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Dental Traumatology : Official... Aug 2023Surgical procedures and post-traumatic management of dental patients require effective pain management during treatment, but being considerably more invasive than... (Review)
Review
Surgical procedures and post-traumatic management of dental patients require effective pain management during treatment, but being considerably more invasive than conservative treatments, pain management is required into the postoperative period. Clinical trials on pain intensity following dental surgical procedures (e.g., 3rd molar extraction, implant placement, periodontal, and endodontic surgery) have shown that pain is most intense approximately 5-6 h after completion of the procedure, reaching its peak levels during the first postoperative day. Greatest consumption of analgesics occurs during the first 48-72 h after 3rd molar extraction. For the management of perioperative pain associated with either conservative or surgical dental treatment, the local anesthetics articaine, lidocaine, mepivacaine, and prilocaine are preferred. These drugs, with a vasoconstrictor, provide a rapid onset and a duration of pulpal anesthesia adequate to complete most dental and surgical procedures painlessly. For management of post-traumatic and postsurgical pain, bupivacaine-administered by an appropriate nerve block-near the conclusion of a surgical procedure, can provide the patient with a pain-free period of up to 12 h. Nonsteroidal anti-inflammatory drugs represent the most effective drugs for the management of dental postsurgical pain. NSAIDs, as a group in therapeutic doses, have numbers needed to treat (NNTs) ranging from 2 to 3, while opioid analgesics do not approach those for NSAIDs. A protocol for management of pain following surgical procedures and traumatic injuries is discussed in this paper and includes preemptive NSAID; perioperative pain management; postoperative pain management-local anesthesia; postoperative pain management-analgesics; postoperative telephone call.
Topics: Humans; Pain Management; Anesthetics, Local; Pain, Postoperative; Analgesics; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 36961318
DOI: 10.1111/edt.12840 -
Journal of Plastic, Reconstructive &... Dec 2023Local anesthetics (LAs) are routinely administered in plastic and reconstructive surgery, e.g., as tumescent anesthesia adjunct in liposuction. Historically, these...
INTRODUCTION
Local anesthetics (LAs) are routinely administered in plastic and reconstructive surgery, e.g., as tumescent anesthesia adjunct in liposuction. Historically, these substances were assumed to act cytotoxically. Thus, the application of LA was avoided when handling adipose stem cells (ASCs). We recently determined that most LAs are not cytotoxic when ASCs are exposed to concentrations used for tumescent liposuction. However, there is limited information when combining LA with epinephrine and about the effects of prilocaine on ASCs.
METHODS
We analyzed the effects of prilocaine or lidocaine in co-exposure with epinephrine on the viability of primary human ASCs, i.e., proliferation, metabolic activity, and cytotoxicity, using crystal violet-staining, PrestoBlue®-, and WST-1 assay. We quantified the impact of short-term incubation of lidocaine and epinephrine on the differentiation of ASCs into the adipogenic, chondrogenic, and osteogenic lineage.
RESULTS
After 2 h, prilocaine (10 mM) significantly reduced metabolic activity and cell numbers, whereas lidocaine only inhibited metabolic activity. After 6 h, prilocaine (10 mM) and lidocaine significantly decreased metabolic activity as well as cell numbers. The application of high concentrations of epinephrine did not affect cell numbers but diminished metabolic activity. Combining lidocaine with epinephrine had no additional cytotoxic effect. Differentiation into the chondrogenic lineage was significantly inhibited by epinephrine.
CONCLUSIONS
Deducing from our data, neither lidocaine combined with epinephrine nor prilocaine has a cytotoxic impact on ASCs in vitro at concentrations equivalent to those in tumescent anesthesia and has no long-lasting effect on the differentiation capacity of ASCs into the osteogenic and adipogenic lineage.
Topics: Humans; Lidocaine; Prilocaine; Anesthetics, Local; Epinephrine; Anesthesia, Local; Cell Differentiation; Stem Cells
PubMed: 37939646
DOI: 10.1016/j.bjps.2023.10.104 -
Atherosclerosis Nov 2023To understand pathophysiological mechanisms underlying migraine as a cardiovascular risk factor, we studied neuropeptide action and endothelial function as measures of...
