A Valuable Addition to the Armamentarium for Certain Types of Acute Pain Management

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, 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, antidepressants, and even 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 56-mg and tramadol hydrochloride 44-mg) 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 acute pain in appropriate patients. SEGLENTIS provides effective multimodal pain relief via four complementary analgesic mechanisms; celecoxib is believed to inhibit COX-2 thereby mediating analgesia by inhibition of prostaglandin synthesis while tramadol is believed to act as a partial μ-opioid receptor agonist and a weak inhibitor of serotonin and norepinephrine reuptake. The recommended daily dose of SEGLENTIS is 2-100 mg (56 mg celecoxib/44 mg tramadol hydrochloride) tablets twice daily which provides a unique total daily dose of 224 mg of celecoxib and 176 mg of tramadol hydrochloride and SEGLENTIS is not available in other strengths or formulations. The Centers for Disease Control and Prevention (CDC) sought to address opioid-related mortality by recommending the use of opioid agents for the shortest duration consistent with individual treatment goals, as well as by assessing the daily morphine milligram equivalents (MME) to gauge overall daily opioid exposure. The CDC has set forth recommendations cautioning prescribers of the increased risk of opioid-related deaths in patients prescribed ≥50 MME/day compared to those at <20 MME/day, while avoiding increasing dosages to ≥90 MME/day.⁸ A defined, unmet need exists for options that deliver <20 MME/day that provide adequate analgesia while minimizing risks associated with opioid use. SEGLENTIS provides less (176 mg) than half of the maximum prescribed dose of tramadol hydrochloride alone (400 mg daily) and thus its maximum MME/day is 17.6 compared with 40 MME/day for the maximum prescribed dose of tramadol hydrochloride for acute pain management.^6,7,9,10

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, (eg, 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 SEGLENTIS contains celecoxib and tramadol hydrochloride and thus contains a Boxed Warning for each medication including information on addiction, abuse, and misuse; life-threatening respiratory depression; cardiovascular thrombotic events; gastrointestinal bleeding, ulceration, and perforation; ultra-rapid metabolism of tramadol and other risk factors for life-threatening respiratory depression in children; neonatal opioid withdrawal syndrome and others. A Risk Evaluation and Mitigation Strategy (REMS) has also been implemented to provide HCP education regarding opioids and the risks associated with their use. 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. Co-crystal technology has rarely been applied to other disease states, and this application is the first in the acute pain space and offers an effective treatment modality for acute pain severe enough to require an opioid.^11,12

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 and celecoxib from SEGLENTIS compared to all other treatment groups are shown in Figure 1. The C_max and T_max of the tramadol component of SEGLENTIS were 241 ng/mL and 3.0 h, respectively, compared with tramadol hydrochloride administered alone (305 ng/mL and 2.0 h, respectively) or the co-administration with celecoxib (312 ng/mL and 1.9 h, respectively).⁶ Both single-dose and multi-dose PK studies demonstrated supportive pharmacokinetic profiles for tramadol and celecoxib across these study groups.¹³

Figure 1

Figure 1. Summary of the pharmacokinetics of tramadol and celecoxib for the four treatment groups. ⁶ Supportive pharmacokinetic profiles of tramadol and celecoxib for each treatment group were observed in an additional single dose, four way crossover, random sequence study.¹³ *Arithmetic mean (%CV). †Celecoxib has been shown to be an inhibitor of CYP2D6 in in vitro studies , ^‡Median (minimum, maximum) , ^§ n=32 , ^II n=31 , ^¶ n=28 , ^#n=27 , ^**n=21.

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 pivotal Phase 3 clinical study conducted across 6 US-based research centers using a well-established acute pain model, bunionectomy with osteotomy.^6,14 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.^15,16,17 This randomized, double-blind, parallel-group clinical trial studied 637 patients aged 18 and older with acute post-operative pain (mean baseline pain intensity was 6.7 on the numeric pain rating scale) 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 (SPID48). 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 statistically significantly better LS mean SPID48 scores in patients with moderate-to-severe postoperative pain: -139 (SEGLENTIS) vs -109 (tramadol hydrochloride, P=0.0008), -104 (celecoxib, P<0.0001) and -75 (placebo, P<0.0001) (Figure 2).^6,14

Figure 2

The overall safety profile of SEGLENTIS is similar to that of tramadol hydrochloride at the doses studied, and the adverse reactions reported by >5% of patients in any treatment group, and greater in SEGLENTIS than placebo, were nausea (30%), vomiting (16%), dizziness (17%), headache (12%), and somnolence (8%) (Figure 2).^6,14 Discontinuation due to AEs occurred in <2% of patients receiving SEGLENTIS and those receiving tramadol hydrochloride, as well as none in those receiving celecoxib or placebo. 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.^6,14

SEGLENTIS is the first co-crystal for acute pain management with unique dosing of tramadol hydrochloride and celecoxib, demonstrating statistically significantly better LS mean SPID48 scores compared to the other treatment arms after bunionectomy at the doses studied. The safety of SEGLENTIS was similar to tramadol hydrochloride at the doses studied. The complementary analgesic mechanisms that SEGLENTIS offers can provide an additional option for physicians to implement a multimodal approach to acute pain management.

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 acute pain management and risk-mitigation by employing a multimodal approach. Dr. Eugene R. Viscusi, Phase 3 trial clinical investigator and Vice Chair of Pain Management at Thomas Jefferson University said, “Now that multimodal analgesia has become the standard for acute pain treatment, we are excited that the results of this study demonstrate that SEGLENTIS is efficacious and safe in its unique co-crystal combination of tramadol hydrochloride and celecoxib. This novel multimodal form of analgesia may be an important alternative option for treating appropriate adults with certain types of acute pain.”

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 REMS which aims to provide HCP education on the risks of opioid use. 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 for acute pain by providing effective pain relief via a multimodal approach that is in line with CDC recommendations on reducing daily MMEs of opioids prescribed, and using those opioids 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.”