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Background: The aim of this study was to investigate if intramuscular injection of sterile water can be used as a human experimental pain model that resembles clinical craniofacial muscle pain and to analyse if the effects differ between sexes., Methods: This randomised, double-blind, placebo-controlled cross-over study included 30 healthy age-matched women and men (23.6 ± 2.4 years). At three sessions, with at least one week of washout in between, 0.2 mL of either sterile water (test-substance), hypertonic saline (58.5 mg/mL; active control) or isotonic saline (0.9 mg/mL; passive control) was randomly injected into the right masseter muscle. Pain intensity (VAS) was continuously assessed during 5 min whereafter pain duration (s) and pain area (au) were calculated; pressure pain thresholds (PPT;kPa) were recorded every 5 minutes during 30 minutes., Results: Sterile water evoked pain of similar intensity (74.5 ± 49.9) as hypertonic saline (74.0 ± 50.5); whereas, isotonic saline evoked low-intensity pain (11.4 ± 23.4). The pain induced by sterile water and hypertonic saline had higher intensity (P < 0.001), longer duration (P < 0.001) and larger pain area (P < 0.001) than isotonic saline. There were no significant differences in any pain variable between sterile water and hypertonic saline. The PPT did not change significantly after any substance, except for in women 5 minutes after sterile water injection (P < 0.002). Pain duration was longer in the men for all substances (P < 0.006), while the pain area was larger in women after injection of hypertonic saline (P < 0.003)., Conclusion: These results indicate that pain evoked by sterile water resembles clinical muscle pain and may offer a novel and simpler alternative to hypertonic saline injections., (© 2020 The Authors. Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)

Background: Music is used to evoke audio analgesia during dental procedures, but it is unknown if experimental pain and music interact. This study aimed to explore the multisensory interaction between contrasting types of music and experimentally induced muscle pain., Methods: In 20 healthy women, 0.3 mL sterile hypertonic saline (5.8%) was injected into the masseter muscle during three sessions while contrasting music (classical and black metal) or no music was played in the background. Pain intensity was assessed every 15 seconds with a 0-100 mm visual analogue scale (VAS) until pain subsided. Pain spread (pain drawings), unpleasantness (VAS), anxiety (VAS), and pain quality (McGill Questionnaire) were assessed after the last pain assessment., Results: Pain of high intensity was evoked at all sessions with a median (interquartile range) peak pain intensity of 78 (30) in the black metal music, 86 (39) in the classical music, and 77 (30) in the control session. The pain duration was 142 (150) seconds in the black metal music, 135 (150) seconds in the classical music, and 135 (172) seconds in the control session. The corresponding pain-drawing areas were 42 (52), 37 (36), and 44 (34), arbitrary units respectively. There were no differences in any of these variables (Friedman's test; P´s > .368), or in unpleasantness, anxiety, or pain quality between sessions (P´s > .095)., Conclusions: Experimentally induced muscle pain does not seem to be influenced by contrasting types of background music. Further studies exploring the multisensory integration between music and experimental muscle pain are needed., (© 2020 The Authors. Journal of Oral Pathology & Medicine published by John Wiley & Sons Ltd.)

This study investigated if repeated buffered acidic saline infusions into the masseter muscles induced muscle pain and mechanical sensitization. Fourteen healthy men participated in this double-blind, randomized, and placebo-controlled study. Two repeated infusions (day 1 and 3) were given in the masseter muscles with either a buffered acidic saline solution (pH 5.2) or an isotonic saline solution (pH 6) as control. After 10 days of wash-out, the experiment was repeated with the other substance. Pressure pain thresholds (PPT), pain intensity, maximum unassisted mouth opening (MUO), and pain drawings were assessed before, directly following, and after each infusion at 5, 15, and 30 min and on day 4 and 7. Fatigue and pain intensity were assessed after a one-minute chewing test 30 min after infusions and day 4 and 7. Acidic saline induced higher pain intensity than control day 3 up to 5 min after infusions, but did not affect PPT. The chewing test did not evoke higher fatigue during chewing or MUO or after acidic saline infusion compared to control. Repeated acidic saline infusions in the masseter muscles induced a short-lasting muscle pain without mechanical hyperalgesia or functional pain. Hence, this model might not be superior to already existing experimental muscle pain models.

