Neuropathic Pain: Diagnosis, Treatment, and the Pharmacist's Role in Patient Care

Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

• Review the types and prevalence of neuropathic pain.
• Understand the direct and indirect costs of neuropathic pain.
• Discuss the diagnosis of neuropathic pain and why thiscondition can be misdiagnosed.
• Review the benefits and risks associated with currenttreatments.
• Evaluate new and emerging treatments for neuropathic pain.
• Specify the role of the pharmacist in providing medicationtherapy management services to the patient with neuropathicpain.
• Provide counseling points for patients with neuropathic pain.
• Review resources available to the pharmacist about chronicand neuropathic pain.

See Exam on Page 107

This educational lesson will be available to pharmacists on-line at www.pharmacytimes.com.

Neuropathic pain afflicts an estimated4 million people in theUnited States.¹ The conditionoriginates from an injury to either theperipheral or central nervous system(CNS) or to both and develops into achronic disorder. Examples of neuropathicpain syndrome include diabeticperipheral neuropathy (DPN), phantomlimb pain, HIV sensory neuropathy,postherpetic neuralgia (PHN), centralpoststroke pain, low back and neckpain with a neuropathic origin, complexregional pain syndrome, and multiplesclerosis pain. It is estimated thatof the 18 million patients with diabetesin this country, 5% to 50% are affectedby DPN, with the incidence and prevalenceincreasing over the number ofyears with diabetes.² About 800,000people in the United States each yeardevelop shingles, with 25% to 50%developing PHN as a complication ofthe herpes zoster virus.³ Being 50 yearsof age or older is a risk factor for developingPHN following herpes zoster.This painful condition severely affectsthe ability of the individual to performdaily activities and ultimately affectshis or her overall quality of life. Centralneuropathic pain is estimated to occurin 2% to 8% of all stroke patients.⁴Neuropathic pain is also associatedwith chemotherapy and direct traumaticinjury to the nerves. Table 1 listscommon underlying causes of neuropathicpain.

Neuropathic pain is classified as atype of chronic pain. It differs fromacute nociceptive pain, which is paincaused by the normal activation ofneural pathways in response to a pain-initiatingstimulus. Hallmark characteristicsof neuropathic pain are loweringof the pain threshold andexcitation of the nerve pathways longafter the initial injury has healed. Thepain becomes chronic in nature, andsevere, and often is not responsive tothe usual treatments for acute pain.The CNS is composed of the brain andspinal cord, whereas the peripheralnervous system includes nerves to thehands, feet, legs, and arms, and thelink, at the dorsal horn, between thespinal cord and the rest of the body.Neuropathic pain results from damageto or changes in the central andperipheral nervous systems. The injuryand malfunction to the nervous systembecome the source of pain and becomea chronic disease.

An understanding of the pathophysiologyof neuropathic pain allows theclinician to target particular neurochemicalsand receptor sites withappropriate rational pharmacotherapy.The pathophysiology of neuropathicpain is complex and mediated througha variety of mechanisms. Beginningwith injury to the nerve, sensitizationand overstimulation of the nerve pathwaysoccurs, along with release of excitatoryneurochemicals and inflammatoryneuropeptides. C fibers are thesmall unmyelinated or unsheathedafferent nerves taking impulses fromthe periphery to the spinal cord. Theyconduct nerve impulses relatively slowly,are of a low threshold nature, andpenetrate deep into the spinal cord.Repetitive stimulation of the C fibersresults in prolonged discharge or spontaneousactivity of the neuron in thedorsal horn of the spinal cord. Thissensitization leads to release of excitatoryamino acids such as glutamate.Glutamate is a neurochemical that canattach itself to the N-methyl-D aspartate(NMDA) receptor site and furtherexcite other neurons. It follows thatagents that are NMDA-receptor antagonists,such as ketamine, dextromethorphan,and memantine, could blockthis excitation. Sensitization in thedorsal horn eventually leads toincreased activity of neurons or hyperexcitabilityof the nerves and adecrease in the pain threshold. Anincreased number of adrenergic receptorscan develop along the length ofthe C fibers, resulting in increased sensitivityand an increase in sympatheticallymediated pain signals. Agentsthat prevent reuptake of catecholaminesat these receptor sites, such astricyclic antidepressants (TCAs), areeffective in preventing pain signaltransmission. Nerve injury in theperiphery also can result in the releaseof inflammatory neuropeptides, substanceP, and prostaglandins. Anothermechanism of pain transmission is thecontinuous electrical discharge alongthe nerve fiber resulting in "ectopic"activity. These electrical dischargescontinue to fire, generating impulseseven in the absence of stimulation orinjury and are related to an increase inthe number of sodium channels.Sodium channels facilitate sodiuminflux, enabling continuation of theaction potential or electrical impulse totravel along the nerve pathway. Anticonvulsantagents are useful in blockingthese channels. Ectopic dischargesalso occur in the cells at the dorsal rootand lead to hyperactivity of the neuronsin the spinal cord.

