Case Report #40: Managing Pain in Adult Burns by Dr Harriet Scott and Dr Joe Hussey

Pain mechanisms in burns injury

Skin is the largest organ of the human body. Heat, cold, chemical and mechanical stimuli activate nociceptors. Signals are transmitted by A-δ   and C fibres to the dorsal horn.

Burn injuries initiate a multifaceted response in pain signalling with peripheral and central changes. These combine to create nociceptive, inflammatory and neuropathic features.

Peripheral pain mechanisms in burn injuries

A thermal insult to the skin triggers a cascade of alterations in pain signalling.

The group thermosensitive channels transient receptor potential vanilloids (TRPV) 1–4 and transient receptor melastatin (TRPM) 3 are activated by different temperatures: TRPV1 at 43°C, TRPV2 at 52°C, TRPV3 at 33°C and TRPV4 at 25°C.⁷

Once activated, they release calcitonin gene–related peptide (CGRP), intracellular calcium levels rise and ATP is released which acts on P2X receptors on primary sensory nerves.⁷

There is upregulation of P2X receptors on primary sensory neurons.⁷

Elevated circulatory levels of CGRP and substance P are found in patients with burns.⁷

Local tissue trauma and the systemic response to a large burn causes development of an inflammatory milieu. Loss of membrane integrity causes leakage of cell contents and release of damage-associate molecular pattern molecules (DAMPs). Histamine, catecholamines, TNF-α  , IL-1β , IL-6, IL-8, oxygen free radicals, nitric oxide, bradykinin, eicosanoids, 5-hydroxytryptamine (5-HT) activate or sensitise peripheral nerve endings, contributing to hyperalgesia.⁷

Activation of voltage-gated sodium channel Na_V1.7 causes allodynia. Conversely, patients with a congenital mutation of their Na_V1.7 channel may present with painless burn injuries.⁷

Damage to peripheral nociceptive neurons triggers ectopic firing, felt by the patient as ‘burning, hot, stabbing’ neuropathic pains.

Central pain mechanisms in burn injuries

Animal studies have demonstrated upregulated calcitonin gene-related peptide and Substance P in the dorsal horn contralateral to an induced burn injury, likely due to central sensitisation.⁷

Hyperexcitability of wide range dynamic range neurons, microglial activation and NMDA glutamate receptor activation in the spinal cord have been implicated in central sensitisation.⁷

Systemic activation of damage-associate molecular pattern molecules (DAMPs) and the systemic inflammatory milieu causes loss of integrity of the blood-brain barrier, cerebral inflammation, seen clinically as delirium and dizziness.⁷

Prostaglandin production in the brain contributes to centrally-mediated hyperalgesia.⁷

It is likely that descending modulation of pain pathways is also altered in burns injuries.

In addition to pharmacodynamic changes described above, burns lead to significant pharmacokinetic changes that influence gut absorption, distribution, metabolism and excretion of many drugs, including analgesics.