Association between gabapentin use and risk of dementia in adults with chronic pain: A nested case-control study.

STUDY OBJECTIVE: To explore the association between gabapentin use and the risk of dementia in patients with chronic pain, considering the rising concerns of dementia in an aging population and the potential cognitive impacts of chronic pain management. DESIGN: A nested case-control study utilizing data from a longitudinal health insurance database. SETTING: The study is based on a longitudinal health insurance database spanning 2000-2019 in Taiwan. PATIENTS: A total of 201,492 patients aged 50 years and older diagnosed with chronic pain between 2001 and 2017 were included. The study focused on individuals with chronic pain, excluding those diagnosed with dementia a year before or after their chronic pain diagnosis. INTERVENTION: Analysis of gabapentin prescription history was conducted, considering the cumulative dose from the chronic pain diagnosis date to the dementia diagnosis date or equivalent period for controls. MEASUREMENT: Data included demographics, gabapentin prescription history, and comorbidities. Logistic regression was used to estimate odds ratios for dementia risk. MAIN RESULTS: No significant difference in the risk of dementia was found between low and high cumulative doses of gabapentin. The adjusted odds ratio for dementia risk associated with gabapentin use was 0.91 (95 % C.I. 0.83-1.01), indicating no substantial increase in risk. CONCLUSION: Long-term Gabapentin therapy for chronic pain is not associated with a differential risk of dementia across dosage levels, irrespective of age or gender. Further study into its potential cognitive impacts is essential.

Ultramicronized N-palmitoylethanolamine associated with analgesics: Effects against persistent pain.

Current epidemiological data estimate that one in five people suffers from chronic pain with considerable impairment of health-related quality of life. The pharmacological treatment is based on first- and second-line analgesic drugs, including COX-2 selective and nonselective nonsteroidal anti-inflammatory drugs, paracetamol, antidepressants, anti-seizure drugs and opioids, that are characterized by important side effects. N-palmitoylethanolamine (PEA) is a body's own fatty-acid ethanolamide belonging to the family of autacoid local injury antagonist amides. The anti-inflammatory and pain-relieving properties of PEA have been recognized for decades and prompted to depict its role in the endogenous mechanisms of pain control. Together with its relative abundance in food sources, this opened the way to the use of PEA as a pain-relieving nutritional intervention. Naïve PEA is a large particle size lipid molecule with low solubility and bioavailability. Reducing particle size is a useful method to increase surface area, thereby improving dissolution rate and bioavailability accordingly. Micron-size formulations of PEA (e.g., ultramicronized and co-(ultra)micronized) have shown higher oral efficacy compared to naïve PEA. In particular, ultramicronized PEA has been shown to efficiently cross the intestinal wall and, more importantly, the blood-brain and blood-spinal cord barrier. Several preclinical and clinical studies have shown the efficacy, safety and tolerability of ultramicronized PEA. This narrative review summarizes the available pharmacokinetic/pharmacodynamic data on ultramicronized PEA and focuses to its contribution to pain control, in particular as 'add-on' nutritional intervention. Data showing the ability of ultramicronized PEA to limit opioid side effects, including the development of tolerance, have also been reviewed.

[Pharmacological pain management in cancer patients]. / Medikamentöse Schmerztherapie bei Patienten mit Tumorerkrankungen.

Pharmacological pain therapy in cancer patients is based on guideline recommendations, which, however, do not fully coincide in all aspects due to varying weighting of evidence. The present article discusses current issues including the decreasing significance of the World Health Organization (WHO) analgesic ladder, with its distinction between step 2 and 3 being increasingly questioned. Risks of nonopioid analgesics such as paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), particularly in older populations, are discussed. Paracetamol may potentially reduce the effectiveness of immunotherapies. Aspects of administering analgesics via a feeding tube are considered. Recommendations for the treatment of episodic pain, transitioning between different opioids, and some relevant interactions are also discussed.

Unsatisfactory response to acute medications does not affect the medication overuse headache development in pediatric chronic migraine.

