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      Sustained analgesic effect of clonidine co-polymer depot in a porcine incisional pain model

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          Abstract

          Background

          Previous research suggests that the α 2 adrenergic agonist clonidine, a centrally acting analgesic and antihypertensive, may also have direct effects on peripheral pain generators. However, aqueous injections are limited by rapid systemic absorption leading to off target effects and a brief analgesic duration of action.

          Purpose

          The aim of this study was to examine the efficacy of a sustained-release clonidine depot, placed in the wound bed, in a pig incisional pain model.

          Methods

          The depot was a 15 mm ×5 mm ×0.3 mm poly(lactide-co-caprolactone) polymer film containing 3% (w/w) clonidine HCl (MDT3). Fifty-two young adult mix Landrace pigs (9–11 kg) were divided into seven groups. All subjects received a 6 cm, full-thickness, linear incision into the left lateral flank. Group 1 served as a Sham control group (Sham, n=8). Group 2 received three placebo strips (PBO, n=8), placed end-to-end in the subcutaneous wound bed before wound closure. Group 3 received one MDT3 and two PBO (n=8), Group 4 received two MDT3 and one PBO (n=8), and Group 5 received three MDT3 (n=8). Positive control groups received peri-incisional injections of bupivacaine solution (Group 6, 30 mg/day bupivacaine, n=8) or clonidine solution (Group 7, 225 µg/day, n=4).

          Results

          The surgical procedure was associated with significant peri-incisional tactile allodynia. There was a dose-dependent effect of MDT3 in partially reversing the peri-incisional tactile allodynia, with maximum pain relief relative to Sham at 72 hours. Daily injections of bupivacaine (30 mg), but not clonidine (up to 225 µg), completely reversed allodynia within 48 hours. There was a statistically significant correlation between the dose of MDT3 and cumulative withdrawal threshold from 4 hours through the conclusion of the study on day 7.

          Conclusion

          These data suggest that a sustained-release clonidine depot may be a viable nonopioid, nonamide anesthetic therapy for the treatment of acute postsurgical nociceptive sensitization.

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          Most cited references 25

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          The prevalence of postoperative pain in a sample of 1490 surgical inpatients.

          To measure the prevalence of postoperative pain, an assessment was made of 1490 surgical inpatients who were receiving postoperative pain treatment according to an acute pain protocol. Measurements of pain (scores from 0 to 100 on a visual analogue scale) were obtained three times a day on the day before surgery and on days 0-4 postoperatively; mean pain intensity scores were calculated. Patients were classified as having no pain (score 0-5), mild pain (score 6-40), moderate pain (score 41-74) or severe pain (score 75-100). Moderate or severe pain was reported by 41% of the patients on day 0, 30% on days 1 and 19%, 16% and 14% on days 2, 3 and 4. The prevalence of moderate or severe pain in the abdominal surgery group was high on postoperative days 0-1 (30-55%). A high prevalence of moderate or severe pain was found during the whole of days 1-4 in the extremity surgery group (20-71%) and in the back/spinal surgery group (30-64%). We conclude that despite an acute pain protocol, postoperative pain treatment was unsatisfactory, especially after intermediate and major surgical procedures on an extremity or on the spine.
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            Effects of local anesthetics on articular cartilage.

            Recent basic science studies have demonstrated local anesthetic chondrotoxicity in vivo and in vitro in both human and animal cartilage. Clinically, chondrolysis associated with the use of intra-articular local anesthetic pain pumps has been described by several groups. This has raised concern regarding the clinical use of intra-articular local anesthetics. The authors undertook a review of the current orthopaedic literature on local anesthetic chondrotoxicity and its potential relationship to clinical chondrolysis. Local anesthetics such as bupivacaine, lidocaine, and ropivacaine are chondotroxic to human articular cartilage in vitro, although ropivacaine is less so. The evidence suggests that there is a greater risk for chondrolysis with a longer exposure to a higher concentration of local anesthetic, such as with a pain pump, than with a single injection. However, late cellular and metabolic changes are seen after even a single injection of bupivacaine in animal models, and the loss of an intact cartilage matrix also leads to more extensive chondrocyte death. Some studies suggest that additives and the pH of the local anesthetic solution may also play a role in chondrotoxicity. Intra-articular local anesthetics should be used with caution, especially continuous infusions of bupivacaine and lidocaine at high concentrations in joints with compromised cartilage. The consequences of a single intra-articular injection of local anesthetic remains unclear and requires further investigation. Intra-articular use of local anesthetics may have lasting detrimental effects on human articular cartilage and chondrocytes, although the clinical relationship between local anesthetic exposure and chondrolysis requires further study.
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              A phase 3, randomized, placebo-controlled trial of DepoFoam® bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy.

              DepoFoam® bupivacaine (Pacira Pharmaceuticals, Inc., San Diego, CA, USA), an extended-release liposomal bupivacaine-based analgesic, was compared with placebo for the prevention of pain after bunionectomy in a randomized, multicenter, double-blind phase 3 clinical study. Patients received placebo (n = 96) or DepoFoam bupivacaine 120 mg (n = 97) via wound infiltration prior to closure. Pain intensity was assessed using a numeric rating scale (NRS) from time 0 through to 72 hours postsurgically. The primary efficacy measure was area under the curve (AUC) of NRS scores through 24 hours. Other efficacy measures included AUC of NRS at other time points, proportion of patients who were pain-free, time to first opioid use, and total postsurgical consumption of supplemental opioid medication. Adverse events were also assessed. The AUC for NRS scores was significantly less in patients treated with DepoFoam bupivacaine versus patients receiving placebo at 24 hours (P = 0.0005) and 36 hours (P < 0.0229). More patients treated with DepoFoam bupivacaine avoided use of opioid rescue medication during the first 24 hours (7.2% vs. 1%; P < 0.0404) and were pain-free (NRS ≤ 1) at 2, 4, 8, and 48 hours. Median time-to-first-opioid use was delayed in favor of DepoFoam bupivacaine (4.3 vs. 7.2 hours; P < 0.0001). Fewer adverse events were reported by patients treated with DepoFoam bupivacaine (59.8%) versus placebo (67.7%). DepoFoam bupivacaine, a long-acting local analgesic, provided extended pain relief and decreased opioid use after bunionectomy, compared with placebo.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2018
                09 April 2018
                : 11
                : 693-701
                Affiliations
                Medtronic Spine Division, Memphis, TN, USA
                Author notes
                Correspondence: Jared T Wilsey, Medtronic Spinal and Biologics Division, 2600 Sofamor Danek Drive, Memphis, TN 38132, USA, Tel +1 901 399 2630, Fax +1 901 399 2560, Email jared.t.wilsey@ 123456medtronic.com
                Article
                jpr-11-693
                10.2147/JPR.S157018
                5898591
                © 2018 Wilsey and Block. 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.

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                Original Research

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