Mixed Pain States
Chronic pain is a multifaceted disease often requiring multimodal treatment. The elucidation of both peripheral and central nervous system pain mechanisms, outlined in more detail below, has provided insights into the biochemical, molecular, and neuroanatomic correlates of chronic pain. Treatment selection should be guided by comprehensive assessment of the phenomenology and inferred pathophysiology of the pain syndrome (ei, mechanism-based treatment); patient goals, preferences, and expectations; behavioral, cognitive, and physical function; and level of risk for adverse events and observant behaviors.
The experience of either acute or chronic pain involves a complex process associated with the activation of multiple neuronal signaling pathways within the peripheral nervous system (PNS) and central nervous system (CNS).75-77 Additionally, inhibitory and excitatory processes mediated through multiple descending pathways, including the opioid, monoaminergic and other pathways, may modulate pain transmission, resulting in either antinociceptive or pronociceptive effects.78,79 The variety of mechanisms involved in pain signaling and modulation provides a number of potential targets for different pharmacological interventions.80 Clinical observation suggests that single analgesic therapies are often insufficient to provide adequate pain relief, and are consistent with findings regarding the complexity of pain signaling and the recognition that mixed mechanisms of pain often underlie a patient's chronic pain complaints.81,82 These observations have led not only to the recognition of the conceptual framework of "mixed pain" but also to the practice of utilizing analgesic agents (multidrug therapy) with different mechanisms of action in an attempt to maximize efficacy and tolerability.81,82 This approach has become a recommended treatment strategy for different types of acute and chronic pain.83-85
Exploring Key Mechanisms of Pain Transmission and Its Modulation
Pain perception results from a series of neurophysiologic events occurring within the PNS and CNS.75 Transduction is the process by which noxious stimuli are converted into electrical activity within the PNS and it begins with activation of specialized nerve endings known as peripheral nociceptors.76, 79 Painful stimuli cause the opening of various ion channels and flux of ions across cell membranes within the peripheral nociceptive afferent.76, 85 Certain stimuli may result in depolarization and generation of action potentials that are then conducted via peripheral afferents to the dorsal horn of the spinal cord with the subsequent release of excitatory neurotransmitters (eg, glutamate), neuropeptides (eg, substance P), and neuromodulators (eg, brain-derived neurotrophic factor [BDNF]) from axon terminals into the synapse within the dorsal horn.76, 79, 85 These neurotransmitters/modulators then bind to and activate receptors on the postsynaptic nerve terminal, including N-methyl-D-aspartic acid (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), G protein–coupled receptors and tyrosine kinase receptors.79,85 Should these presynaptic action potentials occur at a sufficient frequency and duration, the activity in the postsynaptic terminal will increase, and another action potential will be propagated. Those impulses generated in the dorsal horn travel through ascending pathways (eg, the spinothalamic tract) to the brain, where the signals are processed and pain is perceived.75, 79
Peripheral nociceptive afferent activity can be augmented if tissue damage has occurred due to the release of pro-inflammatory factors, such as bradykinin, prostaglandin E2, nerve growth factor, and tumor necrosis factor-alpha (TNF-α).76, 79, 86 These mediators, after binding to specific receptors on neuronal terminals, may initiate a cascade of events that results in an altered state of sensitivity.79, 86, 87 Specifically, these inflammatory mediators can depolarize primary afferents directly by activating sodium ion channels, though in most cases they sensitize the nerve terminal (ie, lower the threshold for activation) rather than directly activating it.76, 88 Furthermore, glial cells (ie, Schwann cells, microglia, astrocytes, and oligodendrocytes), are now known to play a key role in the initiation and maintenance of increased nociception following peripheral tissue injury.89, 90 Under normal conditions, glial cells are quiescent.76 However, upon activation by tissue damage or inflammation, glial cells are capable of releasing a variety of nociceptive sensitizing agents, such as TNF-α,90 interleukin (IL)-1,90 nitric oxide,90 arachadonic acid,91 and excitatory amino acids,92 which directly increase nerve excitability, indicating a role for these cells in the initiation and maintenance of enhanced pain states, including neuropathic pain.93, 94 Sensory nerve gene expression following an inflammatory response can also augment peripheral nociceptive afferent activation.95 These alterations amplify input to the spinal cord, creating an increased state of excitability and increased sensitivity to nociceptive input (peripheral sensitization).95, 96