Economic, Human, andSocietal Costs

Neuropathic pain is costly. Individualsaffected by neuropathic pain areoftentimes high users of the health caresystem as they search for relief frompersistent suffering. Much of the availablecost data defines costs relative tochronic pain in general so that costsattributable to neuropathic pain arecontained with those numbers. TheAmerican Pain Society conducted a surveydemonstrating that most peoplewith chronic/persistent pain had beenexperiencing their pain for more than 5years, and one third described the painas the "worst ever." Many sufferers hadto visit multiple physicians to achieveonly partial relief from their pain.⁵Direct and indirect costs of persistentpain, including neuropathic pain, arederived from economic, human, andsocietal components. The economicburden relates to direct medical costsand productivity loss in the workplace.Chronic pain sufferers may becomeunemployable or remain underemployed.The National Institute forOccupational Safety and Health estimatesthat chronic pain costs $100 billionannually in lost workdays, medicalexpenses, and other benefit costs.⁶ Interms of human costs, living withchronic pain affects patients' day-todayability to function. Physical andmental problems include difficulties insleeping, impaired concentration, anddecline in cognitive abilities. Pain contributesto disruption of sleep patterns,which can foster irritability, leading toenhanced sensitivity to pain, and thepatient becomes caught up in a viciouscycle. Anger, fear, depression, and anxietyare common and may lead to suicidalideations, attempted suicide, orsuccessful suicide.

Neuropathic pain is also responsiblefor societal burdens. The patient withneuropathic pain becomes isolatedbecause of the loss of functioning, andthe impact on the family can strainrelationships. For these reasons, patientsbenefit from a multidisciplinaryapproach to treatment. Team memberssuch as a psychiatrist, psychologist,social worker, occupational and physicaltherapist, nurse, pharmacist, andphysician are integral to treating thepatient holistically.

Diagnosis of Neuropathic Pain: The Role of thePharmacist

Neuropathic pain can be misdiagnosedand treated as musculoskeletalpain. When the diagnosis of neuropathicpain is overlooked, the patientmay be treated inappropriately, leadingto months or even years of mismanagedchronic persistent pain anddecreased function. The pharmacistcan assist in the recognition of thiscondition, which manifests in heterogeneoussymptoms (Table 2).

It can be difficult for the patient toseparate the neuropathic pain fromother chronic pain, particularly if thereis tissue damage. In addition, patientsmay be unfamiliar with the terminologyto describe this type of pain, or donot think this complaint is importantenough to share with the physician,adding to the difficulty in diagnosingthis type of pain. Patients may find itdifficult to describe the pain and complainof exaggerated responses toslightly painful stimuli. The pain maypresent months after the initial nerveinjury. Common questions that pharmacistsmay face include, what is neuropathicpain, and why do I experiencethis type of pain? What is the differencebetween nerve and muscle pain,and is this type of pain serious? Cannerve pain have a variety of symptoms,and can it affect my sleep? Can nervepain be cured?

When assessing the patient, variousbits of information should be obtained.Pharmacists can assess patients for painin a primary care/ambulatory carepractice as part of the vital signs package,pain being the 5th vital sign, andupon follow-up to determine therapeuticeffect of interventions, which areprimarily pharmacologic. The pharmacistshould review all the componentsof pain assessment, such as the onset/duration of pain, location, quality,intensity, aggravating or relieving factors,and emotional factors contributingto or the result of pain. Certain keyterms used to describe the pain are specificto neuropathic pain, includingburning, tingling, electric shock-like,shooting, radiating, or statements suchas "it feels like I am walking on brokenglass." For example, diabetic neuropathyhas been described as pins and needlesin the feet, legs, or hands.Descriptions of constant, stabbing, andelectric shock-like sensation can be representativeof PHN. Other associatedcharacteristic descriptions of neuropathicpain are related to the uniquephysiology of this type of pain. Thepatient may say that even the bedsheets hurt. Such patients may be sufferingfrom allodynia associated withthe neuropathic pain. Allodynia is theperception of pain to a greater degreethan would be expected consideringthe pain stimulus. More specific diagnosisby the physician may reveal theunderlying cause of the neuropathy.See Table 3 for diagnostic testing performedby the physician.

Patients suffering with chronic pain/neuropathic pain usually have a longhistory of seeking treatment, becausethe relief achieved is usually only partial.Patients should be questioned as tothe current and prior attempts to managetheir own pain, and what treatmentor strategy was successful andwhat was not. Treatment strategiesinclude pharmacologic treatments,alternative treatments such as chiropracticand acupuncture, and copingstrategies. It is useful to explore thepatient's history of medical problemsrelative to surgeries and accidents; psychosocialhistory such as job stressors,unemployment, compensation issues;family history focusing on interpersonaldynamics; and psychological effectsof the persistent pain on mental statusand emotions to get a comprehensivepicture of the patient. The patient'sfunctional baseline should also beassessed as it relates to the patient'swork, family activities, care for thehouse and other family members, andthe ability to participate in sports orhobbies.

