Treatment of Neuropathic Pain

Introduction

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.^1,2 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.² 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.”¹ 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.² 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.² 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.² Potential causes of such neuropathies include, but are not limited to, diabetes, traumatic nerve injuries, autoimmune disorders, genetic disorders, and medications.² 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.⁷ There are 2 classes of antidepressants whose pharmacologies involve the aforementioned mechanism: tricyclic antidepressants (TCAs) and selective serotonin-NE reuptake inhibitors (SNRIs).^7,8 Specific serotonin inhibitors lack quality evidence for efficacy to treat neuropathic pain.⁹

Common TCAs used in the treatment of neuropathic pain include amitriptyline, desipramine, doxepin, imipramine, nortriptyline, and trimipramine.¹⁰ 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.⁸ Their history is quite extensive, and their role in the treatment of neuropathic pain has been highlighted by an assortment of randomized controlled trials.⁷ 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).¹¹ 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.⁷ 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.⁷ 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.⁷ 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.^7,12 This selectiveness remarkably reduces the risk of AEs compared with TCAs; nevertheless, SNRI are still susceptible to their own degree of adverse reactions.⁷ 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.¹³

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.^8,14,15 As shown in the Table, 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.^14-16

Drug Name (Brand)

FDA-approved Pain Management Indication

Mechanism of Inducing Neuropathic Pain

Metabolism/Elimination

Other Metabolism/Transport Effects

Common Adverse Effects

Tricyclic Antidepressants

Amitriptyline (Elavil)

• None

• Inhibits the reuptake of NE

• 18% renally excreted
• 82% hepatically metabolized into active (nortriptyline) and inactive metabolites

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

Desipramine (Norpramin)

• None

• Inhibits the reuptake of NE

• 70% renally excreted
• 30% hepatically metabolized

• Moderately inhibits CYP2A6
• Weakly inhibits CYP2E1

Doxepin (Silenor)

• None

• Inhibits the reuptake of NE

• Primarily metabolized through CYP2C19 and CYP2D6

• None

Imipramine (Tofranil)

• None

• Inhibits the reuptake of NE

• Primarily metabolized through CYP2D6 into an active metabolite (desipramine) and inactive metabolites

• Weakly inhibits CYP1A2, 2C19, and 2E1

Nortriptyline (Pamelor)

• None

• Inhibits the reuptake of NE

• Primarily hepatic metabolism through CYP2D6

• Weakly inhibits CYP2E1

Trimipramine (Surmontil)

• None

• Inhibits the reuptake of NE

• Primarily hepatic metabolism through CYP2C19, 2D6, and 3A4

• None

Selective Serotonin-Norepinephrine Reuptake Inhibitors

Venlafaxine (Effexor)

• None

• Inhibits the reuptake of NE

• Primarily metabolized through CYP2D6 into active metabolite

• Weakly inhibits CYP2D6

Desvenlafaxine (Pristiq)

• None

• Inhibits the reuptake of NE

• About 50% renally excreted
• 50% phase 2 metabolism

• Weakly inhibits CYP2D6
• Weakly induces CYP3A4

Duloxetine (Cymbalta)

• Diabetic peripheral neuropathy
• Fibromyalgia
• Chronic musculoskeletal pain

• Inhibits the reuptake of NE

• Almost entirely metabolized through CYP1A2 and CYP2D6

• Moderately inhibits CYP2D6

Milnacipran (Savella)

• Fibromyalgia

• Inhibits the reuptake of NE

• 55% renally excreted
• About 45% hepatically metabolized

• None

Levomilnacipran (Fetzima)

• None

• Inhibits the reuptake of NE

• 58% renally excreted
• 42% hepatically metabolized

• None

Anticonvulsants

Gabapentin (Neurontin)

Postherpetic neuralgia

Inhibits the alpha 2 delta subunit on voltage-gated calcium channels presynaptically, thus inhibiting the release of excitatory neurotransmitters

100% renally excreted

None

Dizziness, somnolence, confusion, and peripheral edema.

Pregabalin (Lyrica)

• Fibromyalgia
• Neuropathic pain associated with diabetic peripheral neuropathy
• Neuropathic pain associated with spinal cord injury
• Postherpetic neuralgia

• Inhibits the alpha 2 delta subunit on voltage-gated calcium channels presynaptically, thus inhibiting the release of excitatory neurotransmitters

• 90% renally excreted

• None

• Dizziness, somnolence, dry mouth, edema, blurred vision, and weight gain.

