Day-of-Surgery Gabapentinoids and Prolonged Opioid Use: A Retrospective Cohort Study of Medicare Patients Using Electronic Health Records.

BACKGROUND: While preoperative gabapentinoids are commonly used in surgical multimodal analgesia protocols, little is known regarding the effects this therapy has on prolonged postsurgical opioid use. In this observational study, we used data from a large integrated health care system to estimate the association between preoperative day-of-surgery gabapentinoids and the risk of prolonged postsurgical opioid use. METHODS: We identified adults age ≥65 years undergoing major therapeutic surgical procedures from a large integrated health care system from 2016 to 2019. Exposure to preoperative gabapentinoids on the day of surgery was measured using inpatient medication administration records, and the outcome of prolonged opioid use was measured using outpatient medication orders. We used stabilized inverse probability of treatment-weighted log-binomial regression to estimate risk ratios and 95% confidence intervals (CIs) of prolonged opioid use, comparing patients who received preoperative gabapentinoids to those who did not and adjusting for relevant clinical factors. The main analysis was conducted in the overall surgical population, and a secondary analysis was conducted among procedures where at least 30% of all patients received a preoperative gabapentinoid. RESULTS: Overall, 13,958 surgical patients met inclusion criteria, of whom 21.0% received preoperative gabapentinoids. The observed 90-day risk of prolonged opioid use following surgery was 0.91% (95% CI, 0.77-1.08). Preoperative gabapentinoid administration was not associated with a reduced risk of prolonged opioid use in the main analysis conducted in a broad surgical population (adjusted risk ratio [adjRR], 1.19 [95% CI, 0.67-2.12]) or in the secondary analysis conducted in patients undergoing colorectal resection, hip arthroplasty, knee arthroplasty, or hysterectomy (adjRR, 1.01 [95% CI, 0.30-3.33]). CONCLUSIONS: In a large integrated health system, we did not find evidence that preoperative gabapentinoids were associated with reduced risk of prolonged opioid use in patients undergoing a broad range of surgeries.

Efficacy of a fixed combination of palmitoylethanolamide and acetyl-l-carnitine (PEA+ALC FC) in the treatment of neuropathies secondary to rheumatic diseases.

BACKGROUND: The neurologic complications of rheumatic diseases (RDs) are highly variable, and their manifestations are linked to the pathogenesis and clinical phenotype of the specific RDs. In rheumatoid arthritis, for example, the peripheral nervous system is most commonly involved and mononeuritis multiplex, nerve entrapment and vasculitic sensorimotor neuropathies are not uncommon. Often the therapy for these disorders is not easy and is characterized by the use of different drugs. Palmitoylethanolamide (PEA) has been tested in a wide variety of animal models and has been evaluated in several clinical studies for nerve compression syndromes, demonstrating that PEA acts as an effective and safe analgesic compound. Acetyl-L-Carnitine (ALC) has also been shown to be an effective and safe treatment in painful peripheral neuropathy. In the last years the synergistic effect between PEA and ALC has been demonstrated. The aim of our study was to evaluate the efficacy of supplementation of standard therapy (STh) with Kalanit® (Chiesi Italia Spa; Parma, Italy) in patients with peripheral neuropathy secondary to RDs. METHODS: Patients at the time of enrollment were affected by RDs with neuropathy from <12 months, documented by electromyography. The analyzed patients were treated with the STh chosen according to their rheumatic disease (RA or SpA) and for their neuropathy (e.g. analgesic, NSAIDs, pregabalin or gabapentin) as per clinical practice. The sample was divided into 2 groups: group 1, patients treated with STh, to which a fixed combination of PEA (600 mg) + ALC (500 mg) (Kalanit®) was added twice a day for 2 weeks and then once a day for 6 months; group 2, patients treated only with STh. Each patient underwent clinical evaluations and questionnaires were administered in order to evaluate their neuropathy and the efficacy of the therapy. RESULTS: In group 1, 18 patients suffering from sciatic pain, 16 patients from carpal tunnel syndrome and 8 patients with peripheral neuropathy of the lower limbs were included and PEA + ALC FC was added to STh. These patients were compared with patients from group 2, who had the same pathology and demographic characteristics: 20 patients with sciatic pain, 15 with carpal tunnel syndrome and 5 with peripheral neuropathy of the lower limbs, respectively; this group was treated with STh only. Patients treated with PEA + ALC FC had a significant improvement in pain VAS compared to patients treated with group 2 in all the diseases analyzed (P value: sciatic pain 0.032, carpal tunnel syndrome 0.025 and lower limbs neuropathy 0.041). Patients in group 1 showed a significant improvement compared to patients treated in group 2 also from a specific score. Specifically, LBP-IQ showed significant improvement in group one (P value: 0.031), as did CHFD (P=0.011) and NPQ (P=0.025). CONCLUSIONS: The synergistic effect of PEA and ALC seems to have a further advantage in the treatment of this type of pathology, including the anti-inflammatory effect but also in terms of therapy optimization and therefore of better adherence to treatments. Our study shows that it is important to identify the type of pain to follow an accurate diagnostic algorithm, considering the clinical characteristics of the patient and carefully evaluate the indication, preferring a multimodal approach.

