Pharmacological evaluation and phytochemical profiling of butanol extract of L. edodes with in- silico virtual screening.

L. edodes (L. edodes) is the most consumed mushroom in the world and has been well known for its therapeutic potential as an edible and medicinal candidate, it contains dietary fibers, vitamins, proteins, minerals, and carbohydrates. In the current study butanolic extract of mushroom was used to form semisolid butanol extract. The current study aimed to explore biometabolites that might have biological activities in n-butanol extract of L. edodes using FT-IR and GC-MS and LC-MS. The synergistic properties of bioactive compounds were futher assessed by performing different biological assays such as antioxidant, anti-inflammatory and antidiabetic. FTIR spectra showed different functional groups including amide N-H group, Alkane (C-H stretching), and (C = C stretching) groups at different spectrum peaks in the range of 500 cm-1 to 5000 cm-1 respectively. GC-MS profiling of n-butanol extract depicted 34 potent biomolecules among those dimethyl; Morphine, 2TMS derivative; Benzoic acid, methyl ester 1-(2-methoxy-1-methylethoxy)-2-propanol were spotted at highest range. Results indicate that L. edodes n-butanol extract showed a maximum anti-inflammatory potential 91.4% at 300 mg/mL. Antioxidant activity was observed by measuring free radical scavenging activity which is 64.6% at optimized concentration along with good antidiabetic activity. In-silico study executed the biopotential of active ingredient morphine which proved the best docking score (- 7.0 kJ/mol) against aldose reductase. The in-silico drug design analysis was performed on biometabolites detected through GC-MS that might be a potential target for sulfatase-2 to treat ruminated arthritis. Morphine binds more strongly (- 7.9 kJ/mol) than other bioactive constituents indicated. QSAR and ADMET analysis shown that morphine is a good candidates against ruminated arthritis. The current study showed that L. edodes might be used as potent drug molecules to cure multiple ailments. As mushrooms have high bioactivity, they can be used against different diseases and to develop antibacterial drugs based on the current situation in the world in which drug resistance is going to increase due to misuse of antibiotics so new and noval biological active compounds are needed to overcome the situation.

Proposal for the classification of sinomenine alkaloids.

The chemical structure of sinoacutine is formed by a phenanthrene nucleus and an ethylamine bridge. Because it has a similar parent structure to morphine, it is subdivided into morphinane. At present, all reports have pointed out that the basic skeleton of morphine alkaloids is salutaridine (the isomer of sinoacutine), which is generated by the phenol coupling reaction of (R)-reticuline. This study shows that the biosynthetic precursors of sinoacutine and salutaridine are different. In this paper, the sinoacutine synthetase (SinSyn) gene was cloned from Sinomenium acutum and expressed SinSyn protein. Sinoacutine was produced by SinSyn catalyzed (S)-reticuline, according to the results of enzyme-catalyzed experiments. The optical activity, nuclear magnetic resonance, and mass spectrum of sinoacutine and salutaridine were analyzed. The classification and pharmacological action of isoquinoline alkaloids were discussed. It was suggested that sinoacutine should be separated from morphinane and classified as sinomenine alkaloids.

Structurally diverse analgesic diterpenoids from the flowers of Rhododendron molle.

Thirteen diterpenoids (1-13), classified into four structurally diverse carbon skeletons, including 1,5-seco-kalmane (1 and 6), grayanane (2-11), kalmane (12), and rhodomollane (13), were isolated from the flowers extract of Rhododendron molle. Among them, rhodomollinols A - E (1-5) were five new diterpenoids and their structures were elucidated by extensive spectroscopic methods including HRESIMS, UV, IR, 1D and 2D NMR, as well as quantum ECD calculations. Rhodomollinol A (1) is the first representative of a 6-deoxy-1,5-seco-kalmane diterpenoid. The abnormal NMR phenomenon of the presence of only 9 carbon resonances instead of 20 carbons in the 13C NMR spectrum of 1 was observed and elucidated by the quantum NMR calculations. All diterpenoids 1-13 showed significant analgesic activities in an acetic acid-induced writhing model. It's the first time to report the analgesic activity of a rhodomollane-type diterpenoid. At a dose of 1.0 mg/kg, diterpenoids 1-3, 6, 8, 9, and 12 reduced the writhe numbers with inhibition rates over 50%, and 9 exhibited stronger analgesic activity with a writhe inhibition rate of 89.7% than that of the positive control morphine. Importantly, even at the lowest dose of 0.04 mg/kg, rhodomollinols A (1) and B (2), rhodomollein X (7), and 2-O-methylrhodojaponin VI (9) still showed more potent analgesic effects than morphine with the writhe inhibition rates of 51.8%, 48.0%, 61.7%, and 60.0%, respectively. A preliminary structure-activity relationship might provide some clues to design potential analgesics on the basis of structurally diverse Ericaceae diterpenoids.

