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Background: Trigeminal neuralgia is characterized by paroxysmal facial pain attacks. Adequate prophylactic drug therapy is often limited by the lack of efficacy and intolerance due to central nervous system side effects. Subcutaneous injections of botulinum toxin type A are a promising treatment option for patients with unsatisfactory response to drug therapy or neurosurgical intervention. Its effects are expected to last for at least 3 months, so it could be a potential long-term treatment. This is the study protocol of a prospective, placebo-controlled, double blind clinical trial investigating the add-on therapy of subcutaneous administration of botulinum toxin type A injections to standard treatment in therapy-refractory classical trigeminal neuralgia., Methods and Design: BoTN is a prospective, double blind, placebo-controlled trial with a randomized withdrawal design in which a single blind phase is followed by a double blind phase (see also Methods and design). Eligible patients with classical trigeminal neuralgia who are otherwise refractory to medical and neurosurgical treatment will receive subcutaneous injections of botulinum toxin type A into injection sites of the affected trigeminal branch. In the first phase all patients will receive botulinum toxin type A in a single blinded intervention. Twelve weeks later therapy responders will be allocated to the verum or placebo (saline) arm in a double blind, randomized manner. These injections will be performed at the same sites as the first injections. This trial will be conducted in a tertiary outpatient clinic specialized in the treatment of headache and facial pain. There will be three investigators performing the injections who are experienced in the treatment of headache and facial pain and trained in botulinum toxin type A injections., Discussion: BoTN is designed to assess the efficacy and safety of subcutaneous botulinum toxin type A injections in addition to standard prophylactic treatment in therapy-refractory trigeminal neuralgia., Trial Registration Number: EU Clinical Trials Register: EudraCT-No: 2014-001959-24 https://www.clinicaltrialsregister.eu/ctr-search/rest/download/trial/2014-001959-24/DE Date of trial registration 26 August 2014.

Activation of the trigeminal system plays an important role in the pathomechanism of headaches. A better understanding of trigeminal pain processing is expected to provide information helping to unravel the background of these diseases. ATP, a key modulator of nociceptive processing, acts on ligand-gated P2X receptors. Antagonists of the P2X7 receptors, such as Brilliant Blue G (BBG), have proved effective in several models of pain. We have investigated the effects of BBG after electrical stimulation of the trigeminal ganglion and in the orofacial formalin test in the rat. The right trigeminal ganglion of male rats was stimulated either with 5 Hz, 0.5 mA pulses for 5 min (mild procedure) or with 10 Hz, 0.5 mA pulses for 30 min (robust procedure), preceded by 50 mg/kg i.v. BBG. The animals were processed for c-Fos and calcitonin gene-related peptide (CGRP) immunohistochemistry. In the orofacial formalin test, 50 μL of 1.5 % formalin was injected into the right whisker pad of awake rats, following the pre-treatment with BBG. Behaviour was monitored for 45 min, and c-Fos and CGRP immunohistochemistry was performed. BBG attenuated the increase in c-Fos-positive cells in the caudal trigeminal nucleus (TNC) after robust stimulation, but not after mild stimulation. No alterations in CGRP levels were found with either methodology. BBG did not mitigate either the behaviour or the increase in c-Fos-positive cells in the TNC during the orofacial formalin test. These results indicate that P2X7 receptors may have a role in the modulation of nociception in the trigeminal system.

A B S T R A C T The drugs available for the management of acute orofacial pain have changed very little since the introduction of ibuprofen into practice 40 years ago. Orally effective opioids, acetaminophen, aspirin and NSAIDs remain the mainstay of analgesic therapy. Increased recognition of the societal and personal impact of opioid diversion and abuse requires re-examination of the traditional approach of prescribing an opioid-containing analgesic combination to be administered by the patient "as needed" (PRN) starting postoperatively.

For neuropathic pain, the three medications to use are gabapentinoids, tricyclic antidepressants and serotonin norepinephrine reuptake inhibitors plus topical anesthetics. Beta-blockers, tricyclic antidepressants and anti-epileptic drugs are effective preventive medications for daily migraine headaches. The three FDA-approved drugs for fibromyalgia, pregabalin, duloxetine and milnacipran, are not robust. For osteoarthritis, nonsteroidal anti-inflammatories have good efficacy, and when gastritis contraindicates them, corticosteroid injections are helpful.

Combination therapy with two or more analgesics is widely used for conditions associated with moderate to severe pain. Combinations of diverse analgesics with different modes of action can improve the risk-benefit ratio of analgesic treatments. The aim of this study is to evaluate the antinociceptive effect of tapentadol (TAP) and flupirtine (FLP), when administered separately or in combination, as well as their synergistic interaction in the orofacial formalin test in rats. After i.p. injection of TAP at different doses (2, 5, 10 and 15mg/kg), the biphasic nociceptive behavior was reduced in a dose-dependent manner in both phase I and II. Conversely, i.p. injection of FLP at different doses (0.6, 1.6, 3.3, 6.6, 16.6 and 22.2mg/kg) induced a dose-dependent antinociceptive effect in phase II only. TAP was found to be more effective than FLP. The interaction between TAP and FLP was synergistic in phase II with an interaction index (γ) of 0.50±0.24. The data reported in this study indicate that FLP enhances the antinociceptive effect of TAP and this drug combination might be potentially useful in the treatment of chronic pain., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Temporomandibular disorders (TMDs) are orofacial pains within the trigeminal distribution, which involve the masticatory musculature, the temporomandibular joint or both. Their pathophysiology remains unclear, as inflammatory mediators are thought to be involved, and clinically TMD presents pain and sometimes limitation of function, but often appears without gross indications of local inflammation, such as visible edema, redness and increase in temperature. Calcitonin gene-related peptide (CGRP) has been implicated in other pain disorders with trigeminal distribution, such as migraine, of which TMD shares a significant co-morbidity. CGRP causes activation and sensitization of trigeminal primary afferent neurons, independent of any inflammatory mechanisms, and thus may also be involved in TMD. Here we used a small molecule, selective CGRP receptor antagonist, MK-8825, to dissect the role of CGRP in inducing spontaneous nociceptive facial grooming behaviors, neuronal activation in the trigeminal nucleus, and systemic release of pro-inflammatory cytokines, in a mouse model of acute orofacial masseteric muscle pain that we have developed, as a surrogate of acute TMD. We show that CFA masseteric injection causes significant spontaneous orofacial pain behaviors, neuronal activation in the trigeminal nucleus, and release of interleukin-6 (IL-6). In mice pre-treated with MK-8825 there is a significant reduction in these spontaneous orofacial pain behaviors. Also, at 2 and 24h after CFA injection the level of Fos immunoreactivity in the trigeminal nucleus, used as a marker of neuronal activation, was much lower on both ipsilateral and contralateral sides after pre-treatment with MK-8825. There was no effect of MK-8825 on the release of IL-6. These data suggest that CGRP may be involved in TMD pathophysiology, but not via inflammatory mechanisms, at least in the acute stage. Furthermore, CGRP receptor antagonists may have therapeutic efficacy in the treatment of TMD, as they do with migraine., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Patients suffering from persistent orofacial pain may sporadically report that the painful area feels "swollen" or "differently," a phenomenon that may be conceptualized as a perceptual distortion because there are no clinical signs of swelling present. Our aim was to investigate whether standardized experimental pain and sensory deprivation of specific orofacial test sites would lead to changes in the size perception of these face areas. Twenty-four healthy participants received either 0.2 mL hypertonic saline (HS) or local anesthetics (LA) into six regions (buccal, mental, lingual, masseter muscle, infraorbital and auriculotemporal nerve regions). Participants estimated the perceived size changes in percentage (0 % = no change, -100 % = half the size or +100 % = double the size), and somatosensory function was checked with tactile stimuli. The pain intensity was rated on a 0-10 Verbal Numerical Rating Scale (VNRS), and sets of psychological questionnaires were completed. HS and LA were associated with significant self-reported perceptual distortions as indicated by consistent increases in perceived size of the adjacent face areas (P ≤ 0.050). Perceptual distortion was most pronounced in the buccal region, and the smallest increase was observed in the auriculotemporal region. HS was associated with moderate levels of pain VNRS = 7.3 ± 0.6. Weak correlations were found between HS-evoked perceptual distortion and level of dissociation in two regions (P < 0.050). Experimental pain and transient sensory deprivation evoked perceptual distortions in all face regions and overall demonstrated the importance of afferent inputs for the perception of the face. We propose that perceptual distortion may be an important phenomenon to consider in persistent orofacial pain conditions.