Neuropathic pain in the diabeticpatient can be thought of as the forgottensymptom, being lost in the myriadof other higher-priority medical problems.The pharmacist can conductbaseline and periodic assessment of thepatient's reported pain by using thevisual analog scale or the numeric ratingscale (NRS) along with the neuropathicpain scale (NPS) and by performinga filament examination of thefeet. The NPS might help the clinicianto identify distinct pain symptoms andtarget specific treatment depending onthe quality of the pain reported. Thescale focuses on adjectives that havebeen shown to be associated with neuropathicpain. In the NPS scale, thepatient is asked to measure intensity,severity, and qualities such as sharp,hot, dull, cold, sensitive, itchy, deeppain, or surface pain.⁷

The physician will perform the neurologicexamination and possiblyorder various diagnostic studies toassist in the assessment of thepatient's pain. The neurologic exambegins with sensory testing for touch,pain, temperature, and vibration. Thepatient will also be assessed for painperception—allodynia is assessedwith a nonpainful stimulus, andhyperalgesia is assessed with pinpricks.Muscle strength, coordination,and gait pattern can be observed as anindication of limitations imposed bynerve pain, which can compromisethe skeletal structure over time.Additional diagnostic studies such asx-ray, computed axial tomography(CAT) scan, or magnetic resonanceimaging (MRI) can be ordered to ruleout medical problems that could betreated, leading to a resolution of thepain complaint. Underlying causes ofnerve pain include diseases such asacquired immune deficiency syndrome(AIDS), diabetes, cancer, orshingles. Peripheral neuropathy maybe associated with diabetes, renal failure,chemotherapy, amyloidosis,infections such as HIV, PHN, nerveentrapment, amputation, or ischemia.Central neuropathy follows aninjury to the CNS secondary to trauma,malignancy, inflammation, vascularproblems, cerebrovascular accident,or multiple sclerosis.

Laboratory and serologic analysismay also be used to rule out medicalproblems. Electromyography andnerve conduction velocity tests havelimitations in that these do not necessarilyassess the specific function ofthe small nerve fibers and the C fibersinvolved in the pathophysiology ofneuropathic pain.

The Pharmacist's Plan of Care

The pharmacist's plan of careinvolves a discussion of the expectationsand goals of treatment. A clearunderstanding of the treatments orderedcan be reviewed along with theschedule for monitoring therapies andlaboratory follow-up. Because neuropathicpain takes a chronic course, it isusually only partially responsive totreatments. The pain more than likelywill not be totally eradicated, so thepatient needs to be counseled aboutsetting realistic expectations andachievable goals. Questions to considerinclude "What are the functional abilitiesthe patient hopes to achieve, suchas the ability to ambulate? What willbe the overall quality of life the patienthopes to achieve?"

Patients with neuropathic pain frequentlydevelop comorbidities such asinsomnia, depression, and anxiety. Thepharmacist assessing the patient forinsomnia should ask the followingquestions:

• "Do you have difficulty getting tosleep or staying asleep?"
• "Do you wake up early in themorning such as by 3:30 or 4 AM?"

The pharmacist should also reviewsleep hygiene in general, includingnapping patterns during the day. All ofthese efforts will contribute to improvedsleep patterns and decreasedfatigue and drowsiness the next day,contributing to a better quality of life.Depression and anxiety can be assessedusing standard self-rating scales and bychecking for the presence of symptomslisted in the Diagnostic and StatisticalManual of Mental Disorders, RevisedFourth Edition (DSM-IV-R). Such symptomsinclude feelings of guilt or lack ofself-worth, isolation from family andfriends, crying spells, lack of appetite,weight loss, waking early in the morning,difficulty in concentrating, irritability,and feelings of fatigue.Symptoms of anxiety include excessiveworry about events or activities wherethe individual cannot control thesefeelings, restlessness and feeling edgy,fatigue, trouble concentrating, irritability,insomnia, increased muscle tension.In depression and anxiety, the symptomsare considered severe enough toimpair the patient's ability to work orimpair social, family, or personal relationships.

Current Treatments

Treatments for neuropathic paincover a wide range of options reflectingthe multidisciplinary nature of care forthe patient (Table 4). Treatmentsinclude psychological management ofthe chronic pain through stress management,relaxation, biofeedback, cognitivebehavioral techniques, andcounseling by a psychologist or psychiatrist.In addition, multiple agents areoffered as pharmacologic treatment ofneuropathic pain. Often these agentsare used in combination, with continuedevaluation for efficacy being a crucialelement of the managementprocess. Patients may respond poorlyto any single agent or a combination ofagents. Finding the effective treatmentis often a challenging and labor-intensivejourney.

Pharmacologic Agents

A number of pharmacologic agentsare available for the treatment of neuropathicpain (Table 5). First-lineagents include TCAs, gabapentin, topicallidocaine, opioids, and tramadol.⁸Pharmacotherapy is considered notonly for pain management but also totreat common comorbidities such asdepression and anxiety. The TCAs andantidepressants exhibiting the mixedmechanism of serotonergic and adrenergicreuptake blockade are more effectivefor the treatment of neuropathicpain than the selective serotonin reuptakeinhibitors. Clinical trials of TCAshave demonstrated efficacy in DPN,although the drugs are not FDA-approvedfor this indication. Clinicaltrials have evaluated amitriptyline,clomipramine, desipramine, imipramine,and nortriptyline. In these combinedclinical trials of approximately300 people participating in the active-therapy group, approximately onethird of the patients received a 50%reduction in pain.⁸ In general, dosingmay be initiated at 10 mg to 25 mg atbedtime with weekly increments of 25mg to a target dose of 150 mg daily.Pharmacists are well aware of the side-effectprofiles of TCAs, such as drymouth, constipation, increase in appetiteand weight gain, urinary retention,and somnolence. The tertiaryamines, such as desipramine and nortriptyline,may be preferred overamitriptyline, because they are bettertolerated by the patient. Serious risks,especially in the elderly, are cardiacconduction disturbances and orthostatichypotension.⁹

