17.1 Chronic Trigeminal Neuropathy

When the phrase chronic trigeminal neuropathy is used this could mean several things, so it is appropriate to define it before talking about diagnosing and managing patients with such a problem.^1,2 By “chronic” we mean that the problem is ongoing in spite of treatment and there is usually a minimum period of 3–6 months before a pain is labeled as chronic or persistent. By “trigeminal” we mean it is localized to the region of the trigeminal nerve, which in most cases means pain in the teeth, alveolar bone, or gingival mucosa. Occasionally this pain may be extraoral, if some form of neural injury occurs. By “neuropathy” we mean a continuous noxious activity generated within the nervous system without adequate stimulation of its peripheral sensory endings. The International Association for the Study of Pain (IASP) introduced the term neuropathic pain and defined it as “pain initiated or caused by a primary lesion or dysfunction in the nervous system.” Other names for a chronic trigeminal neuropathy are chronic trigeminal neuropathic pain, persistent orodental pain, atypical odontalgia,^3,4 and phantom tooth site pain.⁵ When the term atypical or idiopathic is added in front of the phrase “chronic trigeminal neuropathy,” this usually means that the cause of the pain is unknown or not yet identified. The background history and prior names used to describe this problem are reviewed later in this chapter. What is not covered in this chapter is the episodic trigeminal nerve pain known as trigeminal neuralgia. This disorder is reviewed and discussed in the chapter on anticonvulsants.

17.1.A Prevalence of Chronic Trigeminal Neuropathy

A 2008 article put forth the following definition for neuropathic pain: “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.”⁶ They also suggested a grading system for neuropathic pains using the terms (1) definite, (2) probable, or (3) possible neuropathic pain. They proposed that the grades probable and definite require confirmatory evidence from a neurologic examination. Of course, such a system needs to be evaluated and then adopted by group like the IASP. Even with a definition and a grading system it is still moderately difficult to determine when an idiopathic chronic trigeminal neuropathic pain exists. This is because there are no “disease defining” physical examination or radiologic features and there are multiple other sources of pain in the dental–mucosal–alveolar region, such as failing dental restorations, tooth fractures, pulpitis, pulpal necrosis, or periodontal and maxillary sinus inflammation or infections. Fortunately, most of these other pain-inducing problems do not produce continuous chronic pain (lasting greater than 3–6 months) since either the cause is transient, so the problem goes away, or successful treatment is initiated. These other problems will also have physical examination or radiologic evidence of the pathology that is causing the pain.

By default, treatment failure is often the single most common defining feature for chronic trigeminal neuropathy. A far too common story told by patients seeking help in a chronic pain center is that they have seen multiple dentists and have had multiple unsuccessful irreversible procedures performed (root canal therapies, apical surgeries, or extractions) and they still have pain. It is usually at this point that a diagnosis of neuropathy is considered.⁷ Unfortunately, while the number of patients with chronic orodental pain that have had failures in usual and customary treatment are many, the number of reports in the literature are few. While this could mean there are few cases of treatment failure, a more likely explanation for this is that no one likes to broadcast their failures. There are, however, a few such reports; a 2003 article described 38 patients (32%) who had failed invasive therapies for their orofacial pain, taken from a case series of 120 consecutive patients. These patients all attended a university-based hospital pain center for treatment of their orofacial pain.⁸ The report categorized patient self-reports of prior irreversible dental procedures for their pain (e.g., endodontics [30%], extractions [27%], and apicoectomies [12%]). By definition, all 38 of these failed patients still had pain and 21 of 38 (55%) of them further reported that these treatment interventions actually exacerbated their pain. A more recent 2007 study described 44 of 100 (44%) consecutive nondental orofacial pain patients who had previously received inappropriate extractions or endodontics.⁹ To some degree these seemingly inappropriate treatments happen because of a lack of understanding of the disease and the lack of authoritative disease criteria.¹⁰