Ultrasound-Guided Transversus Abdominis Plane Blocks Versus Local Infiltration Anesthesia on Postanesthesia Care Unit Pain Control in Patients Undergoing Abdominoplasty.

GOALS/PURPOSE: The goal of this study was to compare ultrasound-guided transversus abdominis plane (TAP) blocks to local infiltration anesthesia with or without blind rectus sheath blocks in patients who underwent abdominoplasty at an outpatient surgery center. METHODS/TECHNIQUE: A retrospective review was conducted of patients who underwent outpatient abdominoplasty performed by the senior surgeon (J.T.L.). Group 1 received local infiltration anesthesia with or without blind rectus sheath blocks between April 2009 and December 2013. Group 2 received surgeon-led, intraoperative, ultrasound-guided, 4-quadrant TAP blocks between January 2014 and December 2021. Outcomes measured were opioid utilization (morphine milligram equivalents), pain level at discharge, and time spent in postanesthesia care unit (PACU). RESULTS: Sixty patients in each of the 2 study groups met the study criteria for a total of 120 patients. The study groups were similar except for a lower average age in group 1. Patients who received TAP blocks (group 2) had significantly lower morphine milligram equivalent requirements in the PACU (3.07 vs 8.93, P = 0.0001) and required a shorter stay in PACU (95.4 vs 117.18 minutes, P = 0.0001). There were no significant differences in pain level at discharge. CONCLUSIONS: Surgeon-led, intraoperative, ultrasound-guided, 4-quadrant TAP blocks statistically significantly reduced opioid utilization in PACU by 65.6% and average patient time in the PACU by 18.5% (21.8 minutes).

Combined multiple regional anesthesia for microwave ablation of liver Tumors: Initial experience.

OBJECTIVE: This study aims to assess the feasibility and safety of combined multiple regional anesthesia (CMRA) as a potential strategy to decrease pain and reliance on intravenous analgesics during and after ultrasound-guided microwave ablation (US-guided-MWA) of liver tumors. METHODS: A cohort of 75 patients with a total of 99 liver tumors who underwent US-guided-MWA of liver tumors were enrolled. These patients were randomly allocated into three groups: A, B, and C. Prior to the ablation procedure, Group A patients received a combination of hepatic hilar block (HHB), Transversus abdominis plane block (TAPB), and local anesthesia (LA). Patients in Group B were administered HHB in conjunction with LA, while those in Group C received TAPB and LA. Evaluative parameters included the Numerical Rating Scale (NRS) scores, consumption of morphine, incidence of complications, and factors influencing perioperative pain. RESULTS: All patients successfully underwent US-guided-MWA. The peak NRS scores for pain during ablation across the three groups were 2.36 ± 1.19, 3.28 ± 1.59, and 4.24 ± 1.42 respectively (P < 0.01), while the count of patients requiring morphine were 4/25, 8/25, and 13/25 respectively (P < 0.01). Postoperative NRS scores for the three groups at 4, 8, 12, 24, and 36-hour intervals demonstrated a pattern of initial increase followed by a decrease, with the order at each interval being: Group A < Group C < Group B. Factors associated with increased pain included larger tumor size, greater number of tumors, and longer procedure and ablation time (P < 0.05). No major complications were recorded across the three groups. CONCLUSION: CMRA offers an effective and safe modality to manage pain during and after US-guided-MWA of liver tumors.

The Effect of Aromatherapy in the Management of Cancer-Related Pain at the End of Life: A Pilot Study.

BACKGROUND: The use of clinical aromatherapy for managing pain has been studied in surgical patients and in women during childbirth. However, there are limited data on the use of aromatherapy for alleviating cancer-related pain, particularly at the end of life. OBJECTIVES: This pilot study identifies the pre- and postimplementation effects of aromatherapy on pain level, pain perception, and the use of oral morphine equivalent among patients with cancer at the end of life. METHODS: A survey was conducted to assess participant pain levels preimplementation of aromatherapy. Participants were then asked to rate their pain and describe how they felt 15 minutes postimplementation of aromatherapy. A chart review comparing oral morphine equivalent use pre- and postimplementation of aromatherapy was also performed. FINDINGS: Postimplementation of aromatherapy, mean pain scores and 24-hour oral morphine equivalent use decreased. Participants also described an improved pain experience and found aromatherapy to be soothing.

Acupuncture and laserpuncture as a therapeutic approach for nociception and inflammation: An experimental study in mice.

