Orofacial pain for clinicians: A review of constant and attack-like facial pain syndromes.

BACKGROUND: Primary headache syndromes such as migraine are among the most common neurological syndromes. Chronic facial pain syndromes of non-odontogenic cause are less well known to neurologists despite being highly disabling. Given the pain localization, these patients often consult dentists first who may conduct unnecessary dental interventions even if a dental cause is not identified. Once it becomes clear that dental modalities have no effect on the pain, patients may be referred to another dentist or orofacial pain specialist, and later to a neurologist. Unfortunately, neurologists are also often not familiar with chronic orofacial pain syndromes although they share the neural system, i.e., trigeminal nerve and central processing areas for headache disorders. CONCLUSION: In essence, three broad groups of orofacial pain patients are important for clinicians: (i) Attack-like orofacial pain conditions, which encompass neuralgias of the cranial nerves and less well-known facial variants of primary headache syndromes; (ii) persistent orofacial pain disorders, including neuropathic pain and persistent idiopathic facial/dentoalveolar pain; and (iii) other differential diagnostically relevant orofacial pain conditions encountered by clinicians such as painful temporomandibular disorders, bruxism, sinus pain, dental pain, and others which may interfere (trigger) and overlap with headache. It is rewarding to know and recognize the clinical picture of these facial pain syndromes, given that, just like for headache, an internationally accepted classification system has been published and many of these syndromes can be treated with medications generally used by neurologists for other pain syndromes.

Orofacial Migraine or Neurovascular Orofacial Pain from Pathogenesis to Treatment.

The purpose of the present study is to examine possible differences between orofacial migraine (OFM) and neurovascular orofacial pain (NVOP). Facial presentations of primary headache are comparable to primary headache disorders; but occurring in the V2 or V3 dermatomes of the trigeminal nerve. These were classified and recently published in the International Classification of Orofacial Pain, 1st edition (ICOP). A category in this classification is "orofacial pains resembling presentations of primary headaches," which encompasses OFM and NVOP. The differences between NVOP and OFM are subtle, and their response to therapy may be similar. While classified under two separate entities, they contain many features in common, suggesting a possible overlap between the two. Consequently, their separation into two entities warrants further investigations. We describe OFM and NVOP, and their pathophysiology is discussed. The similarities and segregating clinical signs and symptoms are analyzed, and the possibility of unifying the two entities is debated.

Genetic variation in catechol-O-methyltransferase is associated with individual differences in conditioned pain modulation in healthy subjects.

BACKGROUND: Genetic variation in the catechol-O-methyltransferase (COMT) gene is associated with sensitivity to both acute experimental pain and chronic pain conditions. Four single nucleotide polymorphisms (SNPs) have traditionally been used to infer three common haplotypes designated as low, average and high pain sensitivity and are reported to affect both COMT enzymatic activity and pain sensitivity. One mechanism that may partly explain individual differences in sensitivity to pain is conditioned pain modulation (CPM). We hypothesized that variation in CPM may have a genetic basis. METHODS: We evaluated CPM in 77 healthy pain-free Caucasian subjects by applying repeated mechanical stimuli to the dominant forearm using 26-g von Frey filament as the test stimulus with immersion of the non-dominant hand in hot water as the conditioning stimulus. We assayed COMT SNP genotypes by the TaqMan method using DNA extracted from saliva. RESULTS: SNP rs4680 (val158 met) was not associated with individual differences in CPM. However, CPM was associated with COMT low pain sensitivity haplotypes under an additive model (p = 0.004) and the effect was independent of gender. CONCLUSIONS: We show that, although four SNPs are used to infer COMT haplotypes, the low pain sensitivity haplotype is determined by SNP rs6269 (located in the 5' regulatory region of COMT), suggesting that inherited variation in gene expression may underlie individual differences in pain modulation. Analysis of 13 global populations revealed that the COMT low pain sensitivity haplotype varies in frequency from 13% to 44% and showed that two SNPs are sufficient to distinguish all COMT haplotypes in most populations.

Exercise induced hypoalgesia profile in rats is associated with IL-10 and IL-1 ß levels and pain severity following nerve injury.