BACKGROUND AND AIMS
To understand pathophysiological mechanisms underlying migraine as a cardiovascular risk factor, we studied neuropeptide action and endothelial function as measures of peripheral microvascular function in middle-aged women with or without migraine.
METHODS
We included women with the endocrine disorder polycystic ovary syndrome (PCOS), a population with supposed elevated cardiovascular risk, with and without comorbid migraine. In 26 women without and 23 women with migraine in the interictal phase (mean age 50.8 ± 2.9 years) local thermal hyperemia (LTH) of the skin of the volar forearm was measured cross-sectionally under control conditions, after inhibition of neuropeptide release by 5% lidocaine/prilocaine (EMLA) cream application, and after inhibition of nitric oxide formation by iontophoresis of NG-monomethyl-l-arginine (L-NMMA). Hereafter, changes in the natural logarithm of the reactive hyperemia index (lnRHI) and augmentation index (AI) during reperfusion after occlusion-derived ischemia were measured.
RESULTS
While mean values under control conditions and L-NMMA conditions were similar, migraine patients had a significantly higher mean area of the curve (AUC) of the total LTH response after EMLA application than those without (86.7 ± 26.5% versus 67.9 ± 24.2%; p = 0.014). This was also reflected by a higher median AUC of the plateau phase under similar conditions in women with migraine compared to those without (83.2% (IQR[73.2-109.5]) versus 73.2% (IQR[54.3-92.0]); p = 0.039). Mean changes in lnRHI and AI scores were similar in both groups.
CONCLUSIONS
In PCOS patients with migraine, neuropeptide action was lower compared with those without migraine. While larger studies are warranted, these findings provide a potential mechanism supporting previous findings that migraine may be independent from traditional risk factors, including atherosclerosis.
Topics: Middle Aged; Humans; Female; omega-N-Methylarginine; Polycystic Ovary Syndrome; Vasodilation; Risk Factors; Migraine Disorders
PubMed: 37400308
DOI: 10.1016/j.atherosclerosis.2023.06.078 -
Clinical Drug Investigation Jul 2023PSD502 is a metered-dose spray for premature ejaculation. The two trials aimed to evaluate the safety and pharmacokinetics of PSD502 in healthy Chinese male and female... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
PSD502 is a metered-dose spray for premature ejaculation. The two trials aimed to evaluate the safety and pharmacokinetics of PSD502 in healthy Chinese male and female individuals.
METHODS
Two phase I, randomized, double-blind, placebo-controlled trials were conducted in men (Trial 1) and women (Trial 2). The participants were randomized 3:1 to receive PSD502 (7.5 mg of lidocaine and 2.5 mg of prilocaine per spray) or a placebo. For male individuals, a single dose (three sprays) once daily was applied to the glans penis for 21 days except for nine sprays (three doses) on days 7 and 14, 4 h apart for each dose. For female individuals, two sprays were applied to the vagina and one to the cervix once daily for 7 days. The primary endpoint was safety. Pharmacokinetics analysis was also performed.
RESULTS
Twenty-four male and 24 female individuals were recruited. Treatment-emergent adverse events occurred in 38.9% (7/18) of male individuals and 66.7% (12/18) of female individuals in the PSD502 group, respectively. Both trials reported 50.0% (3/6) treatment-emergent adverse events for the placebo. No grade ≥ 3 treatment-emergent adverse events, serious adverse events, or treatment-emergent adverse events leading to early withdrawal or discontinuation occurred. After consecutive applications, lidocaine and prilocaine cleared rapidly in both trials. Plasma concentrations exhibited high inter-individual variability. The maximum plasma concentrations of active ingredients were far below the anticipated minimum toxic concentrations. The area under the plasma concentration-time curve of metabolites were ≤ 20% of the parent drugs. No clinically significant accumulations were observed in the two trials.
CONCLUSIONS
PSD502 was well tolerated and showed low plasma concentrations in healthy Chinese male and female individuals.