Inflammation and pain are consequences of injuries or diseases that affect a large number of people. This study aims to evaluate the effect of acupuncture and laserpuncture on nociception and inflammation in mice compared to the effects of morphine and dexamethasone. 140 male Swiss mice were used. Treatment with acupuncture and laserpuncture were performed at the acupoints LI11, ST36, GB34, and BL60 in mice. To evaluate the effect of acupuncture and laserpuncture on nociception, the hot plate test and intraplantar formalin injection were used. The effect of acupuncture and laserpuncture on the inflammation was evaluated through carrageenan-induced paw edema. Thermographic analysis was also applied to evaluate the anti-inflammatory effects. An antinociceptive effect (≈57%) was observed in treatments with acupuncture and laserpuncture, equivalent to the effect of morphine. Laserpuncture and acupuncture decreased paw edema by ≈25%. Acupuncture had an effect equivalent to dexamethason, basides reducing the neurogenic phase by 35% and the inflammatory phase in formalin-induced nociception by 40%, equivalent to the effects of morphine. In thermographic analysis, acupuncture, laserpuncture, morphine, and negative control had paw temperature of ≈27 °C, while formalin treatment was 31°C. Acupuncture and laserpuncture proved to be effective therapies for the treatment of inflammatory and painful processes.

Opium alkaloids, biosynthesis, pharmacology and association with cancer occurrence.

Papaver somniferum L. (Family: Papaveraceae) is a species well known for its diverse alkaloids (100 different benzylisoquinoline alkaloids (BIAs)). L-tyrosine serves as a precursor of several specific metabolites like BIAs. It has been used as an antitussive and potent analgesic to alleviate mild to extreme pain since ancient times. The extraction of pharmaceutically important alkaloids like morphine and codeine from poppy plant reflects the need for the most suitable and standard methods. Several analytical and extraction techniques have been reported in open literature for morphine, codeine and other important alkaloids which play a vital function in drug development and drug discovery. Many studies suggest that opioids are also responsible for adverse effects or secondary complications like dependence and withdrawal. In recent years, opium consumption and addiction are the most important risk factors. Many evidence-based reviews suggest that opium consumption is directly linked or acts as a risk factor for different cancers. In this review, we highlight significant efforts related to research which have been done over the past 5 decades and the complete information on Papaver somniferum including its phytochemistry, pharmacological actions, biosynthetic pathways and analytical techniques of opium alkaloid extraction and the link between opium consumption and cancer-related updates.

Potential anti-arthritic and analgesic properties of essential oil and viridiflorol obtained from Allophylus edulis leaves in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Viridiflorol was identified and isolated from the essential oil of Allophylus edulis leaves (EOAE). A. edulis was used as "tereré", which is a drink made by the infusion of herbs in cold water, to treat pain (toothache and headache). All anti-nociceptive (analgesic) and anti-arthritic properties of EOAE and viridiflorol have not been completely scientifically clarified. AIM OF THE STUDY: The aim of the present study was to investigate the analgesic (anti-hyperalgesic and anti-nociceptive) and anti-arthritic properties of EOAE and viridiflorol using in vivo models. MATERIALS AND METHODS: The oral administration (p.o.) of EOAE (30, 100 and 300 mg/kg), viridiflorol (30, 100 and 200 mg/kg), morphine (1 mg/kg, subcutaneous route (s.c.)) and the intraplantar (local) administration (i.pl.) of viridiflorol (100 µg/paw) were tested using formalin model in Swiss mice. EOAE (100 mg/kg, p.o.), viridiflorol (200 mg/kg, p.o.), and dexamethasone (1 mg/kg, s.c.) were tested by zymosan-articular inflammation and in open-field models. Viridiflorol (0.3, 20 and 200 µg/paw) was also tested in carrageenan model, and viridiflorol (200 µg/paw) was also tested in tumor necrosis factor-α (TNF-α), and dopamine (DOPA) models. RESULTS: The oral administration of EOAE (100 and 300 mg/kg, p.o.), viridiflorol (200 mg/kg, p.o.), morphine (1 mg/kg, s.c.) (MOR) and local administration of viridiflorol (100 µg/paw) significantly inhibited edema and nociception in formalin model. Oral treatments with EOAE and viridiflorol (200 mg/kg) did not cause motor impairment in the open field test since they did not reduce locomotor activity. EOAE, viridiflorol and dexamethasone significantly reduced mechanical hyperalgesia, edema, total leukocytes, polymorphonuclear cells, nitric oxide and protein exudation in the zymosan-induced articular inflammation model. The local administration of viridiflorol (200 µg/paw, i.pl.) significantly inhibited mechanical hyperalgesia and edema induced by carrageenan, TNF-α and DOPA. CONCLUSIONS: This study confirms the potential anti-arthritic, anti-nocicepttive and anti-hyperalgesic properties of EOAE and viridiflorol. These properties could explain, at least in part, the folk use of A. edulis against including pain (toothache and headache). Viridiflorol could be partially responsible for the EOAE anti-hyperalgesic, anti-nociceptive and anti-arthritic properties and its mechanism of action could involve the inhibition of TNF-α and DOPA pathways.