Tolosa-Hunt syndrome, an idiopathic granulomatous inflammation of the cavernous sinus, is primarily a diagnosis of exclusion. The majority of patients present with unilateral orbital pain and features suggestive of paralysis of one or more of the cranial nerves passing through the cavernous sinus and/or superior orbital fissure. MRI of the head may show unilateral enhancement of the cavernous sinus and orbital apex. Treatment is with high-dose intravenous steroids followed by tapering oral steroids. Rapid amelioration of pain within 24-48 h supports this rare diagnosis. Resolution of neuropathies may take longer. We describe a case of a young man who presented with left periorbital pain, complete ophthalmoplaegia and ptosis of the left eye. MRI showed enhancement of the left cavernous sinus and orbital apex. High dose steroids led to complete resolution of pain, while ptosis and ophthalmoplaegia improved gradually., (2015 BMJ Publishing Group Ltd.)

Background: Tumor necrosis factor alpha (TNFα) is increased in patients with headache, neuropathic pain, periodontal and temporomandibular disease. This study and others have utilized TNF receptor 1/2 (TNFR1/2) knockout (KO) animals to investigate the effect of TNFα dysregulation in generation and maintenance of chronic neuropathic pain. The present study determined the impact of TNFα dysregulation in a trigeminal inflammatory compression (TIC) nerve injury model comparing wild-type (WT) and TNFR1/2 KO mice., Methods: Chromic gut suture was inserted adjacent to the infraorbital nerve to induce the TIC model mechanical hypersensitivity. Cytokine proteome profiles demonstrated serology, and morphology explored microglial activation in trigeminal nucleus 10weeks post., Results: TIC injury induced ipsilateral whisker pad mechanical allodynia persisting throughout the 10-week study in both TNFR1/2 KO and WT mice. Delayed mechanical allodynia developed on the contralateral whisker pad in TNFR1/2 KO mice but not in WT mice. Proteomic profiling 10weeks after chronic TIC injury revealed TNFα, interleukin-1alpha (IL-1α), interleukin-5 (IL-5), interleukin-23 (IL-23), macrophage inflammatory protein-1β (MIP-1β), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased more than 2-fold in TNFR1/2 KO mice compared to WT mice with TIC. Bilateral microglial activation in spinal trigeminal nucleus was detected only in TNFR1/2 KO mice. p38 mitogen-activated protein kinase (MAPK) inhibitor and microglial inhibitor minocycline reduced hypersensitivity., Conclusions: The results suggest the dysregulated serum cytokine proteome profile and bilateral spinal trigeminal nucleus microglial activation are contributory to the bilateral mechanical hypersensitization in this chronic trigeminal neuropathic pain model in the mice with TNFα dysregulation. Data support involvement of both neurogenic and humoral influences in chronic neuropathic pain., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

This article reviews the diagnoses and treatment of temporomandibular disorders (TMD) and outlines of the role of botulinum toxin (BoNT) in the treatment of myofacial TMD. This manuscript includes a brief history of the use of BoNT in the treatment of pain, the mechanism of action of BoNT, and the techniques for injections, adverse effects and contraindications when using BoNT to treat mayofacial pain caused by TMD.

Nicotinic acetylcholine and opioid receptors are involved in modulation of pain. In the present study, we investigated the effects of microinjection of nicotinic acetylcholine and opioid compounds into the ventral orbital cortex (VOC) on the formalin-induced orofacial pain in rats. For this purpose, two guide cannulas were placed into the left and right sides of the VOC of the brain. Orofacial pain was induced by subcutaneous injection of a diluted formalin solution (50μl, 1.5%) into the right vibrissa pad and face rubbing durations were recorded at 3-min blocks for 45min. Formalin produced a marked biphasic pain response (first phase: 0-3min and second phase: 15-33min). Epibatidine (a nicotinic receptor agonist) at doses of 0.05, 0.1 and 0.2μg/site, morphine (an opioid receptor agonist) at doses of 0.5, 1 and 2μg/site and their sub-analgesic doses (0.025μg/site epibatidine with 0.25μg/site morphine) combination treatment suppressed the second phase of pain. The antinociceptive effect induced by 0.2μg/site of epibatidine, but not morphine (2μg/site), was prevented by 2μg/site of mecamylamine (a nicotinic receptor antagonist). Naloxone (an opioid receptor antagonist) at a dose of 2μg/site prevented the antinociceptive effects induced by 2μg/site of morphine and 0.2μg/site of epibatidine. No above-mentioned chemical compounds affected locomotor activity. These results showed that at the VOC level, epibatidine and morphine produced antinociception. In addition, opioid receptor might be involved in epibatidine-induced antinociception, but the antinociception induced by morphine was not mediated through nicotinic acetylcholine receptor., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A model system capable of providing clinically relevant analgesic doses with minimal trauma has been elusive in laboratory animal medicine. Our laboratory has developed an orofacial operant pain system that effectively discriminates between non-noxious and noxious thermal stimuli in rats and mice. Male and female rats (Crl:SD) and mice (Crl:SKR-HR(hr)) were trained to perform a task (placing their face through an opening and having their cheeks stay in contact with thermodes) to receive a reward (a solution of sweetened condensed milk). Currently accepted doses of buprenorphine were tested by using a crossover design. Pain was induced in both species by sensitizing the depilated skin over both cheeks with capsaicin cream or by creating a surgical incision (rats only) and then allowing the animals to contact a temperature-regulated thermode while obtaining a reward. Optimal antinociceptive doses included 0.05 and 0.1 mg/kg in male mice but only 0.05 mg/kg in female mice. In rats, optimal antinociceptive doses included 0.03 and 0.05 mg/kg for male rats but only 0.03 mg/kg for female rats. The 2 pain-induction models in rats (capsaicin cream and surgical incision) did not differ. Our orofacial operant pain assay can determine clinically relevant analgesic doses for rodents in a preclinical assay. The automated, investigator-independent nature of the assay, in conjunction with its high sensitivity, makes this method an improvement over traditional noninvasive methods, providing better data for developing optimal analgesic recommendations for rats and mice.

