Trauma is perhaps the most instantly recognizable cause of acute pain in man and animals and is a common cause of critical
illness. The experience of acute pain is part of an integrated behavioral, hemodynamic, metabolic, and immune response, collectively
known as the stress response, that restores homeostasis and ensures survival following significant injury. This adaptive response
is mediated by the neuroendocrine response to tissue injury and complications such as blood loss, infection, and surgical
interventions. Tissue injury, hypovolemia, and hypotension elicit immediate responses by the autonomic nervous system and
the hypothalamic-pituitary axis. The sympathetic nervous system releases catecholamines from the adrenals and target organs;
these products mediate increased vigor and rate of cardiac contraction, arterial vasoconstriction to organs capable of surviving
on limited energy resources (skin, muscle, bone), and constriction of capacitance veins (e.g., mesenteric veins in the dog)
to direct circulation to tissues with high energy requirements. Energy substrates (glucose, amino acids, and lipids) are mobilized
from the liver, gut, muscle, and adipose tissue. The hypothalamus increases its release of corticotrophin-releasing hormone,
vasopressin, and oxytocin, and the pituitary gland responds with increased production of ACTH, glucocorticoids, and beta-endorphin.
In addition to pituitary release of beta-endorphin, many tissues release the related opioid peptides, enkephalins and dynorphins.
These peptides bind with different affinities to three G-protein coupled opioid receptors: mu, delta, and kappa. Ligand activation
of these receptors initiates a wide range of responses depending on the target cell type.
The interactions between endogenous opioids and the cardiovascular and immune systems have been the subject of much research
interest since observations in the 1970's that the opioid antagonist naloxone can ameliorate hemodynamic instability in hemorrhagic
shock. The mechanisms for improved hemodynamic stability following naloxone treatment are incompletely understood, but include
enhanced catecholamine release and enhanced target tissue response to catecholamines4. Animal models of trauma demonstrate
that circulating concentrations of beta-endorphin increase following crush injury or lipopolysaccharide administration, and
numerous clinical studies in humans demonstrate elevated plasma concentrations of beta-endorphin that positively correlate
with severity of illness. This endogenous opioid release has been traditionally associated with a benefit (analgesia), and
the anti-nociceptive properties of the stress response have been repeatedly demonstrated in experimental animal and human
models of stress and pain. Although these findings may well be properly interpreted as a 'good' consequence of opioid activation,
other opioid-mediated cellular responses are not clearly beneficial and may impair circulatory responses to injury. For example,
endogenous opioids released from cardiac myocytes decouple contraction from excitation, an effect that may protect the heart
from hypoxic and ischemic injury but also impairs circulation during stress. Administration of opioid drugs produces similar
effects on the cardiovascular system. Premedication with morphine increases parasympathetic control of the circulation in
humans, consistent with observations in animal models (and veterinary observations in dogs) of slower heart rates and significant
reduction in blood pressure following administration of opioids.
In spite of the evidence suggesting that opioids mediate earlier decompensation from hemorrhage, and meta-analysis level evidence
for improved mean arterial pressure in humans with shock syndromes, there is currently no clinical trial confirmation that
therapy with naloxone improves the outcome from severe injury or other causes of shock syndrome. However, the likelihood that
endogenous and exogenous opioids mitigate the resuscitation goal of maintaining adequate blood pressure and perfusion in shock
syndromes should be kept in mind when used to treat patients with both pain and shock syndrome.
The postinjury inflammatory response to injury is an essential step toward tissue repair and maintenance of immunocompetence
in the face of compromised tissue integrity. This response is a complex integration of neuroendocrine and cellular responses
that must be carefully matched to stimulus intensity. Tipping the balance of pro- and anti-inflammatory responses too far
towards inflammation yields immediate tissue injury, and too far towards immunosuppression results in host susceptibility
to infection and delayed tissue injury culminating in multiple organ failure. This latter situation is commonly observed as
the 'two-hit' model of injury, wherein a patient suffering initial injury is unable to successfully mount a response to sepsis
later on and succumbs to multiple organ failure. Depending on the model, timing, route of administration, concentration, tissue
location, and stimulus, both endogenous and exogenous opioids can affect the immune response in ways that are either pro-
or anti-inflammatory. However, the bulk of evidence is that at clinically relevant dosages opioid analgesics are on balance
immunosuppressive, a finding that has stimulated interest in sorting out the impact of this effect on patients already immunosuppressed
or at risk of serious infection.