As could be expected, the actual prevalence of patients in the general population who suffer with this problem has not been determined. Most studies in the pain literature have focused on other neuropathic conditions, such as trigeminal neuralgia, postherpetic neuralgia, painful diabetic neuropathy, and phantom limb pain.¹¹ One approach to solving the neuropathic trigeminal pain prevalence dilemma would be to develop a validated questionnaire. For example, a 2006 article described a validated screening questionnaire that claimed to be able to identify neuropathic pain in patients with low back problems without a physical examination, imaging, or diagnostic tests.¹² The study involved prospective, multicenter data collected from approximately 8000 low back pain (LBP) patients. They claimed the questionnaire had high sensitivity and specificity and an excellent positive predictive accuracy (85%, 80%, and 83%, respectively). While a questionnaire, if it is designed properly, can identify with reasonable probability that segment of the population with definite neuropathic pain and who have probably already suffered treatment failure. Used alone such questionnaires will never provide a definitive method for “early” diagnosis of neuropathic pain problems. Early identification of trigeminal neuropathy will require a disease-defining biologic marker that has yet to be identified. While they are not population-based studies using defined criteria, opinions in the existing literature suggest that atypical odontalgia prevalence varies between 3% and 12% of the patients who undergo seemingly successful endodontic treatment.^13–15 Consistent with these opinions is a 2007 report on the diseases and demographic patterns of 1049 consecutive patients attending a university-based orofacial pain and oral medicine center that reported chronic trigeminal neuralgia made up 3% of the total.¹⁶ Of course convenience samples are not prevalence data, but a consistent finding in these studies it that all report a high female preponderance, with the onset starting in the fourth decade of life and with a peak in the fifth or sixth decades. Finally, molars and premolars are more frequently involved, with the maxilla being more often affected than the mandible.¹⁷ It is still unclear why females are more commonly affected than males or why the maxilla is more commonly affected than the mandible. A commonly offered explanation for why some patients get chronic pain and others do not is that they might have a genetic polymorphism that makes them susceptible to neuropathic pain.

17.1.B History and Prior Terminology

Chronic trigeminal neuropathic pain is not a new phenomenon. In 1932, Wilson described a group of patients with atypical facial neuralgia and among them were patients who had dental pain of unknown origin.¹⁸ Since then many others have coined terms for these patients such as idiopathic periodontalgia and atypical odontalgia.^19–23 The term phantom tooth pain (PTP) was applied to the subgroup of these patients who had unexplained chronic dental pain even after the suspected tooth was extracted.^24–27

17.1.C Clinical Characteristics

The lack of a set of disease-defining criteria does not mean chronic neuropathic trigeminal pain is not a real disease or that we know nothing about it. On the contrary, we know quite a lot about this disease. We know women in their 40s are more likely to suffer this disease, we know the most common site of pain is maxillary molars and premolars. We now know that atypical odontalgia and phantom tooth pain are most likely the same disease with the main difference being that an unsuccessful pain-relieving extraction has occurred in the cases of phantom tooth pain. What is also known is that patients with phantom tooth pain have lower somatosensory thresholds in the pain region. While the data is sparse, a 2002 study measured the threshold levels for light touch sensation using an intraoral site in clearly defined group of phantom tooth pain subjects.²⁸ This involved a case–control experimental on 10 PTP patients (mean age 56, range 32–71, 9 females) and 10 controls. The authors found the PTP complaints were predominantly reported in the upper jaw (ratio 8:2), with the majority in the molar region (ratio 5:3). In addition, PTP subjects showed significantly lower threshold levels for light touch sensations on the affected side. While limited in quantity, the data suggests that PTP subjects demonstrate measurable mechanical hyperalgesia and, among all tests performed, mechanical pain threshold was significantly altered on both sides with the greatest change being on the pain side.

