Pain after emergency treatments of symptomatic irreversible pulpitis and symptomatic apical periodontitis in the permanent dentition: a systematic review of randomized clinical trials.

Background: Symptomatic irreversible pulpitis (SIP) or symptomatic apical periodontitis (SAP) are two painful conditions often warranting emergency treatment. The most common emergency treatments supported by evidence are pulpotomy and pulpectomy and are normally performed under time-constrained circumstances. However, there is no strong evidence of which treatment suggested in literature a clinician can use to reduce endodontic pain effectively. Therefore, the aim of this systematic review is to investigate the present knowledge on postoperative pain related to the two types of emergency treatments available for treating SIP and SAP. Methods: Randomized controlled trials investigating postoperative pain after emergency treatments (pulpotomy and/or pulpectomy) on permanent dentition with signs and symptoms of SIP and/or SAP were searched in three major databases from 1978 until 2022. Risk of bias was assessed with Cochrane's tool. Results: Only five studies fulfilled the inclusion criteria. The included studies indicated that pulpotomy and pulpectomy are both suitable treatment options for SAP and SIP, as they provide sufficient alleviation of pain in permanent dentition. However, inconsistent results were found between the included trials on which emergency treatment is more effective in reducing pain. Cochrane's tool revealed that the studies had a low risk of bias. Limitations found in the design of the included randomized control trials decreased the level of evidence. None of the included studies accounted for essential confounding variables, such as factors affecting pain (including the psychological aspects). Moreover, possible non-odontogenic pain was not assessed, and therefore, it was not excluded; hence, affecting the internal validity of the studies. Conclusion: There are controversies within the available randomized control trials on which treatment is most effective in reducing emergency pain. This could be due to some weaknesses in the design of the clinical trials. Thus, further well-designed studies are warranted to draw conclusions on which emergency treatment is more effective in reducing pain. Systematic Review Registration: PROSPERO (CRD42023422282).

Nerve growth factor and glutamate increase the density and expression of substance P-containing nerve fibers in healthy human masseter muscles.

Nocifensive behavior induced by injection of glutamate or nerve growth factor (NGF) into rats masseter muscle is mediated, in part, through the activation of peripheral NMDA receptors. However, information is lacking about the mechanism that contributes to pain and sensitization induced by these substances in humans. Immunohistochemical analysis of microbiopsies obtained from human masseter muscle was used to investigate if injection of glutamate into the NGF-sensitized masseter muscle alters the density or expression of the NMDA receptor subtype 2B (NR2B) or NGF by putative sensory afferent (that express SP) fibers. The relationship between expression and pain characteristics was also examined. NGF and glutamate administration increased the density and expression of NR2B and NGF by muscle putative sensory afferent fibers (P < 0.050). This increase in expression was greater in women than in men (P < 0.050). Expression of NR2B receptors by putative sensory afferent fibers was positively correlated with pain characteristics. Results suggest that increased expression of peripheral NMDA receptors partly contributes to the increased pain and sensitivity induced by intramuscular injection of NGF and glutamate in healthy humans; a model of myofascial temporomandibular disorder (TMD) pain. Whether a similar increase in peripheral NMDA expression occurs in patients with painful TMDs warrants further investigation.

Sex-related differences in response to masseteric injections of glutamate and nerve growth factor in healthy human participants.

The neurophysiological mechanisms underlying NGF-induced masseter muscle sensitization and sex-related differences in its effect are not well understood in humans. Therefore, this longitudinal cohort study aimed to investigate the effect of NGF injection on the density and expression of substance P, NMDA-receptors and NGF by the nerve fibers in the human masseter muscle, to correlate expression with pain characteristics, and to determine any possible sex-related differences in these effects of NGF. The magnitude of NGF-induced mechanical sensitization and pain during oral function was significantly greater in women than in men (P < 0.050). Significant positive correlations were found between nerve fiber expression of NMDA-receptors and peak pain intensity (rs = 0.620, P = 0.048), and expression of NMDA-receptors by putative nociceptors and change in temporal summation pain after glutamate injection (rs = 0.561, P = 0.003). In women, there was a significant inverse relationship between the degree of NGF-induced mechanical sensitization and the change in nerve fiber expression of NMDA-receptors alone (rs = - 0.659, P = 0.013), and in combination with NGF (rs = - 0.764, P = 0.001). In conclusion, women displayed a greater magnitude of NGF-induced mechanical sensitization that also was associated with nerve fibers expression of NMDA-receptors, when compared to men. The present findings suggest that, in women, increased peripheral NMDA-receptor expression could be associated with masseter muscle pain sensitivity.