Objectives: This prospective study examined the relationship between resting blood pressure (BP; primary outcome), demographic features of patients, anatomical characteristics of the extracted teeth, surgery variables (secondary outcomes), and acute postsurgical pain in patients undergoing tooth extraction., Materials and Methods: Standardized surgery was performed under local anesthesia. A composite numerical index, referred to as "postoperative pain/analgesia score" (PPAS), was built out of two intermediate ones, indicating (i) the degree of spontaneous pain reported by the patient (postoperative pain score) and (ii) the amount of analgesic drug intake (postoperative analgesia score)., Results: A total of 293 patients with complete data sets were included in the analysis. Univariate analysis reveals that the intensity of postoperative pain is related to age, history of hypertension and previous oral surgery, number of extracted teeth, duration of surgery, and extraction of the third molar. On the other hand, there is no relationship with gender, anxiety, and operation duration. Multivariate analysis reveals that the intensity of acute postoperative pain is only associated with the location (upper/lower jaw, P = 0.004) and deepness of implantation of the extracted tooth (P < 0.0001), and mean resting BP (P = 0.031)., Conclusions: This large prospective study shows that patients with high resting BP had a lower oral postsurgical pain than those with low resting BP. This suggests that high resting BP is a protective factor against oral postsurgical pain., Clinical Relevance: The measurement of resting BP before surgery may be used in clinical practice to identify patients at risk of developing severe oral postsurgical pain.

Trigeminal (TG) pain often lacks a satisfactory pharmacological control. A better understanding of the molecular cross-talk between TG neurons and surrounding satellite glial cells (SGCs) could help identifying innovative targets for the development of more effective analgesics. We have previously demonstrated that neuronal pro-algogenic mediators upregulate G protein-coupled nucleotide P2Y receptors (P2YRs) expressed by TG SGCs in vitro. Here, we have identified the specific P2YR subtypes involved (i.e., the ADP-sensitive P2Y1 R and the UTP-responsive P2Y2 R subtypes), and demonstrated the contribution of neuron-derived prostaglandins to their upregulation. Next, we have translated these data to an in vivo model of TG pain (namely, rats injected with Complete Freund's adjuvant in the temporomandibular joint), by demonstrating activation of SGCs and upregulation of P2Y1 R and P2Y2 R in the ipsi-lateral TG. To unequivocally link P2YRs to the development of facial allodynia, we treated animals with various purinergic antagonists. The selective P2Y2 R antagonist AR-C118925 completely inhibited SGCs activation, exerted a potent anti-allodynic effect that lasted over time, and was still effective when administration was started 6-days post induction of allodynia, i.e. under subchronic pain conditions. Conversely, the selective P2Y1 R antagonist MRS2179 was completely ineffective. Moreover, similarly to the anti-inflammatory drug acetylsalicylic acid and the known anti-migraine agent sumatriptan, the P2X/P2Y nonselective antagonist PPADS was only partially effective, and completely lost its activity under sub-chronic conditions. Taken together, our results highlight glial P2Y2 Rs as potential "druggable" targets for the successful management of TG-related pain., (© 2015 Wiley Periodicals, Inc.)

Objective: The aim of this study was to test the hypothesis that patients with persistent dentoalveolar pain disorder (PDAP) expresses somatosensory abnormalities through quantitative sensory testing (QST), when compared to healthy controls; and that individuals with PDAP do not have somatosensory alterations after application of a topical anaesthetic gel., Design: QST was performed in 25 subjects with PDAP (19 women and 6 men), at baseline and after topical application of benzocaine 2% (Benzotop 200mg/g, DFL) and compared to 25 matched healthy controls. After "Z" score transformation, results were analyzed using the paired "t" test and "t" test with significance level of 5%., Results: PDAP subjects have lower pain detection thresholds confirmed through mechanical tests; and higher pain intensity report through thermal stimuli tests (heat and cold) when compared to healthy subjects. Topical anaesthesia partially reduces in 60% pain intensity of PDAP patients; and anaesthetic gel increases mechanical detection thresholds and reduces pain intensity report in dynamical mechanical allodynia tests., Conclusions: PDAP patients had abnormal thermal sensory and mechanical allodynia, which is indicative of central sensitization. Moreover, topical anaesthetic incited a significant reduction in pain intensity, and an increase in mechanical and pain detection thresholds, which could be also suggestive of a peripheral disorder., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Detecting behaviors related to orofacial pain in rodent models often relies on subjective investigator grades or methods that place the animal in a stressful environment. In this study, an operant-based behavioral assay is presented for the assessment of orofacial tactile sensitivity in the rat., New Methods: In the testing chamber, rats are provided access to a sweetened condensed milk bottle; however, a 360° array of stainless steel wire loops impedes access. To receive the reward, an animal must engage the wires across the orofacial region. Contact with the bottle triggers a motor, requiring the animal to accept increasing pressure on the face during the test. To evaluate this approach, tolerated bottle distance was measured for 10 hairless Sprague Dawley rats at baseline and 30 min after application of capsaicin cream (0.1%) to the face. The experiment was repeated to evaluate the ability of morphine to reverse this effect., Results: The application of capsaicin cream reduced tolerated bottle distance measures relative to baseline (p<0.05). As long as morphine did not cause reduced participation due to sedation, subcutaneous morphine dosing reduced the effects of capsaicin (p<0.001). Comparison with existing method: For behavioral tests, experimenters often make subjective decisions of an animal's response. Operant methods can reduce these effects by measuring an animal's selection in a reward-conflict decision. Herein, a method to measure orofacial sensitivity is presented using an operant system., Conclusions: This operant device allows for consistent measurement of heightened tactile sensitivity in the orofacial regions of the rat., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Levetiracetam is an antiepileptic drug with analgesic efficacy shown in pain models and small clinical trials. Sumatriptan is used in acute migraine treatment. Caffeine is widely consumed in some beverages/foods and is also an adjuvant in analgesic formulations. We examined the effects of systemic levetiracetam, sumatriptan, and caffeine and their interactions in 2-component combinations in the rat orofacial formalin test, a model of trigeminal pain., Methods: Rats received a subcutaneous injection of formalin solution into the perinasal area, and the total time spent in nociceptive behavior (face rubbing) was quantified. The antinociceptive effect of drugs/drug combinations was assessed 1 hour after per os administration. The type of interaction between levetiracetam/sumatriptan and caffeine was examined by comparing the effects of a fixed, effective dose of levetiracetam/sumatriptan alone with the effects of the same dose applied with increasing, subeffective doses of caffeine. The type of interaction between levetiracetam and sumatriptan was determined by isobolographic analysis., Results: Levetiracetam (1-50 mg/kg) and sumatriptan (0.5-5 mg/kg) produced significant and dose-dependent antinociceptive effects in both phases of the orofacial formalin test (P ≤ 0.001). Caffeine (7.5-100 mg/kg) produced significant antinociception in the second phase of the test (P = 0.04). Caffeine (1-7.5 mg/kg) significantly reduced the antinociceptive effects of levetiracetam (25 mg/kg) (first phase P = 0.002, second phase P < 0.001) and sumatriptan (2.5 mg/kg) (first phase P = 0.014, second phase P = 0.027); dose-dependent inhibition was observed in the second phase. Levetiracetam and sumatriptan exerted an additive interaction in the second phase of the orofacial formalin test., Conclusions: Results indicate that levetiracetam may be useful for treatment of pain in the trigeminal region. Dietary caffeine might decrease the effects of levetiracetam and sumatriptan; this needs to be considered in clinical settings. A levetiracetam-sumatriptan combination could also be useful in trigeminal pain treatment. Its efficacy and adverse effects should be examined clinically.