Neurons in the CNS may also undergo changes that increase their excitability, often as a result of continued impulse activity in the periphery, a situation known as "central sensitization."85, 97 Activation of the NMDA receptor plays a key role in increasing CNS excitability.76, 85, 98 During central sensitization, phosphorylation of NMDA receptors causes their translocation from intracellular stores to the synaptic membrane and increases their responsiveness to the excitatory neurotransmitter glutamate.76 This activity-induced central hyperexcitability causes activation of pain pathways by stimuli that are normally subthreshold (allodynia pain occurring upon normally non-painful stimulation) or cause exaggerated responses to normally suprathreshold stimuli (hyperalgesia greater than normal pain is experienced following a normally painful stimulus).76, 85
To counteract pain facilitatory input, activation of descending pain suppression pathways can either reduce the likelihood that a stimulus is perceived as painful or reduce the perceived intensity of pain. Endogenous opioids are one of the key mediators involved in the descending inhibitory pathways and are released in a variety of locations throughout the CNS, where they can inhibit pain signal transmission.85 Structures in the midbrain, including the periaquiductal grey, send projections to the spinal dorsal horn that modulate nociceptive neuronal activity through release of endogenous opioids.99
Nonopioid processes mediated by monoaminergic neurotransmitters such as norepinephrine, serotonin, and dopamine modulate pain signaling within the dorsal horn, although some of these neurotransmitters can exert either antinociceptive or pronociceptive effects, depending upon the subtype and location of the receptors involved.78 Descending serotonergic pathways can inhibit nociceptive signaling via 5-HT1 receptor activation. Specifically, activation of 5-HT1A receptors inhibits the excitability of spinothalamic projecting neurons and excitatory (ie, pain facilitatory) interneurons.78 Similarly, 5-HT1B/D receptor activation is antinociceptive through inhibition of neurotransmitter release from primary nociceptive afferents.78 In contrast, descending serotonergic pathway activation can promote nociceptive transmission by activating 5-HT2/3 neurons.78, 100
Similar to serotonergic pathways, activation of centrally located descending dopaminergic pathways can either inhibit or facilitate nociceptive signaling. Descending dopaminergic pathways inhibit nociceptive signaling by activating D2 and D3 receptors on primary nociceptive afferents and neurons in the dorsal horn, thus inhibiting presynaptic neurotransmitter release.78, 101, 102 However, dopamine can be pronociceptive if it activates D1 spinothalamic projecting (ie, ascending) neurons.102
In contrast to serotonergic and dopaminergic receptor-mediated activity, each of which have pro- and antinociceptive effects, descending noradrenergic pathway activation is only known to have antinociceptive effects.4 Descending noradrenergic pathways projecting to the spinal dorsal horn originate from several areas within the pontine region of the brain, and inhibit pain signaling by activating α2A receptors on terminals of primary nociceptors, or by activating postsynaptic α1 receptors, causing release of inhibitory neurotransmitters gamma aminobutyric acid (GABA) or glycine from inhibitory interneurons.78
Elucidation of the above mechanisms is helping to shape the manner in which we classify as well as treat acute and chronic pain. In the past, pain has been classified into "simple" categories such as nociceptive, inflammatory, and neuropathic; however, increasingly we have recognized that this may be an oversimplification.
Clinical Examples of Mixed Pain States
How does the information provided above translate into clinical practice? I believe that translation of such occurs in several ways. First is the recognition that acute painful conditions, often associated with acute nociceptive and acute inflammatory mechanisms, may transition to a chronic condition in which more neuropathic mechanisms may ultimately predominate. Such conditions would include acute postmastectomy or postthoracotomy pain transitioning to chronic postmastectomy or chronic postthoracotomy pain as well as pain associated with acute herpetic neuralgia transitioning to chronic postherpetic neuralgia.
Second is the recognition that quite often individuals may experience chronic pain due to more than one painful condition. For example, consider the 55-year-old male with both chronic osteoarthritis-related pain as well as chronic pain as a consequence of his painful diabetic neuropathy. In this instance, his osteoarthritis-related pain is likely to be associated with more inflammatory and nociceptive mechanisms and his diabetic neuropathy-related pain is more likely to be associated with neuropathic pain mechanisms; thus, his chronic pain is associated with mixed pain.
Third is the recognition that certain pain syndromes themselves may be consequent to multiple distinct mechanisms and thus are associated with mixed pain. An example of such would be pain secondary to an acute lumbar radiculopathy caused by an acute disc herniation and nerve root compression. In this instance, inflammatory and neuropathic mechanisms would likely be contributing to the pain.
In conclusion, our increasing awareness of multiple pain mechanisms has also led to our recognition that quite often mixed pain states and mixed pain mechanisms underlie a patient's chronic pain complaints. This in turn has led to our increasing use of multimodal therapies in the management of such conditions since different pharmacologic as well as nonpharmacologic interventions may have distinct mechanisms of action.
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