Analgesic Effects of Topical Amitriptyline in Patients With Chemotherapy-Induced Peripheral Neuropathy: Mechanistic Insights From Studies in Mice.

Oral amitriptyline hydrochloride (amitriptyline) is ineffective against some forms of chronic pain and is often associated with dose-limiting adverse events. We evaluated the potential effectiveness of high-dose topical amitriptyline in a preliminary case series of chemotherapy-induced peripheral neuropathy patients and investigated whether local or systemic adverse events associated with the use of amitriptyline were present in these patients. We also investigated the mechanism of action of topically administered amitriptyline in mice. Our case series suggested that topical 10% amitriptyline treatment was associated with pain relief in chemotherapy-induced peripheral neuropathy patients, without the side effects associated with systemic absorption. Topical amitriptyline significantly increased mechanical withdrawal thresholds when applied to the hind paw of mice, and inhibited the firing responses of C-, Aß- and Aδ-type peripheral nerve fibers in ex vivo skin-saphenous nerve preparations. Whole-cell patch-clamp recordings on cultured sensory neurons revealed that amitriptyline was a potent inhibitor of the main voltage-gated sodium channels (Nav1.7, Nav1.8, and Nav1.9) found in nociceptors. Calcium imaging showed that amitriptyline activated the transient receptor potential cation channel, TRPA1. Our case series indicated that high-dose 10% topical amitriptyline could alleviate neuropathic pain without adverse local or systemic effects. This analgesic action appeared to be mediated through local inhibition of voltage-gated sodium channels. PERSPECTIVE: Our preliminary case series suggested that topical amitriptyline could provide effective pain relief for chemotherapy-induced peripheral neuropathy patients without any systemic or local adverse events. Investigation of the mechanism of this analgesic action in mice revealed that this activity was mediated through local inhibition of nociceptor Nav channels.

Zingiber officinale Roscoe rhizome extract alleviates neuropathic pain by inhibiting neuroinflammation in mice.

BACKGROUND: Current therapies for neuropathic pain are generally symptomatic and possess several side effects, limiting their prolonged usage. HYPOTHESIS/PURPOSE: Thus, it is urgent to develop novel and safe candidates for the management of this chronical condition. For this purpose, we investigated the analgesic effect of a standardized extract from Zingiber officinale Roscoe rhizomes (ZOE) obtained by CO2 supercritical extraction, in a mice model of peripheral neuropathy. We also explored the mechanism of action of ZOE and its main constituents using an in vitro model of neuroinflammation. METHODS: Peripheral mono-neuropathy was induced in mice, by spared nerve injury (SNI). The analgesic effect of ZOE after oral administration was assessed by measuring mechanical and thermal allodynia in SNI mice. The mechanism of action of ZOE and its main constituents were investigated using spinal cords samples and in an in vitro model of neuroinflammation by ELISA, western blotting and immunofluorescence techniques. RESULTS: Oral administration of ZOE 200 mg kg-1 ameliorated mechanical and thermal allodynia in SNI mice, with a rapid and a long-lasting effect. ZOE did not alter locomotor activity. In BV2 cells and spinal cord samples, ZOE, 6-gingerol and 6-shogaol reduced pERK levels, whereas ZOE and terpene fraction reduced HDAC1 protein levels, inhibited NF-κB signalling activation and decreased IL-1ß, TNF-α and IL-6 release. ZOE and each tested constituent had a positive effect on inflammation-impaired SH-SY5Y cell viability. CONCLUSIONS: The oral administration of ZOE attenuated SNI-induced neuropathic pain symptoms by reducing spinal neuroinflammation, suggesting ZOE as a novel and interesting candidate for the management of neuropathic pain.

