Nutrition and chronic musculoskeletal pain: A narrative review and directions for temporomandibular disorder research and management.

BACKGROUND: Recent evidence suggests neuro-immune mechanisms may link dietary patterns to chronic painful conditions (CPC). In the research field of oro-facial pain (OFP), studies focuses primarily on dietary mechanical limitations due to pain and dysfunction. OBJECTIVE: This narrative review aimed to overview the role of nutrition on CPC, with emphasis on temporomandibular disorder (TMD), enlightening OFP researcher on dietary assessment possibilities and providing directions for studies in the field of OFP and nutrition. METHODS: A PubMed database search was performed using the MeSH and non-MeSH descriptors: "temporomandibular joint disorder"; "orofacial pain"; "musculoskeletal pain"; "chronic pain disorders"; "nutrition"; "diet"; "dietary therapy"; "dietary intake" and "inflammation". No time restrictions were applied. Literature reviews, systematic reviews, meta-analyses and clinical and pre-clinical trials were included. RESULTS: Exogenous oxidants from unhealthy dietary patterns may contribute to peripheral and central pro-inflammatory immune signalling leading to peripheral and central sensitization. Furthermore, diets rich in bioactive compounds are suggested to contribute to pain management of CPC. High dietary intake of ultra-processed foods impacts the quality of the diet and shows adverse health outcomes. In this context, the role of nutrition on TMD remains overlooked. CONCLUSION: Considering diet may influence CPC, allied with the scarcity of studies evaluating the role of nutrition on TMD, well-designed clinical trials based on dietary assessments and measurements capable of evaluating food quality, UPF consumption and nutrient adequacy-added to serum nutrient levels evaluation-are suggested.

Fructose malabsorption in asymptomatic children and in patients with functional chronic abdominal pain: a prospective comparative study.

The objective of this prospective cohort study was to compare fructose malabsorption in patients with functional chronic abdominal pain and in healthy children. The sample was divided into two groups: asymptomatic children and pain-predominant functional gastrointestinal disorders according to the Rome IV criteria. All children were tested for fructose malabsorption by a standardized breath hydrogen test. Hydrogen and methane were measured and the test was presumed positive when it exceeded 20 ppm above baseline. If positive, patients were given a low-fructose diet and the response was evaluated. One hundred five children were included (34 healthy children, 71 with functional chronic abdominal pain), with similar demographic characteristics in both groups (35.2% male, age 9.5 ± 2.8 years). Hydrogen levels in breath were tested through a hydrogen test for fructose demonstrating malabsorption in 58.8% of healthy children (95%CI 40.8%-76.8%) and in 40.8% of children with chronic abdominal pain (95%CI 28.7%-53.0%), removing those who had bacterial overgrowth. Twenty-one of 31 patients with symptoms and a positive test (72.4%) reported an improvement on a low-fructose diet.Conclusion: Fructose malabsorption is more common in asymptomatic children than in patients with chronic abdominal pain. Better standardized test conditions are necessary to improve accuracy of diagnosis before using this test in clinical practice. What is Known: • Although fructose malabsorption is believed to be related with chronic abdominal pain, high-quality evidence is lacking. • Concerns have raised regarding the use of breath hydrogen test for fructose malabsorption in children with chronic abdominal pain. What is New: • Fructose malabsorption is not more common in children with pain-predominant functional gastrointestinal disorders than in asymptomatic children. • Improvement in symptoms with low-fructose diet may indicate that, although patients with pain-predominant functional gastrointestinal disorders did not have a higher percentage of malabsorption, they had greater fructose intolerance.

Food pyramid for subjects with chronic pain: foods and dietary constituents as anti-inflammatory and antioxidant agents.

Emerging literature suggests that diet constituents may play a modulatory role in chronic pain (CP) through management of inflammation/oxidative stress, resulting in attenuation of pain. We performed a narrative review to evaluate the existing evidence regarding the optimum diet for the management of CP, and we built a food pyramid on this topic. The present review also describes the activities of various natural compounds contained in foods (i.e. phenolic compounds in extra-virgin olive oil (EVO)) listed on our pyramid, which have comparable effects to drug management therapy. This review included 172 eligible studies. The pyramid shows that carbohydrates with low glycaemic index should be consumed every day (three portions), together with fruits and vegetables (five portions), yogurt (125 ml), red wine (125 ml) and EVO; weekly: legumes and fish (four portions); white meat, eggs and fresh cheese (two portions); red or processed meats (once per week); sweets can be consumed occasionally. The food amounts are estimates based on nutritional and practical considerations. At the top of the pyramid there is a pennant: it means that CP subjects may need a specific customised supplementation (vitamin B12, vitamin D, n-3 fatty acids, fibre). The food pyramid proposal will serve to guide dietary intake with to the intent of alleviating pain in CP patients. Moreover, a targeted diet can also help to solve problems related to the drugs used to combat CP, i.e. constipation. However, this paper would be an early hypothetical proposal due to the limitations of the studies.

