The combination of tramadol and celecoxib into a co-crystal of celecoxib-tramadol provides peripheral and centrally mediated analgesia.
The National Institutes of Health report that pain is the most common reason for seeking medical care.1 Data from 2012 estimate that 126.1 million adults in the United States suffer from pain,2 which may be nociceptive (from tissue damage), neuropathic (from nerve damage), or nociplastic (from a sensitized nervous system). There is also overlap in the different types of pain.3
Multimodal therapy for the treatment of pain is defined by the International Association for the Study of Pain as the simultaneous use of separate therapeutic agents with different mechanisms of action. This combination of agents is intended to address different pain mechanisms.4.5 Co-crystal formulations can be considered as a multimodal therapy.
The FDA defines co-crystals as crystalline materials composed of 2 or more different molecules in the same lattice.6 Combining tramadol and celecoxib into a co-crystal of celecoxib-tramadol (CTC) provides peripheral and centrally mediated analgesia.4
CTC (Seglentis; Kowa Pharmaceuticals America, Inc) is an FDA-cleared Schedule IV controlled substance. It is indicated for the treatment of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
The mechanism of action of tramadol is not fully understood. It is believed to be due to binding to mu-opioid receptors and weak inhibition of norepinephrine and serotonin reuptake. The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via cyclooxygenase-2 (COX-2).7
DOSAGE AND ADMINISTRATION
CTC contains celecoxib 56 mg and tramadol hydrochloride 44 mg. Start treatment with 2 tablets every 12 hours as needed for pain relief. When initiating treatment with this celecoxib-tramadol tablet formulation, consider pain severity, patient response, prior analgesic treatment, and risk factors for addiction, abuse, and abuse.
The full prescribing information recommends discussing the availability of naloxone with the patient. CTC should be used for as short a time as possible consistent with the patient’s treatment goals.7
The efficacy and safety of CTC were evaluated in a randomized, double-blind, parallel group study comparing CTC with tramadol, celecoxib and placebo for acute pain after bunionectomy with osteotomy (bone cutting procedure). The study enrolled patients ≥ 18 years of age with acute postoperative pain (rated >5 and <9 on a 0-10 Numeric Pain Rating Scale [NPRS]). Patients had a mean pain intensity at baseline of 6.7 on the NPRS.7
The primary efficacy endpoint was the time-weighted summed pain intensity difference over 48 hours (SPID48). Researchers reported that patients in the CTC group had statistically significantly better mean SPID48 scores than all other groups after bunionectomy.7
Negative differences in the score corresponded to an improvement in pain. The overall scale ranged from -480 (best) to +480 (worst). A higher negative value of SPID indicated greater pain relief (Table 1).8
Table 1. Outcome measures8
SIDE EFFECTS (AEs)
The most common adverse reactions with an incidence greater than 5% in adults taking CTC are nausea, vomiting, dizziness, headache, and somnolence. There is a boxed warning on the FDA-approved label that describes the risks of addiction, abuse, and abuse. The celecoxib-tramadol tablet is available under the Opioid Analgesic REMS (Risk Evaluation and Mitigation Strategy) program.7
The boxed warning also includes cardiovascular thrombotic events and risk factors for life-threatening respiratory depression in children. It also describes gastrointestinal bleeding, ulceration and perforation.
Cytochrome P450 interactions and risks with concomitant CNS depressants are also explained. Due to the large amount of information contained in the boxed warning, pharmacists should refer to the full prescribing information for comprehensive details.7
CTC is contraindicated in the age of <12 years and during postoperative treatment in children less than 18 years of age after tonsillectomy and/or adenoidectomy. It should not be used in CABG surgery or in individuals with acute or severe bronchial asthma.
CTC is contraindicated in gastrointestinal obstruction and with monoamine oxidase inhibitors (MAOIs) within the past 14 days. It should not be used in individuals with urticaria or other allergic reactions after taking aspirin or other non-steroidal anti-inflammatory drugs. Additional warnings include serotonin syndrome, seizure risk, suicide risk, adrenal insufficiency, renal and hepatotoxicity.7
There is a risk of fetal harm with CTC in pregnant women. Breastfeeding is not recommended. The safety and efficacy of CTC in pediatrics have not been established. Older individuals taking non-steroidal anti-inflammatory drugs have been found to be at greater risk for severe AEs, so individuals taking CTC should be monitored.7
In summary, despite the availability of multiple pharmacotherapies, many individuals
continue to suffer. Because pain can involve multiple mechanisms, combining products with different mechanisms of action, or in the form of a co-crystal formulation, may be a therapeutic option.
- Pain. National Institutes of Health. National Center for Complementary and Integrative Health. Updated June 3, 2022. Accessed June 3, 2022. https://www.nccih.nih.gov/health/pain
- Nahin R. Estimates of the prevalence and severity of pain in adults: United States, 2012. J Pain. 2015;16(8):769-780. doi:10.1016/j.jpain.2015.05.002
- Cohen S., Vase L., Hooten W. Chronic pain: an update on burden, best practices and new developments. Lancet.2021;397(10289):2082-2097. doi: 10.116/S0140-6736(21)00393-7
- Almansa C, Frampton C, Vela J, Whitelock S, Plata-Salamán C. Co-crystals as a novel approach to multimodal analgesia and the treatment of pain. J Pain Res.2019;12:2679–2689
- Raffa R, Pergolizzi J Jr., Tallarida R. Analgesic combinations. J Pain.2010;11(8):701–709. doi:10.1016/j.jpain.2009.12.010
- Regulatory Classification of Pharmaceutical Co-crystals Industry Guidelines. US Food and Drug Administration. February 2018. Accessed 3/6/2022. https://www.fda.gov/media/81824/download
- Seglentis. Prescribing information. Kowa Pharmaceuticals America, Inc.; 2021. Accessed June 1, 2022. https://www.kowapharma.com/documents/SEGLENTIS_Prescribe_Information.pdf
- Seglentis. Efficacy demonstrated in the phase 3 clinical trial. Kowa Pharmaceuticals America, Inc. May 2022. Accessed June 1, 2022. https://www.seglentis.com/clinical-data/efficacy