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      Drug Design, Development and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the design and development of drugs, as well as the clinical outcomes, patient safety, and programs targeted at the effective and safe use of medicines. Sign up for email alerts here.

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      Topical anesthetic analgesic therapy using the combination of ropivacaine and dexmedetomidine: hyaluronic acid modified long-acting nanostructured lipid carriers containing a skin penetration enhancer

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          Abstract

          Purpose

          Hyaluronic acid-poly(ethylene glycol)-distearoyl phosphoethanolamine (HA-PEG-DSPE) modified and tocopheryl polyethylene glycol 1000 succinate (TPGS) contained nanostructured lipid carriers (NLCs) were prepared loading ropivacaine and dexmedetomidine to improve the topical anesthetic analgesic anesthesia efficiency.

          Methods

          NLCs were prepared by the solvent diffusion method. The average particle size, zeta potential, release behavior, and cytotoxicity of the NLCs were tested. Ex vivo skin permeation was studied using a Franz diffusion cell mounted with depilated rat skin. Local anesthesia antinociceptive efficiency was evaluated by rat tail flick latency study in vivo.

          Results

          NLCs have sizes of about 100 nm, with negative zeta potentials. All the NLCs formulations were found to be significantly less cytotoxic than free drugs at equivalent concentrations. The cumulative amount of drugs penetrated through rat skin from NLCs was 2.0–4.7 folds higher than that of the drugs solution. The in vivo anesthesia antinociception study displayed that NLCs showed stronger and longer anesthesia antinociceptive effect when compared with single drugs loaded NLCs and drugs solution even at a lower dosage of drugs.

          Conclusion

          The results demonstrated that the HA modified, TPGS contained, dual drugs loaded NLCs could perform a synergistic effect and may reduce the amount of drugs, which can lower the toxicity of the system and at the meanwhile, increase the anesthesia antinociceptive efficiency.

          Most cited references47

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          Effectiveness of acute postoperative pain management: I. Evidence from published data.

          Elliot Bland, Timothy Cashman, Lev S Dolin (2002)
          This review examines the evidence from published data concerning the incidence of moderate-severe and of severe pain after major surgery, with three analgesic techniques; intramuscular (i.m.) analgesia, patient controlled analgesia (PCA), and epidural analgesia. A MEDLINE search of the literature was conducted for publications concerned with the management of postoperative pain. Over 800 original papers and reviews were identified. Of these 212 papers fulfilled the inclusion criteria but only 165 provided usable data on pain intensity and pain relief. Pooled data on pain scores obtained from these studies, which represent the experience of a total of nearly 20,000 patients, form the basis of this review. Different pain measurement tools provided comparable data. When considering a mixture of three analgesic techniques, the overall mean (95% CI) incidence of moderate-severe pain and of severe pain was 29.7 (26.4-33.0)% and 10.9 (8.4-13.4)%, respectively. The overall mean (95% CI) incidence of poor pain relief and of fair-to-poor pain relief was 3.5 (2.4-4.6)% and 19.4 (16.4-22.3)%, respectively. For i.m. analgesia the incidence of moderate-severe pain was 67.2 (58.1-76.2)% and that of severe pain was 29.1 (18.8-39.4)%. For PCA, the incidence of moderate-severe pain was 35.8 (31.4-40.2)% and that of severe pain was 10.4 (8.0-12.8)%. For epidural analgesia the incidence of moderate-severe pain was 20.9 (17.8-24.0)% and that of severe pain was 7.8 (6.1-9.5)%. The incidence of premature catheter dislodgement was 5.7 (4.0-7.4)%. Over the period 1973-1999 there has been a highly significant (P < 0.0001) reduction in the incidence of moderate-severe pain of 1.9 (1.1-2.7)% per year. These results suggest that the UK Audit Commission (1997) proposed standards of care might be unachievable using current analgesic techniques. The data may be useful in setting standards of care for Acute Pain Services.
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            Perineural administration of dexmedetomidine in combination with bupivacaine enhances sensory and motor blockade in sciatic nerve block without inducing neurotoxicity in rat.