Medical Marijuana Legalization and Opioid- and Pain-Related Outcomes Among Patients Newly Diagnosed With Cancer Receiving Anticancer Treatment.

Importance: The past decade saw rapid declines in opioids dispensed to patients with active cancer, with a concurrent increase in marijuana use among cancer survivors possibly associated with state medical marijuana legalization. Objective: To assess the associations between medical marijuana legalization and opioid-related and pain-related outcomes for adult patients receiving cancer treatment. Design, Setting, and Participants: This cross-sectional study used 2012 to 2017 national commercial claims data and a difference-in-differences design to estimate the associations of interest for patients residing in 34 states without medical marijuana legalization by January 1, 2012. Secondary analysis differentiated between medical marijuana legalization with and without legal allowances for retail dispensaries. Data analysis was conducted between December 2021 and August 2022. Study samples included privately insured patients aged 18 to 64 years who received anticancer treatment during the 6 months after a new breast (in women), colorectal, or lung cancer diagnosis. Exposures: State medical marijuana legalization that took effect between 2012 and 2017. Main Outcomes and Measures: Having 1 or more days of opioids, 1 or more days of long-acting opioids, total morphine milligram equivalents of any opioid dispensed to patients with 1 or more opioid days, and 1 or more pain-related emergency department visits or hospitalizations (hereafter, hospital events) during the 6 months after a new cancer diagnosis. Interaction terms were included between each policy indicator and an indicator of recent opioids, defined as having 1 or more opioid prescriptions during the 12 months before the new cancer diagnosis. Logistic models were estimated for dichotomous outcomes, and generalized linear models were estimated for morphine milligram equivalents. Results: The analysis included 38 189 patients newly diagnosed with breast cancer (38 189 women [100%]), 12 816 with colorectal cancer (7100 men [55.4%]), and 7190 with lung cancer (3674 women [51.1%]). Medical marijuana legalization was associated with a reduction in the rate of 1 or more opioid days from 90.1% to 84.4% (difference, 5.6 [95% CI, 2.2-9.0] percentage points; P = .001) among patients with breast cancer with recent opioids, from 89.4% to 84.4% (difference, 4.9 [95% CI, 0.5-9.4] percentage points; P = .03) among patients with colorectal cancer with recent opioids, and from 33.8% to 27.2% (difference, 6.5 [95% CI, 1.2-11.9] percentage points; P = .02) among patients with lung cancer without recent opioids. Medical marijuana legalization was associated with a reduction in the rate of 1 or more pain-related hospital events from 19.3% to 13.0% (difference, 6.3 [95% CI, 0.7-12.0] percentage points; P = .03) among patients with lung cancer with recent opioids. Conclusions and Relevance: Findings of this cross-sectional study suggest that medical marijuana legalization implemented from 2012 to 2017 was associated with a lower rate of opioid dispensing and pain-related hospital events among some adults receiving treatment for newly diagnosed cancer. The nature of these associations and their implications for patient safety and quality of life need to be further investigated.

Chemical composition and antinociceptive and anti-inflammatory activity of the essential oil of Hyptis crenata Pohl ex Benth. from the Brazilian Amazon.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaf tea of Hyptis crenata has its practical use in the Brazilian Amazon for treating gastrointestinal and liver disorders, sweating induction, and as an anti-inflammatory. AIM OF THE STUDY: Evaluation of the chemical composition, acute oral toxicity, and antinociceptive and anti-inflammatory activities of the H. crenata essential oil. MATERIAL AND METHODS: The essential oil was hydrodistilled and analyzed by GC and GC-MS. The antinociceptive action in mice was evaluated for the peripheral and central analgesic activity (abdominal contortion and hot plate tests), and the xylene-induced ear swelling was carried out for the nociception test. RESULTS: Oxygenated monoterpenes (53.0%) and monoterpene hydrocarbons (38.9%) predominated in the H. crenata oil, being 1,8-cineo1e (35.9%), α-pinene (20.8%), camphor (10.0%), and ß-pinene (7.3%) their primary constituents. The oral oil administration in the mice did not display changes in behavior patterns or animal mortality at 300 and 2000 mg/kg doses. The control group's biochemical parameters (ALP, AST, ALT) displayed a statistical difference from the treated group, unlike the renal parameters, which showed no variation between the groups. Oil reduced the abdominal contortions at doses of 100 (79.5%) and 300 mg/kg (44.4%), while with endodontacin, the dose was 5 mg/kg (75.2%). In addition, the oil could not decrease the paw licking/biting time at doses of 30, 100, and 300 mg/kg. However, it showed a significant antinociceptive effect on the second phase in the formalin test inhibiting licking time, with a reduction of 50.8% (30 mg/kg), 63.4% (100 mg/kg), 58.0% (300 mg/kg), and morphine (4 mg/kg, 78.3%). The oil administration produced significant inhibition of ear edema at all tested doses, with a better effect produced at 30 mg/kg (64.0% inhibition). CONCLUSION: The oil of Hyptis crenata, rich in 1,8-cineole, camphor, α-pinene, and ß-pinene, totaling 74%, displayed low acute toxicity and significant anti-inflammatory activity, with peripheral and no central antinociceptive action. Thus, these results show an actual perspective on using H. crenata oil in developing a phytotherapeutic product.