Gabapentin is FDA-approved forPHN and is used extensively off-labelfor diabetic neuropathy and other neuropathies.The effectiveness of gabapentinin the treatment of DPN andPHN has been demonstrated in 2 largeplacebo-controlled, randomized, double-blind clinical trials.^10,11 Doses usedin these studies ranged from 900 to3600 mg daily given in 3 divided doses.Pain relief was generally achieved earlyin therapy and at doses above 1800 mgper day. In another study, pain scoresof patients with diabetic neuropathydecreased from an average of 6.5 NRSto 4.0, with effective doses rangingfrom 1800 to 2400 mg.¹² In addition, areview has summarized the evidencefor gabapentin in treatment of PHN.¹³The reviewers found 2 randomized,placebo-controlled, parallel-group,multicenter clinical trials demonstratingthe efficacy of gabapentin in PHN atdoses of up to 3600 mg/day. The drugis renally excreted, so there is little tono opportunity for potential druginteractions. The common adverseeffects of gabapentin are somnolence,fatigue, and lack of coordination. Thisnecessitates slow titration of the doseto effective levels. From clinical experience,an appropriate trial to assess painrelief, titrate, and balance side effectswill take at least 2 to 4 weeks. Evenafter this time period, patients mostlikely will have some residual pain.

The topical lidocaine patch is FDA-approvedfor postherpetic pain. Thepatch may be applied locally to relievepain for a period of 12 hours and thenremoved. Several randomized clinicalstudies have demonstrated the efficacyof the patch in the treatment ofPHN.^14-16 The patch was well toleratedwith only mild redness reported at thesite of application.

Historically, opioids have not been awidely accepted treatment for patientswith neuropathic pain. In the elderly,however, opioids may actually be thebest choice to treat moderate-to-severepain because this age group does nottolerate other agents well, and clinicaltrials indicate opioid efficacy in thetreatment of neuropathic pain. Onestudy demonstrated effective use ofopioids in 81 patients with central orperipheral neuropathic pain usingeither a low-or high-dose regimen oflevorphanol.¹⁷ The investigatorsassessed patients for pain relief andquality-of-life indicators, demonstratingimprovement in 1 month. Thequality-of-life indicators include abilityto ambulate, mood, general activitylevel, ability to work, quality of relationships,sleep patterns, and overallenjoyment of life.

Oxycodone has been evaluated inboth PHN and DPN. In a study of 50PHN patients receiving oxycodone,patients reported relief of steady pain,spontaneous pain, and allodynia inthis randomized, double-blind, crossovertrial.¹⁸ The efficacy of timereleasedoxycodone has also been studiedin DPN in a multicenter 6-weekstudy of 159 patients.¹⁹ Oxycodone CRwas effective in treatment of neuropathyas measured by overall averagedaily pain intensity and rating in subjectdiaries on a numeric rating scale.

Although few studies have been publishedreviewing the efficacy ofmethadone in the treatment of persistentneuropathic pain, the author's clinicalexperience has been favorable. Anunderstanding of the pathophysiologyof neuropathic pain and the ability ofmethadone to antagonize the NMDAreceptor site are clinically demonstratedin pain relief reported by patients.In patients on high doses of morphine(>300 mg daily) who remain unresponsiveto this treatment, conversion tomethadone is an option. Careful titrationand respect for the long and variablehalf-life of this compound isessential. The elderly patient with neuropathicpain may respond to very lowdoses, such as 5 mg daily at bedtime.

The reluctance to use opioids inchronic pain patients is in part relatedto the fear of the potential for abuse.Clinicians should be educated as to thelow potential for abuse of opioids inpatients who have no history of substanceabuse, and in patients whohave a positive history for abuse theuse of agreements and ongoing rehabilitationcounseling are useful.Adverse effects include constipationand cognitive and psychomotorimpairment. It is recommended thatmedication be taken on a regularschedule with additional dosesordered for breakthrough pain. Agentsshould be slowly titrated to the effectivedose, and the patient should beprescribed a prophylactic stool softenerwith a mild laxative to avoid constipationduring chronic opioid therapy.

The last of the agents recommendedas first-line treatment for neuropathicpain is off-label use of tramadol. Thisagent was evaluated in a multicenterstudy in patients with diabetic neuropathy.The average daily dose requiredfor pain relief in this study of131 patients was 210 mg.²⁰ The dailyeffective dose ranged between 100 and400 mg. When using this weak mu opioidreceptor agonist, which is aninhibitor of norepinephrine and serotoninreuptake, consideration must begiven to its potential for abuse and sideeffects such as dizziness, headache,somnolence, anxiety, nausea, and constipation.Precipitation of seizures is aconcern at higher doses. Potential druginteractions with drugs having similaraffinity for receptor sites, such asmonoamine oxidase inhibitors, TCAs,and selective serotonin reuptake inhibitorsshould be kept in mind.