BACKGROUND: Chronic migraine (CM) negatively impacts the quality of life of 2 to 4% of pediatric patients. In adults, CM is frequently linked to medication overuse headache (MOH), but there is a much lower prevalence of MOH in children. A suboptimal response to acute therapies may lead to their reduced use, thus preventing MOH development in children and adolescents. The frequency of patients with CM who do not respond to acute therapies was examined in the present study. We investigated whether the prevalence of MOH was different between responders and non-responders. We also examined whether patients receiving prophylactic therapy had an improved response to acute therapy. Finally, we investigated if there was a difference in the frequency of psychiatric comorbidities between responders and non-responders. METHODS: We retrospectively analysed clinical data of all chronic pediatric migraineurs under the age of 18 referred to the Headache Centre at Bambino Gesù Children Hospital in June 2021 and February 2023. ICHD3 criteria were used to diagnose CM and MOH. We collected demographic data, including the age at onset of migraine and the age of the CM course. At baseline and after 3 months of preventive treatment, we evaluated the response to acute medications. Neuropsychiatric comorbidities were referred by the children's parents during the first attendance evaluation. RESULTS: Seventy patients with CM were assessed during the chosen period. Paracetamol was tried by 41 patients (58.5%), NSAIDs by 56 patients (80.0%), and triptans by 1 patient (1.4%). Fifty-one participants (73%) were non-responder to the abortive treatment. The presence of MOH was detected in 27.1% of the whole populations. Regarding our primary aim, MOH was diagnosed in 29% of non-responder patients and 22% of responders (p > 0.05). All patients received preventative treatment. After 3 months of preventive pharmacological therapy, 65.4% of patients who did not respond to acute medications achieved a response, while 34.6% of patients who were non-responder remain non-responder (p < 0.05). Prophylactic therapy was also effective in 69% of patients who responded to acute medication (p < 0.05). Psychiatric comorbidities were detected in 68.6% of patients, with no difference between responders and non-responders (72.2% vs. 67.3%; p = 0.05). CONCLUSIONS: Despite the high prevalence of unresponsiveness to acute therapies in pediatric CM, it does not act as a protective factor for MOH. Moreover, responsiveness to acute drugs is improved by pharmacological preventive treatment and it is not affected by concomitant psychiatric comorbidities.

The analgesic effects of insulin and its disorders in streptozotocin-induced short-term diabetes.

Evidence suggests that insulin resistance plays an important role in developing diabetes complications. The association between insulin resistance and pain perception is less well understood. This study aimed to investigate the effects of peripheral insulin deficiency on pain pathways in the brain. Diabetes was induced in 60 male rats with streptozotocin (STZ). Insulin was injected into the left ventricle of the brain by intracerebroventricular (ICV) injection, then pain was induced by subcutaneous injection of 2.5% formalin. Samples were collected at 4 weeks after STZ injection. Dopamine (DA), serotonin, reactive oxygen species (ROS), and mitochondrial glutathione (mGSH) were measured by ELISA, and gene factors were assessed by RT-qPCR. In diabetic rats, the levels of DA, serotonin, and mGSH decreased in the nuclei of the thalamus, raphe magnus, and periaqueductal gray, and the levels of ROS increased. In addition, the levels of expression of the neuron-specific enolase and receptor for advanced glycation end genes increased, but the expression of glial fibrillary acidic protein expression was reduced. These results support the findings that insulin has an analgesic effect in non-diabetic rats, as demonstrated by the formalin test. ICV injection of insulin reduces pain sensation, but this was not observed in diabetic rats, which may be due to cell damage ameliorated by insulin.

Pregabalin-induced delayed cutaneous hypersensitivity reaction occurring after 40 days of use: a case report.

Pregabalin is the first-line treatment for neuropathic pain. Cases of cutaneous hypersensitivity reactions caused by pregabalin generally occur within 2 weeks of initiating medication. We report a rare case of a delayed cutaneous hypersensitivity reaction caused by pregabalin, which was confirmed by a drug provocation test. A 72-year-old man with severe herpes zoster neuralgia developed maculopapular drug eruption covering 80% to 90% of his total body surface area after 40 days of combined multidrug analgesia. A drug provocation test for pregabalin was positive. The time interval between initiating medication and the onset of the patient's rash was the longest and he also had the largest area of skin affected compared with patients with a similar condition in previous related reports. Remaining vigilant for possible adverse cutaneous hypersensitivity reactions during treatment is important because of the long-term course of pregabalin treatment for neuropathic pain.