Zingiberaceae extracts for pain: a systematic review and meta-analysis.

BACKGROUND: Members of the family Zingiberaceae including turmeric, ginger, Javanese ginger, and galangal have been used for centuries in traditional medicine. Preclinical studies of Zingiberaceae extracts have shown analgesic properties. This study aims to systematically review and meta-analyze whether extracts from Zingiberaceae are clinically effective hypoalgesic agents. METHODS: Literature was screened from electronic databases using the key words Zingiberaceae AND pain OR visual analogue score (VAS) to identify randomized trials. From this search, 18 studies were identified, and of these, 8 randomized, double-blinded, placebo-controlled trials were found that measured pain by VAS for inclusion in the meta-analysis. RESULTS: Findings indicated significant efficacy of Zingiberaceae extracts in reducing subjective chronic pain (SMD - 0.67; 95 % CI - 1.13 to - 0.21; P = 0.004). A linear dose-effect relationship was apparent between studies (R(2) = 0.71). All studies included in the systematic review reported a good safety profile for extracts, without the renal risks associated with non-steroidal anti-inflammatory drugs, and with similar effectiveness. CONCLUSION: Our findings indicated that Zingiberaceae extracts are clinically effective hypoalgesic agents and the available data show a better safety profile than non-steroidal anti-inflammatory drugs. However, both non-steroidal anti-inflammatory drugs and Zingiberaceae have been associated with a heightened bleeding risk, and there have been no comparator trials of this risk. Further clinical studies are recommended to identify the most effective type of Zingiberaceae extract and rigorously compare safety, including bleeding risk.

Nutrients and Nocioception: Diet in the management of pain.

Nutrition can play a pivotal role in the management of pain associated with chronic rheumatic diseases. There is a growing body of research linking certain nutrients from the diet to inflammation. Certain nutrients have been shown to improve pain associated with inflammation. Furthermore, certain dietary patterns have been shown to improve pain across multiple rheumatic conditions. Finally, maintaining a low body mass is associated with improved pain associated with chronic rheumatic diseases.

Exercise and Dietary Recommendations for Women with Chronic Pain: What's Weight and Race Got To Do with It?

Exercise and diet are beneficial for pain, yet many patients do not receive such recommendations from providers. This may be due to biases related to gender, race, and weight. We recruited medical students (N = 90) to view videos of women with chronic back pain performing a functional task; patients varied by weight (overweight/obese) and race (Black/White). For each woman patient, providers rated their likelihood of recommending exercises or dietary changes. Ratings significantly differed across recommendations (F(2.75, 244.72) = 6.19, P < .01) in that providers were more likely to recommend flexibility exercises than aerobic exercises and dietary changes and were more likely to recommend strength exercises than dietary changes. Results also indicated that women with obesity were more likely to receive aerobic (F(1,89) = 17.20, P < .01), strength (F(1,89) = 6.08, P = .02), and dietary recommendations (F(1,89) = 37.56, P < .01) than were women with overweight. Additionally, White women were more likely to receive a recommendation for flexibility exercises (F(1,89) = 4.92, P = .03) than Black women. Collectively, these findings suggest that providers' exercise and dietary recommendations for women with chronic pain are influenced by the weight status and racial identity of the patient. Future studies are needed to identify the reasons underlying these systematic differences, including the stereotypes and attitudes that may be driving these effects. PERSPECTIVE: This article presents results on how patient weight and race impact providers' exercise and diet recommendations for women with chronic back pain. Provider recommendations for these modalities may be systematically biased in a way that impedes care and impacts patient functioning.

The elimination/challenge diet.

Elimination diets can be both a diagnostic tool and a therapeutic intervention for people with a suspected food sensitivity or allergy. They are clinically relevant not only for patients with functional gastrointestinal disorders but also for those with conditions where symptoms are refractory and a diagnosis is elusive. Elimination diets can help a physician make a diagnosis or identify an underlying cause of symptoms. The physician and team treating the patient can then use that information to recommend appropriate dietary and lifestyle changes as well as judicious drug therapy. This article describes the elimination/challenge diet approach and explains the rationale for undertaking it.

