Most pain syndromes involve multiple, often overlapping, neurobiologic mechanisms determined by the stage of the disease process. Current concepts of pain classify these into four main categories: nociceptive, inflammatory, neuropathic, and centralized [15].

Neuropathic pain originates from peripheral or central nervous system injury. Unlike nociceptive and inflammatory pain, the mechanism of neuropathic pain has no adaptive function and is strictly pathologic [4,16]. Acute pain from somatosensory damage is termed "acute neural injury." The term "neuropathic pain" implies pain that persists beyond the period of expected or actual tissue healing, and the underlying mechanism involves a maladaptive alteration in somatosensory nervous system function [11].

In nociceptor neurons, signaling involves three types of primary afferents [17]:

The relationship between emotion and pain perception is complex, and potentially reinforcing and potentiating. Pain involves active CNS regulation through excitatory and inhibitory modulation, primarily involving brainstem nuclei projections to the dorsal horn [15]. Forebrain centers and their products, including cognition, emotion, attention, and motivation, substantially influence brainstem nuclei and subjective pain experience. Specific cognitive styles and personality traits, such as somatization, catastrophizing, and hypervigilance, can amplify pain, sensitize dorsal horn spinal cord neurons and second-order pain pathway neurons, and prolong the development, amplification, and maintenance of persistent pain. Behavioral and cognitive therapies likely affect synaptic transmission in the spinal cord via descending pathways, and thus may prevent or reverse the long-term changes of synaptic strength in pain pathways [19,58,59,60].

Central sensitization is often preceded by peripheral sensitization, the result of alteration in the transduction proteins and ion channels that determine nociceptor terminal excitability. With peripheral sensitization, inflammatory mediators such as adenosine triphosphate (ATP) are released by tissue damage to activate peripheral nociceptor terminals, producing the sensation of pain. Inflammatory cells such as neutrophils become activated and produce other chemical mediators that generate COX-2, which generates prostaglandin PGE2. PGE2 alters pain sensitivity by amplifying response and dropping response threshold to stimuli in peripheral nociceptors.

In general, the development of central sensitization follows several overlapping neurologic events. Peripheral tissue damage generates intense or protracted nociceptive signaling to the dorsal spinal cord. Signaling and molecular barrage from pre-synaptic afferents across the synaptic juncture stresses post-synaptic terminals of second-order ascending neurons. This causes receptor membranes to depolarize and excitatory receptors to activate. A cascade of events is initiated that alters synaptic receptor density, threshold, kinetics, and activation and dramatically increases pain transmission [4,25]. The resultant state of CNS stimulation and dysfunction is characterized by amplified pain signaling, nociceptor excitation, substantial drop in pain response threshold, pathologic loss of anti-nociceptive pain inhibition, and augmented descending pathway facilitation [11,61]. This activity is enhanced by cognitive-emotional factors such as stress, anger, and catastrophic beliefs and fear concerning the future. These factors are known to facilitate pain, in part by inducing a state of cognitive-emotional sensitization within the CNS that results in more severe pain [87]. Pain hypersensitivity, allodynia, hyperalgesia, and enhanced temporal summation of pain perception with central sensitization underlie many chronic pain conditions.

There is evidence that neuroinflammation in the peripheral and central nervous systems plays an important role in promoting central sensitization and the perpetuation of chronic pain [88]. Central to this process is the activation of glial cells (microglia and astrocytes) within the spinal cord and brain that stimulates the release of proinflammatory cytokines and chemokines. Glial cells are part of the non-neuronal matrix within the nervous system that provides supportive physiologic functions. Peripheral nerve injury stimulates the local production of prostanoids, causing widespread induction of COX-2 and macrophage activation. The macrophages activate lymphocytes, which in turn release cytokines and chemokines. These activate microglia and astrocytes, which augment the inflammatory response via the signaling molecules ATP, fractalkine, monocyte chemotactic protein-1, proinflammatory cytokines, nitric oxide and glutamate. Studies show that cytokines and chemokines are powerful neuromodulators that play a role in inducing allodynia and hyperalgesia; their sustained release within the CNS also promotes chronic widespread pain affecting multiple body sites [62,64,88].

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 gastrointestinal (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 [67]. To mitigate risk of GI adverse events, proton pump inhibitors are recommended for use in some patients using NSAIDs [69].

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 serotonin-specific re-uptake inhibitor (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 [66]. 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 [74]. SNRIs are better tolerated than TCAs because they lack affinity for cholinergic, histaminic, and adrenergic receptors [71]. The anti-nociceptive effect of the SNRIs duloxetine and milnacipran primarily involves increasing serotonin and norepinephrine concentrations in descending inhibitory pain pathways, which enhances the suppression of afferent spinal inputs and reduce pain [11].

The endorphinergic pathway is comprised of endogenous ligands and the mu, kappa, and delta opioid receptors. Endorphins, enkephalins, dynorphins, and their receptors are expressed in multiple CNS regions in peripheral nerves and the skin. Opioid analgesics bind to opioid receptors (primarily the mu opioid receptor), mimicking the action of endogenous ligands. In general, opioid drugs produce analgesia through opioid receptor binding on cell membranes, producing simultaneous activity at multiple presynaptic, postsynaptic, and nervous system sites. Presynaptic opioid receptor activation inhibits the release of nociceptive neurotransmitters such as substance P and glutamate. Postsynaptic activation inhibits pain transition by opening potassium or chloride channels to hyperpolarize and inhibit neuronal firing [78]. These actions inhibit pain signal transmission from peripheral afferents to ascending spinal cord neurons; activate descending pathway inhibition; and alter limbic activity, decreasing pain awareness [66].

Botulinum toxin is a neurotoxic protein synthesized by the bacterium Clostridium botulinum with broad clinical application. Botulinum toxin produces analgesia through blocking neurotransmitter release and TRPV1 receptor signaling in C-fibers, which inhibits substance P and CGRP release to reduce neurogenic inflammation and increase heat pain threshold. Trials have shown efficacy in focal painful neuropathies and mechanical allodynia and superior reduction in pain and opioid use versus lidocaine and placebo [37,71]. A 2013 single-dose randomized controlled trial resulted in substantial improvements in pain and sleep outcomes in patients with postherpetic neuralgia [81].

Learning- and memory-related neuroplastic changes that develop with chronic pain require therapies that facilitate extinction of aversive memories and restore body image and normal brain function. Successful approaches include brain stimulation, mirror training, therapeutic virtual reality, and behavioral extinction training [55].