Considered second-line treatments,anticonvulsant agents are frequentlyused in combination with a first-linetreatment option. These agents are notFDA-approved for the treatment ofneuropathic pain with the exception ofcarbamazepine for trigeminal neuralgia.Trials have been published on lamotrigineuse in diabetic neuropathy,HIV-associated neuropathy, trigeminalneuralgia, and central poststroke pain.A trial involving 92 patients with HIVassociatedneuropathy showed thatlamotrigine was more effective thanplacebo in relieving pain. The dosegiven was 400 to 600 mg in divideddoses twice daily.²¹ Lamotrigine, however,does not appear to be useful inthe treatment of neuropathic pain as aresult of central poststroke pain.Adverse effects commonly includeddizziness, unsteadiness, drowsiness,and rash. Rash is a significant concernif the starting dose is too high or thetitration too fast. Overall, resultsremain inconclusive as to lamotrigine'sefficacy in the treatment of neuropathicpain.²² Carroll and colleaguesreviewed case reports and studies onthe role of topiramate in the treatmentof DPN.²³ The drug is usually well toleratedwith slow dose titration initiatedat low doses. Difficulty with concentration,speech hesitancy or word findingdifficulties, somnolence, and fatigueare the most commonly reportedadverse effects. Researchers found 400mg daily to be an effective dose, witheffective dose ranging from a minimumof 50 mg/day to a maximumeffective dose of 600 mg/day. It may benecessary to assess effectiveness over aperiod of 3 to 12 weeks, and weightloss can be troublesome. The drug, aswith lamotrigine, does not appear to beuseful in poststroke pain. A wide varietyof anticonvulsants are used to treatneuropathic pain without large, double-blind, placebo-controlled, randomizedtrial evidence to support their use.These include oxcarbazepine, zonisamide,valproate, tiagabine, and levetiracetam.Published trials are neededto provide evidence-based support fortheir use in the treatment of neuropathicpain.

Other Treatments

The patient suffering from neuropathicpain may have impaired functioningcontributing to decliningsocial function, isolation, and a diminishedquality of life. To address theseissues, nonpharmacologic strategiescan be recommended, such as physical/occupational therapy and rehabilitation,group support therapy withother patients with chronic pain, cognitivebehavioral therapy, interventionaltherapies, and intrathecal analgesicdrug delivery. The pharmacistcan assist the patient in accessing thehealth care system for physical therapyto help with neuromuscular rehabilitationand a possible transcutaneouselectrical nerve stimulation(TENS) trial. The occupational therapistis helpful in transitioning an individualfrom a loss of function to functional,possibly employable, status.Cognitive behavioral therapy consistsof meditation, relaxation, and attention-diversion techniques. Assistingthe patient to normalize sleep routinesemphasizes sleep hygiene methodsand limiting caffeine consumption. Inaddition, the patient can develop anexercise routine with the help of themultidisciplinary pain team members.Finally, interventional treatments canbe suggested for those who are unresponsiveto other approaches. Examplesof interventional treatmentsare sympathetic nerve blocks, implantabletechnologies, or chemical/physical neurolysis. Local anestheticsand corticoid nerve blocks may beused to afford the patient some functionwhile other strategies are beingidentified. Nerve blocks are temporary,and efficacy is controversial as fewplacebo-controlled trials have beenconducted.²⁴ Finally, intrathecal drugdelivery can be considered. Intrathecalpharmacotherapy is delivered usingopioids, clonidine, baclofen, or localanesthetics for those patients whohave intractable pain and require long-termtreatment. Individuals who sufferunmanageable adverse effects fromother treatments yet require chronictherapy and have responded positivelyto a trial are candidates for intrathecaldrug delivery.

New and EmergingTreatments

Duloxetine has received FDA approvalfor treatment of depression andsubsequently for DPN. The drug is aserotonin and norepinephrine reuptakeinhibitor similar to venlafaxine.Two 12-week trials evaluated the efficacyof duloxetine in DPN.^25,26 The averageage of the participants was 60years, mean duration of diabetes was11 years, and duration of DPN was 4years. In total, between the 2 trials,nearly 800 individuals participated.Duloxetine significantly reduced paincompared with placebo at doses of 60mg QD or BID. The higher dose wasnot found to be superior to the dailydose, however. Potential adverse effects,in order of prevalence, includednausea, dry mouth, constipation,insomnia, dizziness, and somnolence.Duloxetine is metabolized through thecytochrome P-450 1A2 and 2D6enzyme systems, requiring the pharmacistto review for potential druginteractions with enzyme inhibitorssuch as ciprofloxacin, cimetidine, orparoxetine. Duloxetine is itself aninhibitor of the 2D6 enzyme system,and this may affect metabolism ofTCAs, phenothiazines, and propafenone.Clinically significant adversedrug interactions as yet have not beenreported. It is recommended that thedrug not be given to patients withrenal impairment, specifically thosewith creatinine clearance <30 mL/min.

