Ami Teague, PharmD, BCPS

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.

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.

 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. 

 A set of consensus guidelines published in 2006 lists duloxetine, pregabalin, and also tricyclics as preferred agents.

 Second-line agents include gabapentin, tramadol, carbamazepine, extended-release venlafaxine, and lamotrigine.

 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.

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.

 Older patient age and more severe rash and acute pain put an individual at greater risk for developing PHN.

One study looked at the early use of amitriptyline to prevent the occurrence of PHN.

 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.

 Pregabalin is approved for the management of PHN.

HIV medications that are associated with the highest risk of neuropathy include stavudine, didanosine, and zalcitabine.

 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.

 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.

 Treatment is the same for either and typically includes gabapentin or TCAs.

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). 

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.

 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.

 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.

 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.

 Many antiepileptics, including phenytoin, valproic acid, lamotrigine, oxcarbazepine, topiramate, and gabapentin have also shown relief in trigeminal neuralgia.

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.

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.

1. Campbell JN, Meyer RA. Mechanisms of neuropathic pain. 

2. Diabetes Control and Complications Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. 

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. 

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

7. Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. 

8. Jung BF, Johnson RW, Griffin DR, Dworkin RH. Risk factors for postherpetic neuralgia in patients with herpes zoster. 

9. Bowsher D. The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, double-blind, placebo-controlled trial. 

10. Alper BS, Lewis PR. Treatment of postherpetic neuralgia: a systematic review of the literature. 

11. Cherry CL, Skolasky MA, Lal L, et al. Antiretroviral use and other risks for HIV-associated neuropathies in an international cohort. 

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. 

15. Cata JP, Weng HR, Lee BN, Reuben JM, Dougherty PM. Clinical and experimental findings in humans and animals with chemotherapy-induced peripheral neuropathy. 

16. Visovsky C. Chemotherapy-induced peripheral neuropathy. 

17. Lee JJ, Swain SM. Peripheral neuropathy induced by microtubule-stabilizing agents. 

18. Edlich RF, Winters KL, Britt L, Long WB 3rd. Trigeminal neuralgia. 

19. Campbell FG, Graham JG, Zilkha KJ. Clinical trial of carbazepine (Tegretol) in trigeminal neuralgia. 

20. Wiffen P, Collins S, McQuay H, Carroll D, Jadad A, Moore A. Anticonvulsant drugs for acute and chronic pain. 

21. Braham I, Saia A. Phenytoin in the treatment of trigeminal and other neuralgias. 

22. Peiris JB, Perera GL, Devendra SV, Lionel ND. Sodium valproate in trigeminal neuralgia. 

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. 

24. Khan OA. Gabapentin relieves trigeminal neuralgia in multiple sclerosis patients. 

25. Zvartau-Hind M, Din MU, Gilani A, Lisak RP, Khan OA. Topiramate relieves refractory trigeminal neuralgia in MS patients. 

26. Zakrzewska JM, Patsalos PN. Oxcarbazepine: a new drug in the management of intractable trigeminal neuralgia. 

Articles

Dr. Teague is a clinical pharmacist with St. George's Clinic at Cooper Green Hospital, Birmingham, Ala.

Neuropathic Pain Calls for aRange of Treatment Options

Many advances have occurredin the treatment of humanimmunodeficiency virus (HIV)and acquired immune deficiency syndrome(AIDS) in the past decade. Currently,21 separate chemical entitieshave been approved by the FDA totreat HIV, along with 5 combinationproducts. Four classes of antiretroviralshave activity against HIV, and newclasses are under investigation. Whatwas once considered a terminal illnesshas progressed to a manageable chronicdisease through the use of theseantiretroviral medications.

While life expectancies as well asmedication exposure have increased,issues such as medication resistanceand long-term adverse effects havefactored into the decision about whento start medication treatment in individualsinfected with HIV. The currentguidelines from both the Departmentof Health and Human Services and theInternational AIDS Society-USA giverecommendations on when to startantiretrovirals (Table 1).

