Purpose: Drug therapy is the main treatment option for the control of neuropathic pain. However, current drugs indeed exert less preventive effect on pain in several patients suffering from neuropathic pain. This notion indicates that new therapeutic agents with different mechanisms of action from drugs currently used are required. We have considered that the dopaminergic nervous system is a strong candidate to be targeted to control pain. This article discusses the contribution of the dopaminergic nervous system in the brain to neuropathic pain based on the current available.
Study selection: This article was written based on “Suppression of orofacial neuropathic pain by dopaminergic nervous system” at the 27^th Annual Meeting of the Japanese Society of Orofacial Pain, held on October 9, 2022, at the basic symposium “Pain Research in Dental Anesthesiologists”.
Results: Mesolimbic system is dopaminergic system and consisted with the brain region, such as ventral tegmental area, nucleus accumbens. Recent studies reported that mesolimbic system is involved in orofacial neuropathic pain. A11 cell group is in the hypothalamus and has dopaminergic projection to trigeminal spinal subnucleus caudalis. Hypothalamic A11 cell group is also reported the involvement of neuropathic pain. The changes of dopaminergic system including expression levels and function of dopamine receptor have also been reported in neuropathic pain.
Conclusion: Although the involvement of dopaminergic system on neuropathic pain is becoming clear gradually, further investigation is required. It can make dopaminergic system a therapeutic target, and intervention therein an option for controlling pain.

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Objective: Knowledge of primary headache is essential for orofacial pain specialists, as indicated by the fact that the International Classification of Orofacial Pain, 1st edition （ICOP-1） describes as 5.1 Orofacial pains resembling presentations of primary headaches.
Methods: We extracted content considered essential for orofacial pain specialists from the International Classification of Headache, 3rd edition, and Headache Practice Guidelines 2021, and conducted literature searches as needed.
Results: Migraine is a typical primary headache disorder that interferes with daily life. It is classified into two types, migraine with aura and migraine without aura, based on the presence or absence of “aura” symptoms that precede the headache. Migraine headaches are paroxysmal, lasting 4 to 72 hours, unilateral, pulsating, disabling, and worsened by physical activity. During headache attacks, the patient feels photophobia and/or phonophobia that would not normally bother him or her unpleasant. Nausea and vomiting are also common. Tension-type headache is the most common primary headache. The headache lasts from 30 minutes to 7 days, is a pressing or tightening, non-pulsating headache, and is often bilateral. The headache is mild to moderate in severity and may interfere with daily activities but does not cause the patient to fall asleep. Trigeminal autonomic cephalalgias （TACs） share the clinical features of unilateral headache and, usually, prominent cranial parasympathetic autonomic features, which are lateralized and ipsilateral to the headache. Cluster headache is a most common type of TACs. The cluster periods usually last from a few weeks to several months.
Conclusion: The characteristics, diagnosis, and treatment of typical primary headaches have been described with the latest information.

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Chronic pain is often intractable due to a vicious cycle of factors, including the cognitive-behavioral attributes of the patient.
Therefore, it is important to use cognitive-behavioral therapy in the treatment of chronic pain.
For this therapy to be effective, establishing a trusting relationship between the dentist and the patient is essential.
This requires acceptance of the patient’s thoughts as well as supportive listening.
When performing cognitive restructuring, it is necessary to apply the Socratic interview and other innovations.
When treating chronic pain, cognitive-behavioral factors must be addressed over time.
Therefore, the end goal of initial treatment should be to accept the pain well, while transforming the cognitive-behavioral factors that cause the pain, rather than curinge it. This will lead to improvement with decreased stress levels.
The dentist should ideally be “the person who intervenes cognitively and behaviorally to support the patient in coping with chronic pain” and the patient “the person who receives support from the dentist but also performs self-care,” with aiming to live with chronic pain in a manner compatible with the patient’s life.

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Purpose: It has been reported that botulinum toxin is effective for myofascial pain, trigeminal neuropathic pain, migraine, etc. in the orofacial area. In this review, we describe basic research on the mechanism of botulinum toxin on trigeminal neuropathic pain.
Botulinum toxin effect mechanisms: We observed that peripheral intradermal administration of botulinum neurotoxin （BoNT） heavy chain 50kDa labeled with Alexa 488 reached sensory ganglia. Peripheral intradermal administration of botulinum toxin was also observed to attenuate peripheral neuropathic pain behavior and inhibited the release of FM4-64 in sensory ganglia.
Conclusion: Through peripheral intradermal administration, botulinum toxin could reach sensory ganglia after axonal transport and inhibit the release of neurotransmitters.