Pregabalin has received FDA approvalfor neuropathic pain associatedwith DPN and PHN. It is pharmacologicallysimilar to gabapentin but has afaster onset of action and shorter titrationperiod. Although the mechanismof action is not completely understood,the target site is the calciumchannel. Researchers have completedthree 12-week trials for each indication.^27-29 Positive response to the drugwas observed within the first week oftreatment. In one of the studies, it wasreported that the drug was well toleratedwith early improvement.²⁸Clinically important improvementwas defined as >50% reduction in painscore as compared with baseline equivalentor a reduction of 3 points on theNRS. Response was not always significantwith the 150-mg strength. The600-mg dose, given in 2 or 3 divideddoses, produced a more significantpain improvement.

Pregabalin is 2.4 times more potentthan gabapentin and has an improvedside-effect profile. Differences inbioavailability allow for a shorter titrationschedule to effective dose. Safetywas shown in studies involving morethan 9000 patients with the most commonside effects reported as dizziness,somnolence, dry mouth, peripheraledema, blurred vision, and weightgain. The drug will be marketed in late2005. The Drug Enforcement Adminstration(DEA) has reviewed the drugand has classified pregabalin as a C-Vdrug. Clinical experience will be neededto evaluate its place in therapy.

NMDA receptors play a key role inthe sensitization of central pain pathwaysin neuropathic pain. Antagonistsat this receptor have been developedand tested, but most of the compoundsdisplay poor side-effect profiles.Memantine shows promise as an analgesicin animal models of pain. A clinicalprogram sponsored by the manufactureris under way to study the useof memantine in neuropathic pain.

Ziconotide, derived from the venomof a marine snail, can be administeredintrathecally as an analgesic for severechronic pain in those who are intolerantor refractory to other treatments.The drug is approved for use only inappropriate programmable microinfusionpumps either implanted or wornexternally for short-term treatment.The mechanism of action is theorizedto be a calcium-channel blocker at theprimary afferent nerve terminal in thedorsal horn. Use will be specialized,due to its complex method of administration.Side effects such as nystagmus,ataxia, sedation, and hallucinationsmay further limit its use.³⁰ Capsaicintransdermal patch is being developedfor treatment of neuropathic pain. Thepatch is applied daily for 1 hour toachieve sustained pain relief. Phase 2trials are ongoing for PHN and diabeticneuropathy.³⁰ GW-1000 (Sativex) is acannabis extract containing delta-9-tetrahydrocannabinol similar to dronabinoland marijuana. GW-1000 hasbeen approved in Canada for managementof neuropathic pain associatedwith multiple sclerosis. It is administeredas an oral spray for use under thetongue or inside the cheek. In theUnited States, GW-1000 is considered aSchedule I drug by the DEA, so importationis currently illegal.³¹

Medication Therapy Management for Persistent Neuropathic Pain

The pharmacist can play a significantand meaningful role in the managementof patients with pain andespecially the complex patient presentingwith persistent neuropathic pain.The core elements for medication therapymanagement (MTM) service³² canbe applied to the patient suffering frompain.

1. Performing or obtaining necessary assessments of the patient's health status:The pharmacist should assess for painas the fifth vital sign and specifically byusing instruments such as the NPS.Pharmacists can conduct foot inspectionand filament testing in the diabeticpatient. Patients may have difficultydescribing neuropathic pain; thereforeit is important to provide specificadjectives describing neuropathic painin your pain quality assessment. Assessthe impact pain has on daily functionand quality of life.

2. Formulating a medication treatment plan, including counseling the patient onexpectations regarding medication therapy:The treatment plan should provide anexplanation of appropriate goal setting.The patient should understandthat pain that is long-standing may notrespond completely to treatments.Patients need to set goals where theycan manage residual pain. The treatmentplan, with provider approval,should include a moderate exerciseprogram. Support should be solicitedfrom family and friends to preventsocial decline and isolation.

3. Monitoring and evaluating patient response to therapy, including safety andeffectiveness: Monitoring, especially inthe first few days of dosage changes orinitiation of new agents, is crucial tothe titration process in treating pain.The pharmacist should closely followpatients in order to achieve optimumbenefits from the regimen prescribedwhile minimizing and addressingadverse events or other complicationsas they arise.

4. Performing a comprehensive medication review to identify, resolve, and preventmedication-related problems, including adverse events related to other medicationsin addition to the pain management regimen and how these interrelate: The individualsuffering from neuropathic painis frequently treated with rationalpolypharmacy designed to treat thepain and other associated symptomssuch as anxiety, depression, and spasm.A prospective drug regimen review bythe pharmacist on the patient's first visitis essential to optimizing treatment.

5. Documenting the care delivered andcommunicating information to other careproviders: The patient may have multipleproviders, including the physician,physical therapist, psychologist, andothers involved in the treatment of thechronic pain. The pharmacist is often ahub of information for these membersof the health care team, and he or sheshould act as a central communicator.

6. Educating the patient on the understanding and appropriate use of medications:Medications used in the treatmentof neuropathic pain frequentlyare prescribed off-label, and patientinformation sheets are not useful inthis setting. Anticonvulsant drugs,some of the opioids, and TCAs are allused off-label for the treatment of neuropathicpain. The pharmacist shouldtake extra time to explain these offlabelmedications to the patients.