Topics: Female; Humans; Male; Double-Blind Method; East Asian People; Healthy Volunteers; Lidocaine; Lidocaine, Prilocaine Drug Combination; Prilocaine; Premature Ejaculation; Administration, Topical; Penis; Vagina; Cervix Uteri
PubMed: 37380910
DOI: 10.1007/s40261-023-01277-4 -
The Cochrane Database of Systematic... Sep 2023Lumbar puncture (LP) is a common invasive procedure, most frequently performed to diagnose infection. Physicians perform LP in newborn infants with the help of an... (Review)
Review
BACKGROUND
Lumbar puncture (LP) is a common invasive procedure, most frequently performed to diagnose infection. Physicians perform LP in newborn infants with the help of an assistant using a strict aseptic technique; it is important to monitor the infant during all the steps of the procedure. Without adequate analgesia, LP can cause considerable pain and discomfort. As newborns have increased sensitivity to pain, it is crucial to adequately manage the procedural pain of LP in this population.
OBJECTIVES
To assess the benefits and harms, including pain, discomfort, and success rate, of any pharmacological intervention during lumbar puncture in newborn infants, compared to placebo, no intervention, non-pharmacological interventions, or other pharmacological interventions.
SEARCH METHODS
We searched CENTRAL, PubMed, Embase, and three trial registries in December 2022. We also screened the reference lists of included studies and related systematic reviews for studies not identified by the database searches.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) and quasi-RCTs comparing drugs used for pain management, sedation, or both, during LP. We considered the following drugs suitable for inclusion. • Topical anesthetics (e.g. eutectic mixture of local anesthetics [EMLA], lidocaine) • Opioids (e.g. morphine, fentanyl) • Alpha-2 agonists (e.g. clonidine, dexmedetomidine) • N-Methyl-D-aspartate (NMDA) receptor antagonists (e.g. ketamine) • Other analgesics (e.g. paracetamol) • Sedatives (e.g. benzodiazepines such as midazolam) DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used the fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) or standardized mean difference (SMD) for continuous data, with their 95% confidence intervals (CIs). Our main outcomes were successful LP on first attempt, total number of LP attempts, episodes of bradycardia, pain assessed with validated scales, episodes of desaturation, number of episodes of apnea, and number of infants with one or more episodes of apnea. We used the GRADE approach to evaluate the certainty of the evidence.
MAIN RESULTS
We included three studies (two RCTs and one quasi-RCT) that enrolled 206 newborns. One study included only term infants. All studies assessed topical treatment versus placebo or no intervention. The topical anesthetics were lidocaine 4%, lidocaine 1%, and EMLA. We identified no completed studies on opioids, non-steroidal anti-inflammatory drugs, alpha-2 agonists, NMDA receptor antagonists, other analgesics, sedatives, or head-to-head comparisons (drug A versus drug B). Based on very low-certainty evidence from one quasi-RCT of 100 LPs in 76 infants, we are unsure if topical anesthetics (lidocaine), compared to no anesthesia, has an effect on the following outcomes. • Successful LP on first attempt (first-attempts success in 48% of LPs in the lidocaine group and 42% of LPs in the control group) • Number of attempts per LP (mean 1.9 attempts, [standard error of the mean 0.2] in the lidocaine group, and mean 2.1 attempts [standard error of the mean 2.1] in the control group) • Episodes of bradycardia (0% of LPs in the lidocaine group and 4% of LPs in the control group) • Episodes of desaturation (0% of LPs in the lidocaine group and 8% of LPs in the control group) • Occurrence of apnea (RR 3.24, 95% CI 0.14 to 77.79; risk difference [RD] 0.02, 95% CI -0.03 to 0.08). Topical anesthetics compared to placebo may reduce pain assessed with the Neonatal Facial Coding System (NFCS) score (SMD -1.00 standard deviation (SD), 95% CI -1.47 to -0.53; I² = 98%; 2 RCTs, 112 infants; low-certainty evidence). No studies in this comparison reported total number of episodes of apnea. We identified three ongoing studies, which will assess the effects of EMLA, lidocaine, and fentanyl. Three studies are awaiting classification.
AUTHORS' CONCLUSIONS
The evidence is very uncertain about the effect of topical anesthetics (lidocaine) compared to no anesthesia on successful lumbar puncture on first attempt, the number of attempts per lumbar puncture, episodes of bradycardia, episodes of desaturation, and occurrence of apnea. Compared to placebo, topical anesthetics (lidocaine or EMLA) may reduce pain assessed with the NFCS score. One ongoing study will assess the effects of systemic treatment.