Carbamazepine (Tegretol)

• Trigeminal neuralgia
• Glossopharyngeal neuralgia

• Inhibits voltage-dependent sodium channels, reducing ectopic nerve discharges and stabilization of neural membranes

• Primarily metabolized through CYP3A4 into active metabolite

• Strongly induces CYP3A4, 1A2, 2C19, 2C8, 2C9, P-glycoprotein, and UGT1A1
• CYP3A4 auto-induced
• Moderately induces CYP2B6

• Dizziness, nausea, drowsiness, blurred vision, and ataxia
• Rare, but serious: leukopenia, impairedliver function, and hyponatremia

Oxcarbazepine (Trileptal)

• None

• Inhibits voltage-dependent sodium channels and, to a lesser extent, potassium, thus reducing ectopic nerve discharges and stabilization of neural membranes

• Primarily metabolized by phase 2 metabolism into an active metabolite

• Weakly induces CYP3A4

• Dizziness, somnolence, diarrhea, and nausea/vomiting
• Rare, but serious: dermatologic reactions

Topiramate (Topamax)

• Prophylaxis of migraines

• Prolongation of voltage-sensitive sodium channel inactivation, GABA_A agonism, and NMDA antagonism

• 70% renally excreted
• 30% hepatically metabolized through phase 2 metabolism

• Weakly inhibits CYP2C19

• Somnolence, dizziness, fatigue, paresthesias, nausea, problems with concentration, and weight loss

Lamotrigine (Lamictal)

• None

• Stabilizes neural membranes by blocking the activation of voltage-sensitive sodium channels and inhibits the pre-synaptic release of glutamate

• 10% renally excreted
• 90% hepatically metabolized through phase 2 metabolism

• Inhibits OCT2

• Skin rash, nausea/vomiting, sedation, dizziness, malaise, headaches, and visual disturbances.
• Rare, but serious: Steven Johnson’s Syndrome

Opioids

Tramadol (Ultram)

• Moderate to severe pain

• Agonizes mu-opioid receptors and inhibits serotonin and NE reuptake transporters

• 30% renally excreted
• 60% metabolized via CYP2D6 and CYP3A4 into active metabolite O-desmethyltramadol

• None

• CNS depression, hypoglycemia, seizures, serotonin syndrome, respiratory depression, adrenal insufficiency, and constipation
• Drug abuse and misuse may occur, so appropriate drug monitoring is recommended

Tapentadol (Nucynta)

• Moderate to severe pain
• Pain or neuropathic pain associated with diabetic peripheral neuropathy

• Agonizes mu-opioid receptors and inhibits NE reuptake transporters

• Primarily metabolized by phase 2 metabolism into inactive metabolites

• None

• CNS depression, hypotension, respiratory depression, serotonin syndrome, constipation, and adrenal insufficiency
• Drug abuse and misuse may occur, so appropriate drug monitoring is recommended

Methadone (Dolophine)

• Chronic pain

• Agonizes mu-opioid receptors, antagonizes NMDA receptors, and inhibits serotonin and NE reuptake transporters

• Primarily metabolized via CYP3A4, 2B6, and 2C19 into inactive metabolites

• Weakly inhibits CYP2D6

• CNS depression, hypotension, QTc prolongation, constipation, adrenal insufficiency, and respiratory depression
• Drug abuse and misuse may occur, so appropriate drug monitoring is recommended

Levorphanol

• Moderate to severe pain

• Agonizes mu-, kappa-, and delta- opioid receptors, antagonizes NMDA receptors, and inhibits serotonin and NE reuptake transporters

• Primarily metabolized by phase 2 metabolism into inactive metabolites

• None

• CNS depression, hypotension, respiratory depression, adrenal insufficiency, and constipation
• Drug abuse and misuse may occur, so appropriate drug monitoring is recommended

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.¹⁷ Only gabapentin, pregabalin, and carbamazepine have FDA-approved labels for the treatment of specific types of neuropathic pain.^18-20 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.⁸