Experience of participants with chronic pain in a pilot randomized clinical trial using a ketogenic diet.

Aim: To report the experience of chronic pain participants after a well-formulated ketogenic diet (WFKD) or whole-food diet (WFD). The quantitative outcomes for this trial have been published separately (clinical trial registration number ACTRN12620000946910). Patients & methods: The experience of 24 participants was evaluated after 12 and 24 weeks of dietary intervention using survey responses and open questions. Results & conclusion: Retention rates for the WFKD and WFD groups were 93 and 89%, respectively. Average adherence to the WFKD was 82% and to the WFD was 87%. The WFKD enjoyment was rated at 66 and 81% for the WFD group. The ease of adhering to the diet varied more widely for the WFKD group. Barriers included knowledge integration, time management, navigating social food environments and emotional attachment to eliminated foods. Facilitators included structured support and coaching, and comprehensive learning materials. The WFKD was shown to be a feasible and effective treatment option for chronic pain.

This paper reports the experiences of 24 individuals with chronic pain when undertaking either a whole-food diet or a whole-food ketogenic diet as an intervention for their chronic pain. The diet ran for 12 weeks, and participants were surveyed at the end of the diet and again after another 12 weeks. There was a low dropout rate for both the groups, and participants reported adhering to the diet they were allocated to. Participants in the ketogenic group reported less enjoyment and were more varied in their adherence to the diet; however, the diet was shown to be feasible in this patient population. There were barriers to engaging with the diet including: implementing the rules of the diet, finding the extra time required, eating out and missing high carbohydrate foods. Having good information to follow and someone to coach them assisted participants to successfully implement the diet.

Methodology for altering omega-3 EPA+DHA and omega-6 linoleic acid as controlled variables in a dietary trial.

BACKGROUND & AIMS: Increasing dietary intake of n-3 EPA+DHA and lowering dietary n-6 LA is under investigation as a therapeutic diet for improving chronic pain syndromes as well as other health outcomes. Herein we describe the diet methodology used to modulate intake of n-3 and n-6 PUFA in a free living migraine headache population and report on nutrient intake, BMI and diet acceptability achieved at week 16 of the intensive diet intervention and week 22 follow-up time-point. METHODS: A total of 178 participants were randomized and began one of three diet interventions: 1) a high n-3 PUFA, average n-6 PUFA (H3) diet targeting 1500 mg EPA+DHA/day and 7% of energy (en%) from n-6 linoleic acid (LA), 2) a high-n-3 PUFA, low-n-6 PUFA (H3L6) targeting 1500 mg EPA+DHA/day and <1.8 en% n-6 LA or 3) a Control diet with typical American intakes of both EPA+DHA (<150 mg/day) and 7 en% from n-6 LA. Methods used to achieve diet change to week 16 include diet education, diet counseling, supply of specially prepared foods, self-monitoring and access to online diet materials. Only study oils and website materials were provided for the follow-up week 16 to week 22 periods. Diet adherence was assessed by multiple 24 h recalls administered throughout the trial. Diet acceptability was assessed in a subset of participants at 4 time points by questionnaire. RESULTS: At week 16 H3 and H3L6 diet groups significantly increased median n-3 EPA+DHA intake from 48 mg/2000 kcals at baseline to 1484 mg/2000 kcals (p < 0.0001) and from 44 mg/2000 kcals to 1341 mg/2000 kcals (p < 0.0001), respectively. In the Control group, EPA+DHA intake remained below the typical American intake with baseline median at 60 mg/2000 kcals and 80 mg/2000 kcals (p = 0.6) at week 16. As desired, LA intake was maintained in the H3 and Control group with baseline median of 6.5 en% to 7.1 en% (p = 0.4) at week 16 and from 6.5 en% to 6.8 en% (p = 1.0) at week 16, respectively. In the H3L6 group, n-6 LA decreased from 6.3 en% at baseline to 3.2 en% (p < 0.0001) at week 16. There were no significant changes in BMI or diet acceptability throughout the trial or between diet groups. CONCLUSIONS: We find this diet method to be acceptable to research participants and successful in altering dietary n-3 EPA+DHA with and without concurrent decreases in n-6 LA. If n-6 LA of less than 3 en% is desired, additional techniques to limit LA may need to be employed.

Diet and companionship modulate pain via a serotonergic mechanism.