            Mary A Norat, M M Palmisano, John M Palmisano … (2008)
            The current study was designed to test the hypothesis that high-dose dexmedetomidine added to local anesthetic would increase the duration of sensory and motor blockade in a rat model of sciatic nerve blockade without causing nerve damage. Thirty-one adult Sprague-Dawley rats received bilateral sciatic nerve blocks with either 0.2 ml bupivacaine, 0.5%, and 0.5% bupivacaine plus 0.005% dexmedetomidine in the contralateral extremity, or 0.2 ml dexmedetomidine, 0.005%, and normal saline in the contralateral extremity. Sensory and motor function were assessed by a blinded investigator every 30 min until the return of normal sensory and motor function. Sciatic nerves were harvested at either 24 h or 14 days after injection and analyzed for perineural inflammation and nerve damage. High-dose dexmedetomidine added to bupivacaine significantly enhanced the duration of sensory and motor blockade. Dexmedetomidine alone did not cause significant motor or sensory block. All of the nerves analyzed had normal axons and myelin at 24 h and 14 days. Bupivacaine plus dexmedetomidine showed less perineural inflammation at 24 h than the bupivacaine group when compared with the saline control. The finding that high-dose dexmedetomidine can safely improve the duration of bupivacaine-induced antinociception after sciatic nerve blockade in rats is an essential first step encouraging future studies in humans. The dose of dexmedetomidine used in this study may exceed the sedative safety threshold in humans and could cause prolonged motor blockade; therefore, future work with clinically relevant doses is necessary.
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              Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current.

              William Janda, Francesco Amodeo, Mun Hong … (2011)
              The current study was designed to test the hypothesis that the increased duration of analgesia caused by adding dexmedetomidine to local anesthetic results from blockade of the hyperpolarization-activated cation (I(h)) current. In this randomized, blinded, controlled study, the analgesic effects of peripheral nerve blocks using 0.5% ropivacaine alone or 0.5% ropivacaine plus dexmedetomidine (34 μM or 6 μg/kg) were assessed with or without the pretreatment of α(1)- and α(2)-adrenoceptor antagonists (prazosin and idazoxan, respectively) and antagonists and agonists of the I(h) current (ZD 7288 and forskolin, respectively). Sciatic nerve blocks were performed, and analgesia was measured by paw withdrawal latency to a thermal stimulus every 30 min for 300 min postblock. The analgesic effect of dexmedetomidine added to ropivacaine was not reversed by either prazosin or idazoxan. There were no additive or attenuated effects from the pretreatment with ZD 7288 (I(h) current blocker) compared with dexmedetomidine added to ropivacaine. When forskolin was administered as a pretreatment to ropivacaine plus dexmedetomidine, there were statistically significant reductions in duration of analgesia at time points 90-180 min (P < 0.0001 for each individual comparison). The duration of blockade for the forskolin (768 μM) followed by ropivacaine plus dexmedetomidine group mirrored the pattern of the ropivacaine alone group, thereby implying a reversal effect. Dexmedetomidine added to ropivacaine caused approximately a 75% increase in the duration of analgesia, which was reversed by pretreatment with an I(h) current enhancer. The analgesic effect of dexmedetomidine was not reversed by an α(2)-adrenoceptor antagonist.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Drug Des Devel Ther
                Journal ID (iso-abbrev): Drug Des Devel Ther
                Journal ID (publisher-id): DDDT
                Journal ID (pmc): dddt
                Title: Drug Design, Development and Therapy
                Publisher: Dove
                ISSN (Electronic): 1177-8881
                Publication date (Electronic): 18 September 2019
                Publication date Collection: 2019
                Volume: 13
                Pages: 3307-3319
                Affiliations
                [1 ]Department of Anesthesiology, Jinan Central Hospital Affiliated to Shandong University , Ji’nan, Shandong Province 250013, People’s Republic of China
                Author notes
                Correspondence: Lei Chao Department of Anesthesiology, Jinan Central Hospital Affiliated to Shandong University , No. 105 Jiefang Road, Ji’nan, Shandong Province250013, People’s Republic of ChinaTel +86 05 318 569 5114Email leichaojncp@outlook.com
                Article
                Publisher ID: 211443
                DOI: 10.2147/DDDT.S211443
                PMC ID: 6755955
                SO-VID: 617b5432-2218-41ae-bbab-c112e87eaacc
                Copyright statement: © 2019 Yang et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 08 April 2019
                Date accepted : 19 August 2019
                Page count
                Figures: 6, Tables: 3, References: 52, Pages: 13
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: topical anesthetic analgesic,skin penetration,hyaluronic acid,long-acting nanostructured lipid carriers,tocopheryl polyethylene glycol 1000 succinate
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: topical anesthetic analgesic, skin penetration, hyaluronic acid, long-acting nanostructured lipid carriers, tocopheryl polyethylene glycol 1000 succinate

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