Challenges of acute pain management in older patients.

Adequate management of acute pain in the older population is crucial. However, it is inherently complex because of multiple physiological changes that significantly impact both the pharmacokinetics and pharmacodynamics of medications. Current guidelines promote paracetamol as the first-line analgesic for acute pain in older adults, whereas opioids are advised cautiously for moderate to severe acute pain. However, opioids come with a significant array of side effects, which can be more pronounced in older individuals. Ketamine administered via intranasal (IN) and nebulised inhalation in the emergency department for managing acute pain in older patients shows promising potential for improving pain management and reducing opioid reliance Kampan, Thong-on, Sri-on (2024, Age Ageing, 53, afad255). Nebulised ketamine appears superior in terms of adverse event incidence. However, the adoption of IN or nebulised ketamine in older adult acute pain management remains unclear because of the lack of definitive conclusions and clear guidelines. Nevertheless, these modalities can be valuable options for patients where opioid analgesics are contraindicated or when intravenous morphine titration is impractical or contraindicated. Here, we review these concepts, the latest evidence and propose avenues for research.

Low-dose ketamine safely reduces acute pain in the ED with a more rapid and shorter effect than morphine.

SOURCE CITATION: Guo J, Zhao F, Bian J, et al. Low-dose ketamine versus morphine in the treatment of acute pain in the emergency department: a meta-analysis of 15 randomized controlled trials. Am J Emerg Med. 2024;76:140-149. 38071883.

Cohort profile: The Copenhagen Analgesic Study-The COPANA cohort.

BACKGROUND: Development of the gonads during fetal life is complex and vital for adult reproductive health. Cell and animal studies have shown an alarming effect of mild analgesics on germ cells in both males and females. More than 50% of pregnant women use mild analgesics during pregnancy, which potentially could compromise the reproductive health of the next generation. OBJECTIVES: We present a research protocol designed to evaluate the effect of prenatal exposure to mild analgesics and endocrine-disrupting chemicals on gonadal function in the offspring. POPULATION: Healthy, singleton pregnant women and their partners. DESIGN: The COPANA cohort is a prospective, observational pregnancy and birth cohort. METHODS: Participants were enrolled during the first trimester of pregnancy. Information on the use of mild analgesics was collected retrospectively 3 months prior to pregnancy and prospectively every 2 weeks throughout the study. We collected extensive data on lifestyle and reproductive health. Biospecimens were collected in the first trimester (maternal and paternal urine- and blood samples), in the third trimester in conjunction with a study-specific ultrasound scan (maternal urine sample), and approximately 3 months post-partum during the infant minipuberty period (maternal and infant urine- and blood samples). A comprehensive evaluation of reproductive function in the infants during the minipuberty phase was performed, including an ultrasound scan of the testis or ovaries and uterus. PRELIMINARY RESULTS: In total, 685 pregnant women and their partners were included between March 2020 and January 2022. A total of 589 infants (287 males) and their parents completed the follow-up during the minipuberty phase (December 2020-November 2022). CONCLUSIONS: The Copenhagen Analgesic Study holds the potential to provide novel and comprehensive insights into the impact of early and late prenatal exposure to mild analgesics and other endocrine-disrupting chemicals on future reproductive function in the offspring.

Efficacy and safety of nalbuphine for epidural labor analgesia at high altitude: An observational study.

Xining is located at the eastern edge of the Qinghai-Tibet Plateau, with an average altitude of >7000 feet (>2000 m). Nalbuphine is a kappa-opioid receptor agonist that can provide analgesia with fewer side effects than other opioid analgesics. This study aimed to evaluate pain control, side effects, and neonatal outcomes from combining nalbuphine with sufentanil and ropivacaine in 600 women during epidural anesthesia while giving birth at a high altitude in Xining, China. A total of 600 parturients receiving epidural labor analgesia were randomly divided into 2 groups, each group 300 parturients. The nalbuphine group received nalbuphine, sufentanil, and ropivacain, the control group only received sufentanil and ropivacain. The analgesic effect was evaluated through the Visual Analogue Scale scores. Neonatal outcomes were mainly evaluated through the Apgar Scores. Compared to the control group, the nalbuphine group showed lower Visual Analogue Scale scores at all time points after analgesia (P < .05). In comparison with the control group, parturients in the nalbuphine group showed lower incidence rates of fever at delivery, 24-hour postpartum bleeding, and pruritus (P < .05). However, between the 2 groups, there were no statistically significant differences in the remaining maternal and infant outcomes and neonatal outcomes (P > .05). Moreover, no adverse effects on neonatal outcomes were observed. The findings from this study support findings from previous studies that nalbuphine provided safe epidural analgesia without significant side effects for the mother and infant, and showed both safety and efficacy when used during labor at high altitude.