Atypical Odontalgia Patient Characteristics

Atypical odontalgia presents as a continuous pain located in a tooth, gingiva, or extraction site, and can often involve wider areas of the face. Several reports indicate that the pain usually begins and persists long after a dental or surgical procedure.^29,30 Typically, no obvious tooth or periodontal pathologies are evident and no radiographic signs of pathology are present as a cause of this pain. Local anesthetic block of the involved tooth produces modest to equivocal pain relief.³¹ Atypical odontalgia includes cases with an identifiable causeof the chronic tooth pain, such as a dental abscess that was correctly treated but the patirnt’s pain did not resolve after endodontic therapy. In some of the atypical odontalgia cases a chronic pain develops without clear-cut cause (e.g., no evidence of clear tooth fracture, no dental caries, no periapical lesion, and the teeth test vital with cold testing). In these cases the two explanations most often offered include incomplete tooth fractures and clenching-induced pulpitis (discussed later in this chapter). One study did report that 74% of the atypical odontalgia sufferers were women in their 40s at initial onset, and the pain was usually present in posterior teeth or alveolar arch, with molar teeth affected 58.8% of the time, premolars 26.8%, canines 4.2%, and incisors 12%.³² A second study, which evaluated 120 subjects complaining of atypical odontalgia, had 80.8% women between the ages of 23 and 60 years, with a mean age of 43 ± 13.9 years.³³ Making the assumption that inflammation of the pulp is an underlying mechanism for the pain, an explanation is needed regarding why the pulpal tissue of women over 30 years of age would cause pain in the their posterior teeth. The above data suggests that changes in both the nervous system and in the teeth themselves with age must play a role in producing tooth pain or pulpal inflammation. Moreover, given the predilection of the posterior teeth to show this disease it seems again that some factor related to bite force, which is far greater on the posterior teeth than the anterior, might play a role. Finally, some factor that is more evident in women than men must be involved and fortunately the literature sheds some light on these issues.

Phantom Tooth Pain Patient Characteristics

When tooth pain becomes chronic and root canal treatment is unsuccessful in stopping the pain, the treating dentist commonly elects to extract the tooth hoping that the pain symptoms will stop. If the tooth is the source of the pain and extrapulpal trigeminal neuropathic changes have not occurred, then the pain should stop. If, however, there are extrapulpal neuropathic changes, this results in chronic tooth-site pain that is commonly called phantom tooth pain. It should be stated that while the phrase “phantom tooth pain” is commonly used, it would be more accurate to describe it as chronic, unexplained pain at the site of the extracted tooth. There are no patients who describe feeling the phantom presence of their tooth as occurs in phantom limb patients, where they actually feel the missing limb. Instead what would be a more accurate analogy is that these patients are experiencing tooth stump pain, which is the term used to describe chronic limb pain when a phantom limb presence is not part of the clinical pain pattern.

Other Characteristic of Trigeminal Neuropathic Pains

While this chapter focuses on the above two chronic trigeminal neuropathies, this category would also include burning mouth syndrome³⁴ and autoimmune trigeminal neuropathic pain.³⁵ Trauma can also induce a chronic trigeminal nerve pain, which is presumably neuropathic. For example, chronic nerve pain is reported with implant inferior alveolar nerve impingement³⁶ and chronic dysesthesia is reported after a local anesthetic injection into the nerve.³⁷ Nerve pain can occur after mandibular fracture or after orthognathic-surgery-related nerve injury.³⁸ Nerve compression is known to occur after osseous growth compression injury,³⁹ neoplastic perineural invasion injury, and infection-related damage to the nerve itself such as with a trigeminal herpes zoster and herpes simplex infection.⁴⁰ In addition, neuropathic pain can be caused by diabetic-related neural injury and altered sympathetic nervous system related neuropathy. The literature describes several medications and other chemical toxins that cause neuropathic pain and all branches of the trigeminal nerve can be involved including the lingual,⁴¹ inferior alveolar, mental nerve, auriculotemporal, and infraorbital nerves,⁴² as well as trigeminal neuroma pain after surgical transaction of a nerve.⁴³

Finally, some patients with temporomandibular joint (TMJ) pain develop a chronic TMJ pain that is resistant to anti-inflammatory medications and may be neuropathic. Sensitization of the auriculotemporal nerve may account for the reason some patients have sustained unchanging pain even after direct corticosteroid injection into the joint itself. Proof of auriculotemporal nerve change was provided in recent study that used quantitative sensory testing on 72 patients (44 who had arthralgia and 28 who had chronic myalgia) and 22 healthy controls.^44,45 Nerve response threshold was tested with electrical stimulation applied bilaterally in three trigeminal nerve sites (cheek, temple, and chin). By comparing the affected-side threshold with the control (nonaffected) side, the authors found that the electrical detection threshold ratio for the three sites did not vary from the expected value of 1 in the controls. However, for the patients with arthralgia the mean ratio obtained for stimulation at the temple site was significantly lower compared with the other sites, and this was not so for the cheek or chin sites. This data suggests that the auriculotemporal nerve, which innervates both the TMJ and the temple, was sensitized and had a lower threshold.