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The term “nociplastic pain,” a recently proposed novel mechanistic descriptor of chronic pain, is defined as pain that arises from altered nociception without nociceptor activation and nerve injury^1）. Diseases with the nociplastic pain include fibromyalgia, complex regional pain syndrome, irritable bowel syndrome, chronic primary temporomandibular disorder pains, and burning mouth syndrome. Since there is no established pharmacotherapy for these diseases, developing drugs that effectively mitigate aberrant nociception in conditions characterized by nociplastic pain becomes an urgent issue. However, the limited availability of preclinical murine models hampers the evaluation of nociplastic pain without nociceptor activation or injury^2）.
In this context, we present our recently developed model for nociplastic pain. Through a single subcutaneous injection of formalin into the upper lip, sustained sensitization lasting over 13 days at the bilateral hind paws occurs despite the absence of injury or neuropathy in rats and mice^3）. Using this nociplastic pain model, we demonstrated that repeated daily injections of pregabalin （PGB）, a drug conventionally employed to treat neuropathic pain, transiently attenuated sensitization in bilateral hind paws for the first 6 days following the initial inflammation^4）. By the 10th day of formalin injection, hindlimb sensitization was significantly reduced, even without PGB, implying its action site within the brain’s pain network^4）. This review encompasses the presentation of our obtained results, along with a discussion of potential future strategies for nociplastic pain treatment.

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Purpose: While carbamazepine administered orally remains highly effective for many trigeminal neuralgia patients, alternative medications like gabapentin and pregabalin are considered when encountering side effects. In recent years, Kampo medicine has emerged as a potential second-line option. This study approaches trigeminal neuralgia treatment with Kampo medicines through the perspectives of “treatment by medical diagnosis” and “treatment of pattern identification”.
Study Selection: Kampo medicines were evaluated alongside the guidelines outlined in “Pharmacologic Management of Neuropathic Pain, 2nd Revised Edition, 2016” by the Committee for the Guidelines for the Pharmacologic Management of Neuropathic Pain of the JSP, “Clinical Practice Guideline for Chronic Pain, 2018” by the Clinical Practice Guideline for Chronic Pain Working Group, and “Guidelines for Nonodontogenic Toothache Revised Version 2019” by the Japanese Society of Orofacial Pain. References were also consulted.
Results and Conclusions: After considering “treatment by medical diagnosis” and “treatment of pattern identification” for trigeminal neuralgia, 12 types of Kampo medicines （Keishikajutsubuto, Goreisan, Bushimatsu, Rikosan, Yokukansan, Sokeikaketsuto, Goshakusan, Makyoyokukanto, Keishito, Kakkonto, Saikokeishito, Shakuyakukanzoto） were identified as candidates. Kampo medicine can be positioned as a useful adjunctive therapy to Western medicine.

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Diseases that may involve nociplastic pain mechanisms in dentistry include burning mouth syndrome （BMS）, persistent idiopathic facial pain （PIFP）, and persistent idiopathic dentoalveolar pain （PIDAP）, which are classified as idiopathic orofacial pain in the International Classification of Orofacial Pain, 1st edition （ICOP-1）.
Both of these diseases were conventionally thought to be caused by peripheral neuropathic pain, and most of the recommended medical treatments are topically administered, but their efficacy has been inadequate. This paper describes the characteristics of these diseases and the currently recommended treatment methods, with a literature review of our own case studies, followed by a description of the pharmacological therapies, involving tricyclic antidepressants, used by the authors.
The authors used amitriptyline as their first choice. In our case-study of 195 patients （71 with BMS and 124 with PIDAP）, 63.4％ of BMS and 63.7％ of PIDAP patients achieved pain resolution in approximately 4 months and 4.5 months, respectively, at a mean dose of 59.2mg and 78.9mg/day, respectively. The mean dose of amitriptyline used was 59.2 and 78.9mg/day, respectively. If amitriptyline alone is not effective, the cure rate can be further increased by switching to another antidepressant within the same tricyclic antidepressant class or by newly adding an antipsychotic.
The authors believe that idiopathic orofacial pain disorders respond well to antidepressants, and that early diagnosis and initiation of treatment can lead to cure without chronicity.

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Purpose: Treatments for classical trigeminal neuralgia include drug therapy, nerve block therapy, and surgical treatment. There is no doubt that carbamazepine is the first choice for medication treatment. However, carbamazepine is also known as a drug with a high incidence of side effects. On the other hand, drug therapy for the pathology of neuropathic pain is challenging and stable effects have not been obtained. Recently, it has been reported that botulinum toxin treatment is effective for intractable trigeminal neuralgia and neuropathic pain. A meta-analysis of botulinum toxin on trigeminal neuralgia and neuropathic pain confirmed its analgesic effect, which was an essential index of the study. On the other hand, since the units used （25-100units） differ for each study, various indicators such as the number of seizures are used for each study. It is positioned botulinum toxin should be used as an additional therapy for carbamazepine-resistant patients. In this review, we describe the efficacy of botulinum toxin for trigeminal neuralgia and neuropathic pain based on clinical studies.

