Postoperative pain remains a major barrier to early mobilization, respiratory function, patient satisfaction, and recovery after surgery. Historically, moderate-to-severe postoperative pain has often been managed using strong opioids, such as morphine, fentanyl, or oxycodone. Although effective, these medicines can cause dose-related nausea, vomiting, sedation, respiratory depression, ileus, pruritus, urinary retention, and delayed functional recovery. Reducing the amount of strong opioid required after surgery is therefore a central objective of enhanced-recovery pathways^[1].

Multimodal analgesia involves combining drugs or techniques that act through different mechanisms. Paracetamol provides central analgesic effects, dexketoprofen is a nonsteroidal anti-inflammatory drug (NSAID) that reduces prostaglandin-mediated nociception and inflammation, and tramadol provides weak mu-opioid receptor activity together with inhibition of serotonin and norepinephrine reuptake. This combination may permit lower requirements for potent opioids such as morphine^[2].

Importantly, tramadol is still an opioid. Therefore, a regimen containing paracetamol, tramadol, and dexketoprofen should not be labelled “opioid-free analgesia.” The appropriate claim is that it may be strong-opioid-sparing or may reduce total postoperative opioid exposure, depending on how tramadol use is counted and reported^[1].

Pharmacological Rationale

The proposed regimen combines three mechanisms:

By targeting pain through different mechanisms, this approach may achieve analgesia comparable to a strong opioid-based regimen while reducing morphine-equivalent exposure. However, its suitability depends on renal function, gastrointestinal bleeding risk, cardiovascular risk, drug interactions, seizure history, serotonergic co-medication, and the expected severity of procedure-specific pain.

Evidence for Opioid-Sparing Effects

Dexketoprofen versus placebo or opioid-only rescue analgesia

A randomized, double-blind trial in 75 patients undergoing lumbar disc surgery compared preoperative oral dexketoprofen 25 mg, paracetamol 500 mg, and placebo. All groups received postoperative morphine patient-controlled analgesia. Mean 24-hour morphine consumption was 28.1 mg with dexketoprofen, 40.6 mg with paracetamol, and 43.6 mg with placebo. Thus, dexketoprofen reduced morphine consumption by 15.5 mg, corresponding to an approximately 35.6% reduction relative to placebo, with no significant between-group differences in mean pain scores or reported adverse effects^[1].

In a separate randomized trial of 172 patients undergoing major orthopedic surgery, dexketoprofen 50 mg intramuscularly every 12 hours reduced mean cumulative 24-hour morphine use to 39 mg, compared with 64 mg in the placebo group. This represents a reduction of 25 mg or approximately 39.1%. Pain-intensity scores were also lower in active-treatment groups, while measured wound bleeding did not significantly differ among groups^[2].

A review of 32 perioperative NSAID studies found that conventional NSAIDs reduced opioid consumption in postoperative patient-controlled analgesia settings. For dexketoprofen specifically, the reported opioid-sparing range was 36%–50%. Across the included studies, lower opioid use was commonly accompanied by similar or improved pain scores and, in some studies, lower rates of opioid-related nausea, vomiting, sedation, and pruritus^[3].

Paracetamol and dexketoprofen in hysterectomy

In a randomized placebo-controlled study of 60 patients undergoing total abdominal hysterectomy, all patients received morphine patient-controlled analgesia. Total morphine volume was 72.3 ± 38.0 mL in the paracetamol group, 69.3 ± 24.1 mL in the dexketoprofen group, and 129.3 ± 22.6 mL in the placebo group. With morphine concentration set at 0.2 mg/mL, these volumes correspond approximately to 14.5 mg, 13.9 mg, and 25.9 mg of morphine, respectively. Although both non-opioid regimens reduced morphine use versus placebo, pain scores and nausea/vomiting rates were not significantly different among groups^[4].