Prospective Evaluation of a Standardized Opioid Reduction Protocol after Anorectal Surgery.

BACKGROUND: Surgery for anorectal disease is thought to cause significant postoperative pain. Our previous work demonstrated that most opioids prescribed after anorectal surgery are not used. We aimed to evaluate a standardized protocol for pain control after anorectal surgery. METHODS: We prospectively evaluated a standardized opioid reduction protocol over a 13-mo period for all patients undergoing elective anorectal surgery at our institution. Protocol components include preoperative query, procedural local-anesthetic blocks, first-line nonopioid analgesic use ± opioid prescription of five pills, and standardized postoperative instructions. Patients completed questionnaires at postoperative follow-up. Patients with history of opioid abuse or use within 30 d of operation, loss to follow-up, or surgical complications were excluded. Primary outcome was quality of pain control on a five-point scale. Secondary outcomes included use of nonopioid analgesics, opioids used, and need for refill. RESULTS: A total of 55 patients were included. Mean age was 47 ± 17 y with 23 women (42%). Anorectal abscess/fistula procedures were the most common (69%) followed by pilonidal procedures (11%) and hemorrhoidectomy (7%). Most had general anesthesia (60%) with the remainder local anesthesia ± sedation. Fifty-four (98%) had procedural local-anesthetic blocks. Twenty-six patients (47%) were prescribed opioids with a median of five pills. Forty-seven patients (85%) reported the use of nonopioid analgesics. Forty-six patients (84%) reported excellent to very good pain control. About 220 opioid pills were prescribed, and 122 were reported to be used. One patient (2%) received an opioid refill. CONCLUSIONS: Satisfactory pain control after anorectal surgery can be achieved with multimodality therapy with little to no opioid use for most patients.

The Headache Pipeline: Excitement and Uncertainty.

There are many new treatment options available for migraine and more are coming. Three calcitonin gene-related peptide (CGRP) antagonist monoclonal antibodies have been approved and a 4th is due in early 2020. Small molecule CGRP receptor-blocking oral compounds, both for acute care and prevention, are also coming. Four neurostimulators are available, with others on the way. New acute treatments coming soon include the 5HT1F agonist lasmiditan, a zolmitriptan intradermal micro-needle patch, and a nasal mist sumatriptan with a permeability enhancer. Farther out, three novel dihydroergotamine delivery systems, and a liquid-filled capsule of celecoxib show early promise. A new, safer form of methysergide is in the works, as is a longer-duration onabotulinumtoxinA. As always with new products, questions regarding safety, tolerability, cost, and insurance coverage will need to be addressed. Despite these concerns and uncertainties, a robust headache treatment pipeline is good for patients who are not satisfied with the results of their treatment and/or cannot tolerate existing treatments.

The Effect of Intravenous Acetaminophen on Patient Outcomes within a Large Integrated Delivery Network.

OBJECTIVE: To evaluate the impact of intravenous acetaminophen on patient outcomes. METHODS: In this retrospective observational analysis, 54,742 patients were identified from 19 Catholic Health Initiatives hospitals during a 12-month period. Charges were used to identify patients who received intravenous acetaminophen during their encounter. The control group included patients who did not receive intravenous acetaminophen. Five outcomes were measured: total length of stay, intensive care unit (ICU) length of stay, total narcotic use (in morphine milligram equivalents [MME]), likelihood of receiving a narcotic prescription at discharge, and 30-day readmission rate. Patients undergoing five procedures were evaluated: total knee replacements, total hip replacements, cesarean section, coronary artery bypass graft (CABG), and gallbladder resection. These patients were also evaluated in a combined group. RESULTS: After matching, population imbalances for patient characteristics were addressed. Combined with the five outcomes, 25 populations had a sufficient number of matched pairs for analysis. Six of the 25 tests showed a significant difference favoring the control group. Total length of stay was shorter for the control group in the combined population (-0.18 days [4 hours], 95% confidence interval (CI) -0.26 to -0.11). Total narcotic use was lower for the control group in the caesarean section (-10 MME, 95% CI -16 to -5), CABG (-26 MME, 95% CI -41 to -12), and combined (-13 MME, 95% CI -16 to -11) populations. The control group was less likely to be discharged with a narcotic prescription for the caesarean section (odds ratio (OR) -1.39, 95% CI -1.00 to -1.92) and combined (OR -1.14, 95% CI -1.04 to -1.24) populations. CONCLUSIONS: Intravenous acetaminophen was not associated with improvement in the following patient outcomes: total length of stay, ICU length of stay, total narcotic use, likelihood of receiving a discharge narcotic prescription, and 30-day readmission rate. Based on these findings, clinicians may reconsider the routine use of intravenous acetaminophen.