Effects of major analgesics on male fertility: A systematic literature review.

OBJECTIVE: To verify, based on a systematic literature review, the effects of the main analgesics on male fertility. DATA SOURCES: The studies were analyzed from the PubMed, SciELO and LILACS databases. STUDY SELECTION: The articles selected for the present review included: cohort studies; cross-sectional studies, clinical trials; complete studies; studies with animal models that addressed the proposed theme and that were published within the stipulated period from March 1, 2013, to March 31, 2023, in English, Portuguese and Spanish. These would later have to go through inclusion stages such as framing the type of study and exclusion criteria. DATA COLLECTION: Author's name, year of publication, study population, number of patients, analgesic, administration time, dose, and effect. CONCLUSIONS: There are in vitro and in vivo studies that link paracetamol and ibuprofen to endocrine and seminal changes that are harmful to male fertility. However, more clinical research is needed to determine the doses and timing of administration that affect fertility. The effects of aspirin on male fertility are still unclear due to the lack of studies and consistent methodologies. There is not enough research on dipyrone and its relationship with male fertility, requiring more studies in this area.

Blocking the dopaminergic receptors within the hippocampal dentate gyrus reduced analgesic responses induced by restraint stress in the formalin test.

Previous studies have shown that various receptors, including dopamine receptors, are expressed in the hippocampal dentate gyrus (DG). Besides, indicatively, dopamine receptors play an essential role in the modulation of pain perception. On the other hand, stressful experiences can produce analgesia, termed stress-induced analgesia (SIA). The current study examined the probable role of dopamine receptors within the DG in antinociception induced by restraint stress (RS). Ninety-seven male albino Wistar rats were unilaterally implanted with a cannula in the DG. Animals received intra-DG microinjections of SCH23390 or Sulpiride (0.25, 1, and 4 µg/rat) as D1-and D2-like dopamine receptor antagonists, respectively, five minutes before RS. Ten minutes after the end of the induction of RS for three hours, 50 µl 2.5% formalin was injected subcutaneously into the plantar surface of the hind paw to induce persistent inflammatory pain. Pain scores were evaluated at 5-minute intervals for 60 minutes. These findings showed that; exposure to RS for three hours produced SIA in both phases of the formalin test, while this RS-induced analgesia was attenuated in the early and late phases of the formalin test by intra-DG microinjection of SCH23390 and Sulpiride. The results of the present study suggested that both D1- and D2-like dopamine receptors in the DG have a considerable role in the induced analgesia by RS.

Inhibitory effect of acupoint electrostimulation with different layers and intensities on muscular inflammatory pain and spinal WDR neuron activity. / ç©´ä½ä¸åŒå±‚æ¬¡å’Œå¼ºåº¦ç”µåˆºæ¿€ç¼“è§£è‚Œè‚‰ç‚Žæ€§ç—›åŠå¯¹è„Šé«“èƒŒè§’å¹¿åŠ¨åŠ›ç¥žç»å ƒçš„æŠ‘åˆ¶ä½œç”¨.

