Treatment of Neuropathic Pain – Pharmacy Times – Jeffrey Fudin, PharmD, DAAPM, FASHP, FCCP; Jeffrey Bettinger, PharmD Candidate; and Erica Wegrzyn, BA, BS, PharmD – Apr 2017
INeuropathic 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
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.2-6
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,
- tingling, or
- hypersensitivity to temperature or touch.
Potential causes of such neuropathies include, but are not limited to,
- traumatic nerve injuries,
- autoimmune disorders,
- genetic disorders, and
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 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.
…adverse events (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.
As shown in the Table, the many pharmacokinetic differences exhibited between these agents may play a role in selection
Anticonvulsants: Pharmacology in Neuropathic Pain
Many anticonvulsants are used to manage neuropathic pain, each varying significantly in its pharmacodynamic mechanism.
Commonly used agents include gabapentin, pregabalin, carbamazepine, oxcarbazepine, topiramate, and lamotrigine.
Only gabapentin, pregabalin, and carbamazepine have FDA-approved labels for the treatment of specific types of neuropathic pain.
Furthermore, gabapentin and pregabalin are recommended as first-line treatment for specific neuropathies, whereas lamotrigine and carbamazepine are recommended as second-line choices by the IASP
Gabapentin and pregabalin primarily exert their activity by inhibiting the alpha 2 delta subunit receptors on voltage-gated calcium channels presynaptically, thereby reducing the release of stimulatory neurotransmitters.
Carbamazepine and oxcarbazepine both act by inhibiting voltage-dependent sodium channels, resulting in a reduction of ectopic nerve discharges and stabilization of neural membranes.
Lamotrigine also blocks the activation of voltage-sensitive sodium channels stabilizing neural membranes and inhibits the pre-synaptic release of glutamate.
Topiramate has many pharmacologic properties that may help attenuate certain neuropathies, including prolonging the voltage-sensitive sodium channel inactivation state, agonizing GABAA receptors, and antagonizing NMDA receptors
Opioids: Pharmacology in Neuropathic Pain and Pharmacokinetics
Opioids primarily relieve pain by agonizing mu opioid receptors in both the central and peripheral nervous systems
Outside of this overarching ability to bind and agonize mu-receptors for their primary efficacy, certain opioids have additional actions that can specifically reduce neuropathic pain.
Many opioids, including morphine, oxycodone, fentanyl, tramadol, tapentadol, methadone, and levorphanol, have shown efficacy in peripheral neuropathic pain;
However, only tramadol, tapentadol, methadone, and levorphanol have well established mechanisms that substantially reduce neuropathic pain.
To note, the mechanism proposed for morphine, oxycodone, and fentanyl relieving neuropathic pain is associated with their ability to inhibit voltage-gated sodium channels (similar to many anticonvulsants).
Tramadol is a relatively weak opioid agonist, with 6000 times less binding affinity to the mu-opioid receptor than that of morphine; however, it potently inhibits the reuptake of serotonin and NE, thus providing an effect similar to that of the antidepressants used to treat neuropathic pain.
Tapentadol [Nucynta] is similar to tramadol in that it only inhibits the reuptake of NE, but differs in that it agonizes the mu-receptor to a greater extent.
Methadone is an extremely potent and strong mu-agonist that also functions as a noncompetitive inhibitor of NMDA receptors and inhibits the reuptake of serotonin and NE.
Levorphanol, another potent mu-receptor agonist, is a noncompetitive antagonist of NMDA receptors and an inhibitor of serotonin and NE reuptake transporters.
Neuropathic pain is connected to many diverse mechanisms and is associated with multiple disease states and medications.
A wide range of therapeutic options exist for the management of neuropathic pain that differ pharmacologically and pharmacokinetically, as well as in their AE profiles.
This allows providers to individualize therapy and create the most optimal pharmaceutical regimen that directly attenuates neuropathic pain