17.1.D Psychiatric Co-Morbid Disease

Psychiatric assessment of chronic pain subjects with failed treatment was described in a 1983 case series report on 21 patients with atypical facial pain.⁴⁶ These patients had had a total of 65 irreversible dental and oral surgical treatments (3 per patient) trying to solve their pain; only one patient reported showing less pain as a result of the treatment. Each of the patients in this report also had a full psychiatric assessment. Based on these data, these authors concluded that failed-treatment patients with chronic trigeminal pain suffered a high degree of psychiatric illnesses. The authors recommended psychiatric assessment before repeated dental and surgical procedures are performed in this population. While the need for a psychiatric assessment by a mental health professional is easy to comprehend and implement in the patient with chronic multiple treatment failures, it is harder to justify and implement if the patient has not yet failed treatment and presents with a single symptom such as toothache and no obvious behavioral abnormalities. Whether psychological pathoses in this population precedes, or is a consequence of, chronic pain is unknown. Consistent with this case series is a 2007 study that reported on the clinical and psychosocial characteristics of 46 consecutive atypical odontalgia patients compared with 35 age- and gender-matched control subjects.⁴⁷ The patients were found to have significantly more TMD pain, tension-type headaches, and widespread pain than the controls. They also had significantly higher scores for somatization, depression, and limitations in jaw function and significantly lower scores on quality of life.

Of cours, observing that two problems are strongly associated does not prove that one is the cause of the other. The relationship between psychological factors and future chances of neuropathic pain was examined in a study on knee surgery patients.⁴⁸ This study looked to see if any preoperative psychological characteristic would predict the presence of chronic pain following total knee arthroplasty. These authors studied 77 patients having this surgery and all completed a battery of psychometric tests assessing various characteristics. They reported that patients with higher preoperative anxiety scores and more preoperative pain predicted the presence of chronic regional pain syndrome symptoms at follow-up. However, a high tendency for anxiety was not a strong predictor of postsurgical complications (sensitivity of 73% and a specificity of 56%). What these numbers imply is that it is not easy to predict who will get neuropathic pain. Moreover, pretreatment depression or anxiety as a psychological characteristic does not dictate that the individual to become a neuropathic pain sufferer in the future.

An alternate explanation for the strong association between psychological disturbance and neuropathic pain is that the unrelenting nature of the pain itself alters the patient’s personality. In fact,a more recent study examined the relative contribution of catastrophic thinking (i.e., rumination, magnification, helplessness) to the pain experience in 80 neuropathic pain patients.⁴⁹ This study reported that individuals who scored higher on a measure of catastrophic thinking also rated their pain as more intense, and rated themselves to be more disabled due to their pain. Catastrophizing thinking predicted pain-related disability over and above the variance accounted for by pain severity; combined, these data suggest that unrelenting pain without highly effective treatment methods may induce helplessness in patients and shift them to express more psychopathology and mood disorders.

17.2 Neuropathic Pain Mechanisms

This section of the chapter reviews the neuronal changes (categorized by mechanism) that are known to occur when a patient has neuropathic pain. This is important to know because if you knew exactly how the nerve was injured and how it has changed as a result of the injury, you would understand which ion channels or receptors have also changed. With this knowledge you might be able to better select an appropriate therapy or medication based on the neuropathic mechanism. Unfortunately, while we know how nerves change with experimental injury and we even how and where the various anticonvulsant medications act on nerve transmission, this does not mean we have designer medications that can be targeted to a specific neuropathic mechanism, but this may occur in the future. Designer pain medications are what the drug manufacturers and pain doctors trying to help their patients hope for, but it is still an elusive target.^50–52 What is now known is that painful neuropathic pain will occur with quite different clinical manifestations (e.g., stimulus-independent constant pain; stimulus-dependent paroxysmal pain). Moreover, one or several types of pain may be present in the same patient. These different types of pain may be caused by distinct pathophysiologic mechanisms, such as spontaneous activity of damaged C-nociceptors, increased sensitization of afferent nerves and neurons to noxious and non-noxious stim­ulation, sympathetic hyperactivity, or a loss of central inhibition.⁵³ Given this, it is unlikely that a single drug with a single mechanism of action will relieve neuropathic pain, especially if we are not sure which of the above pathophysiological processes are present in the patient.

