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      IV Tramadol – A New Treatment Option for Management of Post-Operative Pain in the US: An Open-Label, Single-Arm, Safety Trial Including Various Types of Surgery

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          Abstract

          Purpose

          There is a need to reduce exposure to Schedule II opioids in the United States (US) due to the ongoing opioid epidemic. Schedule II opioids have higher potential for abuse and misuse than Schedule IV opioids. This Phase 3, multicenter, single-arm, open-label, multiple-dose US trial evaluated the safety and tolerability of intravenous tramadol 50 mg, a Schedule IV opioid, in the management of postoperative pain in a real-world setting, where intravenous tramadol is not yet approved for use.

          Patients and Methods

          Patients undergoing a range of soft-tissue and orthopedic surgeries were enrolled. Intravenous tramadol 50 mg was given at hours 0, 2, 4, and every 4 h thereafter through up to 7 days of treatment. Non-opioid medications per treating physicians’ discretion were allowed if additional pain relief was needed. Endpoints included treatment-emergent adverse events (TEAEs), laboratories, vital signs, electrocardiograms (ECGs), and patient global assessment (PGA) of effectiveness.

          Results

          A total of 251 patients were enrolled, with 4% discontinuing due to TEAE; no patient discontinued due to a lack of efficacy. Patients averaged 13 doses, resulting in average 48 h of exposure. Intravenous tramadol was well tolerated, with TEAEs consistent with known tramadol pharmacology. No unexpected findings were observed, with 95% of patients reporting study medication was good, very good, or excellent for controlling pain.

          Conclusion

          Outcomes from this real world use study demonstrated intravenous tramadol 50 mg was safe and well tolerated in the management of postoperative pain where intravenous conventional opioids are often used. Intravenous tramadol alone or coadministered with non-opioid medication (when needed) as a multimodal combination analgesia approach resulted in high patient satisfaction with their pain relief. In light of the US opioid epidemic, reducing the exposure to conventional opioids in these patients via use of IV tramadol may be possible.

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          Most cited references 5

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          Clinical Pharmacology of Tramadol

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            A Systematic Review of Laboratory Evidence for the Abuse Potential of Tramadol in Humans

            Background: Tramadol is an opioid-analgesic that has shown epidemiological evidence of abuse. This review evaluates the evidence for tramadol abuse potential in humans. Methods: A systematic literature search for human abuse liability examinations of tramadol was conducted in September 2018 and yielded 13 total studies. Studies were all within-subject, double-blind, placebo-controlled human laboratory comparisons of tramadol to opioid comparators. Results are organized based upon the route of tramadol administration (oral, parenteral) and the participant population (persons with and without current opioid physical dependence). Outcomes were categorized into self-report ratings of positive and negative effects, observer-ratings of effects, time course of effects, likelihood tramadol was identified as an opioid, and tramadol self-administration. Results: Results indicated the relative abuse potential of tramadol was lower than the opioids to which it was compared. Tramadol produced highest positive effect ratings when administered orally to persons with no opioid physical dependence. Relative to other opioids, it produced substantial negative ratings, generally demonstrated a slower onset of effects, and was less likely to be identified by participants as an opioid, though it did produce a higher rate of self-administration relative to other opioids in the one study reporting that outcome. Results suggest that the abuse potential of tramadol is highest when it is administered orally to non-dependent individuals, and that it likely decreases as the dose increased and when it was administered parentally or to persons with opioid physical dependence. Conclusion: Taken together, individuals may be less likely than with other opioids to escalate tramadol doses, transition from oral to parenteral routes of administration, or continue using tramadol once opioid physical dependence develops. In that way, the human abuse potential of tramadol appears to be different from and lower than other opioid analgesic medications.
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              Comparing the Pharmacokinetics of 2 Novel Intravenous Tramadol Dosing Regimens to Oral Tramadol: A Randomized 3‐Arm Crossover Study

              Abstract Tramadol is a dual‐mechanism (opiate and monoamine reuptake inhibition) analgesic. Intravenous (IV) tramadol has been widely prescribed outside the United States. However, there have not been studies comparing the pharmacokinetics (PK) of IV dosing regimens to that of oral tramadol. In this phase 1, open‐label, single investigational center, 3‐treatment, 3‐period, multidose crossover study, we compared 2 novel IV dosing regimens (IV tramadol 75 mg and IV tramadol 50 mg) to oral tramadol 100 mg given every 6 hours (the highest approved oral dosage in the United States) Compared to the oral regimen, IV tramadol 50 mg administered at hours 0, 2, and 4 and every 4 hours thereafter reached initial tramadol peak serum concentration (Cmax) more rapidly, while resulting in similar overall steady‐state Cmax and area under the plasma concentration–time curve. IV tramadol 75 mg administered at hours 0, 3, and 6 and every 6 hours thereafter had higher Cmax and greater fluctuation in peak to trough tramadol concentration. The primary metabolite M1 (a potent μ agonist) had lower area under the plasma concentration–time curve and Cmax for both IV regimens than for the oral regimen. IV tramadol at both doses was well tolerated, with adverse event profiles consistent with the known pharmacological effects of tramadol. IV tramadol 50 mg is now in phase 3 development in patients with postsurgical pain.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                JPR
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                22 May 2020
                2020
                : 13
                : 1155-1162
                Affiliations
                [1 ]Clinical Research, HD Research , Bellaire, TX, USA
                [2 ]Clinical Operations, Avenue Therapeutics , New York, NY, USA
                [3 ]Clinical Research, Lotus Clinical Research , Pasadena, CA, USA
                Author notes
                Correspondence: Lucy Lu Email llu@avenuetx.com
                Article
                251175
                10.2147/JPR.S251175
                7250287
                32547178
                © 2020 Minkowitz et al.

                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).

                Page count
                Figures: 1, Tables: 4, References: 11, Pages: 8
                Categories
                Clinical Trial Report

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