Trigeminal neuralgia is a rare cause of episodic unilateral facial pain and often in the initial presentation dental causes need to be eliminated, as it frequently presents in the lower trigeminal divisions. The pain description is characteristic of electric shock-like pain that is light-touch provoked, paroxysmal, and occurring daily; the condition can go into remission for weeks or months, however. The first-line drug is either carbamazepine or oxcarbazepine and has to be started in low doses. Over 70% of patients will initially obtain immediate relief. If efficacy or tolerability becomes a problem, then referral to a secondary care specialist should be made. Magnetic resonance imaging (MRI) scans can determine if there is a symptomatic cause and whether surgery is indicated. Surgical options provide longest pain relief periods. Patients need to be given information about all treatment options so they can make a decision about treatment. This report is adapted from paineurope 2014; Issue 4, © Haymarket Medical Publications Ltd., and is presented with permission. paineurope is provided as a service to pain management by Mundipharma International, Ltd., and is distributed free of charge to health care professionals in Europe. Archival issues can be viewed via the Web site: www.paineurope.com , at which health professionals can find links to the original articles and request copies of the quarterly publication and access additional pain education and pain management resources.

The aim of this study was to evaluate the interaction between tramadol and parecoxib in the orofacial formalin test. Tramadol (10, 31.6, 56, and 100 mg/kg ip) or parecoxib (31.6, 56, 100, and 178 mg/kg ip) were administered 10 min before formalin (2.5%) injection into the upper lip to characterize the dose-response curve of each individual drug in the orofacial pain test in mice. Once the dose-response curve of each drug was obtained, an experimental effective dose 50 (ED50 ) value was determined for each drug. The tramadol-parecoxib combination was evaluated in four different groups of animals. The isobolographic analysis and the interaction index were used to evaluate the nature of interaction between both drugs. The isobologram and the interaction index showed increased in the antinociceptive effect of the combination. The tramadol-parecoxib combination produces a synergism in the second phase of the orofacial formalin test., (© 2015 Wiley Periodicals, Inc.)

Our aim was to find out whether pain was better controlled if morphine or tramadol was injected intra-articularly after arthrocentesis with Ringer's lactate in patients with painful temporomandibular joints (TMJ). This placebo-controlled, double-blind study involved 30 patients who had not responded to conservative treatment and who were divided randomly into 3 groups of 10 patients each. All patients had arthrocentesis, and the drugs were given as intra-articular injections immediately after the procedure. One group was give 5% Ringer's lactate 1ml, the second morphine 1mg, and the third tramadol 50mg. Visual analogue scales (VAS) for pain were recorded at maximum mouth opening and at rest before intra-articular injection and after 15 and 30min; at 1, 2, 3, 8, 12, 24, 36 and 48h; and at 1, 3, and 6 monthly follow-up. The mean (SD) VAS decreased from 6.90 (1.45) to 2.6 (2.5) in the control group, from 7.30 (1.64) to 1.20 (0.79) in the morphine group (p=0.005), and from 7.10 (1.73) to 1.50 (1.78) in the tramadol group (p=0.005). We conclude that morphine given by intra-articular injection after arthrocentesis gives a significant, sustained (6 months) improvement in pain relief compared with simple arthrocentesis alone. The effect was similar with tramadol except that it was shorter lived., (Copyright © 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Unilateral ligation of the tendon of anterior superficial part of rat masseter muscle (TASM) leads to long-lasting allodynia. Sex differences in peripheral mu-opioid receptor (MOR)-mediated analgesia under persistent myogenic pain are not well understood. In this study, we examined (1) whether locally applied MOR agonists attenuate persistent pain following TASM ligation in a sex dependent manner, (2) whether there are sex differences of MOR expression changes in rat trigeminal ganglia (TG). The effects of MOR agonist, D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin acetate salt (DAMGO), were assessed 14 days after TASM ligation in male, female and orchidectomized (GDX) male rats. MOR mRNA and protein levels in TG 14 days following tendon ligation were also determined. The mechanical thresholds of the injured side were significantly decreased in both male and female rats, from 3 days to 28 days after TASM ligation. A10 μg DAMGO significantly attenuated allodynia in male rats. A 10-fold higher dose of DAMGO was required in female and GDX male rats to produce the level of anti- allodynia achieved in male rats. The level of MOR mRNA in TG from male rats was significantly greater 14 days after TASM ligation compared with the sham-operated male rats, but not from female and GDX male rats. After TASM ligation, males had significantly more MOR immunoreactivity in TG compared to sham-operated males. The MOR levels increased to 181.8% of the sham level in male rats receiving tendon injury. But there was no significant change in female rats receiving tendon injury compared to the sham female rats. Taken together, our data suggest that there were sex differences in the effects of peripheral MOR agonists between male and female rats under TASM ligation developing long-lasting pain condition, which is partly mediated by sex differences in the changes of MOR expressions and testosterone is an important factor in the regulation of MOR.