Treatment of severe chronic and acute pain in sickle cell disease (SCD) remains challenging due to the interdependence of pain and psychosocial modulation. We examined whether modulation of the descending pain pathway through an enriched diet and companionship could alleviate pain in transgenic sickle mice. Mechanical and thermal hyperalgesia were reduced significantly with enriched diet and/or companionship. Upon withdrawal of both conditions, analgesic effects observed prior to withdrawal were diminished. Serotonin (5-hydroxytryptamine, 5-HT) was found to be increased in the spinal cords of mice provided both treatments. Additionally, 5-HT production improved at the rostral ventromedial medulla and 5-HT accumulated at the dorsal horn of the spinal cord of sickle mice, suggesting the involvement of the descending pain pathway in the analgesic response. Modulation of 5-HT and its effect on hyperalgesia was also investigated through pharmaceutical approaches. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, showed a similar anti-nociceptive effect as the combination of diet and companionship. Depletion of 5-HT through p-chlorophenylalanine attenuated the anti-hyperalgesic effect of enriched diet and companionship. More significantly, improved diet and companionship enhanced the efficacy of a sub-optimal dose of morphine for analgesia in sickle mice. These findings offer the potential to reduce opioid use without pharmacological interventions to develop effective pain management strategies.

Nutritional intervention in chronic pain: an innovative way of targeting central nervous system sensitization?

INTRODUCTION: Few treatment programs for chronic pain nowadays take a dietary pattern or adipose status into account. AREAS COVERED: An important role of neuroinflammation in chronic pain is now well established, at least in part due to increased central nervous system glial activation. Based on preclinical studies, it is postulated that the interaction between nutrition and central sensitization is mediated via bidirectional gut-brain interactions. This model of diet-induced neuroinflammation and consequent central sensitization generates a rationale for developing innovative treatments for patients with chronic pain. Methods: An umbrella approach to cover the authors' expert opinion within an evidence-based viewpoint. EXPERT OPINION: A low-saturated fat and low-added sugar dietary pattern potentially decreases oxidative stress, preventing Toll-like receptor activation and subsequent glial activation. A low-saturated fat and low-added sugar diet might also prevent afferent vagal nerve fibers sensing the pro-inflammatory mediators that come along with a high-(saturated) fat or energy-dense dietary pattern, thereby preventing them to signal peripheral inflammatory status to the brain. In addition, the gut microbiota produces polyamines, which hold the capacity to excite N-methyl-D-aspartate receptors, an essential component of the central nervous system sensitization. Hence, a diet reducing polyamine production by the gut microbiota requires exploration as a therapeutic target for cancer-related and non-cancer chronic pain.

Dietary Patterns and Interventions to Alleviate Chronic Pain.

Pain is one of the main problems for modern society and medicine, being the most common symptom described by almost all patients. When pain becomes chronic, the life of the patients is dramatically affected, being associated with significant emotional distress and/or functional disability. A complex biopsychosocial evaluation is necessary to better understand chronic pain, where good results can be obtained through interconnected biological, psychological, and social factors. The aim of this study was to find the most relevant articles existent in the PubMed database, one of the most comprehensive databases for medical literature, comprising dietary patterns to alleviate chronic pain. Through a combined search using the keywords "chronic pain" and "diet" limited to the last 10 years we obtained 272 results containing the types of diets used for chronic pain published in the PubMed database. Besides classical and alternative methods of treatment described in literature, it was observed that different diets are also a valid solution, due to many components with antioxidant and anti-inflammatory qualities capable to influence chronic pain and to improve the quality of life. Thirty-eight clinical studies and randomized controlled trials are analyzed, in an attempt to characterize present-day dietary patterns and interventions to alleviate chronic pain.

The Low Glutamate Diet Effectively Improves Pain and Other Symptoms of Gulf War Illness.

