Elsevier

Burns

Volume 40, Issue 4, June 2014, Pages 759-771
Burns

A rat model of full thickness thermal injury characterized by thermal hyperalgesia, mechanical allodynia, pronociceptive peptide release and tramadol analgesia

https://doi.org/10.1016/j.burns.2013.10.011Get rights and content

Abstract

Opioid-related side effects are problematic for burn patients. Dual mechanism therapeutics targeting opioid and non-opioid mechanisms may have reduced side effects with similar analgesic efficacy. Tramadol combines mu opioid receptor agonism with norepinephrine reuptake inhibition and has been effective in treating some types of pain. The effectiveness of tramadol in treating pain associated with burns is unclear. We hypothesized that tramadol is effective in reducing thermal injury-evoked pain behaviors in a rat model. Rats were anesthetized and a 100 °C metal probe was placed on the hindpaw for 30 s to induce a full thickness thermal injury. A subset of rats was perfusion fixed and hindpaw tissue and spinal cord collected for anatomical analysis. Rats received morphine (5 mg/kg; i.p.), tramadol (10–30 mg/kg; i.p.) or vehicle and latency to paw withdrawal from a noxious thermal or non-noxious mechanical stimulus was recorded every 10 min over 70 min and again at 2 h. We report that pain behaviors developed within 48 h and peaked at 1 week; paralleled by enhanced expression of pronociceptive neuropeptides in the spinal cord. Morphine and tramadol significantly attenuated hyperalgesia and allodynia, while not significantly altering motor coordination/sedation. These data indicate dual mechanism therapeutics may be effective for treating pain associated with burns.

Introduction

Blast and burn insults account for over half of modern warfare casualties [1] and advances in battlefield medical techniques, protective armor, and medical care during evacuation have led to an impressive >90% survival rate [2]. Concurrent with this improvement in battlefield survival is an increase in the number of patients needing treatment for substantive pain evoked by traumatic injuries as evidenced by a cohort of 162 soldiers receiving treatment at Walter Reed Army Medical Center who reported an average visual analogue scale (VAS) pain score of 5.9 out of 10 [3]. Burned Service Members represent one patient population in the military medical care system in need of optimal pain control, reduced incidence of chronic pain and reduced risk of tolerance and addiction [4].

Opioid-based narcotics are the most prevalent therapeutics for the management of severe pain in civilian and military inpatient settings [5]. Because traumatic injuries, including burns, require multiple painful treatments, including wound debridements, dressing changes and lengthy rehabilitation, tolerance to opioids resulting in dose-escalation during treatment is common [4]. This may lead to addiction, as evidenced by the near tripling of prescription drug abuse among active duty military personnel between 2005 and 2008 (Department of Defense Health Behavior Study, 2008). Reducing reliance on traditional opioid-based narcotics is one way to improve pain management and outcomes in burned Service Members and civilians.

Antidepressants that target the neurotransmitters serotonin (5HT) and norepinepherine (NE), such as amitriptyline and duloxetine, have been successful for a variety of pain conditions [6], [7], [8], with the potential added benefits of mood elevation, sleep pattern normalization and muscle relaxation. However, antidepressants have not been successful for all pain conditions and the pain-relieving properties of antidepressants alone may not be efficacious for pain experienced with severe trauma. Alternatively, pain therapeutics that target dual mechanisms simultaneously may improve pain management in this population. The dual mechanism therapeutic tramadol combines opioid receptor activation and 5HT/NE reuptake inhibition [9], [10], [11]. Both preclinical and clinical research has reported that tramadol reduces acute, postoperative, neuropathic and cancer pain [9], [10], [12], [13], [14] and may have a lower propensity to induce addiction [15] with little to no adverse events compared to morphine [14].

Because of the complexity and severity of pain experienced by burn patients, this population receives multiple pain therapeutics simultaneously; thus, it is difficult to determine the efficacy of a single analgesic in this population. We have developed an animal model of thermal hyperalgesia and mechanical allodynia evoked by full thickness thermal injury that shares pathological characteristics with full thickness burns in patients. We then used this model to test the hypothesis that tramadol is effective in reducing full thickness thermal injury-evoked hyperalgesia and allodynia.

Section snippets

Subjects

A total of 117 adult (250–400 g) intact male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA, USA) were used in these experiments. Rats were pair housed in a 12:12 h light:dark cycle with ad libitum access to food and water. All studies were approved by the U.S. Army Institute of Surgical Research Institutional Animal Care and Use Committee and conform to federal guidelines and guidelines of the Committee for Research and Ethical Issues of the International Association for the

Thermal injury evoked a full thickness burn characterized by damage to the dermis

The area of the burn developed edema, erythema and blister formation during the initial 3 days following injury, followed by scab development from 1 to 3 weeks, with the wound closed by 4 weeks post-injury (Fig. 1A). The uninjured rat hindpaw was approximately 5.59 ± 0.28 mm in diameter from the plantar surface to the dorsal surface. Exposing the plantar surface of the right hindpaw to 100 °C for 30 s produced an average burn depth of 2.04 ± 0.50 mm across the field injury as measured within 5 min

Discussion

We have adapted a rat model of full thickness thermal injury to screen potential therapeutics that may be effective in reducing pain associated with burn. This model, and the testing of both mechanical allodynia and thermal hyperalgesia, may provide a more clinically relevant mechanism for testing the efficacy of acute administration of analgesics in a burn population. Because the most common source of pain in the burn patient is repetitive debridements and dressing changes, testing evoked pain

Conflict of interest statement

The authors report no conflicts of interest. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

Acknowledgements

The authors would like to acknowledge the technical assistance of Zach Silvias, Angie Greer and Alberto Mares. We thank Drs. Kenneth M. Hargreaves and Laura McGhee for helpful comments on study design. This work was supported by the United States Army Medical Research and Materiel Command Combat Casualty Care Research and the Clinical and Rehabilitative Medicine Research programs.

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