Action potentials are changes in polarity along a nerve based on ion flow into and out of the nerve cell. As the action potential travels down the length of the cell, it will end at a point in the nervous system that results in some form of output, either physical (muscle movement) or experiential (pain). Figure 2 shows some of the details of an action potential and provides an extended explanation of their formation. Of particular importance is the quantity of ions moving at any specific time. The primary ions moving after stimulation and reaching threshold are Na+ (sodium, into the cell), K+ (potassium, out of the cell), and Cl- (chloride, into the cell). After the nerve has fired, the sodium/potassium adenosine triphosphate (ATP)-ase pump works to move sodium out of the cell and potassium back into the cell. A pump is needed because the ions are moving against their gradients, and energy is required in the form of ATP to power the pump.

There are two primary types of nerves that carry pain data elicited by stimulation of an FNE: type Aδ or myelinated (fast) nerve fibers and type C or unmyelinated (slow) nerve fibers [5,8]. Myelinated fibers are insulated with Schwann cells, but with gaps (nodes of Ranvier) in which the nerve fiber is exposed to the environment of the extracellular fluid. The myelinated fibers are also referred to as fast fibers because the action potentials can skip between the nodes of Ranvier in a process called saltatory conduction (rather than traveling the entire length of the axon). Sharp or acute pain, especially from traumatic injury, is usually processed in this fashion.

Pain and other impulses originate in the peripheral nervous system (PNS), enter the dorsal horn of the vertebra, and then ascend to the brain along the spinothalamic tract. This is a three-neuron pathway containing first-, second-, and third-order neurons. In Figure 4, the spinothalamic tract can be traced from the primary afferent nerve (receiving the pain signals at the site of injury) to the spinal cord, entering via the dorsal root of the cord. At this point, the first-order neuron synapses with a second-order neuron. Upon entry into the cord, the second-order neuron crosses from the right to the left (or left to right, if it enters the left dorsal root). This is referred to as decussation. The second-order neuron then rises up the cord in either the anterior or later spinothalamic tract, synapsing with a third-order neuron in the thalamus. This neuron leads to the sensory cortex in the brain, which in turn interprets the exact location and degree of pain.

The thalamus also has neuronal branches that help to stimulate the reticular activating system, the portion of the brain responsible for sleep and waking [5]. The thalamus has numerous projections into other areas of the brain, including the prefrontal cortex and the amygdala, the latter of which is part of the limbic system [16,17]. The projections of the neurons into the limbic system account for the suffering aspect of pain, where the sensation is overlaid with an emotional experience. As pain is important in preventing homeostasis damage, including an emotional response to pain (in addition to a sensory response) helps ensure the person experiencing pain will avoid the stimulus that led to the pain.

Pain pathways stimulate many areas of the brain. The brain responds by the release of many neurotransmitters and other hormones to provide a systemic response [10]. As discussed, pain impulses activate the amygdala, which triggers a sympathetic nervous system response, sometimes referred to as the "fight-or-flight" response. The release of norepinephrine and epinephrine results in, among other things, tachycardia, hypertension, and elevated blood glucose levels. Additionally, the local response to the stimulus produces the release of local neurotransmitters, such as substance P, glutamate, CGRP, and brain-derived neurotrophic factor (BDNF) [10,11]. Of perhaps greater concern is the release of cytokines, which results in a profound inflammatory response. The inflammatory response is usually highlighted by hyperalgesia (exaggerated painful response to a painful stimulus) and allodynia (painful response from a non-pain-inducing stimulus). Take the example of a minor sunburn. If the skin is reddened and inflamed, a pat on the back becomes inordinately painful (hyperalgesia) and simply wearing a shirt may be intolerable (allodynia). In addition to these responses, untreated acute pain may lead to the expression of additional FNEs and nociceptors.

Nociceptive pain is a physiologic response to tissue injury, the perception that arises from intense stimulation of specialized peripheral sensory neurons (nociceptors) that respond only to noxious (pain) stimuli. Nociceptive pain is subgrouped by location of involved tissues into somatic pain (muscle or connective tissue) and visceral pain (visceral structures) [38]. Nociceptive pain is considered adaptive during tissue healing but maladaptive and pathologic when it persists after healing has occurred.

Centralized pain results from heightened nociceptive sensitivity in the absence of detectable peripheral stimulus and with negligible peripheral inflammatory pathology. The mechanism is poorly understood and is regarded as strictly pathologic as it lacks any evident adaptive function. Centralized pain disorders include conditions such as fibromyalgia, tension headache, and irritable bowel syndrome [32,38,40].

Naturally occurring opioid compounds are produced in plants (e.g., opium, morphine) and in the body (the endogenous opioids) [43]. Endogenous opioids are peptides that bind opioid receptors, function as neurotransmitters, and help regulate analgesia, hormone secretion, thermoregulation, and cardiovascular function. The three primary endogenous opioid peptide families are the endorphins, enkephalins, and dynorphins, and the three primary opioid receptor types are mu, kappa, and delta [44,45]. A quick overview of this complex pain modulation system is helpful in understanding how opioid analgesics work.