Inflammation of the trigeminal nerve is considered one of the most painful conditions known to humankind. The diagnosis is often difficult; moreover, safe and effective pharmacological treatments are lacking. A new molecule, ADM&#95;12, formed by a lipoic and omotaurine residues covalently linked, is here reported. In vitro and in vivo tests showed that ADM&#95;12 is a very attractive original compound presenting (i) a remarkable safety profile; (ii) a high binding constant versus TRPA1; (iii) an intriguing behavior versus TRPV1; and (iv) the ability to significantly and persistently reduce mechanical facial allodynia in rats. Noteworthy, by testing ADM&#95;12, we shed light on the unprecedented involvement of TRPA1 and TRPV1 channels in orofacial pain.

In our current study, we investigated the role of spinal glutamate recycling in the development of orofacial inflammatory pain. DL-threo-β-benzyloxyaspartate (TBOA) or methionine sulfoximine (MSO) was administered intracisternally to block spinal glutamate transporter and glutamine synthetase activity in astroglia. Intracisternal administration of high dose TBOA (10 μg) produced thermal hyperalgesia in naïve rats but significantly attenuated the thermal hyperalgesia in rats that had been pretreated with interleukin (IL)-1β or Complete Freund's Adjuvant (CFA). In contrast, intracisternal injection of MSO produced anti-hyperalgesic effects against thermal stimuli in CFA-treated rats only. To confirm the paradoxical antinociceptive effects of TBOA and MSO, we examined changes in c-Fos expression in the medullary dorsal horn produced by thermal stimulation in naïve, IL-1β-, or CFA-treated rats, after intracisternal injections of TBOA and MSO. Intracisternal administration of TBOA significantly increased c-Fos immunoreactivity in naïve rats. In contrast, intracisternal administration of TBOA significantly decreased the up-regulation of c-Fos immunoreactivity in the medullary dorsal horn of IL-1β- and CFA-treated rats. However, intracisternal injection of MSO blocked the up-regulation of c-Fos immunoreactivity in CFA-treated rats only. We also investigated the effects of botulinum toxin type A (BoNT-A) on TBOA-induced paradoxical antinociception in CFA-treated rats, as BoNT-A inhibits the release of neurotransmitters, including glutamate. BoNT-A treatment reversed behavioral responses produced by intracisternal administration of TBOA in CFA-treated rats. These results suggest that the paradoxical responses produced by blocking glutamate transporters under inflammatory pain conditions are mediated by the modulation of glutamate release from presynaptic terminals. Moreover, blockade of glutamate reuptake could represent a new therapeutic target for the treatment of chronic inflammatory pain conditions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Diagnosis and treatment of facial pain is a problem for physicians of different specialties (neurologists, dentists, surgeons, oculists, otolaryngologists and psychiatrists). A classification of this pathology is far from ideal and an interdisciplinary comprehensive approach is needed. Current approaches to etiotropic, symptomatic and pathogenetic treatment of patients with most frequent variants of orofacial pain are presented.

Complexity of facial anatomy and its rich innervation complicate the diagnosis of prosopalgias. An acute syndrome, including trigeminal, myofascial and cervical pains, is described. Authors discuss algesic interrelations, combined therapeuric effect and peculiarities of diagnosis.

Objective: To investigate emotional and personality disorders in patients with atypical facial pain., Material and Methods: Forty-five patients (42 women, 3 men, mean age 50±16 years) were examined. Pain severity was assessed with the Visual Analogue Scale. Anxiety and depression levels were measured with the Zung Self-Rating Depression Scale, the State-Trait Anxiety Inventory (Spilberg's tests), the Taylor Manifest Anxiety Scale, The Beck Depression Inventory. Thirty patients with atypical facial pain were treated with noophen. The clinical state of the patients was assessed with the Hamilton Depression Rating Scale (HAM-D). Noophen was administrated in daily dose of 500 mg, the course of the treatment was 8 weeks., Results and Conclusion: Anxiety and depression as well as the domination of functional neurologic symptoms were characteristic of patients with atypical facial pain. Anxiolytic and antidepressive effects of noophen were seen from the 21st day of treatment. A mild stimulation effect and sleep normalization were also observed. An improvement of the mental state was found in 70% patients with atypical facial pain in the end of treatment: 50% patients demonstrated a significant improvement.

Purpose: Post-traumatic oromandibular dystonia (PTOD) is a disorder whose symptoms can include bruxism, muscle pain, and involuntary muscle contraction, among others. The use of onabotulinumtoxinA (ObT-A) is helpful in controlling the symptoms of patients with PTOD. The aim of this study was to evaluate the use of ObT-A in the treatment of PTOD., Materials and Methods: In this prospective case-series study, the population consisted exclusively of patients diagnosed with PTOD, without distinction by age or gender, from January 2007 to December 2010. The patients were diagnosed with PTOD and treated with ObT-A infiltration (primary predictor) at the Department of Maxillofacial Surgery at the Hospital Clínico Mutual de Seguridad (Santiago, Chile). The primary outcome variables were bruxism, muscle pain, and involuntary muscle contraction. The data were obtained through questionnaires registered in tables at each control. Systat 13.1 was used for statistical analysis. The statistical test used to compare patients' evolution over time was the test of signs., Results: Thirty male patients 18 to 65 years old diagnosed with PTOD were treated with ObT-A infiltrations. The signs and symptoms associated with oromandibular dystonia (bruxism, muscle pain, and involuntary muscle contraction) were decreased in all patients after ObT-A infiltrations., Conclusions: The positive results and the absence of complications recommend the use of the infiltration protocol presented in this study for the treatment of PTOD., (Copyright © 2015 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Chronic rhinosinusitis (CRS) has been defined as inflammation of the paranasal sinuses lasting at least 12 weeks with corresponding 2 or more "cardinal symptoms" that include: (1) nasal obstruction; (2) thick nasal discharge; (3) facial pain/pressure; and (4) reduction or loss of sense of smell. Although prior studies have investigated symptoms of CRS after sinus surgery, none have compared the outcomes of these specific symptoms to ongoing medical therapy., Methods: Patients with CRS were prospectively enrolled into a multi-institutional, comparative effectiveness, cohort study. Subjects elected either continued medical management or endoscopic sinus surgery (ESS). Baseline characteristics and objective clinical findings were collected. Cardinal symptoms of CRS were operationalized by 4 questions on the 22-item Sino-Nasal Outcome Test (SNOT-22). Symptom improvement was evaluated in subjects with at least 6-month follow-up., Results: A total of 342 subjects were enrolled, with 69 (20.2%) electing continued medical management, whereas 273 (79.8%) elected ESS. Subjects electing surgical therapy were more likely to have a higher baseline aggregate SNOT-22 score (44.3 (18.9) vs 53.6 (18.8); p < 0.001). All subjects improved across all cardinal symptoms; however, subjects undergoing ESS were significantly more likely (p ≤ 0.013) to experience improvement in thick nasal discharge (odds ratio [OR] = 4.36), facial pain/pressure (OR = 3.56), and blockage/congestion of nose (OR = 2.76). Subjects with nasal polyposis were significantly more likely to report complete resolution of smell/taste following ESS compare to medical management (23.8% vs 4.0%; p = 0.026)., Conclusion: Across a large population, surgical management is more effective at resolving the cardinal symptoms of CRS than ongoing medical management with the exception of sense of smell/taste., (© 2014 ARS-AAOA, LLC.)

