has long been known that these two phenomena can produce numbness and paresthesia. More recently it has been shown that these pathologic entities can cause ectopic discharge or impulse generation from the sites along the axon where the damage has occurred, rather than just at the sensory nerve ending . Demyelination can have a disastrous impact on the individual’s quality of life because spontaneous nociceptive impulses can create severe and unpredictable pain. These same impulses can cause central sensitization, which can lead to a peripheral allodynia and hyperalgesia.
New information reveals that the root of this peripheral problem is not at the synaptic cleft between neurons but rather occurs as a result of membrane hyperexcitability along the axon . Under normal conditions, the sensory nerve endings, and an adjacent region of the axon, bring about the transduction of a stimulus (electrogenesis) to initiate a train of electrical impulses (repetitive firing of the neuron) that are propagated and carried by the axon. Beyond the initial receptors, axons normally have few regions where repetitive firing can originate, with the exception of the nodes of Ranvier . Single impulses (a quick sharp electrical feeling) can originate anywhere, such as can occur with a needle trauma to the lingual or inferior alveolar nerve during a local anesthetic injection.
With demyelination or axotomy, areas of involvement along an axon can become ectopic sites of repetitive firing that occur spontaneously or secondary to a stimulus. This process involves an abnormal “pacemaking” ability whereby the neuronal membrane demonstrates a depolarizing resonance (a fluctuating depolarizing cycle) just below the firing threshold. When combined with a depolarization after potential, it exceeds the threshold and causes repetitive firing . This pacemaking ability can also create spontaneous activity in adjacent uninjured neurons including C-fibers (small-diameter, unmyelinated nociceptive fibers) . C-fiber damage is generally associated with burning neuropathic pain.
Studies have recently demonstrated that membrane remodeling, particularly involving Na + channels, is responsible for the ectopic repetitive firing . There are three primary ways in which sodium channels affect a change in membrane hyperexcitability and repetitive firing in damaged axons. First, there is a change in the rate of protein synthesis of various Na + channels as a result of neuronal injury. More Na + channels mean more sensitivity. For example, Na v 1.3 channels have been found to potentially influence the pacemaking activity previously mentioned. The elevated rate of synthesis of these proteins occurs concurrently with axonal ectopic firing and the initiation of allodynia . Second, there is an intracellular regulation of the Na + channels that allows the channels to remain open longer and create more hypersensitivity and even spontaneous firing of damaged neurons . The third way involves the interruption of axonal transport. If an axon is transected , exposed to certain toxins, or undergoes demyelination , then the axonal transport system responsible for moving Na + channel proteins from the cell nucleus to the axon sensory nerve endings is disrupted. This results in accumulation of transport vesicles at the damaged region. Furthermore, once damage occurs, neuromas (aberrant nerve regeneration) may form. Transport vesicles and Na + channel proteins build up in the multiple sprouting endings of the neuroma endbulb because they can no longer go to their original destination. Apparently, the Na + channels are then inserted into the cellular membrane where the integrity of the myelin sheath has been compromised or in the neuroma causing an abnormal, elevated concentration of these channels. The membrane hypersensitivity is directly dependent upon the concentration of Na + channels . The concentration of Na + channels and hypersensitivity of the neuronal membrane after nerve injury is increased, resulting in spontaneous or easily stimulated repetitive firing of nociceptive neurons, causing the neuropathic pain.
An understanding of the mechanisms of neuropathic pain can provide the clinician/scientist with a basic rationale for treatment. Because the pathogenesis of neuropathic pain has not been determined, the practitioner must be aware of the various classes of pharmacotherapeutic agents that have been suggested to provide relief in selected cases. Pharmacotherapy for neuropathic pain encompasses a variety of agents with analgesic potential. A systematic approach to drug trials and ongoing assessment by a responsible, informed practitioner is key to successful control of neuropathic pain. Diverse agents in numerous classes may be used effectively in the heterogenous population with pain of neuropathic nature. Adjuvant analgesics are drugs that have primary indications other than pain but may be analgesic in specific circumstances. Some of the medications that have been suggested to be effective are included in Box 2 .