In addition to opioid-induced constipation, opioid antagonists are U.S. Food and Drug Administration (FDA)-approved for the treatment of alcohol and opioid use disorder (naltrexone 50–100 mg/day oral) and opioid overdose (naloxone 0.4–1.0 mg/dose IV or IM). In pain medicine, the dose ranges of naltrexone and naloxone are substantially lower. Of the two, naltrexone is much more widely used, and published pain medicine studies have used dose ranges of 1–5 mg (termed "low-dose") or <1 mg in microgram amounts (termed "ultra-low-dose") [65]. For example, case studies have reported dramatic improvement in refractory pain with intrathecal administration of an opioid agonist combined with ultra-low-dose naloxone in the low nanogram range [68].

NSAIDs alleviate pain by inhibiting the conversion of arachidonic acid to prostaglandins catalyzed by COX isozymes. Nonselective NSAIDs inhibit COX-1 and COX-2 and include ibuprofen, aspirin, and naproxen. The nonselective action inhibits the formation of both gastroprotective-mediating prostaglandins and pain-promoting prostaglandins, increasing the risk of serious toxicities such as GI ulceration and bleeding. This prompted the development of selective COX-2 inhibitors, which produce fewer GI side effects but are linked with an increased risk of cardio-renal morbidities [71]. To mitigate risk of GI adverse events, proton pump inhibitors are recommended for use in some patients using NSAIDs [72].

The gabapentinoids, gabapentin and pregabalin, are widely used in the management of both postoperative and chronic pain relief. Their names may give the impression they interact with gamma-amino butyric acid (GABA), but this is not the case [86,87]. Gabapentin and pregabalin are anticonvulsants that are also effective in a wide range of neuropathic pain conditions. Their mechanism of action involves selective binding to and blockade of the α2δ1 subunit of voltage-gated calcium channel in various brain regions and the superficial dorsal spine. This inhibits the release of glutamate, norepinephrine, and substance P to decrease spinal cord levels of neurotransmitters and neuropeptides [76,88,89]. The binding affinity of pregabalin for the calcium channel α2δ1 subunit is six times greater than gabapentin, which is reflected in the greater efficacy of pregabalin at lower doses. Because gabapentin possesses a shorter half-life and nonlinear absorption, pregabalin is easier to titrate and better tolerated [89].

While more commonly associated with the autonomic nervous system and its functions, alpha-adrenergic agonists can also function in the relief of pain, as well as decreasing the sympathetic side effects which accompany pain, including hypertension and tachycardia. Antinociceptive activity of the α-2 adrenoceptor agonists clonidine and tizanidine includes modulating dorsal horn neuron function and norepinephrine and 5-HT release, potentiating mu-opioid receptors, and decreasing neuron excitability through calcium channel modulation [92]. Clonidine is available as a transdermal patch for use in neuropathic pain states. Local use enhances release of endogenous enkephalin-like substances. Intrathecal or epidural administration with opioids and/or local anesthetics is favored in treating neuropathic pain because the synergistic effect improves pain control. Tizanidine is used as a muscle relaxant and antispasticity agent; its use in the management of musculoskeletal pain is off label [76,79].

Dexmedetomidine was originally approved as a short-term sedative analgesic for mechanically ventilated patients in the intensive care unit [93]. Dexmedetomidine is far more selective as an alpha-adrenergic agonist and has the same central action around the locus coeruleus [93]. As time passed since its introduction, the use of dexmedetomidine has increased, especially among patients with comorbidities (e.g., heart and vascular disease, morbid obesity). Its cardiovascular stability, along with its minimal effect on respiratory drive after the infusion is terminated, have made this agent popular in both the intensive care unit and the operating room. Aside from its use as a sedative or aesthetic agent, use of dexmedetomidine has been explored in patients with refractory end-of-life pain. In a case study, a male patient, 58 years of age, with chronic pancreatitis secondary to alcoholism reported inadequate pain relief despite receiving a combination of oxycodone, nortriptyline, and lorazepam. Increased inpatient intravenous opioids and ketamine still brought the patient no relief, and dexmedetomidine was attempted as a last resort. An infusion of dexmedetomidine brought the patient's pain under greater control, to the extent that he was able to sit in a recliner and visit with family [94]. Based on this and other reports, dexmedetomidine is being explored as a possible option in palliative care.

Ketamine is a phencyclidine anesthetic given parenterally, neuraxially, nasally, transdermally or orally in subanesthetic doses to alleviate a variety of pain conditions, including severe acute pain, chronic or neuropathic pain, and opioid tolerance [79]. The mechanism of analgesic effect primarily involves NMDA receptor inhibition. Thus, patients with NMDA-mediated central sensitization are likely to realize significant benefit from treatment with ketamine. Ketamine also has activity on nicotinic, muscarinic, and opioid receptors and exerts both anti-nociceptive and anti-hyperalgesic effects, with the latter produced at lower dose ranges [98].

The dual serotonergic and noradrenergic re-uptake inhibitors (SNRIs) duloxetine, venlafaxine, and milnacipran are widely used in the treatment of neuropathic pain conditions. Duloxetine is used in painful diabetic neuropathy, with demonstrated efficacy at 60–120 mg/day. Venlafaxine behaves like a SSRI at doses of ≤150 mg/day and like an SNRI at doses >150 mg/day; a dose ≥150 mg/day is often necessary to achieve pain control [76]. Of the three available SNRIs, milnacipran has the greatest affinity for norepinephrine, duloxetine has the greatest potency in blocking serotonin, and venlafaxine selectively binds to the serotonin but not the norepinephrine transporter [115].