7. Providing information, support, and resources to enhance patient adherence:The patient with neuropathic pain isfrequently using a complex regimen ofmedications not only for the treatmentof pain but also for the treatment ofother comorbidities. Nonadherence isa risk in such patients. Pharmacists arespecialists in counseling patients onmedication use and adherence and canimprove patient adherence throughappropriate counseling.

8. Coordinating and integrating MTMservices within the broader health caremanagement services brought to thepatient: The pharmacist can educatepatients and families in general aboutnerve pain, explain its pathophysiologyin simple terms, provide educationon the wide variety of treatmentoptions, and refer the patient to othermembers of the multidisciplinary teamas necessary.

Counseling Points for the Patient with Neuropathic Pain

• A combination of treatment strategiesis essential to achieve somedegree of relief from chronic painbecause the pain is the result ofmultiple causes.
• Understand medications, dosingschedules, side effects. You mayhave to keep track of multiple medications.
• Realize that medications may notbe FDA-approved for treatment ofneuropathic pain, and referenceinformation may not be readilyavailable.
• Be cautious about using alternativeor natural medicines to providerelief. These usually are not effectiveand can be expensive.
• Physical therapy, exercise, and psychologicaltreatments are importantto the treatment plan. Keepappointments and be patient withexpectations.
• Set reasonable goals for pain relief.Pain most likely will not be able tobe completely cured.
• Understand neuropathic pain.Being knowledgeable about yourcondition gives you an opportunityto have input into the treatmentplan.
• Become proactive about yourhealth, and achieve your own successes.

Resources for Pharmacists and Patients

www.theacpa.org The AmericanChronic Pain Association (ACPA) israising awareness about neuropathicpain. Pharmacists can facilitate this initiativeby identifying patients withneuropathic pain and educatingpatients and families. A survey sponsoredby the ACPA found that neuropathicpain is not well understood bythe public.³³ The survey was a randomsampling of 939 Americans not employedin the medical field. Nearly34% of the respondents to the telephonesurvey knew someone with orhad the pain described as tingling, pinsand needles, burning, or electric shock-likesensations. Only 6% recognizedthese symptoms as nerve pain. Educatingpatients can empower them tomanage their own pain. The Web siteoffers support resources such as groupsupport by geographical region.

www.medsch.wisc.edu/painpolicyThe University of Wisconsin Web siteoffers information about pain reliefand public policy. The aim is to raiseawareness about pain and to ensureadequate availability of pain medicationsfor patient care while minimizingdiversion and abuse. The Pain andPolicy Studies Group (PPSG) facilitatesthis mission.

www.pharmacy.duq.edu/divPharmPrac.html Duquesne UniversityMylan School of Pharmacy hasestablished an interdisciplinary chronicpain team. The Chronic PainInitiative utilizes the resources of theuniversity to improve the quality of lifeof those with pain and their familymembers through an interdisciplinaryeffort focusing on healing of mind,body, and spirit. The team believes thatthere is much work to be done in educatingnot only patients and families,but also health care professionals aboutpain management. The Chronic PainInitiative involves students early on intheir training as members of the interdisciplinaryteam model of care. Teammembers provide support and informationalresources for patients, families,and caregivers of those sufferingfrom pain to reintroduce hope intotheir lives.

www.ampainsoc.org The AmericanPain Society (APS) is a multidisciplinaryorganization composed of professionalswho are involved in basicresearch, clinical research, treatment,advocacy, and public policy regardingpain. Resources on the Web site includepublications, calendar of events, news,and links to related Web sites.

www.ittakesnerve.org A consumerWeb site for the patients andtheir families who cope with the sufferingfrom neuropathic pain. Informationincludes how to enjoy life and improvethe quality of life despite nerve pain.The site is associated with the AmericanChronic Pain Association (ACPA).

Conclusion

Neuropathic pain is a chronic disorderassociated with much personal suffering,compromised quality of life,and loss of function. The patient isoptimally treated by a multidisciplinaryteam of health care professionalsusing a combination of therapies suchas rational polypharmacy, physical andoccupational therapy, and cognitivetherapies. The pharmacist plays anintegral role on the team treating thepatient with neuropathic pain throughapplication of medication managementprinciples in the community orhospital practice setting. These medicationmanagement principles can optimizetherapeutic outcomes for individualpatients.

Hildegarde J. Berdine, BS, PharmD, BCPS: Assistant Professor of Pharmacy Practice, Duquesne University Mylan School of Pharmacy

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(Based on the article starting on page 97) Choose the 1 most correct answer.

1. Neuropathic pain is costly to ourhealth care system and society. Directand indirect costs are represented by:

• Cost of medication.
• The patient being in pain and notreporting for work.
• The patient in pain reporting tophysical therapy for a scheduledappointment.