BACKGROUND: Pain may undergo modulation in the central nervous system prior to reaching the primary somatosensory cortex and being perceived as pain. Faulty pain modulation mechanisms have been linked to various chronic pain conditions. Cytokines such as IL-10 and IL-1beta, are known to be involved in initiation and maintenance of neuropathic pain. In this study, we investigated the association between pain modulation profile, pain intensity and cytokines (IL-10 and IL-1beta) levels in a rat model of neuropathic pain. METHODS: Exercise-Induced Hypoalgesia (EIH) was assessed by evaluating the percentage of responses to a train of 60g mechanical stimuli before and after 180 seconds of exercise on a rotating rod. The differences in the response rates before and after the exercise were used to divide the rats into low and high EIH responders. Rats from low and high EIH groups underwent constriction injury of the left sciatic nerve. Pain behavior (allodynia and hyperalgesia) were assessed by measuring responses to mechanical and thermal stimuli applied to the plantar surface of the foot. Serum, sciatic nerve and the related Dorsal Root Ganglia (DRG) levels of IL-10 and IL-1beta were determined by ELISA. The DRG mRNA levels of IL-10 and IL-1beta measured with PCR. A comparison between the low and high EIH rats of all measured parameters was made. RESULTS: The low EIH rats developed significantly more severe allodynia and hyperalgesia in the affected paw and allodynia in the contralateral paw compared to the high EIH rats, 7 days following the injury. The low EIH rats had higher IL-1beta protein levels in serum prior to and following injury, higher affected and contralateral sciatic nerve IL-1beta levels following injury and higher IL-1beta levels in the contralateral DRG (protein and mRNA) following injury when compared to high EIH rats. The high EIH rats had higher affected sciatic nerve IL-10 levels following nerve injury and higher IL-10 levels of both protein and mRNA in the affected and contralateral DRG at baseline and following injury. CONCLUSION: EIH profile was found to be predictive of pain behavior following nerve injury, low EIH rats developed more severe allodynia and hyperalgesia. IL-1beta may be associated with painful neuropathy developed in rats with low EIH while the anti-inflammatory cytokine IL-10 may have a protective role, inhibiting the development of painful.

The changing face of trigeminal neuralgia-A narrative review.

OBJECTIVE: This narrative review aims to update the reader on the new classification of trigeminal neuralgia (TN), clinical signs, pathophysiologic evidence, and their implications on management. This review is based on the authors' collective experience and knowledge of the literature in addition to a literature search. BACKGROUND: In recent years, the phenotype of TN has been intensively studied leading to discrete groups of patients. These include patients with TN with additional continuous pain, and patients with and without neurovascular compression of the trigeminal dorsal root entry zone. A number of associated clinical signs such as tearing and sensory changes need further research. METHODS: The literature on TN was searched in PubMed with the aims of providing evidence for the recently published third edition of the International Classification of Headache Disorders (ICHD) and update the clinical phenotype and management of the TN subcategories. RESULTS: The ICHD's new classification for TN is based on reliable clinical data, imaging, and neurophysiologic studies. The TN classification reflects current knowledge and has improved the possibility for clinicians to choose adequate management options. However, there is a lack of effective, safe drugs for the management of TN and sparse, robust data on neurosurgical options. CONCLUSION: Research into all aspects of TN-diagnosis, pharmacotherapy, surgery, long-term management prognosis, and natural history-is needed. Research should adhere to the ICHD's schema for TN. Improved drugs are needed along with rigorous research into surgical options and their efficacy for different subtypes of TN.

Effects of melanocortin-4 receptor (MC4R) antagonist on neuropathic pain hypersensitivity in rats - A systematic review and meta-analysis.

Melanocortin-4 receptor (MC4R) has been investigated as a potential drug target for the treatment of neuropathic pain. The objective of the study was to systematically identify the effects of MC4R antagonists on hypersensitivity in rat models of neuropathic pain. A systematic search was conducted using the following databases: WoS, PubMed, SCOPUS, and MEDLINE. Inclusion criteria were: rat hypersensitivity induced by models of neuropathic pain with reported effects of MC4R antagonist. Two researchers performed the selection process and data extraction. SYRCLE risk of bias tool was used. Standard mean differences (SMD) were calculated and pooled by meta-analysis using random effect models. Ten articles met the eligibility criteria and were included in the systematic review and meta-analysis. The results reveal that, in animals exposed to neuropathic pain, administration of MC4R antagonists significantly increased paw withdrawal threshold (SHU9119 SMD = 1.67, 95% CI: [0.91, 2.44], I2  = 0%; HS014 SMD = 2.2, 95% CI: [0.53, 3.87], I2  = 71%) and heat withdrawal latency (HS014 SMD = 3.35, 95% CI: [0.56, 6.14], I2  = 83%) compared to vehicle-treated animals. MC4R antagonists are effective in the alleviation of hypersensitivity in rodent neuropathic pain models. SHU9119 and HS014 antagonists showed the most prominent results. However, further investigation is needed to determine the optimal dose and time of treatment.

