Pain after biopsy or excision procedures is frequently encountered in clinical practice and may negatively affect patient comfort, recovery, and quality of life. These procedures are widely performed at RSUD Jayapura for diagnostic, therapeutic, or palliative purposes in patients with suspected malignancies or other tissue abnormalities requiring histopathological evaluation. Accurate pain assessment is essential because pain characteristics, intensity, and underlying mechanisms may differ across clinical conditions and cancer-related states. ¹ Regardless of their intent, biopsy and excision frequently result in mild to severe postoperative pain. Inadequately managed pain has been associated with increased anxiety and stress, prolonged hospital stay, poorer quality of life, and higher healthcare costs. ²

In Indonesia, including RSUD Jayapura, intravenous tramadol and metamizole represent two of the most frequently used analgesics for acute and post-procedural pain because they are listed in the National Essential Medicines List, widely available, and covered by the national health insurance system (BPJS Kesehatan). National clinical guidance emphasizes structured pain assessment and rational analgesic selection based on clinical condition and pain intensity. ³ However, analgesic selection often depends more on hospital formulary availability than on high-quality comparative evidence of their clinical effectiveness, safety, and cost-effectiveness in local patient populations. The World Health Organization (WHO) Analgesic Ladder continues to provide a widely accepted framework for selecting analgesic therapy according to pain intensity, supporting the use of non-opioid analgesics and weak opioids such as tramadol for moderate pain management. ^{3 – 5}

Tramadol is widely used for moderate acute pain because it exerts analgesic effects through weak opioid receptor activation and modulation of monoaminergic pathways. ^{5 – 7} It is effective for moderate to severe pain but may cause nausea, vomiting, dizziness, sedation, and, at high doses, an increased risk of seizures and toxicity. ^{7 , 8} Metamizole is a non-opioid analgesic commonly administered for acute pain management because of its analgesic and antipyretic effects. Its mechanism involves cyclooxygenase-3 inhibition, activation of the endocannabinoid system, and modulation of endogenous opioidergic pathways. ^{9 – 11} Previous concerns regarding agranulocytosis have limited metamizole use in several countries; however, recent evidence suggests that short-term administration is generally well tolerated. ^{10 , 12} Metamizole also has a rapid onset of action and favourable tolerability in various acute pain conditions.

Comparative studies show varied results. A previous study reported that tramadol demonstrated slightly greater pre-emptive analgesic effects than metamizole in postoperative hysterectomy patients, although the difference was not statistically significant. ¹³ Other studies indicate that combining tramadol and metamizole may reduce the need for additional opioids in major surgery, achieving analgesic effectiveness comparable to epidural analgesia. ¹⁴ However, most evidence comes from international postoperative settings involving major surgeries and may not reflect outcomes in Indonesian patients undergoing minor invasive procedures such as biopsy and excision. ¹⁵

Evidence directly comparing tramadol and metamizole in Indonesia patients undergoing minor invasive procedures remains limited, particularly in Eastern Indonesia. Clinical decision-making in such settings should also consider pharmacokinetics, safety profile, and patient comorbidities as outlined in pharmacotherapy references. ⁵ Patients in Papua frequently present with more complex clinical characteristics, including limited access to medications, higher rates of comorbidities, nutritional problems, and organ dysfunction, which may influence analgesic response and drug safety.

Given these gaps, this study aims to generate local evidence to support rational selection of analgesics that are clinically effective, safe, and cost-efficient for patients undergoing biopsy or excision at RSUD Jayapura. The findings are expected to contribute to local clinical decision-making and inform recommendations for managing post-procedural pain in diagnostic, therapeutic, and palliative settings.

The present study demonstrated that both tramadol and metamizole provided clinically meaningful pain reduction after biopsy and excision procedures. Both analgesics produced significant pain reduction over a 24-hour observation period, with mean ΔNRS of 3.20 ± 0.76 for tramadol and 3.06 ± 0.69 for metamizole (p = 0.522), indicating comparable clinical effectiveness. The Numerical Rating Scale (NRS) is widely accepted for pain measurement, and its clinical interpretation is supported by evidence defining meaningful change thresholds in pain intensity. ^{16 , 17} In the Indonesian context, NRS has also been validated for acute pain assessment in emergency settings. ¹⁸ Adjustment for procedure type using ANCOVA confirmed that the imbalance in excision versus biopsy distribution did not significantly affect outcomes, although future studies may explore how different procedure intensities impact analgesic response.

No short-term adverse reactions were identified during the 24-hour observation period, supporting the short-term safety profile of both medications. This finding is consistent with previous reports indicating that short-term metamizole administration is generally well tolerated and associated with a low incidence of serious hematological toxicity. ¹⁹ Similarly, tramadol has demonstrated acceptable short-term tolerability and safety in cancer patients when used for acute pain management. ²⁰ However, the study was limited to a single observation period, and the short duration precludes conclusions regarding delayed or cumulative side effects, such as tramadol-induced nausea, dizziness, or sedation, and the rare hematologic toxicity associated with metamizole. ^{6 , 12} Incorporating multiple assessment time points and longer follow-up in future studies would provide a more comprehensive evaluation of safety.

Cost-effectiveness analysis revealed that tramadol had a lower total treatment cost of 240,868 IDR compared to metamizole Antrain at 275,575 IDR. The cost-effectiveness ratio (CER) was 75,271 IDR per 1-point ΔNRS for tramadol, versus 90,057 IDR per 1-point ΔNRS for metamizole. Sensitivity analysis using generic metamizole reduced its total cost to 235,108 IDR, but the CER remained higher than tramadol (76,833 vs 75,271 IDR/unit ΔNRS), indicating that tramadol maintained superior cost-effectiveness regardless of formulation. In the context of limited healthcare resources and BPJS-based reimbursement, the lower CER of tramadol may support its consideration for formulary decision-making in post-procedural pain management. ^{9 , 12}

The study contributes local evidence supporting the effectiveness and safety of both tramadol and metamizole in minor invasive procedures, extending international findings that primarily focus on major surgical interventions. ^{6 , 14 , 21} Nevertheless, limitations include a relatively small sample size, limited comorbidities among participants, incomplete clinical data (e.g., tumor staging), and pain assessments restricted to baseline and 24 hours. Addressing these limitations in future research will enhance generalizability and provide more detailed guidance for analgesic use in outpatient and hospital settings.

This study evaluated the effectiveness, safety, and cost-effectiveness of tramadol versus metamizole for post-procedural pain management following biopsy and excision at RSUD Jayapura. Tramadol and metamizole demonstrated comparable effectiveness for short-term post-procedural pain management, with no significant difference in mean ΔNRS (tramadol 3.20 ± 0.76; metamizole 3.06 ± 0.69; p = 0.522) and no adverse events reported. Cost analysis showed tramadol was more cost-effective than metamizole, even when accounting for generic formulations, although total costs varied by drug type. Limitations include short observation duration, incomplete clinical data, minimal comorbidities, and pain measurements only at baseline and 24 hours.

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and applicable national regulations. Ethical approval was obtained from the Medical and Health Research Ethics Committee (MHREC), Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada–Dr. Sardjito General Hospital (Ref. No. KE/FK/1765/EC/2025; approval date: November 6, 2025).

All eligible patients were informed about the study objectives, procedures, potential risks, and their rights as research participants. Written informed consent was obtained from all participants prior to enrolment. Participation was voluntary, and participants were free to withdraw from the study at any time without affecting their medical care.

To ensure confidentiality, all data were anonymized, coded, and stored securely with access restricted to the research team during the study period. No directly identifiable personal information was collected or published.