The Effectiveness of Topical Cannabidiol Oil in Symptomatic Relief of Peripheral Neuropathy of the Lower Extremities.

BACKGROUND: Peripheral neuropathy can significantly impact the quality of life for those who are affected, as therapies from the current treatment algorithm often fail to deliver adequate symptom relief. There has, however, been an increasing body of evidence for the use of cannabinoids in the treatment of chronic, noncancer pain. The efficacy of a topically delivered cannabidiol (CBD) oil in the management of neuropathic pain was examined in this four-week, randomized and placebocontrolled trial. METHODS: In total, 29 patients with symptomatic peripheral neuropathy were recruited and enrolled. 15 patients were randomized to the CBD group with the treatment product containing 250 mg CBD/3 fl. oz, and 14 patients were randomized to the placebo group. After four weeks, the placebo group was allowed to crossover into the treatment group. The Neuropathic Pain Scale (NPS) was administered biweekly to assess the mean change from baseline to the end of the treatment period. RESULTS: The study population included 62.1% males and 37.9% females with a mean age of 68 years. There was a statistically significant reduction in intense pain, sharp pain, cold and itchy sensations in the CBD group when compared to the placebo group. No adverse events were reported in this study. CONCLUSION: Our findings demonstrate that the transdermal application of CBD oil can achieve significant improvement in pain and other disturbing sensations in patients with peripheral neuropathy. The treatment product was well tolerated and may provide a more effective alternative compared to other current therapies in the treatment of peripheral neuropathy.

Effects of adding dexmedetomidine to local infiltration of bupivacaine on postoperative pain in pediatric herniorrhaphy: a randomized clinical trial.

BACKGROUND: Postoperative pain is a major problem, especially in children, as their tolerance level is lower and several drugs are contraindicated in childhood. This study aimed to compare the effect of dexmedetomidine added to local infiltration of bupivacaine for postoperative pain relief in children undergoing inguinal herniorrhaphy. METHODS: This double-blind, randomized clinical trial included 60 children aged 6-72 months undergoing unilateral herniorrhaphy at selected hospitals in Shiraz, Iran, randomly allocated into two groups, 30 in each group. One group received 1 µg/kg dexmedetomidine plus local infiltration of 0.2 ml/kg bupivacaine 0.5% at the incision site before surgery (BD), and the other group received bupivacaine and normal saline (BO). Analgesic requirements, emergence time, and nausea/vomiting, postoperative pain and sedation scores were assessed for 4 h after the operation. Heart rate (HR), systolic blood pressure (SBP), and oxygen saturation (SaO2) were recorded at baseline, and at 10 and 20 min after injection. RESULTS: Eighty percent were boy in each group; mean age was 22.75 ± 18.63 months. SaO2 and SBP were not different between the groups, while HR was significantly lower in the BD group at 10 and 20 min after injection (P <0.05). BD group had a lower pain score at 1 and 2 h after the operation, a higher sedation score at the first three time intervals, and longer emergence time than BO group (all P <0.001). BD group had a lower pain score at 1 and 2 h after the operation (P < 0.001, P < 0.047 respectively). CONCLUSIONS: Addition of dexmedetomidine to local infiltration of bupivacaine in children undergoing herniorrhaphy significantly reduced postoperative pain and increased sedation.

In vivo effect of Kaempferia parviflora extract on pharmacokinetics of acetaminophen.

