By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

The FDA has approved an analgesic combination of celecoxib, a selective cyclooxygenase-2 inhibitor, and tramadol, an opioid analgesic. The formulation is a co-crystal containing 1:1 molecular ratio of tramadol and celecoxib (CTC). It is distributed as Seglentis.

INDICATIONS

CTC can be prescribed to adults to help them manage acute pain that is severe enough to require an opioid analgesic.1 It should be reserved for patients for whom non-opioid analgesics have not or are not expected to provide adequate analgesia, or for patients who have not tolerated or are not expected to tolerate alternative non-opioid treatments.1 Prescribers should consider prescribing naloxone based on the patient’s risk for overdose.

DOSAGE

Each CTC tablet contains 56 mg of celecoxib as well as 44 mg of tramadol. The recommended initial dose is two tablets every 12 hours as needed for pain relief.1 CTC should be used for the shortest duration possible and prescribers should consider the patient’s pain severity; response; prior analgesic treatment experience; and risk factors for addiction, abuse, and misuse.1 Patients should be monitored for respiratory depression for the first 24-72 hours of treatment.

POTENTIAL ADVANTAGES

This is a first-in-class active pharmaceutical ingredient of co-crystal of tramadol and celecoxib.2 Pharmacologists took compounds with differing physiochemical properties and modified the intrinsic dissolution rate (IDR) profiles of each to provide a coordinated, more synchronized release vs. independent administration of each (separately or in a fixed dose combination). This could produce better pharmacodynamics and, ultimately, bimodal clinical benefit.

POTENTIAL DISADVANTAGES

The co-crystals carry the same warning for tramadol and other opioid analgesics (i.e., addiction, abuse, and misuse). Tramadol can lead to drug-drug interactions involving CYP3A4 and CYP2D6 and could produce serotonin syndrome and seizures. The warning label for celecoxib includes cardiovascular and gastrointestinal risk. The most frequently reported adverse reactions with CTC were nausea (30.1%), vomiting (15.8%), dizziness (16.9%), and headache (11.5%).1 Both individual components are available in generic form at similar dosages. CTC is classified as a Schedule IV controlled substance and requires a Risk Evaluation and Mitigation Strategy.

COMMENTS

The safety and efficacy of CTC was evaluated in a randomized, double-blind, double-dummy, parallel study in subjects with acute postoperative pain following unilateral first metatarsal osteotomy with internal fixation.1 Subjects (n = 637) were randomized at a ratio of 2:2:2:1 to CTC two tablets every 12 hours, tramadol 50 mg every six hours, celecoxib 100 mg every 12 hours, or placebo. Subjects reported a mean baseline pain intensity of 6.7 on a 11-point (0-10) Numeric Pain Rating Scale. The primary efficacy endpoint was the timed weighted summed pain intensity difference over 48 hours (SPID48). The CTC group recorded statistically better mean SPID48 scores than any other groups after bunionectomy.1

CLINICAL IMPLICATIONS

CTC is a novel co-crystal product that synchronizes a bimodal approach of an NSAID and an opioid analgesic. A multimodal approach to pain management generally is recommended, with a goal of reducing opioid use.3 Fixed-dose combinations limit the ability to use the lowest effective opioid dose, with ongoing reassessment of risks and benefits. Tramadol carries risks of addiction, abuse, and misuse. Furthermore, in a matched cohort study (n = 88,902), tramadol was associated with a higher rate of all-cause mortality within one year of initiation among individuals ≥ age 50 years with osteoarthritis vs. celecoxib, diclofenac, naproxen, and a rate similar to codeine (hazard ratios ranged from 1.70 to 1.88 vs. other NSAIDs).4 Although CTC is novel in its bimodal approach for pain that requires an opioid analgesic, wide use in practice may be limited. Launch is planned for early 2022, and pricing is unavailable.

REFERENCES

  1. Kowa Pharmaceuticals America, Inc. Seglentis prescribing information. October 2021.
  2. Gascon N, Almansa C, Merlos M, et al. Co-crystal of tramadol-celecoxib: Preclinical and clinical evaluation of a novel analgesic. Expert Opin Investig Drugs 2019;28:399-409.
  3. Mariano ER, Dickerson DM, Szokol JW, et al. A multisociety organizational consensus process to define guiding principles for acute perioperative pain management. Reg Anesth Pain Med 2021; Sep 22:rapm-2021-103083. doi: 10.1136/rapm-2021-103083. [Online ahead of print].
  4. Zeng C, Dubreuil M, LaRochelle MR, et al. Association of tramadol with all-cause mortality among patients with osteoarthritis. JAMA 2019;321:969-982.