Commonly, antiretroviral regimensinclude at least 2 nucleoside reversetranscriptase inhibitors (NRTIs) combinedwith a non-nucleoside reversetranscriptase inhibitor (NNRTI) or a proteaseinhibitor (PI). Table 2 lists the preferredagents in each class to be usedin patients who have not previouslyreceived antiretrovirals.

NRTIs are the oldest class of antiretrovirals.A combination of medicationsfrom this class is used to createwhat is called the backbone of a patient'sregimen.

All NRTIs except abacavir must bedose-adjusted in patients with renaldysfunction. Every NRTI also carries therare but serious risk of lactic acidosis.The proposed mechanism for thisadverse event is the medication's toxicityto mitochondria. Some NRTIs arethought to carry a higher risk (didanosine,stavudine), whereas others arethought to be less likely to cause lacticacidosis (tenofovir, abacavir, lamivudine,emtracitabine).

reverse transcriptase inhibitor.It does not have to be intracellularlyphosphorylated before becomingactive, as the nucleosides do.

Even though the FDA has approved 3NNRTIs, only 2 are typically used inpractice. These 2 NNRTIs are efavirenzand nevirapine. Etravirine (TMC-125) isan NNRTI currently in phase 3 studies.

NNRTIs do not require dosing adjustmentin patients with renal dysfunction.Efavirenz is teratogenic and shouldbe avoided in pregnant women orthose who may become pregnant. It alsocan cause a false positive on tetrahydrocannabinoldrug screens and hascentral nervous system-related sideeffects. Nevirapine can cause hepatotoxicityand rash and must be dosed athalf the full dose for 2 weeks beforebeing titrated up to the full dosage.

Medication adherence is particularlyimportant with NNRTIs. Only one mutationis required to confer resistance tothe NNRTIs. Newer second-generationNNRTIs, including etravirine, will playan important role in therapy, becausethey will have a different resistanceprofile.

The most recent guidelines publishedin October 2006 stress theimportance of using boosted PI regimens.

Boosting involves using lowdoseritonavir to inhibit the metabolismof the PI in order to get better drugconcentrations. Nelfinavir is the only PIthat cannot be boosted by ritonavir.Regimens that contain a boosted PIshould be taken with food to decreasegastrointestinal upset. Table 3 lists thetypical boosted-PI doses and intervals.

PIs are metabolized hepatically bythe cytochrome P-450 system andtherefore have some significant druginteractions. Some common interactionsinvolve simvastatin, lovastatin,ergot alkaloids, St. John's wort, midazolam,triazolam, phosphodiesterase-5inhibitors (erectile dysfunction drugs),rifampin, and some enzyme-inducinganticonvulsants. Ritonavir, in particular,is a very potent CYP3A4 inhibitor. PIsrequire no dosing adjustments forrenal dysfunction.

Acid suppression can cause decreasedconcentrations of atazanavir.Therefore, proton pump inhibitors arecontraindicated with the use ofatazanavir. Also, histamine

receptorantagonists must be separated fromatazanavir dosing by 10 to 12 hours.

Newer PIs (tipranavir, approved in2005, and darunavir, approved in 2006)have been developed to treat virus thatis resistant to many of the older PIs.The RESIST and POWER trials demonstratedthat adding one of these newPIs to a patient's regimen along withenfuvirtide gave stronger results thanthe addition of the PI alone.

Metabolic syndrome has been associatedwith the long-term use of PIs. Someexperts argue that the virus itself alsocontributes to these effects that includeincreased lipids, increased blood glucose,and fat redistribution (sometimesreferred to as 

The only FDA-approved medicationthat inhibits the entry of the virus intohost cells is enfuvirtide. It acts byinhibiting the fusion of the virus intothe CD

cell membrane. Enfuvirtide isadministered by subcutaneous injectiontwice daily.

This medication is reconstituted bythe patient and is stable for only 24hours once reconstituted. Because itcan take up to 45 minutes for the medicationto fully go into solution, it isusually easier for patients to reconstitute2 doses at a time and store thesecond one in the refrigerator for 12hours until the next injection.