Gulf War Illness (GWI) is a multisymptom disorder including widespread chronic pain, fatigue and gastrointestinal problems. The objective of this study was to examine the low glutamate diet as a treatment for GWI. Forty veterans with GWI were recruited from across the US. Outcomes included symptom score, myalgic score, tender point count, dolorimetry and the Chalder Fatigue Scale. Subjects were randomized to the low glutamate diet or a wait-listed control group, with symptom score being compared after one month. Subjects then went onto a double-blind, placebo-controlled crossover challenge with monosodium glutamate (MSG)/placebo to test for return of symptoms. Symptom score was compared between diet intervention and wait-listed controls with an independent t-test and effect size was calculated with Cohen's d. Change scores were analyzed with Wilcoxon Signed Rank tests. Crossover challenge results were analyzed with General Linear Models and cluster analysis. The diet intervention group reported significantly less symptoms (p = 0.0009) than wait-listed controls, with a very large effect size, d = 1.16. Significant improvements in average dolorimetry (p = 0.0006), symptom score, tender point number, myalgic score and the Chalder Fatigue Scale (all p < 0.0001) were observed after the 1-month diet. Challenge with MSG/placebo resulted in significant variability in individual response. These results suggest that the low glutamate diet can effectively reduce overall symptoms, pain and fatigue in GWI, but differential results upon challenge suggest that other aspects of the diet, or underlying differences within the population, may be driving these changes. Future research is needed to identify potential nutrient effects, biomarkers, and underlying metabolic differences between responders and non-responders.

Food in Chronic Pain: Friend or Foe?

While many still consider food to be innocuous, ongoing research demonstrates food's role, both harmful and protective, in chronic pain [...].

Changes in dietary habits of patients with chronic pain represent contributing factors to decreased pain intensity and improved quality of life. Pilot study from Croatia.

INTRODUCTION: Objectives: to assess the effectiveness of specifically designed nutrition education for the management of chronic pain and whether any change in dietary habits contribute to decrease in pain intensity. Objectives and methods: 40 patients were enrolled in the 4-week interventional observational study. Patients filled-in questionaires regarding their basic characteristics, pain intensity, quality of life, and dietary habits at baseline and post-intervention. Intervention consisted of 1 individual and 2 group counselings based on the nutrition education specifically designed for the chronic pain management. Results: post-intervention, pain intensity decreased in 67.5 % of patients while significantly improving quality of life (from 42.9 ± 31.3 to 70.1 ± 26.2 points, p = 0.015). All patients responded to nutrition education by increasing the number of meals per day (p < 0.001), improving regularity of breakfast (p = 0.005) and by less frequently skipping meals (p = 0.027). Fewer meal skipping (OR = 0.037, 95 % CI (0.003-0.482), p = 0.012) and lower consumption of foods with negative effect on chronic pain (OR = 0.008, 95 % CI (0.000-0.444), p = 0.019) were found to modestly, but independently contribute to decrease in pain intensity. Still, patients with higher BMI and several diagnoses had low resonse. Conclusions: the developed nutrition education is fit for the management of chronic pain. The main benefits are improved meal consumption pattern along with reduced consumption of foods with pro-inflammatory effect and food cravings. The complexity of chronic pain is obvious in low responsiveness among patients with higher BMI and several conditions.

INTRODUCCIÓN: Introducción: el dolor crónico es una entidad compleja con una inmensa carga individual y social. Objetivo: verificar si la educación nutricional diseñada específicamente para el tratamiento del dolor crónico y si algún cambio en los hábitos alimenticios contribuyen a disminuir la intensidad del dolor. Material y métodos: se incluyeron 40 pacientes en el estudio observacional intervencionista de 4 semanas. Los pacientes completaron cuestionarios sobre las características básicas: la intensidad del dolor, la calidad de vida y los hábitos alimenticios al inicio y después de la intervención. La intervención consistió en 1 asesoramiento individual y 2 grupales basados en la educación nutricional diseñada específicamente para el tratamiento del dolor crónico. Resultados: después de la intervención, la intensidad del dolor disminuyó en el 67,5 % de los pacientes al tiempo que mejoró significativamente la calidad de vida (de 42,9 ± 31,3 a 70,1 ± 26,2 puntos, p = 0,015). Todos los pacientes respondieron a la educación nutricional: aumentaron el número de comidas por día (p < 0,001), mejoraron la regularidad del desayuno (p = 0,005) y omitieron las comidas con menos frecuencia (p = 0,027). Menos saltos de comida (OR = 0,037, IC 95 % [0,003-0.482], p = 0,012) y menor consumo de alimentos con efecto negativo sobre el dolor crónico (OR = 0,008, IC 95 % [0,000-0,444], p = 0.019) se encontraron que modestamente, pero, de formma independiente, contribuyen a disminuir la intensidad del dolor. Sin embargo, los pacientes con mayor BMI y varios diagnósticos tuvieron baja resonancia. Conclusión: la educación nutricional desarrollada es adecuada para el manejo del dolor crónico. Los mejores beneficios son un patrón mejorado de consumo de comida junto a un consumo reducido de alimentos con efecto proinflamatorio y antojos de alimentos. La complejidad del dolor crónico es visible en baja respuesta entre pacientes con mayor BMI y varios diagnósticos.