2022 Taiwan Guidelines for Acute Treatment of Migraine.

The Taiwan Headache Society published its guidelines for acute migraine treatment in 2017. Since then, emerging drugs and treatment options have developed rapidly. The migraine-specific drugs gepants and ditans and several noninvasive neuromodulation devices have been approved for use in Europe and the United States. Although not all emerging drugs and treatment options have been approved for use in Taiwan, keeping pace with international trends and updating treatment guidelines are imperative. Therefore, the Treatment Guideline Subcommittee of the Taiwan Headache Society reviewed the quality of recent trials, evaluated the corresponding grade of evidence, and appraised the reported clinical efficacy to reach a new consensus. To ensure that the updated Taiwan guidelines are appropriate and feasible, the subcommittee also referred to the guidelines from the United States, Europe, Canada, and other countries concerning the main roles, recommendation levels, clinical efficacy, and adverse reactions of drugs for the acute migraine treatment. Several types of drugs are currently available for acute migraine treatment in Taiwan. These drugs can be categorized into migraine-specific and migraine-non-specific. Among them, migraine-specific triptans (oral or nasal spray formulations) and migraine-nonspecific acetaminophen and NSAIDs (diclofenac, ibuprofen, naproxen) are highly recommended because they are supported by strong evidence and demonstrate high efficacy. Prochlorperazine injection has been upgraded to a highly recommended level because of the rich clinical experience for this treatment. Ergotamine/caffeine remains a second-line drug because of its lower specificity and efficacy compared with triptans. High-dose aspirin was downgraded to rescue treatment because of potential gastrointestinal side effects. Although evidence supports the combination of oral tramadol and acetaminophen, this combination should be used as a rescue treatment due to concerns about dependence. Evidence supporting the use of intravenous tramadol or morphine is insufficient; therefore, their use is not recommended. As for non-pharmacological approaches, there are only limited controlled data. The choice of treatment for acute migraine attacks should follow the concept of "stratified care." For mild to moderate migraine attacks, oral NSAIDs are the first choice, with combination analgesics, intravenous/intramuscular NSAIDs as alternatives. For moderate to severe attacks, oral or nasal spray triptans and ergotamine/caffeine compounds are recommended and should be administered in the early stage of migraine attacks. Antiemetics can be used as supplements to alleviate nausea and vomiting. Other emerging migraine-specific drugs, such as gepants or ditans, may also have a role in the future. Notably, a combination of a triptan and a NSAID yielded a better efficacy compared with either therapy alone. Parenteral steroids and fluid supply are the first-line treatment for status migrainosus. Acetaminophen is suitable for mild to moderate migraine attacks and remains the first choice for children and pregnant women. To prevent medication overuse headache, the use of acute treatment should be limited to a maximum of 2 days per week. Key words: acute migraine treatment, evidence-based medicine, treatment guidelines, triptans, ergotamine, neuromodulation.

Pharmacokinetics and transplacental transfer of codeine and codeine metabolites from Papaver somniferum L.

