Pain is one of the most ubiquitous human experiences, accounting for up to 42% of all reported patient events in the United States.1 Despite pain being a shared experience among many, its causes, manifestations, and treatment may be complex and highly individual; thus, determining the optimal pain management strategy for each patient requires careful consideration, including selection of appropriate therapy and other pain management strategies. Defining Pain and the Current Treatment Paradigm To aid in the proper diagnosis of pain, 2 broad categories of pain have been defined – acute and chronic – based on the duration of the pain experienced by the patient. Acute pain can be characterized as a sudden sharp pain lasting less than 4 weeks, and chronic pain is characterized by pain which lasts more than 3 months.2,3 Acute pain etiologies include surgical procedures, or non-surgically related acute pain brought on by trauma such as a broken bone. Certain comorbidities further complicate the exact diagnosis and treatment of acute pain including diabetes and cancer. The U.S. Department of Health & Human Services (HHS) has established that several factors can contribute to pain in patients, including biological, environmental, psychological, and social factors and thus physicians should evaluate patients based on these factors to determine an optimal pain management strategy.4 The complexity of pain management strategies lies in the manifold of aforementioned factors that contribute to pain; however, the treatment landscape may also be difficult to navigate for practitioners. Acute pain is frequently treated using non-opioids such as non-steroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, and antidepressants as well as opioids, if pain is severe enough to require them, which are scheduled by the Drug Enforcement Administration (DEA) based on their medical utility and potential for abuse.5 Physicians are frequently faced with balancing effective pain management and risk-mitigation when prescribing analgesics to treat patients with acute pain, which further adds to the complexity. An Alternative Treatment Option for Appropriate Adult Patients with Acute Pain Approved by the U.S. Food and Drug Administration (FDA) in October 2021, SEGLENTIS® (celecoxib and tramadol hydrochloride) C-IV is a co-crystal formulation of two commonly prescribed analgesics, celecoxib and tramadol hydrochloride and provides physicians with an alternative option to consider for the management of certain types of acute pain. SEGLENTIS provides effective pain relief via four complementary analgesic mechanisms; celecoxib inhibits COX-2 and mediates analgesia by inhibition of prostaglandin synthesis while tramadol acts as a partial mu-opioid receptor agonist and a weak inhibitor of serotonin and norepinephrine reuptake. The recommended maximum daily dose of SEGLENTIS is 2-100 mg (56 mg celecoxib/44 mg tramadol hydrochloride) tablets twice daily which provides 224 mg of celecoxib and a total daily dose of 176 mg of tramadol hydrochloride, less than half of the maximum prescribed dose of tramadol hydrochloride alone (400 mg daily).6,7 In accordance with Centers for Disease Control and Prevention (CDC) recommendations include the use of opioid agents for the shortest duration consistent with individual treatment goals and to address opioid-related mortality, by assessing the morphine milligram equivalent (MME) per day. The MME metric is used as a gauge of the overdose potential based on the amount of an opioid agent that is being given at a particular time, and an unmet need exists for options that deliver <20 MME/day. For SEGLENTIS the maximum MME/day is 17.6 compared with 40 MME/day for the maximum prescribed dose of tramadol hydrochloride.8 SEGLENTIS is a Schedule IV controlled substance available in tablet form for oral use and is indicated for the management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate.6 Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, SEGLENTIS should be reserved for use in patients for whom alternative treatment options, (e.g., non-opioid analgesics) have not been tolerated or are not expected to be tolerated and have not provided adequate analgesia or are not expected to provide adequate analgesia.6 Please see Important Safety Information, Including Boxed Warning, below. SEGLENTIS is a unique co-crystal for acute pain consisting of two active pharmaceutical ingredients (APIs), tramadol hydrochloride, a Schedule IV opioid, and celecoxib, an NSAID. While co-crystal technology has been applied to other disease states, this application is the first in the acute pain space and offers an effective treatment modality for pain severe enough to require an opioid.9,10 The co-crystal formulation of SEGLENTIS demonstrates modified physicochemical properties of both APIs that is not achieved with the individual agents.6 Pharmacokinetics of tramadol and celecoxib were compared in a single 4-way cross-over study after single-dose oral administration of SEGLENTIS 200mg (112 mg celecoxib + 88 mg tramadol hydrochloride), or each API alone (100 mg tramadol hydrochloride or celecoxib), or concomitant administration (2 x 50 mg tramadol IR tablets + 1 x 100 mg celecoxib capsule). The rate and extent of absorption of tramadol was altered in the SEGLENTIS treatment group compared to all other treatment groups (Figure 1). Both Cmax and Tmax of the tramadol component of SEGLENTIS changed (241 ng/mL and 3.0 h, respectively) compared with tramadol hydrochloride administered alone (305 ng/mL and 2.0 h, respectively) or co-administered with celecoxib (312 ng/mL and 1.9 h, respectively).6 The differences observed for SEGLENTIS for these PK parameters are reflective of physicochemical changes on intrinsic dissolution rates and thus absorption of its components as a co-crystal formulation as compared to individual agent coadministration or each agent administered alone. Both single dose and multidose PK studies are consistent in demonstrating that the Tmax is earlier for celecoxib from