The main side effect of enfuvirtide islocal injection site reactions. Patientsare advised to rotate injection sitesbetween the thighs, abdomen, andupper arm.

Although no integrase inhibitorshave yet been approved by the FDA, 2are showing promise in clinical trials,MK-0518 and GS-9137. These medicationsinhibit the virus' ability to incorporateitself into host DNA and preventthat cell from producing new virus.

Stavudine and zidovudine are thymidineanalogues and compete for phosphorylationonce inside the cell. Therefore,these 2 medications are antagonisticand should not be used together.

Zidovudine can cause anemia andshould not be combined with othermedications that are myelosuppressive.Other medications that have overlappingtoxicities and should be avoidedtogether include stavudine anddidanosine. Both of these medicationshave a propensity to cause peripheralneuropathy, pancreatitis, and hyperlactatemia.

Didanosine and tenofovir were oncecommonly used together. Studies haveshown, however, that, in addition to apharmacokinetic interaction that can befixed with dose adjustments of didanosine,patients do not have the expectedincrease in CD

count when these 2medications are used together.

Because of the many drug interactions,side effects, and development ofresistance, pharmacists must pay closeattention to the dispensing of antiretrovirals.Pharmacists should instill inpatients the importance of getting alltheir medications from one pharmacyand getting timely medication refills.They also should develop a working relationshipwith patients' physicians. 

1. Department of Health and Human Services Guidelines. Guidelines for the use ofantiretroviral agents in HIV-1-infected adults and adolescents. October 10, 2006.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.

2. Hammer S, Saag M, Schechter M, et al. Treatment for adult HIV infection. 2006recommendations of the International AIDS Society-USA panel. 

3. Moyle G. Mechanisms of HIV and nucleoside reverse transcriptase inhibitorinjury to mitochondria. 

4. Grossman HA, Hicks C, Nadler J, et al. Efficacy and tolerability of TMC125 inHIV patients with NNRTI and PI resistance at 24 weeks: TMC125-c223. Programand abstracts of the 45th Interscience Conference on Antimicrobial Agents andChemotherapy; December 16-19, 2005; Washington, DC. Abstract H-416c.

5. Reyataz package insert. Available at: www.reyataz.com.

6. Agarwala S, Gray K, Wang Y, Grasela D. Pharmacokinetic effect ofomeprazole on atazanavir co-administered with ritonavir in healthy subjects.Abstracts of the 12th Conference on Retroviruses and OpportunisticInfections; February 22-25, 2005; Boston, Mass. Abstract 658.

7. Gazzard B, Antinori A, Cheli C, et al. Combined analysis of RESIST 96-weekdata: durability and efficacy of tipranavir/r in treatment-experienced patients; 8thInternational Congress on Drug Therapy in HIV Infection; November 12-16,2006; Glasgow, UK. Abstract #950386.

8. Wilkin T, Haubrich R, Steinhart C, et al. TMC114/r superior to standard of carein 3 class-experienced patients: 24 wks primary analysis of the Power 2 study(C202). Abstracts of the 45th Interscience Conference on Antimicrobial Agentsand Chemotherapy; December 16-19, 2005; Washington, DC. Abstract H-413.

9. Fuzeon package insert. Available at: www.fuzeon.com.

10. Lalezari JP, Henry K, O'Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor,for drug-resistant HIV infection in North and South America. 

11. Miller M, Witmer M, Stillmock K, et al. Biochemical and antiviral activity ofMK-0518, a potent HIV integrase inhibitor. Abstracts of XVI International AIDSConference; August 13-18, 2006; Toronto, Canada. Abstract THAA0302.

12. DeJesus E, Berger D, Markowitz M, et al. Antiviral activity, pharmacokinetics,and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) intreatment-naive and treatment-experienced patients. 

13. Barrios A, Rend?n A, Negredo E, et al. Paradoxical CD4+ T-cell decline in HIV-infectedpatients with complete virus suppression taking tenofovir anddidanosine. 