OBJECTIVES: To observe the analgesic effects of different levels and intensities of electrical stimulation on the local acupoints in the pain source area and their impact on wide dynamic range (WDR) neurons in the spinal dorsal horn, in order to provide a basis for selecting appropriate parameters for electroacupuncture (EA) stimulation. METHODS: Wistar rats were used in 3 parts of the experiment. Complete Freund's adjuvant was used to establish a model of inflammation-induced pain in the gastrocnemius muscle. After modeling, 6 rats were randomly selected for multi-channel extracellular electrophysiological recording of the electrical activity of WDR neurons, to determine the threshold for activating the A-component (Ta) and the C-component (Tc), which were used as the intervention intensities for skin transcutaneous electrical acupoint stimulation (TEAS) or EA. Thirty-six rats were randomly divided into normal , model , TEAS-Ta , TEAS-Tc, EA-Ta , and EA-Tc groups, with 6 rats in each group. In the pain source area , Ta or Tc intensity of TEAS or EA intervention at"Chengshan"(BL57) was performed for 30 min each time, once a day, for 3 consecutive days. A small animal pressure pain measurement instrument was used to measure the mechanical pressure pain threshold of the gastrocnemius muscle in rats, and the Von Frey filament was used to measure the mechanical pain threshold of the footpad. Thirteen rats were randomly selected to observe the immediate responsiveness of WDR neurons to Ta/Tc intensity of EA or TEAS in BL57. RESULTS: The thresholds of TEAS to activate WDR neuron A-component or C-component were (2.43±0.57) mA and (7.00±1.34) mA, respectively, while the thresholds for EA to activate muscle WDR neuron A-component or C-component were (0.72±0.34) mA and (1.58±0.35) mA, respectively. After injection of CFA into the gastrocnemius muscle, compared with the normal group both the mechanical pressure pain threshold of the gastrocnemius muscle and the mechanical pain threshold of the footpad of rats in the model group were significantly decreased (P<0.001). After TEAS-Ta, TEAS-Tc or EA-Ta intervention in the BL57, both the mechanical pressure pain threshold of the gastrocnemius muscle and the mechanical pain threshold of the footpad were significantly higher than those in the model group (P<0.05, P<0.001). Compared with the normal group, the electrical threshold for evoking WDR neuron C-component discharge was significantly decreased (P<0.001) in the model group, while increased after TEAS-Ta, TEAS-Tc, or EA-Ta intervention (P<0.01) compared with the model group. The evoked discharge frequency of muscle WDR neurons decreased significantly after immediate intervention with TEAS-Ta, TEAS-Tc, or EA-Ta (P<0.01, P<0.05). EA-Tc had no significant improvement on the evoked electrical activity of WDR neurons or pain behavior. CONCLUSIONS: TEAS-Ta, TEAS-Tc, or EA-Ta can all alleviate the local and footpad mechanical pain in rats with muscle inflammation and inhibit the responsiveness of WDR neurons, indicating that different intensities are required for analgesic effects at different levels of acupoints in the pain source area.

Acute effects of military aircraft noise on sedative and analgesic drug administrations in psychiatric patients: A case-time series analysis.

BACKGROUND: Existing evidence suggests that psychiatric patients are highly noise sensitive, and that noise exposure increases the risk for adverse mental health outcomes, such as psychiatric hospitalizations and even suicide. To investigate acute effects of noise in this vulnerable population, we assessed short-term associations between fighter jet noise and on-demand sedative and analgesic drug administrations in a psychiatric clinic located close to a military airfield in Switzerland. METHODS: We applied a case time series analysis with an hourly time resolution using distributed-lag models. Analysis was adjusted for long-term and seasonal trends, day of week, time of day, time-varying weather conditions and the week of stay. Noise exposure (hourly A-weighted equivalent continuous sound pressure levels (LAeq)) was modelled using detailed flight plans and noise footprints for different fighter jet and route combinations. Outcome data were available from the clinic's records. OUTCOMES: During the study period (06/2016-12/2021), 23,486 flights occurred. 5,968 clinical stays with a median length of 41 days (IQR: 28d, 50d) were recorded. The odds ratio (OR) for medication administration over the lag period of 3 hours after exposure was 1.016 (95 %CI: 1.006, 1.026) per 10 dB LAeq for sedatives and 1.032 (95 %CI: 1.016, 1.048) per 10 dB for analgesics. Effects were larger in multimorbid patients. INTERPRETATION: Case time series analysis is a novel method to investigate transient associations in observational data while minimizing risk of bias. Using an objectively recorded outcome measure, our results demonstrate that psychiatric patients are a vulnerable population, in which noise exposure can lead to symptom exacerbations and adverse events.