Kaempferia parviflora is widely used as a food supplement and a herbal medicine for vitalization. Previous study has shown that K. parviflora had CYP2E1 inducer activity. It is likely to affect the metabolism of CYP2E1 substrates such as acetaminophen which is a common household pain relief medicine. This study investigated the possible pharmacokinetic interaction between K. parviflora and acetaminophen in rats. Acetaminophen (100 mg/kg, p.o) was administered to rats for nine consecutive days. On days 4-9, K. parviflora extract (250 mg/kg, p.o) was given to the acetaminophen-treated rats. After co-administration with K. parviflora, the concentrations of acetaminophen during day 5-8 markedly decreased compared with acetaminophen-only group. At day 9, the pharmacokinetic parameters of acetaminophen in the presence of K. parviflora extract also decreased, including area under the concentration-time curve (from 1.68 ± 0.16 to 0.34 ± 0.04 mg.min/mL), the maximum concentration (from 19.10 ± 1.90 to 4.48 ± 0.56 µg/mL), and half-life (from 21.29 ± 1.36 to 10.81 ± 1.24 min). In addition, clearance and the elimination rate constant of acetaminophen were significantly increased (from 0.003 ± 0.000 to 0.006 ± 0.001 L/min and 0.03 ± 0.00 to 0.07 ± 0.01 min-1, respectively) in the presence of K. parviflora extract. These findings provide the data for in vivo herb-drug interaction between K. parviflora extract and acetaminophen. Therefore, the concomitant use of K. parviflora as a food supplement and acetaminophen should occasion therapeutic and safety concerns.

Enhancing Outpatient Dihydroergotamine Infusion With Interdisciplinary Care to Treat Refractory Pediatric Migraine: Preliminary Outcomes From the Comprehensive Aggressive Migraine Protocol ("CAMP").

OBJECTIVE: To determine preliminary outcomes of a treatment for refractory pediatric migraine that integrates outpatient dihydroergotamine (DHE) infusion with interdisciplinary adjunctive care. BACKGROUND: Limited data are available to inform treatment of refractory migraine in children. Intravenous DHE therapy has shown promise but has been implemented in costly inpatient settings and in isolation of nonpharmacological strategies shown to enhance analgesia and functional improvement. METHODS: We conducted a retrospective chart review of 36 patients ages 11-18 with refractory migraine who underwent a pilot treatment program in an outpatient neurology clinic. The treatment integrated up to 5 days of outpatient DHE infusion with adjunctive nonpharmacological care (pain coping skills training, massage, aromatherapy, and school reintegration support). Changes in headache, healthcare utilization, and functional limitations were assessed as indicators of treatment response through 3-month follow-up. RESULTS: On average, headache intensity declined (M = 5.8 ± 2.5 to M = 2.4 ± 2.7; P < .0001) during the treatment period and remained statistically significantly improved through 3-month follow-up. Headache frequency decreased by a mean of 1.5 days per week (M = 6.7 ± 1.0 vs M = 5.2 ± 2.7, P = .012) through 3-month follow-up, with a 27% reduction (from 0.91 to 0.66) in the proportion of patients reporting a continuous headache (P = .009). Over this same follow-up period, there was a reduction in school days missed per month (median [25th, 75th percentile]: 4.5 [0, 21.0] vs 0 [0.0, 0.5]). There also were reductions in headache-related visits per month to the emergency department and medical providers. Adverse effects were common but typically minor and transient. CONCLUSIONS: Combining outpatient DHE infusion with interdisciplinary adjunctive care has promise as an effective treatment option for adolescents with refractory migraine.

Behavioral Pharmacology of Novel Kappa Opioid Receptor Antagonists in Rats.

BACKGROUND: New treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical kappa opioid receptor antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particularly in tests to establish safety. This study was designed to test dose- and time-course effects of novel kappa opioid receptor antagonists with the goal of identifying short-acting lead compounds for future medication development. METHODS: We screened 2 novel, highly selective kappa opioid receptor antagonists (CYM-52220 and CYM-52288) with oral efficacy in the warm water tail flick assay in rats to determine initial dose and time course effects. For comparison, we tested existing kappa opioid receptor antagonists JDTic and LY-2456302 (also known as CERC-501 or JNJ-67953964). RESULTS: In the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 < CYM-52288 < CYM-52220 << JDTic. Furthermore, LY-2456302 blocked the depressive (anhedonia-producing) effects of the kappa opioid receptor agonist U50,488 in the intracranial self-stimulation paradigm, albeit at a higher dose than that needed for analgesic blockade in the tail flick assay. CONCLUSIONS: These results suggest that structurally diverse kappa opioid receptor antagonists can have short-acting effects and that LY-2456302 reduces anhedonia as measured in the intracranial self-stimulation test.

The intraoperative use of non-opioid adjuvant analgesic agents: a survey of anaesthetists in Australia and New Zealand.