Topics: Humans; Infant, Newborn; Analgesics; Anesthetics, Local; Apnea; Bradycardia; Fentanyl; Hypnotics and Sedatives; Lidocaine; Lidocaine, Prilocaine Drug Combination; Pain; Spinal Puncture
PubMed: 37767875
DOI: 10.1002/14651858.CD015594.pub2 -
Journal of Anesthesia, Analgesia and... Oct 2023Spinal anesthesia is considered safe and reliable for most surgical procedures involving the lower part of the body, but its use in the ambulatory setting requires drugs...
Spinal anesthesia is considered safe and reliable for most surgical procedures involving the lower part of the body, but its use in the ambulatory setting requires drugs with rapid onset and regression of the motor and sensory block-like prilocaine.The purpose of this study is to retrospectively analyze data from 3291 procedures recorded in our institutional database, to better define the safety profile of spinal prilocaine and the incidence of complications and side effects.All clinical data, prospectively collected from 2011 to 2019 in an Italian tertiary hospital, of patients treated with spinal anesthesia performed with 40 mg of hyperbaric 2% prilocaine, according to our internal protocol of day surgery, were analyzed.Surgical procedures included saphenectomy (28.5%, n = 937), knee arthroscopy (26.8%, n = 882), proctologic surgery (15.16%, n = 499), and inguinal canal surgery (14.9%, n = 491).Anesthesia-related complication was represented by urinary retention (1.09%, n = 36), lipotimia (0.75%, n = 25), and postoperative nausea (0.33%, n = 11); arrhythmic events were uncommon (0.18%, n = 6). One case of persistent hypotension and 2 cases of persistent hypertension were reported.Persistent motor or sensory block (lasting more than 5 h) was experienced by 7 patients. One patient (0.03%), who underwent knee arthroscopy, experienced pelvic pain lasting for 6 h, compatible with a transient neurological symptom.Proctologic surgery was a factor associated with unplanned admission due to anesthesia-related complications (OR = 4.9; 95% CI: 2-14%).The number of complications related to the method was low as well as the need for hospitalization. This drug is valid and safe for the most performed day surgery procedures; however, further trials are needed to investigate the incidence of complications in the days following the procedure.
PubMed: 37864260
DOI: 10.1186/s44158-023-00122-6 -
BMC Pharmacology & Toxicology Oct 2023EMLA cream is a local anesthetic. The pharmacokinetics and dermal effects of a topical anesthetic formulation has not been evaluated in healthy Chinese volunteers.
BACKGROUND
EMLA cream is a local anesthetic. The pharmacokinetics and dermal effects of a topical anesthetic formulation has not been evaluated in healthy Chinese volunteers.
MATERIALS AND METHODS
The Pharmacokinetics of the lidocaine/prilocaine test (T) or reference (R, EMLA) cream were evaluated in a fasting, single-dose, two-period crossover bioequivalent study conducted in 40 healthy Chinese volunteers. Meanwhile, the dermal effects including blanching, erythema, temperature sensation, edema, and skin rash were also evaluated during the study.
RESULTS
After applied 15 g of the cream for 4 h to a 100 cm area under plastic occlusive film on the skin of the thigh of healthy volunteers, the results of the pharmacokinetic study showed that the active components absorbed in skin from topical products was relatively low compared with most system absorption drugs. After the removal of the residual anesthetic cream, there was a vascular biphasic response with initial transient blanching which reaches a peak at 4.5 h and later more persisting period erythema. The change of temperature sensory sensitivity reached the peak value at 4.5-6 h.There was no statistically significant difference of the changes after application the lidocaine/prilocaine T or R cream in subjects. In general, the lidocaine/prilocaine T or R cream was well tolerated.
CONCLUSION
The method described a model for investigations of pharmacokinetics and pharmacodynamics of topical lidocaine/prilocaine cream. Except the plasma drug level indicator, these pharmacodynamics data should also be evaluated in the anesthetic transdermal pharmacokinetics study.
CLINICAL TRIAL REGISTRATION
CTR20211544; registered in http://www.chinadrugtrials.org.cn/ at September 2021.
Topics: Humans; Lidocaine, Prilocaine Drug Combination; East Asian People; Healthy Volunteers; Drug Combinations; Anesthetics, Local; Prilocaine; Lidocaine; Erythema
PubMed: 37828535
DOI: 10.1186/s40360-023-00690-x -
Regional Anesthesia and Pain Medicine Oct 2023The addition of adjuvants to short-acting local anesthetics (LA) is common practice in clinical routine to speed up block onset and decrease pain on injection. In a...