All of the above

2. Persistent neuropathic pain can leadto which of the following comorbidmedical problems?

• Multiple sclerosis
• Depression
• Anxiety

b and c

3. The diagnosis of neuropathic pain isoften overlooked because:

• The patient is not asked aboutspecific symptoms indicatingneuropathy.
• The physician quickly diagnosesthe pain as musculoskeletal pain.
• The patient cannot understand thenumeric rating scale.

a and b

4. Which of the following characteristicsdescribes neuropathic pain?

• Throbbing headache and eye pain
• Deep muscular pain in theshoulder
• Burning, tingling, radiating paindown the leg

Itching sensation

5. Peripheral neuropathy may beassociated with which of the followingetiologies?

• Lung cancer
• Chemotherapy
• Stroke

Abdominal pain

6. Tricyclic antidepressants (TCAs) maybe used for the treatment of neuropathicpain. Which of the following is true?

• Tertiary amines are the worst-toleratedcompounds in termsof side effects.
• Dry mouth, constipation, andurinary retention may be troublesomeside effects.
• The potential for cardiac arrhythmiasis of particular concern in the20-to 40-year-old age group.

The FDA has approved neuropathicpain as an indication for the use ofTCAs.

7. The pharmacist can counsel thediabetic patient taking gabapentin fortingling and burning in the feet onwhich of the following points?

• The medicine should be taken inlow doses to begin with and thenincreased.
• The patient should perform a dailyfoot inspection.
• The pain may be only partiallyrelieved.

All of the above

8. Relief from pain is not the only measureof therapeutic success in patientssuffering from neuropathic pain. Whatother indicator(s) is (are) measured fortreatment success?

• Regular sleeping patterns
• Complete resolution of pain
• Using only one dose of oxycodonedaily

None of the above

9. Methadone can be a useful agent intreating which of the followingpatient(s)?

• A patient who is treated with highdoses of ibuprofen and remains inpain
• A patient who chronicallycomplains of radiating, tinglingpain in the arm
• A patient who complains of severeback pain due to muscle spasm

A patient who has occasionalabdominal pain

10. Patients receiving chronic opioidtherapy should be counseled by thepharmacist on the following point(s):

• You will become addicted to thismedication in several weeks.
• Be aware of side effects associatedwith your medication, such asdrowsiness and nausea.
• Use a Fleet enema daily to preventconstipation.

Take the medication only whenyou have severe pain.

11. The treatment plan written for apatient afflicted with neuropathic paincould include which of the followingrecommendations?

• Consult with a psychologist tolearn meditation techniques.
• Use multiple medications, such asopioids and anticonvulsants.
• Consult with a physical therapistfor strengthening exercises.

All of the above

12. A variety of anticonvulsants havebeen used in the treatment ofneuropathic pain. Which of thefollowing statements is true?

• Anticonvulsants are suggested asfirst-line treatment options forneuropathic pain.
• There is solid evidence-basedliterature to support the use oflamotrigine in the treatment ofneuropathic pain.
• Topiramate usually is initiated at alow dose and titrated slowly to amaximum tolerated and effectivedose.

Rash is a common adverse effectassociated with the use ofcarbamazepine.

13. Intrathecal drug delivery may beaccomplished by using which of thefollowing agent(s)?

• Baclofen
• Hydrocodone
• Celecoxib

None of the above

14. A new drug treatment for neuropathicpain is duloxetine. All of thefollowing statements describe duloxetineexcept:

• The drug should not beadministered to a patient whosecreatinine clearance is less than30 mL/min.
• The drug is used in the treatmentof depression.
• The drug is approved for use in thetreatment of postherpetic neuralgia.

The drug is associated with theadverse effects of nausea, drymouth, and constipation.

15. Pregabalin is a new agent used in thetreatment of diabetic neuropathy andpostherpetic neuralgia. It is closelyrelated to gabapentin. How doespregabalin differ from gabapentin?

• Pregabalin is much more potentmilligram per milligram thangabapentin.
• An increase in the patient's bloodpressure is seen with the use ofpregabalin.
• Pregabalin is prescribed as once-adaydosing.

Pregabalin is extensively metabolizedthrough the cytochromeP-450 enzyme system.

16. The pharmacist can providemedication therapy management (MTM)services to the patient with neuropathicpain in which of the following way(s)?

• The pharmacist can assess theimpact pain has on the ability ofthe patient to perform activities ofdaily living.
• The pharmacist can assess the fifthvital sign.
• The pharmacist can discuss ways inwhich the family can support thepatient with persistent pain, such asassisting with medication adherence.

All of the above

17. The patient suffering from neuropathicpain is frequently receivingcomplex medication regimens. Thepharmacist's role in providing MTMservices includes which of the following?

• Assisting the patient in setting andachieving realistic goals withrespect to pain
• Following up with the patientwhen a dose of medication ischanged to assess therapeutic effect
• Telling the patient to abruptlydiscontinue a medicationineffective for pain control

a and b

18. The pharmacist can educate thepatient suffering from pain with respect to:

• The pathophysiology of nerve painin simple terms
• Expectations from medicationtherapy
• The use of nonpharmacologictreatment options

All of the above

19. Ziconotide is a new agent for thetreatment of neuropathic pain. Which ofthe following characteristics describesziconotide?

• The drug is derived from thevenom of a spider.
• The drug is given by the intrathecalroute of administration.
• The drug is available in both anoral and a sublingual tablet.

The drug is associated withneutropenia in the first 3 monthsof therapy, and blood count mustbe monitored.

20. A new agent containing cannabisextract and approved for the treatmentof neuropathic pain associated withmultiple sclerosis, available in Canadabut not the United States, is:

• Ziconotide
• Pregabalin
• Sativex

Duloxetine

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