SEGLENTIS as compared with individual agent co-administration or celecoxib alone, while the Cmax of celecoxib from SEGLENTIS is shown to be greater than the co-administration of each individual agent. For tramadol, the effect of the co-crystal is to delay the Tmax and reduce the Cmax for tramadol as compared with coadministration of individual agents or tramadol hydrochloride alone.11 Figure 1 The PK parameters of the M1 metabolite of tramadol from Seglentis were consistent with that observed for its tramadol component and compared with the coadministration of each individual agent and the tramadol hydrochloride-only group. The efficacy of SEGLENTIS was established in a Phase 3 clinical study conducted across 6 US-based research centers using a well-established acute pain model, bunionectomy with osteotomy. Though the surgical procedure is more typically performed in women than men, and in generally older cohorts, it remains a common surgery and an adequate acute pain model.12 This randomized, double-blind, parallel-group clinical trial studied 637 patients aged 18 and older with acute post-operative pain who were randomized at a ratio of 2:2:2:1 to SEGLENTIS 200 mg BID, tramadol hydrochloride 50 mg QID, celecoxib 100 mg BID, or placebo. The primary efficacy endpoint reported was time-weighted summed pain intensity difference over 48 hours (SPID-48). Rescue medication was allowed during the study, patients which required rescue medication had a sequential offering of IV acetaminophen, 1 g q4-6 h (not to exceed 4 g/24 h),and those patients who did not tolerate or experience sufficient analgesia were offered immediate-release oxycodone, 5 mg orally q4-6 h (not to exceed 30 mg/24 h).Patients receiving SEGLENTIS demonstrated significantly superior pain relief in patients with moderate-to-severe postoperative pain as evidenced by improved LS mean SPID48 scores: -139 (SEGLENTIS) vs -109 (tramadol hydrochloride, P=0.0008), -104 (celecoxib, P<0.0001) and -75 (placebo, P<0.0001) (Figure 2).6 The overall safety profile of SEGLENTIS is similar to that of tramadol hydrochloride, and the adverse reactions reported by >5% of patients in any treatment group, and greater in SEGLENTIS than placebo, were nausea, vomiting, dizziness, headache, somnolence, and decreased appetite (Figure 2).6 Discontinuation due to AEs occurred in <2% of patients receiving SEGLENTIS and those receiving tramadol hydrochloride. The adverse reactions that led to discontinuation of study drug were nausea (1.1%) and pruritus/rash (0.5%) in the SEGLENTIS group, and vomiting (1.1%) and supraventricular tachycardia (0.5%) in the tramadol hydrochloride group.6 SEGLENTIS is the first co-crystal for acute pain management, with demonstrated modified physicochemical properties and unique dosing, demonstrating superior analgesia compared to the other treatment arms in an established model of acute pain while retaining a similar safety profile to a similar dose of tramadol hydrochloride. The complementary analgesic mechanisms that SEGLENTIS offers can provide an additional option for physicians to implement a multimodal approach to acute pain management. Figure 2 Expanding Treatment Alternatives in the Management of Acute Pain The addition of SEGLENTIS as an alternative treatment option could potentially aid physicians in balancing effective pain management and risk-mitigation by employing a multimodal approach to pain management. Dr. Ira J. Gottlieb, SEGLENTIS clinical trial investigator and Medical Director, Chesapeake Research Group, adds, “Acute pain can be complex to treat – it is not a one size fits all approach for every patient. I believe the availability of SEGLENTIS will offer physicians an important alternative option for treating appropriate adults with acute pain that is severe enough to warrant use of an opioid and for which alternate treatments are inadequate.” Kowa’s Commitment to Responsible Opioid Use SEGLENTIS is now available for prescribing in the United States and is subject to the FDA-approved Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS). Kowa Pharmaceuticals America, Inc. is also implementing other measures to encourage safe and appropriate use of the medication. “We believe SEGLENTIS offers physicians an important alternative treatment option by providing effective pain relief via a multimodal approach that is in line with CDC recommendations on reducing MMEs of opioids prescribed, and using those opioids for the shortest duration possible at the lowest effective dose possible,” said Craig A. Sponseller, MD, Chief Medical Officer of Kowa Pharmaceuticals America, Inc. “To support the responsible commercialization of SEGLENTIS, and as part of our commitment to patients and healthcare providers, Kowa will be continuously listening to and securing feedback from physicians and patients in the community to understand how we can best support them and help shape our ongoing efforts to foster responsible use of SEGLENTIS.” REFERENCES ESTEVE, data on file. Aggregated claims data deliverable from Symphony’s APLD offering. Dowell D. Draft Updated CDC Guidelines for Prescribing Opioids: Background, Overview, and Progress. https://www.cdc.gov/injury/pdfs/bsc/BSC_Background_Overview_Progress-GL-Update_6_28_cleared_final_D_Dowell-508-fx.pdf Published July 16, 2021. Accessed January 25, 2022 DHHS Pain Management Best Practices Inter-Agency Task Report, May 2019. Accessed November 17, 2021 Manion J et al. Front Neurosci. 2019;13:1370 Congressional Research Service R45948. https://crsreports.congress.gov Accessed November 17, 2021 SEGLENTIS® (celecoxib and tramadol hydrochloride) [prescribing information]. Montgomery, AL: Kowa Pharmaceuticals America, Inc.;2021 Drug Enforcement Administration Drug & Chemical Evaluation Section-Tramadol. March 2020 https://www.deadiversion.usdoj.gov/drug_chem_info/tramadol.pdf. Accessed January 25, 2022 CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. Accessed January 25, 2022 ENTRESTO [prescribing information]. 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