Acute pain, i.e., pain that has a sudden onset, limited duration, and is caused by injury, illness, or disease, is a highly prevalent condition affecting millions of people annually [1,2,3,4,5]. Patients often report acute pain of moderate-to-severe intensity, defined as a score of 4–10 on a standard 0–10 numerical rating scale (NRS; where 0 = no pain, 10 = worst possible pain) [1], following surgery, trauma, musculoskeletal injury, or illness [3, 6,7,8,9]. Patients with chronic pain can also report acute pain due to flare-ups; these are referred to as temporary, intense episodes of pain that are more severe than a patient’s usual chronic pain [10]. These flare-ups are of limited duration and can be spontaneous, due to stress or caused by activity [10]. Unfortunately, management of acute pain has been reported to be inadequate across healthcare services, such as in emergency departments [1, 6, 11,12,13,14,15], pre-hospital [1, 16], and in post-surgical settings, including after discharge [17, 18].

Poor management of acute pain can greatly impact patients’ quality of life and functioning [17,18,19,20,21]. Conversely, effective management is associated with enhanced recovery, improved rehabilitation, shortened hospital stays, and decreased costs [22]. A wide range of systemic analgesic agents are available to treat moderate-to-severe acute pain, including paracetamol, non-steroidal anti-inflammatory drugs (non-selective agents and cyclo-oxygenase [COX]-2 inhibitors), and opioids [1, 7, 23]. However, the use of many of these medications is limited by toxicities, ceiling effects, administration challenges, and the potential for misuse [7]. Among the most commonly used medications, opioid analgesics are efficacious in the treatment of acute pain of moderate-to-severe intensity [1, 23]. However, bothersome opioid-associated adverse effects such as nausea, vomiting, constipation, and somnolence are commonly reported [24,25,26,27,28] and can lead to treatment discontinuation [24, 27]. These tolerability issues, coupled with the potential for misuse and dependence, may lead to undertreatment or treatment hesitancy [1, 21, 23, 26, 29]. Consequently, there is a need for new pain therapies with improved efficacy and tolerability compared with current options. These new treatments must overcome the dose-limiting side effects and subsequent limited therapeutic window that are often seen with the use of single-agent analgesics [7, 30].

Co-crystal of tramadol-celecoxib (CTC) is the first analgesic co‐crystal that contains two active pharmaceutical ingredients (APIs), racemic tramadol hydrochloride (a weak opioid analgesic) and celecoxib (a COX-2 inhibitor), in a supramolecular crystal network at a 1:1 molecular ratio [31, 32]. It is formulated as an orally administered, 100-mg immediate-release tablet (44 mg of tramadol/56 mg of celecoxib). CTC 200 mg (2 × CTC 100 mg; 88 mg of tramadol/112 mg of celecoxib) taken orally twice daily (BID) was first approved in the USA in 2021 [33] and subsequently received European regulatory approval in Spain in September 2023 for the management of acute moderate-to-severe somatic pain in adults [34].

CTC’s multi-modal action targets multiple pain pathways (μ-opioid agonism, norepinephrine and serotonin reuptake inhibition, and COX-2 inhibition), facilitating analgesic efficacy with lower daily doses of tramadol compared with tramadol alone, potentially with an improved side-effect profile [7, 35]. Non-clinical and clinical data suggest that the co-crystallization of tramadol and celecoxib in CTC alters the physicochemical properties and dissolution profiles of both tramadol and celecoxib [31, 32, 36,37,38]. The data also show that co-crystallization alters the pharmacokinetic properties of tramadol and celecoxib when compared with either agent alone or in concomitant administration (also known as ‘free combination’). In phase 1 clinical trials, tramadol from CTC exhibited a lower maximum plasma concentration, at a later timepoint post dose, compared with when immediate-release tramadol was administered alone or in free combination with celecoxib [36,37,38]. This effect was coupled with a shorter time to reach the maximum plasma concentration of celecoxib following CTC administration compared with the free combination or celecoxib alone.

As co-crystallization of tramadol and celecoxib in CTC modifies their physicochemical properties and bioavailability [31, 32, 36,37,38], it is important to understand how the efficacy and safety profiles of CTC may differ from those of its individual components. In phase 3 trials in patients with moderate-to-severe acute pain, CTC 200 mg BID (88 mg of tramadol/112 mg of celecoxib) demonstrated greater and more rapid analgesic efficacy than 50 mg of oral immediate-release tramadol taken four times a day (QID) [35, 39]. It also showed greater efficacy than 100 mg of oral immediate-release tramadol QID [35, 39, 40, 41]. Additionally, CTC 200 mg BID reduced rescue medication use, thus permitting lower exposure to opioid-containing medications [35, 39, 40, 41].

Although reported to be common in acute pain, side effects of opioids vary by agent [1, 42, 43] and are dose dependent [28, 42, 44]. Common side effects reported with tramadol include nausea, vomiting, and dizziness [1]. In acute pain, immediate-release tramadol is typically initiated at 100 mg, followed by 50 mg to 100 mg every 4 to 6 h as needed, with a maximum daily dose of 400 mg [1, 45]. As the dosage of tramadol with CTC 200 mg is somewhat higher than the lowest available oral tramadol dose (88 vs. 50 mg, respectively [34, 45]), it is reasonable that doubts may arise regarding the tolerability of the tramadol content in CTC.

Phase 3 clinical data in patients with moderate-to-severe acute pain have shown that CTC 200 mg BID given over a 48-h treatment period is better tolerated than immediate-release tramadol 100 mg QID (with a lower prevalence of opioid-related adverse reactions) and has similar tolerability to immediate-release tramadol 50 mg QID [46]. However, it is not known how the tolerability of CTC compares to tramadol following first-dose administration, when adverse reactions and treatment discontinuations may first occur. With this in mind, we have performed a post hoc analysis of common opioid-related adverse reactions occurring following first-dose administration of CTC 200 mg (containing 88 mg of tramadol) or immediate-release tramadol 50 mg using safety data from one of the pivotal phase 3 clinical trials of CTC in patients with moderate-to-severe acute postoperative pain [39].