BACKGROUND: Opioids have long been the mainstay of drugs used for intra-operative analgesia. Due to their well-known short and long term side effects, the use of non-opioid analgesics has often been encouraged to decrease the dose of opioid required and minimise these side effects. The trends in using non-opioid adjuvants among Australian Anaesthetists have not been examined before. This study has attempted to determine the use of non-opioid analgesics as part of an opioid sparing practice among anaesthetists across Australia and New Zealand. METHODS: A survey was distributed to 985 anaesthetists in Australia and New Zealand. The questions focused on frequency of use of different adjuvants and any reasons for not using individual agents. The agents surveyed were paracetamol, dexamethasone, non-steroidal anti-inflammatory agents (NSAIDs), tramadol, ketamine, anticonvulsants, intravenous lidocaine, systemic alpha 2 agonists, magnesium sulphate, and beta blockers. Descriptive statistics were used and data are expressed as a percentage of response for each drug. RESULTS: The response rate was 33.4%. Paracetamol was the most frequently used; with 72% of the respondents describing frequent usage (defined as usage above 70% of the time); followed by parecoxib (42% reported frequent usage) and dexamethasone (35% reported frequent usage). Other adjuvants were used much less commonly, with anaesthetists reporting their frequent usage at less than 10%. The majority of respondents suggested that they would never consider dexmedetomidine, magnesium, esmolol, pregabalin or gabapentin. Perceived disincentives for the use of analgesic adjuvants varied. The main concerns were side effects, lack of evidence for benefit, and anaesthetists' experience. The latter two were the major factors for magnesium, dexmedetomidine and esmolol. CONCLUSION: The uptake of tramadol, lidocaine and magnesium amongst respondents from anaesthetists in Australia and New Zealand was poor. Gabapentin, pregabalin, dexmedetomidine and esmolol use was relatively rare. Most anaesthetists need substantial evidence before introducing a non-opioid adjuvant into their routine practice. Future trials should focus on assessing the opioid sparing benefits and relative risk of using individual non-opioid adjuvants in the perioperative period for specific procedures and patient populations.

Pharmacokinetic Analysis and Biomarker-Assisted Safety Assessment of Acetaminophen in Combination With Ojeok-san Compared With Acetaminophen Alone.

Acetaminophen and Ojeok-san are both frequently used analgesics. In this study, we evaluated acetaminophen pharmacokinetics (PK) and changes in microRNA-122 (miR-122) levels after multiple dosing of acetaminophen with or without Ojeok-san. An open-label, 1-sequence, 2-period, 2-treatment crossover study was conducted in 18 subjects. In period 1, 500 mg of acetaminophen was administered 3 times on day 1 and once on day 2. In period 2, after the administration of 14.47 g of Ojeok-san twice on day 2 and 3 times daily on days 3 to 7, Ojeok-san and acetaminophen were coadministered 3 times each on day 8 and once each on day 9. The geometric mean ratios (90% confidence intervals) of acetaminophen with Ojeok-san to acetaminophen alone were 0.98 (0.87 to 1.10) and 1.02 (0.98 to 1.05) for the maximum plasma concentration (Cmax ) and the area under the plasma concentration-time curve during the dosing interval (AUC0-τ ), respectively, of acetaminophen at steady state. The alanine aminotransferase (ALT) levels were within the reference range in all the participants throughout the study period, although the mean fold changes in both serum miR-122 and ALT levels from baseline tended to increase on days 2 to 5. In conclusion, the PK properties of acetaminophen were not significantly affected by Ojeok-san coadministration. For osteoarthritis patients taking acetaminophen with or without Ojeok-san, monitoring potential liver toxicity using miR-122 as a biomarker may be useful.

Effect of eryngo (Eryngium caucasicum Trautv) on primary dysmenorrhea: A randomized, double-blind, placebo-controlled study.