This result illustrates an important point: an opioid-sparing effect does not always translate into a large difference in pain scores, particularly when patient-controlled rescue morphine is available to all groups. Reduced opioid consumption with maintained analgesia is nonetheless clinically meaningful because it indicates that comparable pain control was achieved with less strong opioid exposure.

Dexketoprofen with tramadol-based analgesia

In patients undergoing major abdominal surgery and receiving tramadol patient-controlled analgesia, adding intravenous dexketoprofen was associated with lower pain scores, reduced tramadol consumption, less need for supplemental rescue analgesia, and fewer side effects than tramadol alone. This supports the use of dexketoprofen as an adjunct to tramadol-based postoperative analgesia, although the identified report does not establish the efficacy of the exact paracetamol–tramadol–dexketoprofen three-drug regimen against a strong-opioid-only protocol^[5].

Summary of Quantitative Findings

The evidence indicates that dexketoprofen can reduce postoperative strong opioid requirements while maintaining acceptable pain control. The magnitude of opioid sparing reported in randomized trials—approximately 35% after lumbar disc surgery and 39% after major orthopedic surgery—is clinically relevant. The broader perioperative literature similarly suggests that dexketoprofen may reduce opioid requirements by approximately 36%–50% when incorporated into multimodal protocols[1,2,3,6,7]. Paracetamol may contribute to this strategy by providing baseline analgesia, although its independent opioid-sparing effect varies by procedure, dose, timing, and comparator. In the hysterectomy study, both paracetamol and dexketoprofen reduced morphine consumption compared with placebo, but neither produced a statistically significant improvement in pain scores. This pattern is consistent with a multimodal design in which rescue morphine equalizes pain outcomes while the adjunctive drugs reduce the amount of morphine required[4,8]. Tramadol may be useful where a weaker opioid is preferred over morphine or other potent opioids. However, the terminology used in future research should be precise. A paracetamol–tramadol–dexketoprofen regimen is not non-opioid analgesia because tramadol has opioid activity. A more accurate description is multimodal analgesia with reduced strong-opioid exposure. Current postoperative pain guidelines support acetaminophen and NSAIDs, when not contraindicated, as foundational components of postoperative analgesia to improve pain control and reduce opioid consumption[6].The regimen should still be individualized because dexketoprofen may be unsuitable in patients with renal impairment, active peptic ulcer disease, significant bleeding risk, NSAID hypersensitivity, or certain cardiovascular conditions. Tramadol should be used cautiously in individuals receiving serotonergic drugs, those with a seizure disorder, or patients at heightened risk of opioid-related respiratory adverse effects[1,3,8]. Limitations of the Evidence The principal limitation is the scarcity of direct trials comparing the exact combination of paracetamol + tramadol + dexketoprofen with a standardized strong opioid-based regimen. Existing evidence is largely indirect: studies evaluate dexketoprofen against placebo, paracetamol against dexketoprofen, or dexketoprofen added to tramadol-based patient-controlled analgesia. Future trials should use standardized outcomes, including: 1. Cumulative 24-hour and 48-hour opioid consumption in oral morphine milligram equivalents. 2. Pain scores at rest and during movement. 3. Incidence of postoperative nausea and vomiting. 4. Sedation and respiratory adverse events. 5. Time to ambulation, return of bowel function, and discharge readiness. 6. Patient satisfaction. 7. Persistent opioid use after discharge.

Paracetamol–tramadol–dexketoprofen multimodal analgesia is a rational strategy for reducing reliance on strong opioids after surgery. The strongest available evidence supports dexketoprofen as an effective opioid-sparing component: randomized trials have shown reductions in 24-hour morphine requirements of approximately 35%–39%, and broader perioperative evidence suggests opioid reductions of 36%–50% with dexketoprofen-containing regimens.

The exact three-drug regimen requires direct procedure-specific randomized comparisons with strong opioid-based analgesia. Until then, it should be described as a strong-opioid-sparing multimodal regimen, rather than opioid-free analgesia.