17.2.A Local Nerve Injuries

All neuropathic pain begins with a nerve injury and, unfortunately, there are many ways a nerve can be injured. In some clinical situations we know exactly what the injury was (e.g., an infected tooth pulp or an improperly positioned implant), but in most cases we are only guessing at the type of injury. Injuries to the trigeminal nerve can be due to injection of a neurotoxic substance into or very near the neural sheath, traumatic or even iatrogenic crush, inadvertent neural transection, hypoxia, strangulation, abrasion, compression, bacterial or viral insult, neurodegenerative disease, tumor-induced compression, or neural invasion of a tumor into the nerve, autoimmune-related inflammation, and chemical- and medication-induced toxicity to name a few. In the specific case of postherpetic neuralgia the injury is a viral-induced damage to the nerve itself. In the case of dental implant pain, the surgical removal of bone, if too deep, can surgically burr and cut the nerve or the implant, when placed into the bone can crush the nerve in the inferior alveolar canal. Third-molar extraction is a common cause for inferior alveolar nerve and lingual nerve damage, causing altered sensation on the distribution of the nerve affected.^54–58

After injury, there are a variety of changes in the gene and in the proteins produced by the gene that occur within a first-order nerve. A recent study examined the issue of the tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 (SNS1/PN3) in human pulp tissue associated with irrerversible pulpitis.⁵⁹ This receptor is expressed by nociceptors and may play a role in pain states and using specific antibodies for immunohistochemistry, we studied Nav1.8 immunoreactivity in human dental pulp in relation to the neuronal marker neurofilament. Human tooth pulp was extracted from teeth harvested from a total of 22 patients (14 without dental pain, 8 with dental pain). Fibers immunoreactive for Nav1.8 were significantly increased on image analysis in the painful group: median (range) Nav1.8 to neurofilament percentage area ratio, nonpainful 0.059 versus painful 0.265; this fourfold difference is statistically significant and is likely why the alveolar nerve supplying the tooth has sponta­neous activity and is more difficult to block with a local anesthetic.

17.2.B Nerve Sprouting and Ectopic Neural Activity

After crushing or cutting a nociceptive nerve, the nerve will attempt to restore its continuity through axonal sprouting. These new nerve sprouts and neuromas are unusually sensitive to mechanical, thermal, and chemical stimulation and even are known to have spontaneous discharge. These new nerve sprouts and neuroma are also spontaneously active, forming what is called an ectopic generator causing tingling, itching, or electrifying dysesthetic sensations in patients.⁶⁰ Sometimes, these nerve sprouts mature and normal sensitivity to stimuli returns but in some cases, especially with neuromas, the sensitivity is ongoing.

17.2.C Demyelination of Nerves

Painful ectopic neuronal discharges occur secondary to demyelination that results from a neurodegenerative disease such as multiple sclerosis or due to a vascular-compression-related nerve injury as in trigeminal neuralgia. Neuropathic pain due to multiple sclerosis, such as trigeminal neuralgia, painful spasms, and painful dysesthesias and paresthesias, are usually treated with anticonvulsants. Carbamazepine has proven to be efficient in controlling the trigeminal-neuralgia-like symptoms. Oxcarbazepine can be used as the alternative drug for carbamazepine. The other anticonvulsants are often used as the second line of treatment.⁶¹ A randomized, double-blind, placebo-controlled, two-period, crossover, pilot trial of lamotrigine showed no difference in comparison with placebo group in the treatment of central pain in multiple-sclerosis patients.⁶²

17.2.D Peripheral Sensitization

If a peripheral nerve starts to fire spontaneously and continuously, this causes the nerve to start to release inflammatory and other excitatory mediators (e.g., substance P, calcitonin gene–related peptides) at the terminus of the nerve. These chemicals further stimulate the nerve and keep the nerve firing.⁶³ In addition to inflammation induced neuronal activity, the nerve begins to change. The most commonly described change is that the fast-firing, hard-to-block atypical sodium channels are upregulated and begin to populate the nerve axon and the axon in the ganglion itself.^64–66 Blockage of these sodium channel subtypes may be an important issue in treating patients with neuropathic pain. While the number of atypical sodium channels are known to increase in response of nerve injury and continuous activity, this same phenomenon is not proven for calcium channels. Nevertheless, the entry of calcium ions into the nerve endings through calcium channels regulates growth-related proteins. Recently N- and L-type calcium channels have been found to contribute to calcitonin gene–related peptide (CGRP) release from injured nerve endings in vitro.⁶⁷ Blockade of N-, T-, and P-type calcium channels has been found to block experimental neuropathic pain.^68,69 These results suggest that calcium channels may play a role in the expression of the neuropathic state. Selective calcium channel blockers, such as gabapentin, oxcabazepine, and lamotrigine may have significant potential in the treatment of neuropathic pain. Conotoxins are neurotoxic peptides that block the activity of ion channels. The mu subtype of these conotoxins has been shown to specifically block tetrodotoxin-resistant voltage-gated sodium channel Na(v)1.8 and to decrease allodynia and hyperalgesia in an animal model.⁷⁰