Gabapentin for Postoperative Pain Control and Opioid Reduction in Scrotal Surgery: A Randomized Controlled Clinical Trial.

PURPOSE: To assess the safety and efficacy of gabapentin in reducing postoperative pain among patients undergoing scrotal surgery for male infertility by conducting a randomized, double-blind, placebo-controlled trial. MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled trial, healthy men undergoing scrotal surgery with a single surgeon were randomized to receive either (1) gabapentin 600 mg given 2 hours preoperatively and 300 mg taken 3 times a day postoperatively for 3 days, or (2) inactive placebo. The primary outcome measure was difference in postoperative pain scores. Secondary outcomes included differences in opioid usage, patient satisfaction, and adverse events. RESULTS: Of 97 patients screened, 74 enrolled and underwent randomization. Of these, 4 men were lost to follow-up, and 70 were included in the final analysis (35 gabapentin, 35 placebo). Both differences in initial postoperative mean pain score (-1.14, 95% CI -2.21 to -0.08, P = .035) and final mean pain score differences (-1.27, 95% CI -2.23 to -0.32, P = .0097) indicated lower gabapentin pain compared to placebo. There were no statistically significant differences in opioid usage, patient satisfaction, or adverse events. CONCLUSIONS: These data suggest that perioperative gabapentin results in a statistically and clinically significant decrease in pain following scrotal surgery. While there was no evidence of an impact on opioid usage or patient satisfaction, given the low risk of adverse events, it may be considered as part of a multimodal pain management strategy.

The crosstalk between subjective fibromyalgia, mental health symptoms and the use of over-the-counter analgesics in female Syrian refugees: a cross-sectional web-based study.

Suboptimal fibromyalgia management with over-the-counter analgesics leads to deteriorated outcomes for pain and mental health symptoms especially in low-income countries hosting refugees. To examine the association between the over-the-counter analgesics and the severity of fibromyalgia, depression, anxiety and PTSD symptoms in a cohort of Syrian refugees. This is a cross-sectional study. Fibromyalgia was assessed using the patient self-report survey for the assessment of fibromyalgia. Depression was measured using the Patient Health Questionnaire-9, insomnia severity was measured using the insomnia severity index (ISI-A), and PTSD was assessed using the Davidson trauma scale (DTS)-DSM-IV. Data were analyzed from 291. Among them, 221 (75.9%) reported using acetaminophen, 79 (27.1%) reported using non-steroidal anti-inflammatory drugs (NSAIDs), and 56 (19.2%) reported receiving a prescription for centrally acting medications (CAMs). Fibromyalgia screening was significantly associated with using NSAIDs (OR 3.03, 95% CI 1.58-5.80, p = 0.001). Severe depression was significantly associated with using NSAIDs (OR 2.07, 95% CI 2.18-3.81, p = 0.02) and CAMs (OR 2.74, 95% CI 1.30-5.76, p = 0.008). Severe insomnia was significantly associated with the use of CAMs (OR 3.90, 95% CI 2.04-5.61, p < 0.001). PTSD symptoms were associated with the use of CAMs (ß = 8.99, p = 0.001) and NSAIDs (ß = 10.39, p < 0.001). Improper analgesics are associated with poor fibromyalgia and mental health outcomes, prompt awareness efforts are required to address this challenge for the refugees and health care providers.

Efficacy and safety of pregabalin vs carbamazepine in patients with central post-stroke pain.

OBJECTIVE: To compare the efficacy and safety of pregabalin and carbamazepine in patients with central post-stroke pain (CPSP). METHODS: Patients included in the study were randomly assigned to either flexible-dose pregabalin treatment group or carbamazepine treatment group. The primary efficacy variable was face visual analog scale (F-VAS), the second efficacy assessment was used to assess the effect of treatment on mental health by Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD). RESULTS: The mean baseline pain score F-VAS was 6.47 in the pregabalin group and 6.58 in carbamazepine treatment group. F-VAS was significantly lower in the pregabalin group (1.64) than (3.94) carbamazepine treatment group after treatment. Pregabalin was significantly superior to carbamazepine in endpoint assessments on the HAMA and HAMD after treatment. F-VAS and HAMD were showed efficacy as early as week 2 and maintained for whole duration of the study. The average pregabalin dose in the 12-week study was 214.6 (150-375) mg/day. The mean dose (range) of carbamazepine received by the patients was 275.0 (200-400) mg/day. Mild or moderate, typically transient, somnolence and dizziness were the most common adverse events (AES). The differences of the side effects between the two groups were not significant. CONCLUSIONS: Pregabalin, but not carbamazepine, may be effective in improving F-VAS, HAMA and HAMD in patients with CPSP.

