Neuropathic Pain Calls for aRange of Treatment Options

Pain of neuropathic origin can result from multiple causes, including certain infections, disease states, or even medications. Some of the more common causes include herpes zoster (shingles), diabetes mellitus, HIV, certain chemotherapeutic and antiretroviral (ARV) medications, and trigeminal neuralgia. Neuropathic pain can manifest as ongoing pain, stimulusdependent pain called hyperalgesia, or even pain resulting from light touch called allodynia.¹

Neuropathic pain may not be relieved by medications typically used in many other pain conditions, including nonsteroidal anti-inflammatory drugs and acetaminophen. Some medications that have been studied to treat neuropathic pain include tricyclic antidepressants (TCAs), gabapentin and other antiepileptics, topical lidocaine, selective serotonin/norepinephrine reuptake inhibitors, and topical capsaicin.

In the case of diabetes, it is important to encourage glycemic control to minimize the risk of peripheral neuropathies (PN). The Diabetes Control and Complications Trial demonstrated a reduction in diabetic neuropathy with tighter blood-glucose control.² In contrast to painful neuropathy, some patients may experience numbness or tingling.

It is still uncertain how much improvement can be attained from tight glucose control in existing neuropathy.

Duloxetine (Cymbalta) and pregabalin (Lyrica) are both approved by the FDA for the management of neuropathic pain caused by diabetic peripheral neuropathy. ^3,4 A set of consensus guidelines published in 2006 lists duloxetine, pregabalin, and also tricyclics as preferred agents.⁵ Second-line agents include gabapentin, tramadol, carbamazepine, extended-release venlafaxine, and lamotrigine.⁵ Alpha-lipoic acid has also been studied and demonstrated favorable outcomes in improving the symptoms of diabetic neuropathy at a dose of 600 mg daily.⁶

The long-term pain associated with herpes zoster is called postherpetic neuralgia (PHN). Some refer to PHN as pain that is present for >4 months after the initial rash caused by herpes zoster.⁷ Older patient age and more severe rash and acute pain put an individual at greater risk for developing PHN.⁸

One study looked at the early use of amitriptyline to prevent the occurrence of PHN.⁹ Amitriptyline 25 mg daily was initiated at rash onset and continued for 90 days. The treatment group had almost half the pain prevalence as the placebo group at 6 months. Medications that have been studied and found effective in treating PHN include tricyclic antidepressants, opioids, tramadol, topical capsaicin, gabapentin, pregabalin, and topical lidocaine patches.¹⁰ Pregabalin is approved for the management of PHN.⁴

HIV medications that are associated with the highest risk of neuropathy include stavudine, didanosine, and zalcitabine.¹¹ With the introduction of many new medications to treat HIV, these agents are used less in current practice and are not preferred for first-line treatment, according to the 2006 Department of Health and Human Services Guidelines for the Use of Antiretroviral Agents in HIV-1- Infected Adults and Adolescents.¹² For patients who have been or are receiving these ARVs and experience painful neuropathy, an attempt should be made to switch patients to other effective ARVs that will minimize the progression of this effect.

HIV itself may have some role in neuropathic pain. It is hard to distinguish between HIV-related and ARV-related neuropathy. Risk factors for neuropathy in HIV-infected individuals include exposure to non-nucleoside reverse transcriptase inhibitors, patient age, and diagnosis of AIDS.¹³ Treatment is the same for either and typically includes gabapentin or TCAs.¹⁴

Chemotherapeutic agents used to treat cancer that have been associated with peripheral neuropathy include vinca alkaloids (vincristine, vinblastine), taxanes (paclitaxel, docetaxel), and platinum- based medications (cisplatin, carboplatin). ^15,16

Duration of infusion, dose per cycle, cumulative dose, and concomitant comorbidities are risk factors for the development of peripheral neuropathy. Patient age and administration of more than 1 neurotoxic agent may also be risk factors.¹⁷ Symptoms usually improve once the offending medication is discontinued or the dose is reduced.

Currently, no chemoprotective agents have proven to reduce the instance of PN in patients receiving offending chemotherapy, although several agents are under investigation.¹⁷ As in other instances of neuropathic pain, gabapentin or amitriptyline may be effective.