Disorders involving the orofacial area represent a major medical and social problem. They are a consequence of central nociceptive processes associated with stimulation of the trigeminal nerve nucleus. A rat model of trigeminal pain, utilizing tongue jerks evoked by electrical tooth pulp stimulation during perfusion of the cerebral ventricles with various neuropeptide solutions, can be used in the pharmacological studies of nociception in orofacial area. The investigated neuropeptides diffuse through the cerebroventricular lining producing an analgesic effect either directly, through the trigemino-hypoglossal reflex arc neurons or indirectly through the periaqueductal central gray, raphe nuclei or locus coeruleus neurons. The aim of this review is to present the effect of pharmacological activity of various neuropeptides affecting the transmission of the sensory information from the orofacial area on the example of trigemino-hypoglossal reflex in rats.

Probenecid has been widely used in the treatment of gout, but evidence suggests that it may also have antinociceptive effects in different inflammatory and pain conditions. We examined the potential modulatory effects of probenecid on behavioural and morphological markers in the orofacial formalin test of the rat. One hour after pre-treatment with vehicle or probenecid (1 mmol/kg body weight) intraperitoneally, 50μl 1.5% formalin solution or physiological saline was injected subcutaneously into the right whisker pad of rats. The rubbing activity directed to the injected whisker pad was then measured for a period of 45 minutes. Four hours after formalin injection, the caudal part of spinal trigeminal nucleus was removed and subjected to c-Fos and neuronal nitric oxide synthase (nNOS) immunohistochemistry and to interleukin-1β and, Nad(p)h: quinone oxidoreductase 1 (NQO1) Western blot. There was a significant decrease in formalin-induced biphasic behavioural response and c-Fos and nNOS immunoreactivity in the rats that were pre-treated with probenecid. However there were no alterations in expression of interleukin-1β or NQO1 after formalin administration. Our results suggest that probenecid has an anti-nociceptive effect in the trigeminal inflammatory pain model. This effect may be through influencing the release of prostaglandin E2 or desensitizing the transient receptor potential channel subtype A member 1 or the transient receptor potential channel subtype V member 2 or the effect may be through modulating kynurenic acid levels in the central nervous system. Thus, probenecid might be a potential candidate for the treatment of trigeminal activation related pain conditions.

Although the administration of clonidine, an alpha-2 adrenoceptor agonist, significantly attenuates nociception and hyperalgesia in several pain models, clinical trials of clonidine are limited by its side effects such as drowsiness, hypotension and sedation. Recently, we determined that the sigma-1 receptor antagonist BD1047 dose-dependently reduced nociceptive responses in a mouse orofacial formalin model. Here we examined whether intraperitoneal injection of clonidine suppressed the nociceptive responses in the orofacial formalin test, and whether co-administration with BD1047 enhances lower-dose clonidine-induced anti-nociceptive effects without the disruption of motor coordination and blood pressure. Formalin (5%, 10 µL) was subcutaneously injected into the right upper lip, and the rubbing responses with the ipsilateral fore- or hind-paw were counted for 45 min. Clonidine (10, 30 or 100 µg/kg) was intraperitoneally administered 30 min before formalin injection. Clonidine alone dose-dependently reduced nociceptive responses in both the first and second phases. Co-localization for alpha-2A adrenoceptors and sigma-1 receptors was determined in trigeminal ganglion cells. Interestingly, the sub-effective dose of BD1047 (3 mg/kg) significantly potentiated the anti-nociceptive effect of lower-dose clonidine (10 or 30 µg/kg) in the second phase. In particular, the middle dose of clonidine (30 µg/kg) in combination with BD1047 produced an anti-nociceptive effect similar to that of the high-dose clonidine, but without a significant motor dysfunction or hypotension. In contrast, mice treated with the high dose of clonidine developed severe impairment in motor coordination and blood pressure. These data suggest that a combination of low-dose clonidine with BD1047 may be a novel and safe therapeutic strategy for orofacial pain management.

Aims: To clarify the antiallodynic effects of the α2-adrenergic receptor antagonist mirtazapine compared with those of gabapentin and pregabalin in a rat model of orofacial neuropathic pain., Methods: Mirtazapine (10, 30, and 100 μg), gabapentin (10, 30, and 100 μg), and pregabalin (3, 10, and 30 μg) were administered intrathecally to eight male Sprague-Dawley rats with orofacial neuropathic pain induced by chronic constriction injury of the infraorbital nerve that had been carried out 2 weeks previously. Stimulation using von Frey filaments (1.0 to 15.0 g) applied to skin innervated by the injured infraorbital nerve enabled the measurement of mechanical thresholds 0 to 180 minutes after drug injection. Time-course data for the dose-response effects were analyzed using two-way analysis of variance and the posthoc Tukey-Kramer multiple-comparison test., Results: Intrathecal administration of not only gabapentin and pregabalin but also mirtazapine reversed the lowered mechanical nociceptive thresholds produced by the nerve injury. The ED50 (95% confidence interval) was (in μg) 49.00 (39.71-58.29) for mirtazapine, 54.84 (46.12-63.56) for gabapentin, and 13.47 (11.24-15.69) for pregabalin., Conclusion: Intraspinal administration of either mirtazapine, gabapentin, or pregabalin reverses the lowered facial mechanical thresholds produced in a rat model of trigeminal neuropathic pain.