Ayahuasca and its major component harmine promote antinociceptive effects in mouse models of acute and chronic pain.

ETHNOPHARMACOLOGICAL RELEVANCE: Ayahuasca (AYA) is a psychedelic brew used in religious ceremonies. It is broadly used as a sacred medicine for treating several ailments, including pain of various origins. AIM OF THE STUDY: To investigate the antinociceptive effects of AYA and its mechanisms in preclinical models of acute and chronic pain in mice, in particular during experimental neuropathy. MATERIALS AND METHODS: The antinociceptive effects of AYA administered orally were assessed in the following models of pain: formalin test, Complete Freund's Adjuvant (CFA)-induced inflammation, tail flick test, and partial sciatic nerve ligation model of neuropathic pain. Antagonism assays and Fos immunohistochemistry in the brain were performed. AYA-induced toxicity was investigated. AYA was chemically characterized. The antinociceptive effect of harmine, the major component present in AYA, was investigated. RESULTS: AYA (24-3000 µL/kg) dose-dependently reduced formalin-induced pain-like behaviors and CFA-induced mechanical allodynia but did not affect CFA-induced paw edema or tail flick latency. During experimental neuropathy, single treatments with AYA (24-3000 µL/kg) reduced mechanical allodynia; daily treatments once or twice a day for 14 days promoted consistent and sustained antinociception. The antinociceptive effect of AYA (600 µL/kg) was reverted by bicuculline (1 mg/kg) and methysergide (5 mg/kg), but not by naloxone (5 mg/kg), phaclofen (2 mg/kg), and rimonabant (10 mg/kg), suggesting the roles of GABAA and serotonergic receptors. AYA increased Fos expression in the ventrolateral periaqueductal gray and nucleus raphe magnus after 1 h, but not after 6 h or 14 days of daily treatments. AYA (600 µL/kg) twice a day for 14 days did not alter mice's motor function, spontaneous locomotion, body weight, food and water intake, hematological, biochemical, and histopathological parameters. Harmine (3.5 mg/kg) promoted consistent antinociception during experimental neuropathy. CONCLUSIONS: AYA promotes consistent antinociceptive effects in different mouse models of pain without inducing detectable toxic effects. Harmine is at least partially accountable for the antinociceptive properties of AYA.

Optimizing the use of ketamine to reduce chronic postsurgical pain in women undergoing mastectomy for oncologic indication: study protocol for the KALPAS multicenter randomized controlled trial.

BACKGROUND: Mastectomies are commonly performed and strongly associated with chronic postsurgical pain (CPSP), more specifically termed postmastectomy pain syndrome (PMPS), with 25-60% of patients reporting pain 3 months after surgery. PMPS interferes with function, recovery, and compliance with adjuvant therapy. Importantly, it is associated with chronic opioid use, as a recent study showed that 1 in 10 patients continue to use opioids at least 3 months after curative surgery. The majority of PMPS patients are women, and, over the past 10 years, women have outpaced men in the rate of growth in opioid dependence. Standard perioperative multimodal analgesia is only modestly effective in prevention of CPSP. Thus, interventions to reduce CPSP and PMPS are urgently needed. Ketamine is well known to improve pain and reduce opioid use in the acute postoperative period. Additionally, ketamine has been shown to control mood in studies of anxiety and depression. By targeting acute pain and improving mood in the perioperative period, ketamine may be able to prevent the development of CPSP. METHODS: Ketamine analgesia for long-lasting pain relief after surgery (KALPAS) is a phase 3, multicenter, randomized, placebo-controlled, double-blind trial to study the effectiveness of ketamine in reducing PMPS. The study compares continuous perioperative ketamine infusion vs single-dose ketamine in the postanesthesia care unit vs placebo for reducing PMPS. Participants are followed for 1 year after surgery. The primary outcome is pain at the surgical site at 3 months after the index surgery as assessed with the Brief Pain Inventory-short form pain severity subscale. DISCUSSION: This project is part of the NIH Helping to End Addiction Long-term (HEAL) Initiative, a nationwide effort to address the opioid public health crisis. This study can substantially impact perioperative pain management and can contribute significantly to combatting the opioid epidemic. TRIAL REGISTRATION: ClinicalTrials.gov NCT05037123. Registered on September 8, 2021.