Chronic orofacial pain.

While pain chronicity in general has been defined as pain lasting for more than 3 months, this definition is not useful in orofacial pain (OFP) and headache (HA). Instead, chronicity in OFP and HA is defined as pain occurring on more than 15 days per month and lasting for more than 4 h daily for at least the last 3 months. This definition excludes the periodic shortlasting pains that often recur in the face and head, but are not essentially chronic. Although the headache field has adopted this definition, chronic orofacial pain is still poorly defined. In this article, we discuss current thinking of chronicity in pain and examine the term 'chronic orofacial pain' (COFP). We discuss the entities that make up COFP and analyze the term's usefulness in clinical practice and epidemiology.

Molecular mechanisms of painful traumatic trigeminal neuropathy-Evidence from animal research and clinical correlates.

Painful traumatic trigeminal neuropathy (PTTN) may occur following major craniofacial or oral trauma, or may be subsequent to relatively minor dental interventions. Following injury, pain may originate from a peripheral nerve, a ganglion, or from the central nervous system. In this review, we focus on molecular mechanisms of pain resulting from injury to the peripheral branch of the trigeminal nerve. This syndrome has been termed painful traumatic trigeminal neuropathy (PTTN) by the International Headache Society and replaces previous terms including atypical odontalgia, deafferentation pain, traumatic neuropathy and phantom toothache. We emphasize the scientific evidence supporting the events purported to lead to PTTN by reviewing the pathophysiology of PTTN based on relevant animal models. Additionally, we briefly overview clinical correlates and pathophysiological manifestations of PTTN.

Muscle tenderness score in temporomandibular disorders patients: A case-control study.

BACKGROUND: The total tenderness score (TTS) is commonly used in headache practice and contributes valuable information. OBJECTIVE: To assess muscle tenderness scores in patients diagnosed with Temporomandibular disorders (TMD) and analyse their associations with various demographic and clinical parameters. METHODS: Masticatory (MTS), cervical (CTS) and TTSs were analysed in this case-control study among 192 TMD patients and 99 controls. The study included a questionnaire and a clinical examination following RDC/TMD guidelines. Data were analysed using: Pearson's chi-square, analysis of variance, t test and Bonferroni post hoc. To examine the factors associated with MTS score in a multivariate manner, a conceptual hierarchical multiple regression model was adopted. RESULTS: Masticatory and TTS differed between TMD sub-groups and controls. Muscle tenderness was positively associated with: female sex, whiplash history, parafunction, co-morbid pains such as headaches and body pain, pain intensity, onset, frequency and duration. In the conceptual hierarchical multiple regression model, pain onset, frequency and duration, co-morbid pains were mediators in the relationship between TMD diagnosis and MTS. CONCLUSION: Muscle tenderness scores were positively associated with TMD disease characteristics and co-morbid pain conditions, which may reflect associations with disease severity. MTS differed between TMD populations and may be used in routine patient workup, to assess MMD severity and changes over time as well as treatments response and as a research tool. MTS can be used as a common methodology to describe both headaches and masticatory muscle disorders and to facilitate interprofessional research and crosstalk between a headache and oro-facial pain practitioners.

Persistent idiopathic facial pain.