ETHNOPHARMACOLOGICAL RELEVANCE: Papaveris Pericarpium, which is the dried husk of Papaver somniferum L., has been used as a phytomedicine to relieve cough, diarrhea and pain. The alkaloid codeine contained therein via biotransformation converts to morphine and potentially produces addictive and toxic effects. Due to the healthy concern for a pregnant woman, our hypothesis is that codeine and its metabolites can penetrate the placental barrier to reach the foetus and amniotic fluid, and these processes may be modulated by the transporter. AIM OF THE STUDY: Because codeine is also considered a prodrug of morphine, it has a good analgesic effect. It is often used by pregnant women but may expose the foetus to the risk of morphine harm. The aim of this study is to investigate the metabolic rate, distribution and transplacental transfer mechanism of codeine and its metabolites morphine and morphine-3-glucuronide (M3G) in pregnant rats and to assess the risk of medication for pregnant women. MATERIALS AND METHODS: Ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) combined with a microdialysis system was developed to monitor codeine, morphine and M3G in multiple sites of maternal blood, placenta, foetus and amniotic fluid after codeine administration. A compartmental model was used to calculate the pharmacokinetic parameters of codeine in blood after codeine administration (10 mg/kg, i.v.). The area under the concentration (AUC) ratio of AUCmetabolite/AUCcodeine and AUCtissue/AUCblood was used to represent the metabolic biotransformation ratio and the drug from blood-to-tissue transfer ratio, respectively. RESULTS: The pharmacokinetic results demonstrated that codeine fit well with a two-compartment model and went through rapid metabolism to morphine and M3G in pregnant rats after codeine administration (10 mg/kg, i.v.). The biotransformation ratios of AUCmorphine/AUCcodeine, AUCM3G/AUCmorphine and AUCM3G/AUCcodeine were 0.12 ± 0.03, 54.45 ± 20.61 and 6.53 ± 2.47, respectively, after codeine administration (10 mg/kg, i.v.), which suggested that codeine was easily metabolized into M3G through morphine. The tissue distribution results demonstrated that all of the analytes penetrated into the foetus through the placenta; however, the blood-to-tissue transfer ratio (AUCtissue/AUCblood) of morphine and M3G was relatively lower than that of codeine after codeine administration (10 mg/kg, i.v.), which suggested that the blood-placenta barrier blocks the penetration of morphine and M3G into the foetus. Thus, the tissue transfer of morphine in the placenta and foetus was significantly enhanced by treatment with corticosterone, an inhibitor of organic cation transporter (OCT). CONCLUSION: Based on microdialysis coupled to a validated UHPLC-MS/MS system, the pharmacokinetics and metabolic biotransformation of codeine and its metabolites were analyzed and clarified. The potential mechanism of morphine placental transfer was modulated by OCT transporters.

Dorsal Root Ganglion Stimulation as a Salvage Therapy Following Failed Spinal Cord Stimulation.

INTRODUCTION: Spinal cord stimulation (SCS) can provide long-term pain relief for various chronic pain conditions, but some patients have no relief with trial stimulation or lose efficacy over time. To "salvage" relief in patients who do not respond or have lost efficacy, alternative stimulation paradigms or anatomical targets can be considered. Dorsal root ganglion stimulation (DRG-S) has a different mechanism of action and anatomical target than SCS. OBJECTIVES: We assessed DRG-S salvage therapy outcomes in patients who did not respond to SCS or had lost SCS efficacy. MATERIALS AND METHODS: We retrospectively included consecutive patients from 2016 to 2020 who were salvaged with DRG-S after failed SCS trials (<50% pain reduction) or who had lost efficacy after permanent SCS. We compared numerical rating scale (NRS) pain, Oswestry disability index (ODI), health-related quality of life (EuroQol five-dimensions five-level), and oral morphine equivalent (OME) opioid requirements before DRG-S salvage and at patients' last follow-up. RESULTS: A total of 60 patients who had failed SCS were salvaged with DRG-S. The mean age was 56 ± 12 years, and the most common diagnoses were complex regional pain syndrome (n = 24) and failed back surgery syndrome (n = 24). The most common failed modalities included tonic (n = 32), Burst (n = 18), and high-frequency (n = 10) SCS. The median follow-up duration of salvage DRG-S was 34 months. With DRG-S, NRS decreased (8.7 ± 1.2 to 3.8 ± 2.1), and OME declined (median 23 mg to median 15 mg), whereas EuroQol 5D scores increased (0.40 ± 0.15 to 0.71 ± 0.15), and ODI improved (64 ± 14% to 31 ± 18%) (all p < 0.05). CONCLUSIONS: DRG-S can be used in patients with chronic pain who have previously failed to receive persistent benefit from SCS.

Perioperative Analgesic Efficacy of Yamamoto New Scalp Acupuncture for Canine Mastectomy Combined with Ovariohysterectomy: a Randomized, Controlled Clinical Trial.

