Anesthesia adjuncts in the management of pain in trauma patients: New blocks and other techniques to combat the opioid epidemic

Physiologic stress response to trauma

The stress response induced after trauma is a protective mechanism to promote the return to normal steady-state physiology. However, when the stressors remain well after the inciting event, the response can result in a deleterious effect on convalescence. Reducing the stressors and supporting the return to health is paramount to enhancing recovery in trauma patients.

Ascending pain pathway

Traumatic injury results in the release of factors known as damage-associated molecular pattern (DAMP) activators or alarmins ( Fig. 1 ). The release of alarmins set in motion multiple intertwined neuronal, inflammatory, and endocrine cascades, mounting the complex stress response to insult. Nociceptors are pain-sensing neurons located in the periphery ( Fig. 1 ). As DAMPs are released from traumatized tissues, transcriptional changes, such as increased expression proinflammatory mediators like tumor necrosis factor-alpha (TNFα) and interleukin (IL)-6, are induced in macrophages. Signaling molecules accumulate and then trigger an action potential, which is transduced to the substantia gelatinosa in the dorsal horn of the spinal cord. Here, chemical neurotransmitters such as Substance P and glutamate are released into the synapse, which activate the action potential in the second-order neurons. The signal travels via the spinothalamic tract to the thalamus, where signaling to a third-order neuron occurs. The signal then travels to the area within the somatosensory cortex that correlates with the location of the injury. The cortex is where the perception of pain occurs.

Repeated stimulation of the nociceptor leads to a wind-up phenomenon, known as central sensitization. When this occurs, synaptic efficacy is increased, and modulation from the descending pathway is lessened. The second-order neurons become hyperexcitable leading to hypersensitivity, hyperalgesia, and allodynia, where there is pain response disproportionate to the stimuli. Glutamate and substance P act to promote excitability at these synapses. When central sensitization persists beyond the time it takes for the tissues to heal, chronic or persistent pain syndromes can occur.

Pain modulation and the descending pathway

Modulation of the pain signal occurs along the entire pain pathway. The descending pathway acts to modulate pain signals from the ascending pathway. The descending pathway neurons arise in midbrain from regions rich in norepinephrine (NE) and serotonin (5-HT). It also receives input from the ascending pathway, the sensory cortex, and limbic nuclei. The fibers descend down the spinal cord to the substantia gelatinosa of the dorsal horn where they synapse with inhibitory interneurons by releasing 5-HT or NE. Inhibitory interneurons, in turn, synapse with the nociceptive neurons and second-order neurons ( Fig. 1 ). Endogenous opioids, cannabinoids, NE, γ-aminobutyric acid (GABA), and adenosine modulate inhibitory effects on these synapses. Enkephalins, endorphins, and dynorphins are released by the interneurons, which reduce the action potentials that are propagated to the second-order neurons of the ascending pathways, thus decreasing the pain signals to the CNS.

Neuropathic pain

Neuropathic pain arises from direct injury of the peripheral or CNS. Lesions in the neuron lead to physical and functional changes with the end result of central sensitization. Increased expression of ion channels (voltage gated Na channels) and N -methyl- d -aspartate (NMDA) receptors lead to spontaneous firing of action potentials, known as ectopic discharges. Repeated action potentials from the periphery leads to accumulation of glutamate and substance P in the substantia gelatinosa. These changes cause neuroplastic postsynaptic modifications in second-order neurons resulting in allodynia and hyperalgesia. Then, when a nerve injury occurs, inhibitory GABAergic interneurons are lost, resulting in an increased pain sensation.

Analgesic strategies

Within the pain pathway are multiple opportunities to suppress pain through various modalities. In the past, analgesic strategies for acute pain in trauma patients have been dominated by unimodal opioid administration. MMA strategies are aimed at multiple targets throughout the pain pathway, instead of only opioid receptors. By using several different interventions, lower doses of medications may be employed, decreasing medication-associated adverse events. In addition, these strategies can reduce or even eliminate the use of opioids to hasten recovery and avoid ORADEs. Utilization of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen (APAP), gabapentinoids, antidepressants, NMDA receptor antagonists and RA can produce excellent analgesia by targeting several receptors within the nociceptive pathway.

NSAIDs

During injury, damaged tissue and immune cells convert phospholipids to prostaglandins (PGs) via the arachidonic acid (AA) pathway. Nociceptor receptors bind PGs triggering action potentials in the ascending pathway. PGs also contribute to localized edema and inflammation. The AA pathway is catalyzed by cyclooxygenase (COX) isoenzymes COX-1 and COX-2. COX-1 is a constitutively expressed enzyme that maintains physiologic balance in tissues such as the stomach and kidneys, as well as in platelets. COX-2 expression is induced in areas of inflammation, increasing the PG levels in tissues and promoting inflammation.

NSAIDs are potent analgesics that also have antipyretic and anti-inflammatory activity. These medications work by inhibiting the formation of PG. Nonselective (ns) NSAIDs, such as ibuprofen, ketorolac, and meloxicam, inhibit both COX-1 and COX-2 enzymes, whereas selective NSAIDs, such as celecoxib, inhibit only COX-2 enzymes. NSAIDs are available as oral, topical, parenteral, and rectal preparations.

While NSAIDs provide excellent opioid-sparing analgesia, careful consideration of the patient’s injuries and comorbidities should weigh in the decision to utilize these medications in trauma patients. Inhibition of COX-1 by nsNSAIDs blocks the formation of thromboxane A2 (TXA2) in platelets, impairing platelet function. Avoidance of nsNSAIDs may be considered in trauma patients who may be at risk for bleeding from their injuries in the setting of platelet dysfunction. Selective COX-2 inhibitors do not reduce TXA-2 production and may be considered for such patients. In addition to platelet dysfunction, COX-1 inhibition can result in dyspepsia, gastrointestinal bleeding, acute renal failure, hypertension, and exacerbations of myocardial and cerebrovascular events.

For trauma patients with musculoskeletal injuries, nsNSAIDs have been often avoided out of concern for impairment of the healing of long bone fractures. Much of this theory is now being reconsidered. In a study looking at humeral shaft fractures, both nsNSAIDs and opioid administration in the third month after the injury was associated with nonunion. When the data were further analyzed, it was realized that patients were receiving these therapies because they were suffering pain from already nonhealing fractures. A meta-analysis also concluded that the risk of nonunion was not associated with NSAID exposure when high-quality studies were reviewed. Given the nature and complexity of trauma patients, each patient should be evaluated on an individual basis for the appropriateness of NSAID therapy.