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Antidepressants
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Tricyclic antidepressants
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Amitriptyline
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Nortriptyline
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Imipramine
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Serotonin–norepinephrine selective reuptake inhibitors
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Venlafaxine
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Duloxetine
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Anticonvulsants/antiepileptic drugs
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Carbamazepine
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Oxcarbazepine
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Phenytoin
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Gabapentin
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Pre-gabalin
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Lamotrigine
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Topiramate
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Tiagabine
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Levetiracetam
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Clonazepam
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Valproic acid
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Zonisamide
Local anesthetics
Muscle relaxants
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Lioresal
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Tizanidine
Because the synaptic cleft is not predictably involved in the etiology of neuropathic pain, it is not surprising that drugs that inhibit synaptic transmission are many times ineffective; however, these drugs should remain a consideration. Examples of drugs that act at the synaptic cleft include clonidine or benzodiazepines. Rather, the membrane-stabilizing drugs, such as the anticonvulsant drugs (eg, carbamazepine, lamotrigine, oxcarbazepine, and phenytoin), are more predictably effective because they suppress the hyperexcitability of the axonal membrane . Tricyclic antidepressants, such as amitriptyline, may be effective at low dosages because they also work as membrane stabilizers in addition to their trans-synaptic effects .
Local anesthesia has been used as diagnostic aid in the evaluation of the patient who has orofacial pain. Devor has suggested that a positive response to local anesthetic provides validation of the axonal membrane etiology for neuropathic pain. Local anesthetics have a membrane-stabilizing effect and provide an additional treatment consideration for neuropathic pain. One study demonstrates the effectiveness of lidocaine for the suppression of nerve growth factor and the resultant sympathetic neurite sprouting in the dorsal root ganglion and in peripheral nerves . This could suppress pain connections in the dorsal root ganglion and the hypersensitivity peripherally. Systemic lidocaine also was demonstrated to have a selective depression of C-fiber activity in the spinal cord, which could affect transmission of certain neuropathic pain types . In summary, lidocaine can be applied topically with other medication in transdermal preparations, injected locally, or administered systemically for therapeutic benefit and not just for short-term pain relief .
Pathophysiology
The pathophysiology of neuropathic orofacial pain has not been fully elucidated, but a number of mechanisms have been suggested. Change in excitability of primary nociceptive afferents may be the single most important factor in generation and maintenance of acute chemogenic pain or chronic neuropathic pain in humans .
Deafferentation is defined as a continuous pain after complete or partial damage to a nerve. It may occur after facial trauma, dental extraction, placement of dental implants, endodontic therapy (surgical and nonsurgical), crown preparation, periodontal therapy, and bleaching of teeth. It may develop after the most perfect procedure if there is a predisposition or if peripheral or central neural sensitization occurs.
Deafferentation pain is associated with the following clinical characteristics: pain in the structure before amputation, persistent pain after the injured tissue has healed, discrete trigger areas in the affected region, and pain that is refractory to usually effective treatments. The estimated incidence of deafferentation pain postendodontic treatment has been reported to be 3 to 6% . Pulpal extirpation is followed by a degenerative process of primary trigeminal axons and neurons in the spinal trigeminal nucleus, specifically in subnucleus caudalis. This finding suggests that a central mechanism plays a role in the ongoing pain condition .
Demyelination is a degenerative process that is associated with a loss of integrity of the myelin sheath that normally protects nerve fibers. This may result in an aberration in nerve impulse generation and conduction. Demyelination can occur peripherally or centrally. Multiple sclerosis is the most well known example of a central demyelinating disease. When the disease affects the trigeminal ganglion, it can present as trigeminal neuralgia. The peripheral nervous system neurons can undergo pathologic damage from numerous sources, such as vascular compression, radiation, inflammation, trauma, infection, and exposure to neurotoxins . This damage occurs in two primary ways: demyelination and axotomy (deafferentation with severance of the axon). It has long been known that these two phenomena can produce numbness and paresthesia. More recently it has been shown that these pathologic entities can cause ectopic discharge or impulse generation from the sites along the axon where the damage has occurred, rather than just at the sensory nerve ending . Demyelination can have a disastrous impact on the individual’s quality of life because spontaneous nociceptive impulses can create severe and unpredictable pain. These same impulses can cause central sensitization, which can lead to a peripheral allodynia and hyperalgesia.