Background: Yamamoto New Scalp Acupuncture (YNSA) is a therapy based on the stimulation of points on the scalp and applied to treat different states of pain. Objectives: To investigate the analgesic efficacy of YNSA for dogs undergoing radical unilateral mastectomy with ovariohysterectomy. Methods: Twenty-four dogs were randomly distributed into two treatments (n = 12, per group): bilateral stimulation of basic B, D, and E points (YNSA group) and no application of acupuncture (control group). All dogs were sedated with morphine; anesthesia was induced with propofol and maintained with isoflurane. Fentanyl was intraoperatively administered to control cardiovascular responses to surgical stimulation. Postoperative pain was assessed using an interactive visual analog scale (IVAS) and the short-form of the Glasgow Composite Pain Scale (CMPS-SF). Morphine was administered as rescue analgesia. Data were analyzed using t-tests, Fisher's exact test, Mann-Whitney U test, and Friedman test (p < 0.05). Results: Intraoperatively, the number of dogs requiring supplemental analgesic and the number of doses of fentanyl were lower in the YNSA group than in the control group (p = 0.027-0.034). The IVAS pain scores recorded from 0.5 h to 1 h post-extubation in the YNSA group were lower than those in the control group (p = 0.021-0.023). Postoperative rescue analgesia and CMPS-SF pain scores did not differ between the groups. Conclusion: YNSA decreases intraoperative fentanyl requirements and provides minimal postoperative analgesic benefits to dogs undergoing unilateral mastectomy with ovariohysterectomy.

Association Between Exposure to Complementary and Integrative Therapies and Opioid Analgesic Daily Dose Among Patients on Long-term Opioid Therapy.

OBJECTIVES: To describe the association between exposure to selected complementary and integrative health (CIH) modalities and the trajectory of prescribed opioid analgesic dose within a national cohort of patients receiving long-term opioid therapy (LTOT) in the Veterans Health Administration (VHA). MATERIALS AND METHODS: Using national data from VHA electronic health records between October 1, 2017 and September 30, 2019, CIH use was analyzed among 57,437 patients receiving LTOT within 18 VHA facilities serving as evaluation sites of VHA's Whole Health System of Care. Using linear mixed effects modeling controlling for covariates, opioid dose was modeled as a function of time, CIH exposure, and their interaction. RESULTS: Overall, 11.91% of patients on LTOT used any of the focus CIH therapies; 43.25% of those had 4 or more encounters. Patients used acupuncture, chiropractic care, and meditation modalities primarily. CIH use was associated with being female, Black, having a mental health diagnosis, obesity, pain intensity, and baseline morphine-equivalent daily dose. Mean baseline morphine-equivalent daily dose was 40.81 milligrams and dose decreased on average over time. Controlling for covariates, patients with any CIH exposure experienced 38% faster dose tapering, corresponding to a mean difference in 12-month reduction over patients not engaging in CIH of 2.88 milligrams or 7.06% of the mean starting dose. DISCUSSION: Results support the role of CIH modalities in opioid tapering. The study design precludes inference about the causal effects of CIH on tapering. Analyses did not consider the trend in opioid dose before cohort entry nor the use of other nonopioid treatments for pain. Future research should address these questions and consider tapering-associated adverse events.

Curcumin induces peripheral antinociception by opioidergic and cannabinoidergic mechanism: Pharmacological evidence.

BACKGROUND: Curcumin is one of the compounds present in plants of the genus Curcuma sp., being very used not only as condiment but also with medicinal purposes. As an analgesic, papers highlight the efficacy of curcumin in the treatment of various types of pain. AIMS: In this study we evaluated the peripheral antinociceptive effect of curcumin and by which mechanisms this effect is induced. MAIN METHODS: The mice paw pressure test was used on animals which had increased pain sensitivity by intraplantar injection of carrageenan. All the drugs were administered in the right hind paw. KEY FINDINGS: Curcumin was administered to the right hind paw animals induced antinociceptive effect. Non -selective antagonist of opioid receptors naloxone reverted the antinociceptive effect induced by curcumin. Selective antagonists for µ, δ and κ opioid receptors clocinnamox, naltrindole and nor- binaltorphimine, respectively, reverted the antinociceptive effect induced by curcumin. Bestatin, enkephalinases inhibitor that degrade peptides opioids, did not change the nociceptive response. Selective antagonists for CB1 and CB2 cannabinoid receptors, AM251 and AM630, respectively, reversed the antinociceptive effect induced by curcumin. The MAFP inhibitor of the enzyme FAAH which breaks down anandamide, JZL184, enzyme inhibitor MAGL which breaks down the 2-AG, as well as the VDM11 anandamide reuptake inhibitor potentiated the antinociceptive effect of curcumin. SIGNIFICANCE: These results suggest that curcumin possibly peripheral antinociception induced by opioid and cannabinoid systems activation and possibly for endocannabinoids and opioids release.

A proposed approach to confirm heroin administration - Regional differences in heroin purity is a major factor.