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Patient: The patient is a 84-year-old man. He had noticed electric shock-like pain on the right mandible and radix linguae 1 month ago. He had become to have difficulty in opening mouth and swallowing due to pain and was referred to our department for pain control. At first visit, we suspected glossopharyngeal neuralgia because the pain was reduced by spraying lidocaine spray to the radix linguae. Glossopharyngeal nerve block with a low-concentration local anesthetic was performed to control the pain, and the pain was alleviated. The analgesic effect of the first block was temporary, but the analgesic effect continued in the subsequent multiple blocks, and the pain disappeared after the fourth block, so the treatment was terminated.
Discussion: Blocking the peripheral branches of the glossopharyngeal nerve with a low-concentration local anesthetic have the effects that block ephaps transmission and neuronal excitability and lead to a natural refractory period by blocking tactile stimuli from the periphery for a certain period. These effects may lead long-lasting analgesic effect.
Conclusion: Glossopharyngeal nerve block with a low-concentration local anesthetic is effective as a pain control method for glossopharyngeal neuralgia.

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Case Summary: The patient was a woman in her early 70s. About four years before her first visit to our liaison outpatient clinic, the patient experienced severe pain in the left molar area of her mandible that kept her awake at night, and her family dentist diagnosed her with periodontitis of the left second bicuspid 5. The pain disappeared after about one week, but one month later, the patient experienced dull pain and numbness in the same area. The patient underwent removal of root canal filling material and root canal treatment for 5, which had been treated 20 years earlier, but the pain was not relieved. The patient was referred to our clinic after having visited a total of 10 dental facilities over a 4-year period. The patient’s diary led to a diagnosis of postherpetic neuralgia. The authors prescribed neurotropin for 4 months in consideration of complications, and the pain almost disappeared.
Discussion: Postherpetic neuralgia is persistent neuropathic pain that occurs after healing of herpes zoster. When herpes zoster causes toothache in the region of branches Ⅱ and Ⅲ of the trigeminal nerve, the toothache is severe but resolves within about one week. A few days after the toothache, vesicles may appear in the same nerve-controlled area, but vesicles may not appear. Based on this history, it is difficult to diagnose orofacial pain caused by herpes zoster. In the present case, a key diagnostic point was that the toothache described in the patient’s diary started as severe pain that kept her awake at night, resolved once, and appeared one month later as neuropathic pain with a different pathophysiology.
Conclusion: We experienced an elderly woman who developed postherpetic neuralgia without being diagnosed as toothache possibly caused by herpes zoster and continued to complain of orofacial pain for four years. The difficulty in diagnosing orofacial pain caused by herpes zoster and postherpetic neuralgia should be reaffirmed.

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Case Summary: A 41-year-old male presented with tingling and numbness along the left lingual border following the extraction of the left mandibular wisdom tooth by another dentist. He was referred to our department because his symptoms persisted despite oral vitamin B12. Upon evaluation, he was diagnosed with left-sided lingual nerve palsy and left-sided lingual neuropathy. Treatment included vitamin B12 supplementation, pregabalin, Kampo medicine, near-infrared therapy, and electroacupuncture. After 1 year and 5 months, tongue-tingling and numbness improved, and taste threshold on the left side was reduced.
Discussion: The combined approach, including medication, electroacupuncture, and near-infrared therapy, effectively addressed lingual nerve palsy. The use of pregabalin as the primary treatment for neuropathy, along with Kampo medicine, showed efficacy and helped mitigate pregabalin’s side effects, which can be valuable in neuropathy management. Electroacupuncture effectively alleviated pain, enhanced perception threshold, and reduced subjective abnormal sensations. Acupuncture and electrical stimulation might have improved nerve blood flow and enhanced peripheral nerve regeneration. Near-infrared therapy has analgesic effects by enhancing blood circulation and dampening nerve excitability. In the present case, these therapeutic modalities may be an indirect approach to managing lingual nerve palsy.
Conclusion: A comprehensive treatment strategy for lingual nerve palsy encompassing both pharmacotherapy and physiotherapy interventions （acupuncture and near-infrared therapy） can yield favorable results, highlighting the benefits of combining various therapeutic modalities for lingual nerve palsy management.

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