Experimental and pharmacoinformatic approaches unveil the neuropharmacological and analgesic potential of chloroform fraction of Roktoshirinchi (Achyranthes ferruginea Roxb.).

ETHNOPHARMACOLOGICAL RELEVANCE: Achyranthes ferruginea (A. ferruginea) Roxb. is a common plant used in traditional medicine in Asia and Africa. It has a variety of local names, including "Gulmanci" in Nigeria, "Dangar" in Pakistan, "Thola" in Ethiopia, and "Roktoshirinchi" in Bangladesh. It is edible and has several ethnomedical uses for a wide range of illnesses, including hysteria, dropsy, constipation, piles, boils, asthma, and shigellosis. However, the neuropharmacological and analgesic potential of A. ferruginea remains uninvestigated. AIM OF THE STUDY: To assess the neuropharmacological and analgesic potential of A. ferruginea through a multifaceted approach encompassing both experimental and computational models. MATERIALS AND METHODS: Methanol was used to extract the leaves of A. ferruginea. It was then fractionated with low to high polar solvents (n-hexane, chloroform, ethyl acetate, and water) to get different fractions, including chloroform fraction (CLF). The study selected CLF at different doses and conducted advanced chemical element and proximate analyses, as well as phytochemical profiling using GC-MS. Toxicological studies were done at 300 µg per rat per day for 14 days. Cholinesterase inhibitory potential was checked using an in-vitro colorimetric assay. Acetic acid-induced writhing (AAWT) and formalin-induced licking tests (FILT) were used to assess anti-nociceptive effects. The forced swim test (FST), tail suspension test (TST), elevated plus maze (EPM), hole board test (HBT), and light and dark box test (LDB) were among the behavioral tests used to assess depression and anxiolytic activity. Network pharmacology-based analysis was performed on selected compounds using the search tool for interacting chemicals-5 (STITCH 5), Swiss target prediction tool, and search tool for the retrieval of interacting genes and proteins (STRING) database to link their role with genes involved in neurological disorders through gene ontology and reactome analysis. RESULTS: Qualitative chemical element analysis revealed the presence of 15 elements, including Na, K, Ca, Mg, P, and Zn. The moisture content, ash value, and organic matter were found to be 11.12, 11.03, and 88.97%, respectively. GC-MS data revealed that the CLF possesses 25 phytoconstituents. Toxicological studies suggested the CLF has no effects on normal growth, hematological and biochemical parameters, or cellular organs after 14 days at 300 µg per rat. The CLF markedly reduced the activity of both acetylcholinesterase and butyrylcholinesterase (IC50: 56.22 and 13.22 µg/mL, respectively). Promising dose-dependent analgesic activity (p < 0.05) was observed in chemically-induced pain models. The TST and FST showed a dose-dependent substantial reduction in immobility time due to the CLF. Treatment with CLF notably increased the number of open arm entries and time spent in the EPM test at doses of 200 and 400 mg/kg b.w. The CLF showed significant anxiolytic activity at 200 mg/kg b.w. in the HBT test, whereas a similar activity was observed at 400 mg/kg b.w. in the EPM test. A notable increase in the amount of time spent in the light compartment was observed in the LDB test by mice treated with CLF, suggesting an anxiolytic effect. A network pharmacology study demonstrated the relationship between the phytochemicals and a number of targets, such as PPARA, PPARG, CHRM1, and HTR2, which are connected to the shown bioactivities. CONCLUSIONS: This study demonstrated the safety of A. ferruginea and its efficacy in attenuating cholinesterase inhibitory activity, central and peripheral pain, anxiety, and depression, warranting further exploration of its therapeutic potential.