As stated previously, the mechanisms associated with anticonvulsant activity to diminish neuropathic pain are quite diverse, and truly range between different agents. 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.¹⁷ Carbamazepine and oxcarbazepine both act by inhibiting voltage-dependent sodium channels, resulting in a reduction of ectopic nerve discharges and stabilization of neural membranes.¹⁷ Lamotrigine also blocks the activation of voltage-sensitive sodium channels stabilizing neural membranes and inhibits the pre-synaptic release of glutamate.¹⁷ Topiramate has many pharmacologic properties that may help attenuate certain neuropathies, including prolonging the voltage-sensitive sodium channel inactivation state, agonizing GABA_A receptors, and antagonizing NMDA receptors.^17,21

There are also several unique pharmacokinetic properties associated with these anticonvulsants. Neither gabapentin nor pregabalin is hepatically metabolized; however, both are primarily renally excreted and thus require dosage adjustments in patients with renal insufficiency.^18,19 Carbamazepine is primarily metabolized through CYP3A4 and is also a strong inducer of several enzymes, including 3A4 itself.²⁰ Not only does this create the potential for many drug—drug interactions, but this auto-inducing ability increases carbamazepine’s own blood levels at or around 3 weeks from initiation or dosage adjustment. Oxcarbazepine avoids these CYP issues.²⁰ Topiramate and lamotrigine are both metabolized to some degree through phase II metabolism; however, topiramate is over 70% eliminated renally, consequently requiring dose adjustments in renal impairment.^22,23

Opioids: Pharmacology in Neuropathic Pain and Pharmacokinetics

Opioids primarily relieve pain by agonizing mu opioid receptors in both the central and peripheral nervous systems.²⁴ Although this action induces analgesia to a great extent, it can also lead to significant and life-threatening AEs. These include euphoria, which may cause addiction, abuse, and misuse, and a diminished chemoreceptor response to carbon dioxide, which may result in accumulation of carbon dioxide, increasing the risk of lethal respiratory depression.²⁴ 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.^25,26

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.^8,25,26 Furthermore, tapentadol is the only opioid that has FDA-labeling in regard to its treatment of neuropathies.²⁷ 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).²⁶

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.²⁶ Tapentadol 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.²⁶ 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.²⁶ Levorphanol, another potent mu-receptor agonist, is a noncompetitive antagonist of NMDA receptors and an inhibitor of serotonin and NE reuptake transporters.²⁵

Besides the differences in pharmacology, these opioids have diverse pharmacokinetic profiles. Tramadol is essentially a prodrug that requires metabolism, via CYP2D6, into its active metabolite O-desmethyltramadol to provide adequate analgesia.^26,28 Methadone is primarily metabolized through CYP3A4, 2B6, and 2C19, which makes it extremely susceptible to drug—drug interactions and elevates the risk of TdP in with a higher predisposition to poor CYP 2D6 genetic phenotypes.^25,29 Both tapentadol and levorphanol are metabolized through phase 2 glucuronidation into inactive metabolites that are renally excreted, making them viable options in certain patient populations.^25-27,30 Cebranopadol and other similar opioids with unique pharmacology, including affecting NE reuptake and enkephalinase-inhibiting properties, are currently under development, all of which should prove to be superior agent opioids for treating neuropathic pain. ³¹

Conclusion

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.

Dr. Jeffrey Fudin graduated from Albany College of Pharmacy and Health Sciences with a bachelor’s degree and his PharmD. He is a diplomate to the American Academy of Pain Management, a fellow to ACCP, a fellow to ASHP, and a member of several other professional organizations. He is president and director, Scientific and Clinical Affairs, REMITIGATE (remitigate.com), a software platform for interpreting urine drug screens (Urintel) and qualifying patients for naloxone (Naloxotel). He is a clinical pharmacy specialist in pain management at the Stratton VA Medical Center in Albany, New York. Jeffrey J. Bettinger is a 2017 PharmD Candidate at Albany College of Pharmacy and Health Sciences, with a concentration in nephrology. He is a volunteer student pharmacist engaged in the Stratton VA’s national Opioid Safety Initiative under the mentorship of Dr. Fudin. His future plans include a general practice residency followed by a to-be-determined specialty practice PGY2 program. Dr. Erica Wegrzyn is currently completing a PGY-2 pain and palliative care pharmacy residency under the direction of Dr. Fudin at the Stratton VA Medical Center. She received her PharmD from Western New England University College of Pharmacy in Springfield, Massachusetts, and completed a PGY-1 residency at Maine General Medical Center.

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