The aim of this study was to investigate experimentally if 5-HT3 single nucleotide polymorphisms (SNP) contribute to pain perception and efficacy of the 5-HT3-antagonist granisetron and sex differences. Sixty healthy participants were genotyped regarding HTR3A (rs1062613) and HTR3B (rs1176744). First, pain was induced by bilateral hypertonic saline injections (HS, 5.5%, 0.2 mL) into the masseter muscles. Thirty min later the masseter muscle on one side was pretreated with 0.5 mL granisetron (1 mg/mL) and on the other side with 0.5 mL placebo (isotonic saline) followed by another HS injection (0.2 mL). Pain intensity, pain duration, pain area and pressure pain thresholds (PPTs) were assessed after each injection. HS evoked moderate pain, with higher intensity in the women (P = 0.023), but had no effect on PPTs. None of the SNPs influenced any pain variable in general, but compared to men, the pain area was larger in women carrying the C/C (HTR3A) (P = 0.015) and pain intensity higher in women with the A/C alleles (HTR3B) (P = 0.019). Pre-treatment with granisetron reduced pain intensity, duration and area to a lesser degree in women (P < 0.05), but the SNPs did not in general influence the efficacy of granisetron. Women carrying the C/T & T/T (HTR3A) genotype had less reduction of pain intensity (P = 0.041) and area (P = 0.005), and women with the C/C genotype (HTR3B) had less reduction of pain intensity (P = 0.030), duration (P = 0.030) and area compared to men (P = 0.017). In conclusion, SNPs did not influence experimental muscle pain or the effect of granisetron on pain variables in general, but there were some sex differences in pain variables that seem to be influenced by genotypes. However, due to the small sample size further research is needed before any firm conclusions can be drawn., Competing Interests: The authors have declared that no competing interests exist.

Background: Chronic myalgia is associated with higher muscle levels of certain algesic biomarkers. The aim of this study was to investigate if hypertonic saline-induced jaw myalgia also leads to release of such biomarkers and if there were any sex differences in this respect., Methods: Healthy participants, 15 men and 15 aged-matched women (25.7 ± 4.3 years) participated. Intramuscular microdialysis into masseter muscles was performed to sample serotonin (5-HT), glutamate, lactate, pyruvate, glucose and glycerol. After 2 hours 0.2 mL hypertonic saline (58.5 mg/mL) was injected into the masseter on one side and 0.2 mL isotonic saline (9 mg/mL) into the contralateral masseter close to the microdialysis catheter. Microdialysis continued for 1 hour after the injections. Pressure pain thresholds (PPT) and pain were assessed before and after injections., Results: The median (IQR) peak pain intensity (0-100 visual analogue scale) after hypertonic saline was 52.5 (38.0) and after isotonic saline 7.5 (24.0) (p < 0.05). 5-HT, glutamate and glycerol increased after hypertonic saline injection (p < 0.05). Lactate, pyruvate and glucose showed no change. PPT after microdialysis was reduced on both sides (p < 0.05) but without side differences. Pain after hypertonic saline injection correlated positively to 5-HT (p < 0.05) and negatively to glycerol (p < 0.05)., Conclusions: 5-HT, glutamate and glycerol increased after a painful hypertonic saline injection into the masseter muscle, but without sex differences. Since increased levels of 5-HT and glutamate have been reported in chronic myalgia, this strengthens the validity of the pain model. Glycerol warrants further investigations.

Mastication myalgia is the most common cause of non-odontogenic pain in the orofacial region and is often associated with a reduced quality of life. The purpose of this review is to provide an overview of the clinical aspects of myalgia based on available research. The review includes epidemiological, diagnostic, and etiological aspects. In addition, the potential risk factors related to the transition from acute to chronic myalgia are explored and treatment strategies are presented for its management. As a result, this review may increase clinical knowledge about mastication myalgia and clarify strategies regarding prevention, diagnostics, and management to improve prognosis and reduce patient suffering. [ABSTRACT FROM AUTHOR]