In forensic toxicology, a marker of street heroin use is urgent especially in the absence of urinary 6-monoacetylmorphine. ATM4G, the Glucuronide of Acetylated product of Thebaine compound 4 Metabolite (ATM4), arising from byproducts of street heroin synthesis has been considered as a useful marker in some European studies. However, whether ATM4G is a universal marker particularly in Southeast Asia due to 'street' heroin with high purity, it's still unclear. To investigate putative markers for different regions, ATM4G and other metabolites including the Acetylated product of Thebaine compound 3 Metabolite (ATM3) and thebaol, also originated from thebaine were detected in 552 urine samples from heroin users in Taiwan. Results were compared with that from samples collected in the UK and Germany. Only a sulfo-conjugate of ATM4, ATM4S, was detected in 28 Taiwanese users using a sensitive MS3 method whilst out of 351 samples from the UK and Germany, ATM4G was present in 91. Thebaol-glucuronide was first time detected in 118. No markers were detected in urine following herbal medicine use or poppy seed ingestion. The presence of ATM4S/ATM4G might be affected by ethnicities and heroin supplied in regions. Thebaol-glucuronide is another putative marker with ATM4G and ATM4S for street heroin use.

Confirmation of recent heroin abuse: Accepting the challenge.

Confirmation or exclusion of recent heroin consumption is still one of the major challenges for forensic and clinical toxicologists. A great variety of biomarkers is available for heroin abuse confirmation, including various opium alkaloids (eg, morphine, codeine), street heroin impurities (eg, 6-acetylcodeine [6-AC], noscapine, papaverine) as well as associated metabolites (eg, 6-monoacetylmorphine [6-MAM], morphine glucuronides). However, the presence of most of these biomarkers cannot solely be attributed to a previous heroin administration but can, among other things, also be due to consumption of poppy seed products ('poppy seed defense'), opium preparations or specific medications, respectively. A reliable allocation is of great importance in different contexts, for instance in the case of DUID (driving under the influence of drugs) investigations, in driving licence re-granting processes, in workplace drug testing (WDT), as well as in post-mortem identification of illicit opiate use. Additionally, differentiation between illicit street heroin abuse and pharmaceutical heroin administration is also important, especially within the frame of heroin-assisted treatments. Therefore, analysis of multiple biomarkers is recommended when illicit opiate consumption is assumed to obtain the most reliable results possible. Beyond that, interpretation of positive opiate test results requires a profound insight into the great variety of biomarkers available and their validity regarding the alleged consumption. This paper aims to provide an overview of the wide variety of heroin abuse biomarkers described in the literature and to review them regarding their utility and reliability in daily routine analysis.

Evaluation of Analgesia, Tolerance, and the Mechanism of Action of Morphine-6-O-Sulfate Across Multiple Pain Modalities in Sprague-Dawley Rats.

BACKGROUND: Morphine-6-O-sulfate (M6S) is a mixed µ/δ-opioid receptor (OR) agonist and potential alternative to morphine for treatment of chronic multimodal pain. METHODS: To provide more support for this hypothesis, the antinociceptive effects of M6S and morphine were compared in tests that access a range of pain modalities, including hot plate threshold (HPT), pinprick sensitivity threshold (PST) and paw pressure threshold tests. RESULTS: Acutely, M6S was 2- to 3-fold more potent than morphine in HPT and PST tests, specifically, derived from best-fit analysis of dose-response relationships of morphine/M6S half-effective dose (ED50) ratios (lower, upper 95% confidence interval [CI]) were 2.8 (2.0-5.8) in HPT and 2.2 (2.1, 2.4) in PST tests. No differences in analgesic drug potencies were detected in the PPT test (morphine/M6S ED50 ratio 1.2 (95% CI, 0.8-1.4). After 7 to 9 days of chronic treatment, tolerance developed to the antinociceptive effects of morphine, but not to M6S, in all 3 pain tests. Morphine-tolerant rats were not crosstolerant to M6S. The antinociceptive effects of M6S were not sensitive to κ-OR antagonists. However, the δ-OR antagonist, naltrindole, blocked M6S-induced antinociception by 55% ± 4% (95% CI, 39-75) in the HPT test, 94% ± 4% (95% CI, 84-105) in the PST test, and 5% ± 17% (95% CI, -47 to 59) or 51% ± 14% (95% CI, 14-84; 6 rats per each group) in the paw pressure threshold test when examined acutely or after 7 days of chronic treatment, respectively. CONCLUSIONS: Activity via δ-ORs thus appears to be an important determinant of M6S action. M6S also exhibited favorable antinociceptive and tolerance profiles compared with morphine in 3 different antinociceptive assays, indicating that M6S may serve as a useful alternative for rotation in morphine-tolerant subjects.