Purpose: Arthrocentesis (AC) is an acceptable treatment modality in the treatment of internal derangement (ID) pain. This study evaluated outcomes of AC on pain relief of ID pain with or without corticosteroids., Materials and Methods: This single-blind clinical trial was conducted on 60 patients with ID pain who were randomly assigned to 2 groups (30 in each group) for AC. The AC of the upper joint space was then performed by using Ringer lactate under local anesthesia in both groups. In the second group, the procedure was followed by the administration of a single-dose intra-articular dexamethasone (8 mg). Assessments were made at baseline (T0), 1 month (T1), and 6 months (T6) after AC; pain, maximum mouth opening, and joint sounds before and after treatment up to 6 months were evaluated. Pain severity was documented according to Visual Analogue Scale. Age, sex, and skeletal maxillomandibular relationship were considered as variable factors, and irrigation with or without corticosteroids was a predictive factor of the study. Pain, click, and maximum mouth opening were other assessment outcomes of the study., Results: Comparison of age, sex, and skeletal relationship did not show any significant differences between the 2 groups. Results did not demonstrate any difference for click between the 2 groups. Comparison of pain severity in T0, T1, and T2 between the 2 groups did not show any significant differences (P < 0.05). The repeat measure test revealed a significant change in T0, T1, and T2 for both groups (P < 0.001). MMO significantly changed between T0 and T1 and T0 and T6 in the 2 groups without any significant differences between them., Conclusions: The AC is an effective procedure for a short-term reduction of pain in temporomandibular disorder cases. It seems that AC using Ringer solution with or without corticosteroids may have the same effect on pain relief.

Neuropathic orofacial pain (NOP) exists in several forms including pathologies such as burning mouth syndrome (BMS), persistent idiopathic facial pain (PIFP), trigeminal neuralgia (TN) and postherpetic neuralgia (PHN). BMS and PIFP are classically diagnosed by excluding other facial pain syndromes. TN and PHN are most often diagnosed based on a typical history and presenting pain characteristics. The pathophysiology of some of these conditions is still unclear and hence treatment options tend to vary and include a wide variety of treatments including cognitive behaviour therapy, anti-depressants, anti-convulsants and opioids; however such treatments often have limited efficacy with a great amount of inter-patient variability and poorly tolerated side effects. Analgesia is one the principal therapeutic targets of the cannabinoid system and many studies have demonstrated the efficacy of cannabinoid compounds in the treatment of neuropathic pain. This review will investigate the potential use of cannabinoids in the treatment of symptoms associated with NOP., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Patients with temporomandibular muscle and joint disorder (TMJD) increasingly seek and receive treatment for their pain with botulinum toxin (BoNTA; botulinum toxin A). Used intramuscularly in therapeutic doses, it produces localised paresis. Such paresis creates risk of reduced bone mineral density, or 'disuse osteopenia'. Animal studies have frequently used BoNTA as a model of paralysis to induce bone changes within short periods. Osteopenic effects can be enduring in animals but have yet to be studied in humans. This is the first study in humans to examine bone-related consequences of BoNTA injections in the masticatory muscles, comparing oral and maxillofacial radiologists' ratings of trabecular bone patterns in the condyles of patients with TMJD exposed to multiple masticatory muscle injection sessions with BoNTA to a sample of patients with TMJD unexposed to masticatory muscle injections with BoNTA. Cone-beam computed tomography (CBCT)-derived images of bilateral condyles were evaluated in seven patients with TMJD receiving 2+ recent BoNTA treatment sessions for facial pain and nine demographically matched patients with TMJD not receiving BoNTA treatment. Two oral and maxillofacial radiologists evaluated CBCT images for evidence of trabecular changes consistent with osteopenia. Both evaluators noted decreased density in all participants exposed to BoNTA and in none of the unexposed participants (P < 0.001). No other abnormalities associated with reduced loading were detected. These findings need replication in a larger sample and over a longer time period, to ensure safety of patients with TMJD receiving multiple BoNTA injections for their pain., (© 2014 John Wiley & Sons Ltd.)

Background: This study evaluated the involvement of tumour necrosis factor α (TNF-α) in orofacial thermal and mechanical hyperalgesia induced by an inflammatory stimulus or by chronic constriction of the infraorbital nerve (CION) using etanercept (Eta), a TNF-receptor fusion protein that inhibits TNF-α action., Methods: Animals were treated with Eta (0.5 and 5.0 mg/kg, s.c.) or dexamethasone (Dex, 0.5, 1.0 and 2.0 mg/kg, s.c.) and orofacial thermal (cold and heat) and mechanical hyperalgesia induced by an inflammatory stimulus (carrageenan, Cg 50 and 100 μg/lip) or by chronic CION, a model of neuropathic pain in the orofacial region was evaluated. Treatments with Dex or Eta were carried out before Cg or before or after CION., Results: Eta or Dex abolished inflammatory thermal and mechanical hyperalgesia. Also, each drug, when given at the day of the surgery and the subsequent day, was effective to abolish thermal and mechanical hyperalgesia induced by CION, assessed on day 4 and on day 13 after the surgery, respectively. However, Eta, but not Dex, given after the CION, abolished thermal and mechanical hyperalgesia and reduced TNF-α level in the trigeminal ganglion., Conclusions: These results suggest that TNF-α has an important role in cold, heat and mechanical hyperalgesia induced by inflammation or neuropathy in the orofacial region and this may contribute for the establishment of new therapeutic strategies to treat orofacial pain., (© 2014 European Pain Federation - EFIC®)