Background: Chocolate, as a cocoa-derived product rich in flavanols, has been used for medical and anti-inflammatory purposes. Therefore, the aim of this study was to investigate if the ingestion of different percentages of cocoa products affects the experimentally induced pain caused by intramuscular hypertonic saline injections in the masseter muscle of healthy men and women. Methods: This experimental randomized, double-blind, and controlled study included 15 young, healthy, and pain-free men and 15 age-matched women and involved three visits with at least a 1-week washout. Pain was induced twice at each visit with intramuscular injections of 0.2 mL hypertonic saline (5%), before and after intake of one of the different chocolate types: white (30% cocoa content), milk (34% cocoa content), and dark (70% cocoa content). Pain duration, pain area, peak pain, and pressure pain threshold (PPT) were assessed every fifth minute after each injection, up until 30 min after the initial injection. Descriptive and inferential statistics were performed using IBM® SPSS (Version 27); significance level was set to p<0.05. Results: This study showed that intake of chocolate, no matter the type, reduced the induced pain intensity significantly more than no intake of chocolate (p<0.05, Tukey test). There were no differences between the chocolate types. Further, men showed a significantly greater pain reduction than women after intake of white chocolate (p<0.05, Tukey test). No other differences between pain characteristics or sexes were revealed. Conclusion: Intake of chocolate before a painful stimulus had a pain-reducing effect no matter the cocoa concentration. The results indicate that perhaps it is not the cocoa concentration (e.g., flavanols) alone that explains the positive effect on pain, but likely a combination of preference and taste-experience. Another possible explanation could be the composition of the chocolate, i.e. the concentration of the other ingredients such as sugar, soy, and vanilla. ClinicalTrials.gov Identifier: NCT05378984. [ABSTRACT FROM AUTHOR]

Background: The study was aiming to optimize excessive gum chewing as an experimental model to induce jaw muscle pain and fatigue similar to those in painful TMDs with durations that would allow immediate investigations of jaw-motor function. Further, if any sex differences would be detected in the expression of pain. Methods: This randomized, double blinded study included 31 healthy participants of both sexes. A standardized chewing protocol of either 40- or 60-min of chewing was used with a wash-out period of 1 week. Subjective fatigue, pain characteristics and functional measures were assessed. For statistical analyses, Wilcoxon Signed Rank test, Mann–Whitney Rank Sum test and Friedman's ANOVA with Tukey post-hoc test were used. Results: High subjective fatigue scores that lasted up to 20 min after the end of the trial were significantly induced both in the 40- and 60-min chewing trials (P < 0.001*). Significant but mild pain was induced only in the 60-min trial (P = 0.004*) and only in men (P = 0.04*). Also, the induced pain area was significantly bigger in the 60-min trial (P = 0.009*). However, this increase in pain and pain area did not last to the first 10-min follow-up. There were no significant differences neither between the 40- and 60-min chewing trials, except regarding the pain area (P = 0.008*), nor between the sexes. Conclusion: Taken together, excessive chewing in its current form does not seem to be a proper pain experimental model. The model needs further adjustments in order to mimic TMD-pain especially in women and to prolong the pain duration. [ABSTRACT FROM AUTHOR]

Background: The specific serotonin type 3 (5-HT3)-receptor antagonist granisetron effectively reduces clinical as well as experimental muscle pain and hyperalgesia and with a duration that exceeds that of lidocaine. Hence, it may be an alternative to lidocaine as a local anesthetic. There are also some indications that granisetron in addition to 5-HT3 receptors blocks sodium channels. Thus, the local anesthetic effect by granisetron may resemble that of lidocaine, but this has not been tested. The aim of this study was therefore to compare the effect granisetron has on facial skin sensitivity to the effect of lidocaine and isotonic saline. Methods: This was a randomized, controlled, and double-blind study, in which 1 ml of either granisetron (test-substance), lidocaine (positive control), or isotonic saline (negative control) was injected into the skin over the masseter muscle at three different occasions in 18 healthy males (27.2 ± 5.8 years old). Skin detection thresholds and pain thresholds for thermal stimuli as well as mechanical detection thresholds and sensitivity to a painful mechanical (pinprick) stimulus were assessed before (baseline) and 5, 20, 40, and 60 min after injection. The quality and area of subjective sensory change over the cheek were assessed 20 min after injection. Results: All substances increased the mechanical detection threshold (granisetron: p = 0.011; lidocaine: p = 0.016; saline: p = 0.031). Both granisetron and lidocaine, but not isotonic saline, increased the heat detection thresholds (p < 0.001 and p < 0.02, respectively), but not the cold detection thresholds. Granisetron and lidocaine also reduced pinprick pain (p = 0.001 for each comparison). There were no significant differences between granisetron and lidocaine for any of these variables. There was no effect on thermal pain thresholds for any substance. Conclusion: The similar analgesic patterns on mechanical sensory and pain thresholds as well as thermal sensory thresholds over the facial skin by subcutaneous injection of granisetron and lidocaine shown in this study and the absence of paresthesia, in combination with the reduced pain intensity and pressure pain sensitivity shown in previous studies, indicate that granisetron might be a novel candidate as a local anesthetic. [ABSTRACT FROM AUTHOR]