Background Persistent idiopathic facial pain (PIFP) is a chronic disorder recurring daily for more than two hours per day over more than three months, in the absence of clinical neurological deficit. PIFP is the current terminology for Atypical Facial Pain and is characterized by daily or near daily pain that is initially confined but may subsequently spread. Pain cannot be attributed to any pathological process, although traumatic neuropathic mechanisms are suspected. When present intraorally, PIFP has been termed 'Atypical Odontalgia', and this entity is discussed in a separate article in this special issue. PIFP is often a difficult but important differential diagnosis among chronic facial pain syndromes. Aim To summarize current knowledge on diagnostic criteria, differential diagnosis, pathophysiology and management of PIFP. Methods We present a narrative review reporting current literature and personal experience. Additionally, we discuss and differentiate the common differential diagnoses associated with PIFP including traumatic trigeminal neuropathies, regional myofascial pain, atypical neurovascular pains and atypical trigeminal neuropathic pains. Results and conclusion The underlying pathophysiology in PIFP is still enigmatic, however neuropathic mechanisms may be relevant. PIFP needs interdisciplinary collaboration to rule out and manage secondary causes, psychiatric comorbidities and other facial pain syndromes, particularly trigeminal neuralgia. Burden of disease and psychiatric comorbidity screening is recommended at an early stage of disease, and should be addressed in the management plan. Future research is needed to establish clear diagnostic criteria and treatment strategies based on clinical findings and individual pathophysiology.

Neuropathic orofacial pain: Facts and fiction.

Definition and taxonomy This review deals with neuropathic pain of traumatic origin affecting the trigeminal nerve, i.e. painful post-traumatic trigeminal neuropathy (PTTN). Symptomatology The clinical characteristics of PTTN vary considerably, partly due to the type and extent of injury. Symptoms involve combinations of spontaneous and evoked pain and of positive and negative somatosensory signs. These patients are at risk of going through unnecessary dental/surgical procedures in the attempt to eradicate the cause of the pain, due to the fact that most dentists only rarely encounter PTTN. Epidemiology Overall, approximately 3% of patients with trigeminal nerve injuries develop PTTN. Patients are most often female above the age of 45 years, and both physical and psychological comorbidities are common. Pathophysiology PTTN shares many pathophysiological mechanisms with other peripheral neuropathic pain conditions. Diagnostic considerations PTTN may be confused with one of the regional neuralgias or other orofacial pain conditions. For intraoral PTTN, early stages are often misdiagnosed as odontogenic pain. Pain management Management of PTTN generally follows recommendations for peripheral neuropathic pain. Expert opinion International consensus on classification and taxonomy is urgently needed in order to advance the field related to this condition.

Pharmacological Topical Therapy for Intra-Oral Post Traumatic Trigeminal Neuropathic Pain: A Comprehensive Review.

Background: The efficacy of topical treatments in alleviating neuropathic pain is well-established. However, there is a paucity of research on topical interventions designed specifically for intra-oral application, where the tissue composition differs from that of exposed skin. Methods: This comprehensive review endeavors to assess the extant evidence regarding the efficacy of topical treatments in addressing neuropathic pain within the oral cavity. Utilizing combinations of search terms, we conducted a thorough search across standard electronic bibliographic databases-MEDLINE (via PubMed), Embase, Google Scholar, and Up to Date. The variables under scrutiny encompassed topical treatment, local intervention, chronic oral and orofacial pain, and neuropathic pain. All pertinent studies published in the English language between 1992 and 2022 were included in our analysis. Results: Fourteen relevant manuscripts were identified, primarily consisting of expert opinions and case reports. The comprehensive review suggests that topical treatments, especially when applied under a stent, could be effective in mitigating neuropathic pain in the oral area. However, it is crucial to conduct further studies to confirm these preliminary results. The limitations of the reviewed studies, mainly the reliance on expert opinions, small sample sizes, inconsistent study designs, and a lack of long-term follow-up data, highlight the need for more rigorous research. Conclusions: Although initial findings indicate topical treatments may be effective for oral neuropathic pain, the limitations of current studies call for more thorough research. Further comprehensive studies are essential to validate the efficacy of these treatments, standardize procedures, and determine long-term results. This will provide clearer guidance for treating chronic neuropathic pain in the oral cavity.

Post-Traumatic Trigeminal Neuropathy: Neurobiology and Pathophysiology.

Painful traumatic trigeminal neuropathy (PTTN) is a chronic neuropathic pain that may develop following injury to the trigeminal nerve. Etiologies include cranio-orofacial trauma that may result from dental, surgical, or anesthetic procedures or physical trauma, such as a motor vehicle accident. Following nerve injury, there are various mechanisms, including peripheral and central, as well as phenotypic changes and genetic predispositions that may contribute to the development of neuropathic pain. In this article, we review current literature pertaining to the cellular processes that occur following traumatic damage to the trigeminal nerve, also called cranial nerve V, that results in chronic neuropathic pain. We examine the neurobiology and pathophysiology based mostly on pre-clinical animal models of neuropathic/trigeminal pain.