INTRODUCTION
The addition of adjuvants to short-acting local anesthetics (LA) is common practice in clinical routine to speed up block onset and decrease pain on injection. In a previous study, we observed the development of microscopic crystal precipitations after bupivacaine or ropivacaine were mixed with adjuvants; this follow-up study is intended to clarify whether crystallization (A) also occurs in short-acting or intermediate-acting LA-adjuvant mixtures, (B) changes over time, and (C) is associated with the solutions' pH.
METHODS
Lidocaine 2%, prilocaine 2%, mepivacaine 2%, procaine 2% and chloroprocaine 2% were individually mixed with clonidine, dexamethasone, dexmedetomidine, epinephrine, fentanyl, morphine or sodium bicarbonate 8.4% in clinically established ratios. For each mixture, we measured initial pH and recorded crystallization patterns at 0, 15, 30 and 60 min using a standardized, semiquantitative light microscopy approach.
RESULTS
Lidocaine 2% and mepivacaine 2% plus sodium bicarbonate 8.4%, and mepivacaine 2% plus dexamethasone developed delayed grade 5 crystallization over 1 hour. Prilocaine-based, procaine-based and chloroprocaine-based mixtures showed much less pronounced crystallization, with a maximum of grade 2. Initial pH and grade of crystallization showed weak monotonic relationships at time points t, t and t (ρ=-0.17, 0.31 and 0.32, (all p>0.05)) and a moderate relationship time point t (ρ=0.57 (p=0.0003)) CONCLUSIONS: Our study revealed high grades of crystallization in lidocaine/mepivacaine-bicarbonate and mepivacaine-dexamethasone mixtures, although these were previously considered safe for local, perineural or neuraxial use. Our findings cast particular doubt on the safety of preparing these formulations for later use.
Topics: Humans; Anesthetics, Local; Mepivacaine; Sodium Bicarbonate; Crystallization; Follow-Up Studies; Microscopy; Procaine; Bupivacaine; Lidocaine; Prilocaine; Dexamethasone
PubMed: 36928300
DOI: 10.1136/rapm-2023-104398 -
European Journal of Pharmaceutical... Jun 2024Using accurate, sensitive, reproducible and efficient in vivo cutaneous pharmacokinetics (PK)-based bioequivalence (BE) approaches can promote the development of topical...
Cutaneous Pharmacokinetics-Based Bioequivalence: A Clinical Dermal Open Flow Microperfusion Verification Study Using Lidocaine and Prilocaine Combination Topical Products.
BACKGROUND
Using accurate, sensitive, reproducible and efficient in vivo cutaneous pharmacokinetics (PK)-based bioequivalence (BE) approaches can promote the development of topical generic products. A clinical dermal open flow microperfusion (dOFM) study has previously demonstrated the BE of topical drug products containing a hydrophilic drug. However, the utility of dOFM to evaluate the topical BE of drug products containing moderately lipophilic drugs, more representative of most topical drugs, has not yet been established.
OBJECTIVE
To evaluate the ability of a clinical dOFM study to assess BE of topical products containing two moderately lipophilic drugs that have only minor differences in chemical and physical properties.
METHODS
The study included 20 healthy subjects. Four application sites on each thigh were treated with fixed dose lidocaine/prilocaine combination products, and dermal drug concentrations were monitored with two dOFM probes per application site for 12 hours. A reference cream was compared to itself and to an approved generic cream (both serving as positive controls for BE), and to a gel (negative control). BE was established based on AUC and C using the scaled-average-BE approach. Systemic exposure of both drugs was assessed throughout the study.
RESULTS
BE was successfully demonstrated for the positive controls, and not for the negative control, for both drugs. The systemic exposure of both drugs was negligible.
CONCLUSIONS
dOFM accurately demonstrated BE between bioequivalent topical creams, sensitively discriminated between different formulations and differentiated the cutaneous PK of both study drugs, even though they differ only slightly in chemical and physical properties. These results support the utility of dOFM as a cutaneous PK BE approach for topical lipophilic drugs, including lidocaine and prilocaine.
PubMed: 38857708
DOI: 10.1016/j.ejps.2024.106827