Chronic pain in the orofacial region is common worldwide. Pain seems to affect the jaw motor control. Hence, temporomandibular disorders (TMD) are often accompanied by pain upon chewing, restricted mouth opening and impaired maximal bite forces. However, little is known on the effects of pain, in particular the effects of chronic jaw muscle pain on precision biting. The aim of the study was to investigate the effect of chronic and acute jaw muscle pain on oral motor control during precision biting in humans. Eighteen patients with chronic masseter muscle pain and 18 healthy participants completed the experiment. All participants were examined according to the Diagnostic Criteria for TMD. Experimental acute pain was induced by bilateral, simultaneous sterile hypertonic saline infusions into the healthy masseter muscles. A standardized hold and split biting task was used to assess the precision biting. The data was analyzed with non-parametric statistical tests. The results showed no significant differences in the hold forces, split forces, durations of split or peak split rates within or between the pain and pain-free conditions. The mean split rate increased significantly compared to baseline values both in the chronic patients and the pain-free condition. However, this increase was not evident in the experimental acute pain condition. Further, there were no significant differences in the mean split rates between the conditions. The data suggest that jaw muscle pain does not seem to alter precision biting in humans, however, the possibility that a nociceptive modulation of spindle afferent activity might have occurred but compensated for cannot be ruled out. [ABSTRACT FROM AUTHOR]

Aims: To investigate whether static jaw clenching can activate endogenous pain modulation and to compare the magnitude between healthy individuals and patients with temporomandibular disorder (TMD) myalgia. Methods: Thirty-three healthy volunteers (17 women and 16 men) and 20 women with TMD myalgia participated. Exercise-induced hypoalgesia (EIH) was examined by recording pressure pain thresholds (PPTs) in the masseter (MA) and brachioradialis (BR) muscles during tooth clenching until exhaustion. Pain and fatigue were assessed before and after clenching, and pain amplification was examined by applying a painful mechanical pressure at the MA for 2 minutes while assessing pain every 30 seconds. Analyses of data included repeated measures analysis of variance. Results: In the contracting MA, PPTs increased over time in all three groups (P < .001), while PPTs in the relaxed BR increased only in the men (P = .045). Pain intensity and fatigue in the MA increased after contraction in all groups (P < .003) and was higher in the women with TMD than in the healthy women (P < .001). Only the women with TMD showed pain amplification (P < .001). Conclusion: Tooth clenching until exhaustion could activate EIH locally; ie, the magnitude of EIH in the MA was similar in women with TMD myalgia and pain-free women, indicating no deficient EIH in women with TMD. However, only women with TMD showed pain amplification during application of continuous painful pressure. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate experimentally if 5-HT3 single nucleotide polymorphisms (SNP) contribute to pain perception and efficacy of the 5-HT3-antagonist granisetron and sex differences. Sixty healthy participants were genotyped regarding HTR3A (rs1062613) and HTR3B (rs1176744). First, pain was induced by bilateral hypertonic saline injections (HS, 5.5%, 0.2 mL) into the masseter muscles. Thirty min later the masseter muscle on one side was pretreated with 0.5 mL granisetron (1 mg/mL) and on the other side with 0.5 mL placebo (isotonic saline) followed by another HS injection (0.2 mL). Pain intensity, pain duration, pain area and pressure pain thresholds (PPTs) were assessed after each injection. HS evoked moderate pain, with higher intensity in the women (P = 0.023), but had no effect on PPTs. None of the SNPs influenced any pain variable in general, but compared to men, the pain area was larger in women carrying the C/C (HTR3A) (P = 0.015) and pain intensity higher in women with the A/C alleles (HTR3B) (P = 0.019). Pre-treatment with granisetron reduced pain intensity, duration and area to a lesser degree in women (P < 0.05), but the SNPs did not in general influence the efficacy of granisetron. Women carrying the C/T & T/T (HTR3A) genotype had less reduction of pain intensity (P = 0.041) and area (P = 0.005), and women with the C/C genotype (HTR3B) had less reduction of pain intensity (P = 0.030), duration (P = 0.030) and area compared to men (P = 0.017). In conclusion, SNPs did not influence experimental muscle pain or the effect of granisetron on pain variables in general, but there were some sex differences in pain variables that seem to be influenced by genotypes. However, due to the small sample size further research is needed before any firm conclusions can be drawn. [ABSTRACT FROM AUTHOR]