Density of nerve fibres and expression of substance P, NR2B-receptors and nerve growth factor in healthy human masseter muscle: An immunohistochemical study.

BACKGROUND: In skeletal muscle, free nerve endings are mostly located within the connective tissue. However, the distribution of sensory afferent fibres in healthy human masseter muscle tissues has not been studied. OBJECTIVES: Primarily to investigate human masseter muscle nerve fibre densities as well as expression of NR2B receptors, substance P (SP) and nerve growth factor (NGF), and secondarily to compare this between a) nerve fibres associated with myocytes and within connective tissue; b) sexes; and c) ages. METHODS: Microbiopsies of the masseter muscle were obtained from 60 sex- and age-matched healthy participants. Biopsy sections were analysed using immunohistochemistry and were visualised with a Leica TCS SPE confocal microscope. The Mann-Whitney U test was used for statistical analyses. RESULTS: The density of nerve fibres within connective tissue was significantly greater than in nerve fibres associated with myocytes (P < .001). Nerve fibres within connective tissue expressed SP alone or together with NR2B significantly more often than those associated with myocytes (P < .001). The frequency of nerve fibres, which expressed SP alone or in combination with NR2B or NGF, was significantly greater in women than in men (P < .050). Moreover, the co-expression of the three markers together was inversely correlated with age in women (P < .002). CONCLUSIONS: There is a higher density and greater expression of sensory nerve fibres within the connective tissue than associated with myocytes in healthy human masseter muscle. This suggests that nerve fibres within connective tissue are more involved in nociception than nerve fibres associated with myocytes.

Functional Change in Experimental Allodynia After Glutamate-Induced Pain in the Human Masseter Muscle.

Background: Glutamate, as well as nerve growth factor (NGF), is involved in nociception from peripheral tissues, such as muscles. However, the potential interaction between glutamate and NGF still remains unclear. This study investigated the interaction between glutamate-induced masseter muscle pain and NGF-induced allodynia on pain perception and jaw function in healthy individuals, and any possible sex differences in the response. Materials and Methods: Thirty pain-free adult participants (15 men and 15 women, mean age ± SD: 24 ± 4 years) participated in this study consisting of three sessions (Day 0, Day 3, and Day 4). NGF (5 µg/mL, 1.0 mL) was injected into the masseter muscle on Day 0 to induce muscle allodynia. On Day 3, glutamate (1M, 0.2 mL) was injected into the same masseter muscle. Before and after injections on Day 0 and 3, and post-injection (Day 4), spontaneous pain, temporal summation pain, as well as functional pain and fatigue in response to chewing were assessed with validated scales, and the pressure pain threshold (PPT) was recorded. Results: Spontaneous pain intensity was significantly higher after glutamate than NGF (P < 0.001). PPTs, temporal summation pain and functional measures were all reduced 3 days after NGF injection (P's < 0.001). Injection of glutamate on Day 3 did not further affect PPTs or temporal summation pain and there were no sex differences in the effects (P > 0.189). Chewing pain (P = 0.022) and fatigue increased after glutamate injection to a higher degree in the women than men (P = 0.037). Conclusion: Taken together, while glutamate injected into the NGF-sensitized muscle was painful, it did not alter muscle tenderness in women vs. men. However, pain and fatigue evoked by jaw function were higher in women after glutamate injection. This suggest that sex differences reported for masseter myalgia, mimicked by glutamate and NGF mediated pain in this study, may be greater for measures of perceived jaw function, which should be considered in a clinical evaluation.