OBJECTIVE: This study strove to investigate the safety and effectiveness of Eryngo in the treatment of primary dysmenorrhea. MATERIALS AND METHODS: The researchers conducted a blinded, randomized, trial design on 169 women, 15-30 years of age, who had been diagnosed with primary dysmenorrhea at Babol University of Medical Sciences. Subjects were randomly assigned to receive 5 ml syrup of Eryngo, placebo, or Ibuprofen (200 mg) three times a day (15 ml/day), from one day prior to the onset of bleeding for five days. The degree of dysmenorrhea was reported by two measures; Visual analogue scale (VAS), as a primary outcome, and the assessment of dysmenorrhea severity (VMS), as a secondary outcome at 4 menstrual cycles: at pretreatment phase, at the first menstrual cycle, at the second menstrual cycle, and the third menstrual cycle without drug. RESULTS: The reduced peak-pain differed by the treatment length in women treated for two menstrual cycles: 4.2 (1.0) cm in the Eryngo group, 4.3 (0.0) cm in the Ibuprofen group, and 0.9 (0.1) cm in the placebo group (P < 0.0001). No serious side effects were reported in all groups under study. According to the results, minor side effects did not increase in the Eryngo group when compared with the placebo group. CONCLUSION: Eryngo relieved dysmenorrhea as effectively as Ibuprofen did. Thus, Eryngo could be regarded as a new herbal remedy for the treatment of dysmenorrhea. However, in order to prescribe Eryngo as herbal remedy, rigorous research studies are required to establish its efficacy by investigating its chemical, pharmacologic, and therapeutic properties.

Pain therapy for the elderly patient: is opioid-free an option?

PURPOSE OF REVIEW: Chronic noncancer pain is an increasing problem in elderly because of rising life expectancy together with an increase of potentially painful medical conditions. Concomitantly, adequate treatment of elderly is often limited by coexisting diseases and polypharmacy.This review summarizes the most important specifics presented by elderly patients and discusses the pharmacological and nonpharmacological options of pain management. RECENT FINDINGS: A comprehensive pain assessment is a prerequisite for effective pain management. However, this can be a major challenge in patients who are unable to communicate adequately, that is, in patients with dementia. A recently developed electronic tool assessing automated facial expression and clinical behavioral indicators may help to solve this problem. The discussion about benefits and harms of opioids in elderly goes on. Although some authors underline the lack of efficacy together with the potential problems, such as, abuse, others report a beneficial effect in terms of pain relief, functional activities and disability. In addition, opioids have become an important treatment option in patients with restless legs syndrome. Various topical treatment options (i.e. capsaicin patch) and nonpharmacological interventions have been proven to be beneficial in elderly. SUMMARY: Adequate pain management of elderly patients constitutes numerous pharmacological options including nonopioids, opioids, coanalgesics and topical agents. Due to age-related characteristics, all systemic analgesics have to be given very cautiously ('start low, go slow'). Whenever possible, treatment should be performed as a multimodal approach based on the biopsychosocial model of chronic pain.

Coadyuvantes farmacológicos con efecto ahorrador de opioides en el periodo perioperatorio / Farmacologic adyuvants with saving effect of opioids in the perioperative period

En los últimos 15 años, el interés en las vías de recuperación y rehabilitación postoperatorias (ERAS) ha aumentado, ya que los tiempos de recuperación quirúrgica y las estadísticas intrahospitalarias han sido analizados tanto por médicos como por gestores. Aunque el enfoque para reducir la duración de la estancia hospitalaria es multifactorial e incluye objetivos de manejo para varios parámetros como la hemodinámica, administración de fluidos, ventilación, alimentación, motilidad intestinal y movilidad precoz, el manejo del dolor postoperatorio debe ser un área de enfoque fundamental. Los opioides son ampliamente conocidos por tener un perfil de efectos secundarios que ralentiza la recuperación hospitalaria, retrasando tanto el alta hospitalaria como el retorno a la normalidad funcional. Estos efectos secundarios incluyen la disminución de la motilidad intestinal, íleo, náuseas y vómitos postoperatorios, sedación y delirio. Además, se ha sugerido una asociación entre la administración de opioides y la recurrencia del cáncer en la población de oncología quirúrgica, específicamente cáncer de mama y próstata. Los anestesiólogos están bien posicionados para influir en el éxito de los protocolos ERAS para el control adecuado del dolor, teniendo muchas herramientas a su disposición para proporcionar preservación de opioides o incluso libres de ellos durante el periodo perioperatorio. Esta revisión resume la evidencia disponible sobre las terapias farmacológicas para conseguir un ahorro de opioides perioperatorios, exceptuando los antinflamatorios que tienen un efecto demostrado en este campo, y respalda el uso de dexmedetomidina, clonidina, ketamina, pregabalina, lidocaína, magnesio y esmolol como adyuvantes no-opioides dentro de programas multimodales para el tratamiento del dolor postoperatorio. A pesar de ello, se necesitan ensayos adicionales para dilucidar las combinaciones óptimas de estos adyuvantes