Takayasu's arteritis (TA) often referred to as pulseless disease, is a chronic inflammatory disorder affecting the aorta and its main branches. While the first reported case was documented in Japan in 1908, it does occur worldwide, but is more prevalent in young oriental females from China and Southeast Asia. The main complications of the disease are due to occlusion of major branches of the aorta. During the initial stages, one of the presenting symptoms may be jaw pain. This may prove to be a diagnostic challenge for the dentist, since many diseases cause orofacial pain and the diagnosis must be established before final treatment. A literature review of TA is presented along with clinical presentation and treatment modalities. A case report is also presented., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Temporomandibular joint disorders affect a big portion of the population. There are a variety of treatment methods currently in use. Conservative treatment modalities are followed by more invasive approaches like arthrocentesis or arthroscopy. The aim of the study is to compare the effects of intra-articular tenoxicam injection and arthrocentesis plus viscosupplementation on patients in which a previous arthrocentesis plus viscosupplementation has failed to relieve pain and restore function. The study group consists of 18 TMJs in 16 patients (15 female and 1 male) and the patients were randomly divided into two groups as the arthrocentesis plus viscosupplementation group (n: 8) and tenoxicam injection (n: 10). 20 mg of tenoxicam was injected to the upper compartments of 10 joints without arthrocentesis. The other 8 joints were treated with a second arthrocentesis and sodium hyaluronate injection. VAS scores and maximum mouth opening with and without assistance were recorded in the post operative first week, first month and third month. The results show that there is little benefit in using relatively conservative methods once an arthrocentesis together with viscosupplementation has failed to relieve the patients pain. It is concluded that more invasive procedures should be considered for the patients who do not benefit from arthrocentesis., (Copyright © 2013 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Context: Syzygium cumini (L.) Skeels (Myrtaceae) is a tree with dark purple fruits, popularly known as "jambolão" or "jambolan". In folk medicine, this plant is used for the treatment of diabetes and inflammatory conditions., Objective: We investigated the antinociceptive effect of ethanol extract (EE) from S. cumini leaves on orofacial nociception., Material and Methods: The antinociceptive effects of the EE obtained from the leaves of S. cumini were evaluated in mice using formalin- and glutamate-induced orofacial nociception., Results: ESI-MS/MS analyses demonstrated that major constituents in the analyzed samples coincided with the mass of the phenolic acids and flavonoids. In pharmacological approach, pre-treatment with EE (100, 200, or 400 mg/kg, p.o.) significantly reduced (p<0.05 or p<0.01) the percentage of paw licks time during phase 2 (43.2, 47.1, and 57.4%, respectively) of a formalin pain test when compared to control group animals. This effect was prevented by pretreatment with glibenclamide and N(G)-nitro-l-arginine (l-NOARG). The extract, all doses, also caused a marked inhibition (p<0.01 or p<0.001) of glutamate-induced orofacial nociception (38.8, 51.7, and 54.7%) when compared with the control group. No effect was observed with the rota-rod model., Conclusions: We can suggest that the antinociceptive effect of the EE is mediated by peripheral mechanisms, possibly involving KATP channels and the nitric oxide pathways. These effects appear to be related to the presence of flavonoids compounds, such as quercetin.

Background: Patients often present with facial pain ascribed to sinusitis, despite normal nasal endoscopy and sinus computed tomography. Facial pain is increasingly recognised to be of neurological origin., Method: A cohort of 240 patients with chronic facial pain was followed up for 36 months at an otolaryngological practice in Malta. The types of facial pain were classified according to International Headache Classification criteria. The body mass index, occupation and educational level of patients were compared with the general population., Results: Tension-type mid-facial pain and facial migraine without aura were the most common types of chronic facial pain. The sites of pain, symptoms, treatment and outcomes for these principal pain types are discussed. Patients with mid-facial pain were treated with low-dose amitriptyline for eight weeks. After three years, nearly half of the patients were symptom free, and in a third the pain changed from being chronic to being episodic. The treatment of patients with facial migraine was more varied but the length of time until recurrence of pain was similar., Conclusion: The most effective long-term treatments for tension-type mid-facial pain and facial migraine were low-dose amitriptyline and low-dose amitriptyline and triptans, respectively.

The interplay between head pain caused by sinus disease and primary headaches is complex. Classification of secondary headaches, attributed to disorders of the nose or paranasal sinuses has been recently updated. New treatments including office- based procedures are emerging for patients with chronic sinusitis. This paper briefly reviews sinus disease and headache.

Purpose: Painful oral mucositis (OM) is a significant toxicity during radiotherapy for head and neck cancers. The aim of this randomized, double-blind, placebo-controlled trial was to test the efficacy of doxepin hydrochloride in the reduction of radiotherapy-induced OM pain., Patients and Methods: In all, 155 patients were randomly allocated to a doxepin oral rinse or a placebo for the treatment of radiotherapy-related OM pain. Patients received a single dose of doxepin or placebo on day 1 and then crossed over to receive the opposite agent on a subsequent day. Pain questionnaires were administered at baseline and at 5, 15, 30, 60, 120, and 240 minutes. Patients were then given the option to continue doxepin. The primary end point was pain reduction as measured by the area under the curve (AUC) of the pain scale using data from day 1., Results: Primary end point analysis revealed that the AUC for mouth and throat pain reduction was greater for doxepin (-9.1) than for placebo (-4.7; P < .001). Crossover analysis of patients completing both phases confirmed that patients experienced greater mouth and throat pain reduction with doxepin (intrapatient changes of 4.1 for doxepin-placebo arm and -2.8 for placebo-doxepin arm; P < .001). Doxepin was associated with more stinging or burning, unpleasant taste, and greater drowsiness than the placebo rinse. More patients receiving doxepin expressed a desire to continue treatment than did patients with placebo after completion of each of the randomized phases of the study., Conclusion: A doxepin rinse diminishes OM pain. Further studies are warranted to determine its role in the management of OM., (© 2014 by American Society of Clinical Oncology.)

Trigeminal ganglion C-fiber neurons bearing transient receptor potential vanilloid-1 (TRPV1) channels are selectively destroyed by resiniferatoxin (RTX), a potent capsaicin analogue. The current study assessed the effect of an RTX injection (200 ng/4 μl) into the trigeminal ganglion in inflammatory and neuropathic rat models of orofacial thermal hyperalgesia. Intraganglionar RTX injection resulted in trigeminal ganglion C-fiber deletion, which was confirmed by the capsaicin eye wipes test, performed 6 days after the injection. The nociceptive responses induced by 2.5% formalin injected into the orofacial region were unchanged by a previous intraganglionar RTX injection. However, orofacial heat and cold hyperalgesia, induced by carrageenan injected into the upper lip (50 µg/50 μl), was abolished by previous intraganglionar RTX treatment. In addition, the development of orofacial heat and cold hyperalgesia after constriction of the infraorbital nerve was prevented by previous RTX treatment. Thus, trigeminal ganglion neurons expressing TRPV1 are crucial for the development of orofacial inflammatory and neuropathic thermal hyperalgesia.

Aims: To compare the effectiveness of adding cyclobenzaprine, tizanidine, or placebo to patient education and a self-care management program for patients with myofascial pain and specifically presenting with jaw pain upon awakening., Methods: Forty-five patients with a diagnosis of myofascial pain based on the guidelines of the American Academy of Orofacial Pain participated in this 3-week study. The subjects were randomly assigned into one of three groups: placebo group, TZA group (tizanidine 4 mg), or CYC group (cyclobenzaprine 10 mg). Patients were evaluated for changes in pain intensity, frequency, and duration by using the modified Severity Symptoms Index and changes in sleep quality with the use of the Pittsburgh Sleep Quality Index. Data were analyzed by ANOVA and post-hoc or nonparametric statistical tests as appropriate., Results: All three groups had a reduction in pain symptoms and improvement of sleep quality based on a comparison of pretreatment and treatment scores. However, no significant differences among the groups were observed at the posttreatment evaluation., Conclusion: The use of tizanidine or cyclobenzaprine in addition to self-care management and patient education was not more effective than placebo for the management of patients with myofascial jaw pain upon awakening.