Neuropathic pain can be also be induced by inflammation and, while some of the above injury-induced neuroplastic changes are similar to inflammation, some are dissimilar.^71,72 For example, one study examined the effect of interleukin-1-beta (IL-1β) exposure on modulation of the voltage-dependent sodium currents and tetrodotoxin-resistant (TTX-R) sodium channels in capsaicin-sensitive neurons.⁷³ They report that a brief exposure (5 minutes) led to a 28% reduction of TTX-R sodium currents in these neurons, while a 24-hour exposure led to a 67% increase in sodium currents and increased mRNA transcripts of Na(v)1.8. These data demonstrate that prolonged inflammation causes an increase in both the slowly inactivating TTX-R currents in DRG neurons and more Na(v)1.8 sodium channels being produced, rather than the usual downregulation of this sodium channel seen with direct nerve injury. These results suggest the participation of Na(V)1.8 channels in the development and maintenance of chronic inflammatory hyperalgesia.

17.2.E Increased Sympathetic to Afferent Sensory Neuron Activity

Normally sympathetic neurotransmitters do not activate sensory nerves because they are not populated with adrenergic receptors. However, when a nerve has been sensitized due to injury or sustained activity, the nerve upregulates these receptors and therefore participates in the development of sympathetically maintained pain (SMP).^74–77 This pain is usually burning in character and it is associated with one of the following signs: sweating; swelling; abnormal skin temperature in the painful area; changes in skin color (red, purple-bluish). There are several drugs that have been shown to suppress sympathetic activity and that have been used in the treatment of SMP. Alpha-adrenergic antagonists such as phentolamine, phenoxybenzamine, and prazosin are used for the treatment of pain where the involvement of the autonomic nervous system has been demonstrated.^78,79 Clonidine, which is an α-adrenergic agonist also has been used for treatment of this condition;^80–82 however, there is lack of controlled trials for these medications.

17.2.F Cytokines in Neuropathic Pain

There are many different types of cytokines, including those that promote or inhibit inflammation. The role that cytokines play in neuropathic pain has been clarified in several publications.^83,84 Two specific cytokines that are considered important in promoting neuropathic pain are interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α). When an irritating substance is injected into an animal this triggers the development of allodynia and hyperalgesia; it has been shown that giving the animal an endogenous IL-1 receptor antagonist or antibodies to IL-1 will block the hyperalgesia.^85,86 In patients with neuropathy, there is evidence that TNF is elevated also.⁸⁷ Furthermore, there is a difference in the cytokine profile of patients who present with painful neuropathy and those with painless neuropathy. In patients with painful neuropathy there is a increase in the proin­flammatory cytokines TNF-α and interleukin-2 (IL-2). In contrast, in patients with painless neuropathy the anti-inflammatory cytokines IL-10 and IL-4 are found in higher levels than in patients with painful neuropathies or in healthy control subjects.⁸⁸

17.2.G Central Sensitization and Plasticity

The more extensive or longer lasting the peripheral neuronal changes are, the more likely there will be central neuroplastic changes. The location of these central changes can be throughout the afferent pathway to the cortex and may even involve DNA changes to the neurons themselves. Most scientists have focused on the second-order neurons and most specifically on the N-methyl-D-aspartate (NMDA)^89,90 and the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)–kainite receptors. Normally, activation of the NMDA receptor causes an influx of calcium ions and production of the gaseous neurotransmitter nitric oxide (NO). NO is an important neurotransmitter since it is able to diffuse out of the second-order neurons to activate nearby neurons. If the NMDA and the AMPA–kainate receptors, which are normally not easy to activate, undergo change such that they are continuously or very easily activated, this then constitutes central sensitization. With central sensitization, secondary allodynia (pain in response to nonpainful stimuli) and secondary hyperalgesia (exaggerated/>