Association Between Diagnoses of Chronic Noncancer Pain, Substance Use Disorder, and HIV-Related Outcomes in People Living With HIV.

BACKGROUND: Chronic pain is common in people living with HIV (PLWH). Few studies have evaluated the association between the diagnoses of chronic pain, substance use disorder (SUD), and HIV-related outcomes in clinical settings over a 10-year period. METHODS: Using electronic medical records, the study described psychiatric diagnoses, pain medication, and HIV-related variables in PLWH and examined the factors associated with pain diagnosis and HIV-related outcomes. RESULTS: Among 3528 PLWH, more than one-third exhibited a chronic pain diagnosis and more than one-third a psychiatric disorder. Chronic pain diagnosis has been associated with SUD and mood and anxiety disorders and occurred before SUD or psychiatric disorders about half of the time. Opioids have been commonly prescribed for pain management, more often than nonopioid analgesic, without any change in prescription pattern over the 10-year period. A dual diagnosis of pain and SUD has been associated with more psychiatric disorders and had a negative impact on the pain management by requesting more health care utilization and higher frequency of both opioid and nonopioid medication prescriptions. Chronic pain and SUD had a negative impact on ART adherence. SUD but not chronic pain has been associated with an unsuppressed HIV viral load. CONCLUSIONS: In the current intertwining opioid prescription and opioid epidemic, opioids are still commonly prescribed in PLWH in HIV care. A diagnosis of chronic pain and/or SUD worsened the HIV-related outcomes, emphasizing the potential risk of the HIV epidemic. These findings called for a better coordinated care program in HIV clinics.

The analgesic effect of refeeding on acute and chronic inflammatory pain.

Pain is susceptible to various cognitive factors. Suppression of pain by hunger is well known, but the effect of food intake after fasting (i.e. refeeding) on pain remains unknown. In the present study, we examined whether inflammatory pain behavior is affected by 24 h fasting and 2 h refeeding. In formalin-induced acute inflammatory pain model, fasting suppressed pain behavior only in the second phase and the analgesic effect was also observed after refeeding. Furthermore, in Complete Freund's adjuvant-induced chronic inflammatory pain model, both fasting and refeeding reduced spontaneous pain response. Refeeding with non-calorie agar produced an analgesic effect. Besides, intraperitoneal (i.p.) administration of glucose after fasting, which mimics calorie recovery following refeeding, induced analgesic effect. Administration of opioid receptor antagonist (naloxone, i.p.) and cannabinoid receptor antagonist (SR 141716, i.p.) reversed fasting-induced analgesia, but did not affect refeeding-induced analgesia in acute inflammatory pain model. Taken together, our results show that refeeding produce analgesia in inflammatory pain condition, which is associated with eating behavior and calorie recovery effect.

Dual action of amitriptyline on NMDA receptors: enhancement of Ca-dependent desensitization and trapping channel block.

Although the tricyclic antidepressant amitriptyline (ATL) is widely used in the clinic, the mechanism underlying its high therapeutic efficacy against neuropathic pain remains unclear. NMDA receptors (NMDARs) represent a target for ATL and are involved in sensitization of neuropathic pain. Here we describe two actions of ATL on NMDARs: 1) enhancement of Ca2+-dependent desensitization and 2) trapping channel block. Inhibition of NMDARs by ATL was found to be dependent upon external Ca2+ concentration ([Ca2+]) in a voltage-independent manner, with an IC50 of 0.72 µM in 4 mM [Ca2+]. The ATL IC50 value increased exponentially with decreasing [Ca2+], with an e-fold change observed per 0.69 mM decrease in [Ca2+]. Loading neurons with BAPTA abolished Ca2+-dependent inhibition, suggesting that Ca2+ affects NMDARs from the cytosol. Since there is one known Ca2+-dependent process in gating of NMDARs, we conclude that ATL most likely promotes Ca2+-dependent desensitization. We also found ATL to be a trapping open-channel blocker of NMDARs with an IC50 of 220 µM at 0 mV. An e-fold change in ATL IC50 was observed to occur with a voltage shift of 50 mV in 0.25 mM [Ca2+]. Thus, we disclose here a robust dependence of ATL potency on extracellular [Ca2+], and demonstrate that ATL bound in the NMDAR pore can be trapped by closure of the channel.