Time-Course Progression of Whole Transcriptome Expression Changes of Trigeminal Ganglia Compared to Dorsal Root Ganglia in Rats Exposed to Nerve Injury.

Mechanisms underlying neuropathic pain (NP) are complex with multiple genes, their interactions, environmental and epigenetic factors being implicated. Transcriptional changes in the trigeminal (TG) and dorsal root (DRG) ganglia have been implicated in the development and maintenance of NP. Despite efforts to unravel molecular mechanisms of NP, many remain unknown. Also, most of the studies focused on the spinal system. Although the spinal and trigeminal systems share some of the molecular mechanisms, differences exist. We used RNA-sequencing technology to identify differentially expressed genes (DEGs) in the TG and DRG at baseline and 3 time points following the infraorbital or sciatic nerve injuries, respectively. Pathway analysis and comparison analysis were performed to identify differentially expressed pathways. Additionally, upstream regulator effects were investigated in the two systems. DEG (differentially expressed genes) analyses identified 3,225 genes to be differentially expressed between TG and DRG in naïve animals, 1,828 genes 4 days post injury, 5,644 at day 8 and 9,777 DEGs at 21 days postinjury. A comparison of top enriched canonical pathways revealed that a number of signaling pathway was significantly inhibited in the TG and activated in the DRG at 21 days postinjury. Finally, CORT upstream regulator was predicted to be inhibited in the TG while expression levels of the CSF1 upstream regulator were significantly elevated in the DRG at 21 days postinjury. This study provides a basis for further in-depth studies investigating transcriptional changes, pathways, and upstream regulation in TG and DRG in rats exposed to peripheral nerve injuries. PERSPECTIVE: Although trigeminal and dorsal root ganglia are homologs of each other, they respond differently to nerve injury and therefore treatment. Activation/inhibition of number of biological pathways appear to be ganglion/system specific suggesting that different approaches might be required to successfully treat neuropathies induced by injuries in spinal and trigeminal systems.

Anti-nociceptive effect of IL-12p40 in a rat model of neuropathic pain.

IL-12p70 is a proinflammatory cytokine secreted by dendritic cells, monocytes and macrophages. It plays a crucial role in cell-mediated immunity by inducing proliferation of T cell and natural killer cells, and enhancing their cytotoxic activity. In adaptive immune response, it acts on naive T cells to differentiate into Th1-type cells. It is composed of two subunits, p35 and p40. The latter can be secreted in the form of monodimer or heterodimer, which is also referred as IL-12p80. Recently IL-12p70 has been proven to locally provoke nociceptive effect in naïve rats. This study investigated pain response following systemic administration of IL-12p70 and IL-12p40 homodimer in chronic neuropathic pain model, induced by chronic constriction injury. The doses tested were IL-12p40 homodimer or IL12p70 at 15, 150 and 1500ng/kg, respectively. Pain was assessed at 1, 4, 7 and 24h after injection, in the form of tactile allodynia and mechanical hyperalgesia. The side effect of sensory motor disability was measured by rotarod performance. By all behavioral measures, IL-12p70 of any dosage, at any time point, had no significant effect on tactile allodynia and mechanical hyperalgesia. A high dose of IL-12p40 homodimer induced significant analgesic effect by the measure of hind paw tactile allodynia from 1h to 4h after injection. Medium and low doses of IL-12p40 homodimer exerted their analgesic effect 4h post injection. Mechanical hyperalgesia, following high and medium doses of IL-12p40 administration, was significantly reduced at 4h after application. Also, no significant sensory motor dysfunction was detected for all dosage for both homodimers. These findings suggest that systemic application of IL-12p40 homodimer induces time-dependent analgesia to mechanical stimulation in rats exposed to neuropathic pain.

Response profile in a rat model of exercise-induced hypoalgesia is associated with duloxetine, pregabalin and diclofenac effect on constriction-induced neuropathy.