New information reveals that the root of this peripheral problem is not at the synaptic cleft between neurons but rather occurs as a result of membrane hyperexcitability along the axon . Under normal conditions, the sensory nerve endings, and an adjacent region of the axon, bring about the transduction of a stimulus (electrogenesis) to initiate a train of electrical impulses (repetitive firing of the neuron) that are propagated and carried by the axon. Beyond the initial receptors, axons normally have few regions where repetitive firing can originate, with the exception of the nodes of Ranvier . Single impulses (a quick sharp electrical feeling) can originate anywhere, such as can occur with a needle trauma to the lingual or inferior alveolar nerve during a local anesthetic injection.
With demyelination or axotomy, areas of involvement along an axon can become ectopic sites of repetitive firing that occur spontaneously or secondary to a stimulus. This process involves an abnormal “pacemaking” ability whereby the neuronal membrane demonstrates a depolarizing resonance (a fluctuating depolarizing cycle) just below the firing threshold. When combined with a depolarization after potential, it exceeds the threshold and causes repetitive firing . This pacemaking ability can also create spontaneous activity in adjacent uninjured neurons including C-fibers (small-diameter, unmyelinated nociceptive fibers) . C-fiber damage is generally associated with burning neuropathic pain.
Studies have recently demonstrated that membrane remodeling, particularly involving Na + channels, is responsible for the ectopic repetitive firing . There are three primary ways in which sodium channels affect a change in membrane hyperexcitability and repetitive firing in damaged axons. First, there is a change in the rate of protein synthesis of various Na + channels as a result of neuronal injury. More Na + channels mean more sensitivity. For example, Na v 1.3 channels have been found to potentially influence the pacemaking activity previously mentioned. The elevated rate of synthesis of these proteins occurs concurrently with axonal ectopic firing and the initiation of allodynia . Second, there is an intracellular regulation of the Na + channels that allows the channels to remain open longer and create more hypersensitivity and even spontaneous firing of damaged neurons . The third way involves the interruption of axonal transport. If an axon is transected , exposed to certain toxins, or undergoes demyelination , then the axonal transport system responsible for moving Na + channel proteins from the cell nucleus to the axon sensory nerve endings is disrupted. This results in accumulation of transport vesicles at the damaged region. Furthermore, once damage occurs, neuromas (aberrant nerve regeneration) may form. Transport vesicles and Na + channel proteins build up in the multiple sprouting endings of the neuroma endbulb because they can no longer go to their original destination. Apparently, the Na + channels are then inserted into the cellular membrane where the integrity of the myelin sheath has been compromised or in the neuroma causing an abnormal, elevated concentration of these channels. The membrane hypersensitivity is directly dependent upon the concentration of Na + channels . The concentration of Na + channels and hypersensitivity of the neuronal membrane after nerve injury is increased, resulting in spontaneous or easily stimulated repetitive firing of nociceptive neurons, causing the neuropathic pain.
An understanding of the mechanisms of neuropathic pain can provide the clinician/scientist with a basic rationale for treatment. Because the pathogenesis of neuropathic pain has not been determined, the practitioner must be aware of the various classes of pharmacotherapeutic agents that have been suggested to provide relief in selected cases. Pharmacotherapy for neuropathic pain encompasses a variety of agents with analgesic potential. A systematic approach to drug trials and ongoing assessment by a responsible, informed practitioner is key to successful control of neuropathic pain. Diverse agents in numerous classes may be used effectively in the heterogenous population with pain of neuropathic nature. Adjuvant analgesics are drugs that have primary indications other than pain but may be analgesic in specific circumstances. Some of the medications that have been suggested to be effective are included in Box 2 .