In the last 15 years, the interest in the postoperative recovery and rehabilitation pathways (ERAS) has increased since both doctors and managers have analyzed the times of surgical recovery and intrahospital statistics. Although the approach to reduce the length of hospital stay is multifactorial and includes management objectives for various parameters such as hemodynamics, fluid administration, ventilation, feeding, intestinal motility and early mobility, the management of postoperative pain should be an area of basic importance. Opioids are widely known to have a side effect profile that slows down hospital recovery, delaying both hospital discharge and return to functional normalcy. These side effects include decreased bowel motility, ileus, postoperative nausea and vomiting, sedation and delirium. In addition, an association has been suggested between the administration of opioids and the recurrence of cancer in the surgical oncology population, specifically breast and prostate cancer. Anesthesiologists are well positioned to influence the success of ERAS protocols for adequate pain control, having many tools at their disposal to provide opioid preservation or even free of them during the perioperative period. This review summarizes the available evidence on pharmacological therapies to achieve a saving of perioperative opioids, except anti-inflammatories that have a proven effect in this field, and supports the use of dexmedetomidine, clonidine, ketamine, pregabalin, lidocaine, magnesium and esmolol as non opioid adjuvants as agents within multimodal programs for the treatment of postoperative pain Despite this, additional tests are needed to elucidate the optimal combinations of these adjuvants

A pilot study of neuromuscular electrical stimulation for neuropathic pain caused by spinal cord injury.

This pilot study retrospectively investigated the feasible effect and safety of neuromuscular electrical stimulation (NMES) for the management of neuropathic pain (NPP) caused by spinal cord injury (SCI).A total of 54 patient cases with NPP after SCI were included. Of these, 27 cases underwent carbamazepine plus NMES treatment, and were assigned to an NMES group; while the other 27 cases received carbamazepine only, and were assigned to a control group. The primary outcome of pain intensity was measured by numerical rating scale (NRS). The secondary outcome of quality of life was measured by the Short Form 36 (SF-36) Scale. Furthermore, adverse events were also documented in this study. All outcomes were measured and analyzed before and after 3-month treatment.After 3-month treatment, the cases in the NMES group neither reduced the pain intensity of NPP, measured by the NRS (P > .05), nor improved the quality of life, measured by the SF-36 (P > .05), compared with cases in the control group. Moreover, both groups had similar adverse events.The results of this study showed that NMES might be not efficacious for NPP caused by SCI after 3 months treatment with quite low intervention dose.

Dexmedetomidine as an Additive to Local Anesthesia: A Step to Development in Dentistry.

PURPOSE: The study aimed to compare the effect of dexmedetomidine added to lidocaine against epinephrine added to lidocaine on local anesthetic potency and to look for future prospects of dexmedetomidine as an additive to local anesthesia in dentistry. MATERIALS AND METHODS: The study included 25 healthy volunteers in whom extraction of all first premolars was scheduled as part of their orthodontic treatment plan. In this split-mouth, double-blind, crossover, randomized controlled trial, patients were randomized into 2 groups: Group 1 received injection lidocaine plus dexmedetomidine, and group 2 was administered lidocaine plus epinephrine. Patients were assessed for the onset of action of anesthesia, duration of analgesia, pain perception, and vital signs. RESULTS: The mean values (±standard deviations) for the onset of anesthetic action in groups 1 and 2 were 113 ± 24.9 and 141 ± 34.8 seconds, respectively, for the mandible. For the maxilla, the mean values were 113 ± 24.9 seconds for group 1 and 165 ± 43.8 seconds for group 2. The duration of anesthesia was longer in group 1 (lidocaine plus dexmedetomidine), in which the requirement for the first analgesic on request was seen after a longer time interval, when compared with group 2 (lidocaine plus epinephrine). Pain perception elicited statistically significant results with less perception of pain in group 1 (lidocaine plus dexmedetomidine). The vital parameters remained stable, and the results were not statistically significant. CONCLUSIONS: In this study, we observed that the addition of dexmedetomidine to lidocaine for maxillary and mandibular nerve blocks significantly prolonged the block duration and shortened the onset of action, as well as improved postoperative analgesia in terms of the need for fewer analgesics in the postoperative period. Furthermore, the vital parameters remained stable and no complications were encountered. The findings were supportive of the use of dexmedetomidine as an adjunct to local anesthetics in dental procedures.