Erica Wegrzyn, BA, BS, PharmD

Chronic pain has been defined by the International Association for the Study of Pain (IASP) as pain that persists beyond the normal tissue healing time of 3 months, and it may be classified into 3 distinct categories: nociceptive, neuropathic, and a mixture of the two.

 Neuropathic pain is somatosensory system disease or damage, which can be caused by a wide variety of nerve-damaging diseases or medications affecting the peripheral or central nervous system.

 There are many FDA-approved and off-label therapies for the treatment of neuropathic pain that provide effectiveness through a variety of mechanisms and differ vastly in their pharmacokinetic and pharmacodynamic profiles.

Definitions and Pathophysiology of Neuropathic Pain

Neuropathic pain has been described as “pain initiated or caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral or central nervous system.”

 Several mechanisms have been identified in the pathogenesis of neuropathic pain, but it is a lesion to afferent pathways that must be present for the syndrome to even develop.

 These lesions may lead to spontaneous ectopic nerve impulse generation within damaged and neighboring nociceptive fibers (C-fibers and Alpha-delta-fibers); upregulation of voltage-gated sodium channels, which contributes to changes in membrane excitability; central sensitization development as a consequence of ectopic activity; or constant release of excitatory amino acids and neuropeptides throughout the peripheral afferent fibers that leads to excitation of several receptors, such as N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic.

These varying mechanisms contribute to the development of several different types of neuropathy and result in diverse signs and symptoms.

 These varying mechanisms can be used to our advantage when selecting monotherapy or rational polypharmacy. Symptoms may manifest in patients as burning, pins and needles, electrical-type pain that radiates from a central locus, paresthesias, numbness, tingling, or hypersensitivity to temperature or touch.

 Potential causes of such neuropathies include, but are not limited to, diabetes, traumatic nerve injuries, autoimmune disorders, genetic disorders, and medications.

 A multitude of treatments, differing vastly in mechanisms, have been identified and proven to provide relief from these kinds of neuropathies.

Antidepressants: Pharmacology in Neuropathic Pain and Differences

The mechanism by which antidepressants relieve neuropathic pain has been identified as their ability to inhibit the reuptake of serotonin and norepinephrine (NE), with the primary mediator being NE.

 There are 2 classes of antidepressants whose pharmacologies involve the aforementioned mechanism: tricyclic antidepressants (TCAs) and selective serotonin-NE reuptake inhibitors (SNRIs).

 Specific serotonin inhibitors lack quality evidence for efficacy to treat neuropathic pain.

Common TCAs used in the treatment of neuropathic pain include amitriptyline, desipramine, doxepin, imipramine, nortriptyline, and trimipramine.

 Despite none having FDA-approved neuropathic pain management indications, this class of agents is among those preferred as first-line treatment by the IASP evidence-based guidelines for pharmacological management of neuropathic pain.

 Their history is quite extensive, and their role in the treatment of neuropathic pain has been highlighted by an assortment of randomized controlled trials.

 A meta-analysis published by Finnerup et al in 2015 found that the number needed to treat for TCAs was 3.6 (95% CI, 03.0-04.4) and the number needed to harm was 13.4 (95% CI, 9.3-24.4).

 A major limitation, however, is associated with the relative “sloppiness” of these medications: their tricyclic structure allows them to bind to and inhibit histaminergic-1, alpha-adrenergic, and muscarinic receptors.

 This haphazard capability of inhibiting numerous receptors can lead to a profusion of adverse effects (AEs) including cardiac conduction abnormalities, orthostatic hypotension, fatigue, dry mouth, constipation, sweating, or dizziness.

 These AEs greatly diminish the use of TCAs, making them poor choices for a vast majority of patient populations.

Although they primarily inhibit the reuptake of serotonin and NE, SNRIs have nontricyclic structures.

 These agents include venlafaxine, desvenlafaxine, duloxetine, milnacipran, and levomilnacipran. The relative selectiveness of these therapies allows them to bind only to serotonin and NE reuptake transporters, while avoiding the other somatosensory receptors.

 This selectiveness remarkably reduces the risk of AEs compared with TCAs; nevertheless, SNRI are still susceptible to their own degree of adverse reactions.

 Common AEs include nausea, vomiting, headache, dry mouth, sweating, and an increased risk of serotonin syndrome and cardiovascular effects, such as hypertension, with minimal influence on cardiac conduction.

The differences within this class of medications lie in the fact that not all are FDA-approved for pain management due to their notable varied pharmacokinetic profiles. Currently, only duloxetine and milnacipran carry this indication; however, duloxetine and venlafaxine are recommended as first-line treatment for neuropathic pain by the IASP.

, the many pharmacokinetic differences exhibited between these agents may play a role in selection. Duloxetine and venlafaxine are almost entirely metabolized through CYP2D6, whereas milnacipran is almost equally eliminated through renal excretion and hepatic metabolism.

82% hepatically metabolized into active (nortriptyline) and inactive metabolites

Weakly inhibits CYP1A2, 2C19, 2C9, and 2E1

Articles

Chronic pain has been defined by the International Association for the Study of Pain as pain that persists beyond the normal tissue healing time of 3 months, and it may be classified into 3 distinct categories: nociceptive, neuropathic, and a mixture of the two.