Rachman, Achmad Basir and Airlangga, Prananda Surya and Putri, Herdiani Sulistyo and Santoso, Kohar Hari and Wirabuana, Belindo and Mahmudah (2026) Multimodal Burn Pain Management: Cocoa Extract Provides Equivalent TRPV1 Suppression and Pain Reduction to Ibuprofen When Combined with Tramadol in Rats. International Journal of Drug Delivery Technology, 16 (8). 943 - 951.

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Abstract

Background: Burn-induced pain represents one of the most challenging clinical pain syndromes, characterized by persistent hyperalgesia and allodynia mediated in part through upregulation of Transient Receptor Potential Vanilloid 1 (TRPV1) channels. TRPV1, a non-selective cation channel activated by heat, acidic pH, and inflammatory mediators, plays a central role in nociceptive sensitization and the amplification of pain signals in both peripheral and central nervous system tissues. Current multimodal analgesia combining opioids and non-steroidal anti-inflammatory drugs (NSAIDs) remains the standard of care; however, concerns regarding adverse effects including gastric irritation, renal impairment, respiratory depression, and long-term dependence necessitate exploration of safer adjuvant alternatives. Cocoa (Theobroma cacao) contains bioactive flavanols, polyphenols, catechins, epicatechins, and methylxanthines with documented anti-inflammatory and analgesic properties, including reported suppression of TRPV1 expression in neuropathic pain models, making it a promising candidate as a natural analgesic adjuvant. This study aimed to compare the efficacy of cocoa extract versus ibuprofen as a tramadol adjuvant in a rat model of burn-induced pain, by assessing mechanical pain thresholds and TRPV1 protein levels in brain and spinal cord tissues. Methods: This experimental study utilized a randomized post-test only controlled design with 15 healthy male Wistar rats (Rattus norvegicus), weighing 140�180 g and aged 4�6 weeks, equally divided into three groups (n = 5). The control group received no analgesic therapy (placebo), the second group received tramadol 12.5 mg/kg intraperitoneally combined with ibuprofen 15 mg/kg orally, and the third group received tramadol 12.5 mg/kg intraperitoneally combined with cocoa extract 0.5 mg/kg orally. Following a 7-day acclimatization period, second-degree burn injuries were induced by immersing the right hind paw in a thermostatically controlled water bath maintained at 65°C for 3 seconds under ketamine-xylazine-acepromazine anaesthesia. Treatments were administered immediately following burn induction. Mechanical pain thresholds were assessed using an electronic Von Frey anesthesiometer at 24 hours post-injury, while TRPV1 protein levels in brain and spinal cord tissues were quantified by enzyme-linked immunosorbent assay (ELISA). Statistical analyses included one-way ANOVA with Tukey HSD post-hoc for normally distributed data, Kruskal-Wallis with Mann-Whitney post-hoc for non-normally distributed data, and Pearson correlation analysis, with significance set at p < 0.05. Results: Von Frey test results at 24 hours post-injury revealed significant differences in mechanical withdrawal thresholds among the three groups (one-way ANOVA, p = 0.003). The control group exhibited the lowest withdrawal threshold (mean 4.92 g), reflecting significant burn-induced hyperalgesia, whereas the tramadol-ibuprofen group (mean 13.92 g) and tramadol-cocoa group (mean 14.84 g) both showed markedly elevated thresholds compared to control (p = 0.003 for each). No significant difference was observed between the two treatment groups (p = 0.769), indicating equivalent analgesic efficacy. Kruskal-Wallis testing demonstrated significant intergroup differences in brain TRPV1 levels (p = 0.018), with the control group exhibiting the highest concentrations (mean 0.293 ng/mL). Mann-Whitney post-hoc analysis revealed a significant difference between the control and tramadol-ibuprofen groups (p = 0.012), but not between the control and tramadol-cocoa groups (p = 0.151), nor between the two treatment groups (p = 0.143). Spinal TRPV1 levels also differed significantly among groups (p = 0.034), with the tramadol-cocoa group demonstrating the greatest spinal TRPV1 suppression (mean 0.287 ng/mL) compared to control (mean 0.497 ng/mL; p = 0.024), while no significant difference was found between the control and tramadol-ibuprofen groups (p = 0.095) nor between the two treatment groups (p = 1.000). Pearson correlation analysis revealed a significant negative correlation between Von Frey values and brain TRPV1 levels (r = -0.632, p = 0.012) as well as a very strong negative correlation with spinal TRPV1 levels (r = -0.822, p = 0.0002), confirming TRPV1 as a key mediator of burn-induced hyperalgesia. Conclusion: Cocoa extract, when used as an adjuvant to tramadol, provides equivalent analgesic efficacy and TRPV1 suppression to ibuprofen in a rat model of burn-induced pain, supporting its potential as a natural NSAID alternative in multimodal burn pain management strategies. © 2026, Dr. Yashwant Research Labs Pvt. Ltd. All rights reserved.

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