Trigeminal neuralgia is pain occurring in the distribution of the fifth cranial nerve.¹⁸ It is usually unilateral and described as lancinating or stabbing pain. Carbamazepine has shown to be effective and provide pain relief in patients with trigeminal neuralgia.^19,20 Many antiepileptics, including phenytoin, valproic acid, lamotrigine, oxcarbazepine, topiramate, and gabapentin have also shown relief in trigeminal neuralgia.^21-26

If a patient does not respond to medication, there are other treatment options including surgical and gammaknife radiosurgery. Microvascular decompression of the trigeminal root is an open surgical procedure that is effective but is associated with more risk than other less invasive procedures.¹⁸

It is important to remember that there are many causes of neuropathy. Appropriate medication and medical history along with laboratory values should be used to rule out other causes, including vitamin deficiencies. Medication effectiveness is assessed subjectively by a patient?s report of a decrease in pain. Each drug should be titrated up to the effective dose until the maximum daily dose is reached or dose-limiting side effects are experienced. Dose ranges for some of the more commonly used medications are listed in Tables 1 through 3.

Pharmacists can assess patient response at each refill date and make suggestions to the physician in regard to dose escalation or notification of intolerable side effects. Pharmacists should remember that it may take several weeks for some medications to provide maximal benefit.

References

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2. Diabetes Control and Complications Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med. 1995;122:561.

3. Cymbalta. Available at: http://pi.lilly.com/us/cymbalta-pi.pdf.

4. Lyrica: Highlights of prescribing information. Available at: www.pfizer.com/pfizer/download/uspi_lyrica.pdf.

5. Argoff CE, Backonja MM, Belgrade MJ, et al. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin Proc. 2006;81(4 suppl):S12-S25.

6. Ziegler D, Nowak H, Kempler P, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21:114.

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9. Bowsher D. The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage. 1997;13:327-331.

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11. Cherry CL, Skolasky MA, Lal L, et al. Antiretroviral use and other risks for HIV-associated neuropathies in an international cohort. Neurology. 2006;66:867-873.

12. US Department of Health and Human Services Guidelines. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. October 2006.

13. Lopez OL, Becker JT, Dew MA, Caldararo R. Risk modifiers for peripheral sensory neuropathy in HIV infection/AIDS. Eur J Neurol. 2004;11(2): 97-102.

14. AIDS Therapy. 748-751.

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17. Lee JJ, Swain SM. Peripheral neuropathy induced by microtubule-stabilizing agents. J Clin Oncol. 2006;24(10):1633-1642.

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19. Campbell FG, Graham JG, Zilkha KJ. Clinical trial of carbazepine (Tegretol) in trigeminal neuralgia. J Neurol Neurosurg Psychiatry. 1966;29:265-267.

20. Wiffen P, Collins S, McQuay H, Carroll D, Jadad A, Moore A. Anticonvulsant drugs for acute and chronic pain. Cochrane Database Syst Rev. 2000;CD001133.

21. Braham I, Saia A. Phenytoin in the treatment of trigeminal and other neuralgias. Lancet. 1960;2:892.

22. Peiris JB, Perera GL, Devendra SV, Lionel ND. Sodium valproate in trigeminal neuralgia. Med J Aust. 1980;2:278.

23. Zakrzewska JM, Chaudhry Z, Nurmikko TJ, Patton DW, Mullens EL. Lamotrigine (Lamictal) in refractory trigeminal neuralgia: results for a double-blind placebo controlled crossover trial. Pain. 1997;73:223-230.

24. Khan OA. Gabapentin relieves trigeminal neuralgia in multiple sclerosis patients. Neurology. 1998;51:611-614.

25. Zvartau-Hind M, Din MU, Gilani A, Lisak RP, Khan OA. Topiramate relieves refractory trigeminal neuralgia in MS patients. Neurology. 2000;55:1587-1588.

26. Zakrzewska JM, Patsalos PN. Oxcarbazepine: a new drug in the management of intractable trigeminal neuralgia. J Neurol Neurosurg Psychiatry. 1989;52:472-476.