Background: Fibromyalgia syndrome (FMS) is associated with central alterations, but controversies exist regarding the presence and role of peripheral factors. Microdialysis (MD) can be used in vivo to study muscle alterations in FMS. Furthermore for chronic pain conditions such as FMS, the mechanisms for the positive effects of exercise are unclear. This study investigates the interstitial concentrations of algesics and metabolites in the vastus lateralis muscle of 29 women with FMS and 28 healthy women before and after an exercise intervention. Methods: All the participants went through a clinical examination and completed a questionnaire. In addition, their pressure pain thresholds (PPTs) in their upper and lower extremities were determined. For both groups, MD was conducted in the vastus lateralis muscle before and after a 15-week exercise intervention of mainly resistance training of the lower limbs. Muscle blood flow and interstitial muscle concentrations of lactate, pyruvate, glutamate, glucose, and glycerol were determined. Results: FMS was associated with significantly increased interstitial concentrations of glutamate, pyruvate, and lactate. After the exercise intervention, the FMS group exhibited significant decreases in pain intensity and in mean interstitial concentrations of glutamate, pyruvate, and glucose. The decrease in pain intensity in FMS correlated significantly with the decreases in pyruvate and glucose. In addition, the FMS group increased their strength and endurance. Conclusion: This study supports the suggestion that peripheral metabolic and algesic muscle alterations are present in FMS patients and that these alterations contribute to pain. After an exercise intervention, alterations normalized, pain intensity decreased (but not abolished), and strength and endurance improved, all findings that suggest the effects of exercise are partially peripheral. [ABSTRACT FROM AUTHOR]

Salivary alpha-amylase (sAA) is a marker of psychological stress and might also be a potential marker for pain-associated stress due its non-invasive, cost-effective, and stress-free collection. The current study aimed to investigate whether the levels of sAA are influenced by experimentally induced muscle pain. In this study, 26 healthy, pain-free and age-matched participants (23.8 ± 2.6 years) were included, 13 women and 13 men. Prior to the experiment, questionnaires assessing health and anxiety were completed. Muscle pain was then induced through intramuscular injection of 0.4 mL hypertonic saline (56.5 mg/mL) into the masseter muscle and unstimulated whole saliva samples were collected at baseline before injection, 2 min, and 15 min after injection. A commercially available colorimetric assay was used to analyze the sAA. Perceived pain and stress were assessed using a 0–100 Numeric Rating Scale for each sample. There were no significant differences in sAA levels prior and after injection of hypertonic saline (p > 0.05) although sAA levels showed a slight decrease during experimentally-induced muscle pain. However, a strong correlation was observed between self-reported pain and perceived level of stress during experimentally-induced muscle pain (r2 = 0.744; p < 0.0001). Furthermore, there was a moderate correlation between the levels of sAA at baseline and during experimental pain (r2 = 0.687; p < 0.0001). In conclusion, this study could not show any association between the levels of sAA and perceived pain and or/stress. However, since a significant strong correlation could be observed between perceived stress and pain intensity, this study indicates that experimentally-induced muscle pain could be used as a stress model. [ABSTRACT FROM AUTHOR]