BACKGROUND: Exercise is a known trigger of the inhibitory pain modulation system and its analgesic effect is termed exercise-induced hypoalgesia (EIH). Previous studies have demonstrated that rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury compared to rats with substantial analgesic response following exercise. OBJECTIVES: A rat model of EIH as an indicator of the pain inhibitory system's efficiency was used to explore the association between EIH profiles and the effect of pharmacotherapy on rat's neuropathic pain. METHODS: EIH profiles were assessed by evaluating paw responses to mechanical stimuli before and after exercise on a rotating rod. Rats with a reduction of ≤33% in responses were classified as low EIH and those with ≥67% as high EIH. Low and high EIH rats underwent sciatic nerve chronic constriction injury (CCI). Paw responses to mechanical stimuli were measured at baseline, following CCI, and after treatment with diclofenac, duloxetine or pregabalin. In a different group of low and high EIH rats, EIH was measured before and following treatment with the same medications. RESULTS: Low EIH rats developed more significant hypersensitivity following CCI. Duloxetine and pregabalin successfully reduced hypersensitivity, although significantly more so in low EIH rats. Diclofenac had limited effects, and only on low EIH rats. Four days of duloxetine administration transformed low EIH rats' profiles to high EIH. CONCLUSIONS: The findings of this study suggest that EIH profiles in rats can not only predict the development of hypersensitivity following injury but may also support targeted pharmacological treatment. SIGNIFICANCE: Exercise is a known trigger of the inhibitory pain modulation. Rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury. Pain modulation profiles in rats can also support targeted pharmacological treatment; rats with deficient analgesic response following exercise benefit more from treatment with duloxetine and gabapentin. Treatment with duloxetine can improve pain modulation profile.

Effects of intra-nasal melanocortin-4 receptor antagonist on trigeminal neuropathic pain in male and female rats.

Treatment of chronic orofacial pain remains a major therapeutic challenge despite available medications. Melanocortins have been implicated in pathologic pain. Intrathecal administration of MC4R antagonists has been shown to alleviate neuropathic pain (NP) in male rats. However, intrathecal delivery is very invasive and requires surgeon's intervention. Intra-nasal rout offers a non-invasive drug delivery method that can be self-administered making it very attractive clinically. In this study, we investigated the effects of intra-nasally delivered MC4R antagonist (HS014) on trigeminal neuropathic pain (TNP) in male and female rats. We also measured the MC4R protein levels in the trigeminal ganglia (TG) and infraorbital nerve (ION) of rats. We used ION chronic constriction injury (ION-CCI) to induce TNP in rats. We used von Frey and pinprick assays to measure the development of hypersensitivity in the face following ION-CCI. At 22 days post-ION-CCI, we delivered HS014 intra-nasally to measure its effects on TNP in rats. We used enzyme linked immunosorbent assay to measure MC4R protein levels in the TG and ION. ION-CCI resulted in a significant increase of MC4R protein levels in the ipsilateral TG and ION of male and female rats. Intra-nasal delivered HS014 resulted in a significant reduction of ION-CCI induced hypersensitivity in male and female rats. These results demonstrate that intranasal delivery of MC4R antagonist alleviated TNP in male and female rats and suggest that such treatment could be beneficial therapeutically for individuals with chronic NP.

Peripheral painful traumatic trigeminal neuropathy: clinical features in 91 cases and proposal of novel diagnostic criteria.

AIMS: To field-test carefully designed criteria for pain following trigeminal nerve trauma. METHODS: In order to characterize the clinical phenotype, posttraumatic pain patients were studied and compared with classical trigeminal neuralgia patients (CTN, defined according to the International Headache Society's criteria). Based on etiology and features, trigeminal pain following trauma was defined as "peripheral painful traumatic trigeminal neuropathy" (PPTTN). Data were analyzed with t tests, ANOVA, chi-square, and regression analyses. RESULTS: A total of 145 patients were included: 91 with PPTTN and 54 with CTN. Findings indicated that PPTTN criteria are clinically applicable in the detection and characterization of relevant cases. In contrast to accepted characteristics for PPTTN, the observed profile included both continuous and paroxysmal pain that was stabbing and/or burning. The quality, duration, and intensity were significantly different from the CTN patients (P < .05). PPTTN was consistently accompanied by trigeminal sensory abnormalities (96%) that were mostly allodynia, hyperor hypoalgesia, and only 1% of the PPTTN cases had anesthesia. CONCLUSION: Overall, the proposed PPTTN criteria have proven to be clinically useful. In view of these results, modified PPTTN diagnostic criteria are proposed for use in future research.