Neuropathic Pain

Neuropathic pain is a chronic nerve pain that can significantly impair a patient’s functioning and quality of life. Neuropathic pain results from damaged nerves that have been affected by tissue injury due to trauma or disease. Diabetes mellitus and herpes zoster are commonly associated with the development of neuropathies. Other disease states that may result in neuropathic pain include complex regional pain syndrome, radiculopathy, and phantom limb pain. Neuropathic pain can also be medicationrelated, as in the case of nerve damage due to cancer treatment.

Neuropathic pain originates from the reduced inability of a neuron to relay messages to and from the brain because of damage to the nerve. This can cause a person to feel a variety of sensations or hypersensitivities.^1,2 A patient may feel different types of pain, depending on the origin and cause of the pain.

Neuropathic pain can be distinguished from nociceptive pain by determining the quality of the pain. Typically, patients experience variations in sensation or hypersensitivity. Neuropathic pain symptoms can be classified as negative or positive. Negative symptoms of neuropathic pain are described as a loss of sensation or numbness. Positive symptoms are characterized by the increased perception of pain or abnormal sensations. Positive symptoms can be either induced by a stimulus or spontaneous (nonstimulus induced). Table 1 describes the types of symptoms.

PHARMACOLOGIC MANAGEMENT

Various classes of medications have shown benefit for managing neuropathic pain. Medications for neuropathic pain are not likely to completely resolve pain; therefore, health care providers should discuss realistic goals with patients prior to initiating therapy. A reduction in pain of 30% is often considered a reasonable goal, along with potential improvements in sleep and depression, depending on the specific agent used. Patients should also be informed that many agents used for neuropathic pain often require a series of dose titrations and weeks of use to see a benefit. Classes of medications used for neuropathic pain include tricyclic antidepressants (TCAs), serotonin/ norepinephrine reuptake inhibitors (SNRIs), anticonvulsants, and, potentially, opioid therapy.³

Tricyclic Antidepressants

TCAs are often considered first-line for treatment of neuropathic pain and have shown benefit in clinical trials for diabetic peripheral neuropathy and postherpetic neuralgia.⁴ Benefits include low cost, as well as potential improvement in depression and/ or insomnia, which are frequently associated with neuropathic pain. Anticholinergic adverse effects (AEs), including dry mouth, constipation, and drowsiness, are possible with TCAs, although nortriptyline and desipramine are less likely than amitriptyline to cause AEs. Due to the risk of anticholinergic AEs, it is generally recommended to avoid the use of TCAs in the elderly. Use of TCAs should also be avoided in patients with a history of cardiac arrhythmias. TCAs should be initiated at a low dose, and the dose should be increased every 3 to 5 days until a target dose is reached or AEs become intolerable.

Serotonin/Norepinephrine Reuptake Inhibitors

SNRIs is a class of antidepressant medications that can be used to treat neuropathic pain. These medications include venlafaxine, duloxetine, and milnacipran. An advantage to SNRIs, similar to TCAs, is that they can help improve comorbid depression or anxiety. SNRIs should be used cautiously with other serotonergic medications due to the risk of serotonin syndrome. The most common AE associated with this class is nausea.

Anticonvulsants

The anticonvulsants gabapentin and pregabalin are frequently used in the setting of neuropathic pain management. Gabapentin has been studied for managing various types of neuropathic pain, including diabetic neuropathy and postherpetic neuralgia, and gabapentin case study results have shown a benefit to its use over placebo in managing sciatica.^5-7 Pregabalin has also been studied for managing postherpetic neuralgia and diabetic neuropathy, and the drug has shown efficacy in treating pain due to centrally mediated neuropathic pain and due to spinal cord injury.^8-11

Along with TCAs, gabapentin is often considered a first-line agent for managing neuropathic pain. Use of pregabalin may be considered after failure with gabapentin due to a lack of efficacy or to intolerable AEs. Gabapentin and pregabalin are started at low doses and titrated every 3 to 7 days until a target dose is reached or AEs prevent further titrations. Both agents require dose adjustments in patients with renal impairment. Horizant (gabapentin enacarbil) and Gralise (gabapentin), extended-release gabapentin formulations, have been FDA-approved for management of postherpetic neuralgia and are designed to improve absorption of gabapentin; however, the cost of these medications is higher than an immediate-release gabapentin product.

Topiramate is another anticonvulsant that may be used for managing neuropathic pain; however, there is a lack of evidence to support the use of topiramate for managing neuropathic pain, and the study results are inconsistent.² Therefore, topiramate is typically one of the last agents used to treat neuropathic pain. Other anticonvulsants, including carbamazepine, oxcarbazepine, lamotrigine, and lacosamide, have been studied for treating neuropathic pain and the results have been inconsistent, similar to those for topiramate.²

LIDOCAINE PATCHES

Lidocaine patches are an analgesic alternative for managing localized neuropathic pain. This patch is indicated for treating postherpetic neuralgia and allodynia. One to 3 patches can be used at the same time for up to 12 hours. Because lidocaine patches are associated with a low risk of AEs, they are an option for patients at risk of AEs due to oral therapies.

OPIOIDS

Due to the risk of serious AEs, including addiction, abuse, and overdose, opioids are generally considered a last-line option for managing neuropathic pain. If used in this setting, using the lowest possible dose is prudent (Online Table 2).

Table 2: Drugs for Managing Neurophathic Pain

Drug

Mechanism of Action

Advantages

Disadvantages

Dosing

Titration

Tricyclic Antidepressants

Amitriptyline

Increases serotonin and norepinephrine; blocks sodium channels

Sedation; antidepressant effects; less anticholinergic (nortriptyline)

Sedation; anticholinergic effects (amitriptyline); drug—drug interactions; cardiac arrhythmias

Initial: 25 mg/day

Target: 100 mg/day

Increase by 25 mg intervals every 3-5 days

Nortriptyline

Initial: 10 mg daily

Target: 100 mg/day

Increase in 10- mg intervals every 3-5 days

Serotonin/Norepinephrine Reuptake Inhibitors

Venlafaxine

Increases concentrations of serotonin and norepinephrine by inhibiting the reuptake of serotonin and norepinephrine into the synapse

Antidepressant and antianxiolytic effects

Nausea; changes in behavior/mood; hepatic impairment (venlafaxine and duloxetine); renal impairment (venlafaxine and milnacipran); blood pressure changes (venlafaxine and milnacipran)

Initial: 37.5 mg/day

Target: 225 mg/day

Increase by 37.5 mg in the first week, then increase by 75 mg weekly

Duloxetine

Initial: 30 mg/day

Target: 60 mg/day

Increase by 30 mg after first week

Milnacipran

Initial: 12.5 mg/day

Target: 100 mg/day

Increase by 12.5 mg twice daily on days 2-3, and by 25 mg twice daily on days 4-7; then 50 mg twice daily

Calcium channel Alpha₂-Delta Ligands

Gabapentin

Binds to alpha₂-delta subunit of voltage-gated calcium channels and decreases pain mediators substance P, norepinephrine, and glutamate

Inexpensive; sedation

Sedation, weight gain, swelling, mental status changes, pharmacokinetic variability

Initial: 300 mg/day

Target: 1800-2400 mg/day, divided in 3-4 daily doses

Increase by 300 mg every 3 days

Pregabalin

Sedation; consistent pharmacokinetics

Expensive; sedation; weight gain; swelling; mental status changes

Initial: 150 mg/day, divided

Target: 600 mg/day, divided into 2-3 daily doses

Increase by 150 mg every 7 days

Anticonvulsant;

Sodium Channel Blocker

Topiramate

Inhibits voltage-gated sodium channels and antagonizes glutamate receptors

Promotes weight loss; migraine prophylaxis; typically well- tolerated

Mental status changes (trouble with word recall; delayed response); kidney stones; sedation; glaucoma

Initial: 25 mg/day

Target: 200 mg/day, divided into 2 daily doses

Increase by 25 mg every 7 days

Topical Analgesic

Lidocaine patch

Decreases permeability of neurons by sodium ions, which blocks conduction

Minimal systemic absorption; localized anesthetic

Redness; irritation; skin edema

Apply 1-3 patches to painful area; on for 12 hr, then off for 12 hr

No titration needed

THE PHARMACIST’S ROLE

Pharmacists can play a beneficial role in treating patients suffering from neuropathic pain, regardless of the area of specialty. Pharmacists know and understand the risks and benefits of these medications best, and can play an important role in educating patients and other health care providers. Pharmacists can ensure patients are well informed about the risks and can provide reasonable expectations regarding potential improvement in pain.

Ericka Huckle is a PharmD candidate at the UNC Eshelman School of Pharmacy. Lauren McKnight, PharmD, CPP, BCACP, is a clinical pharmacist practitioner at the University of North Carolina (UNC) Medical Center, Department of Pharmacy, and an assistant professor of Clinical Education at the UNC Eshelman School of Pharmacy.

References

• Scholten PM, Harden RN. Assessing and treating patients with neuropathic pain. PM R. 2015;7(11 Suppl):S257-S269. doi: 10.1016/j.pmrj.2015.08.014.
• Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010;9(8):807-819. doi: 10.1016/S1474-4422(10)70143-5.
• Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010;150(3):573581. doi: 10.1016/j.pain.2010.06.019.
• Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;4:CD005454.
• Robertson K, Marshman LA, Plummer D. Pregabalin and gabapentin for the treatment of sciatica. J Clin Neurosci. 2015; in press. doi: 10.1016/j.jocn.2015.05.061. [Epub ahead of print]
• Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011;3:CD007938. doi: 10.1002/14651858.CD007938.pub2.
• Grice GR, Mertens MK. Gabapentin as a potential option for treatment of sciatica. Pharmacotherapy. 2008;28(3):397-402. doi: 10.1592/phco.28.3.397.
• Tölle T, Freynhagen R, Versavel M, Trostmann U, Young JP Jr. Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study. Eur J Pain. 2008;12(2):203-213. Epub 2007 Jul 16.
• Vranken JH, Dijkgraaf MGW, Kruis MR, van der Vegt MH, Hollmann MW, Heesen M. Pregabalin in patients with central neuropathic pain: A randomized, double-blind, placebo-controlled trial of a flexible-dose regimen. Pain. 2008;136(1-2):150-157. Epub 2007 Aug 20.
• Siddall PJ, Cousins MJ, Otte A, Griesing T, Chambers R, Murphy TK. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology. 2006;67(10):1792-1800.
• van Seventer R, Bach FW, Toth CC, et al. Pregabalin in the treatment of post-traumatic peripheral neuropathic pain: a randomized double-blind trial. Eur J Neurol. 2010;17(8): 1082-1089. doi: 10.1111/j.1468-1331.2010.02979.x.