Pharmacy Times

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

Author: Hildegarde J. Berdine, BS, PharmD, BCPS

Behavioral Objectives

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

  1. Review the types and prevalence of neuropathic pain.
  2. Understand the direct and indirect costs of neuropathic pain.
  3. Discuss the diagnosis of neuropathic pain and why this condition can be misdiagnosed.
  4. Review the benefits and risks associated with current treatments.
  5. Evaluate new and emerging treatments for neuropathic pain.
  6. Specify the role of the pharmacist in providing medication therapy management services to the patient with neuropathic pain.
  7. Provide counseling points for patients with neuropathic pain.
  8. Review resources available to the pharmacist about chronic and 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 estimated 4 million people in the United States.1 The condition originates from an injury to either the peripheral or central nervous system (CNS) or to both and develops into a chronic disorder. Examples of neuropathic pain syndrome include diabetic peripheral neuropathy (DPN), phantom limb pain, HIV sensory neuropathy, postherpetic neuralgia (PHN), central poststroke pain, low back and neck pain with a neuropathic origin, complex regional pain syndrome, and multiple sclerosis pain. It is estimated that of the 18 million patients with diabetes in this country, 5% to 50% are affected by DPN, with the incidence and prevalence increasing over the number of years with diabetes.2 About 800,000 people in the United States each year develop shingles, with 25% to 50% developing PHN as a complication of the herpes zoster virus.3 Being 50 years of age or older is a risk factor for developing PHN following herpes zoster. This painful condition severely affects the ability of the individual to perform daily activities and ultimately affects his or her overall quality of life. Central neuropathic pain is estimated to occur in 2% to 8% of all stroke patients.4 Neuropathic pain is also associated with chemotherapy and direct traumatic injury to the nerves. Table 1 lists common underlying causes of neuropathic pain.

Figure

Neuropathic pain is classified as a type of chronic pain. It differs from acute nociceptive pain, which is pain caused by the normal activation of neural pathways in response to a pain-initiating stimulus. Hallmark characteristics of neuropathic pain are lowering of the pain threshold and excitation of the nerve pathways long after the initial injury has healed. The pain becomes chronic in nature, and severe, and often is not responsive to the usual treatments for acute pain. The CNS is composed of the brain and spinal cord, whereas the peripheral nervous system includes nerves to the hands, feet, legs, and arms, and the link, at the dorsal horn, between the spinal cord and the rest of the body. Neuropathic pain results from damage to or changes in the central and peripheral nervous systems. The injury and malfunction to the nervous system become the source of pain and become a chronic disease.

An understanding of the pathophysiology of neuropathic pain allows the clinician to target particular neurochemicals and receptor sites with appropriate rational pharmacotherapy. The pathophysiology of neuropathic pain is complex and mediated through a variety of mechanisms. Beginning with injury to the nerve, sensitization and overstimulation of the nerve pathways occurs, along with release of excitatory neurochemicals and inflammatory neuropeptides. C fibers are the small unmyelinated or unsheathed afferent nerves taking impulses from the periphery to the spinal cord. They conduct nerve impulses relatively slowly, are of a low threshold nature, and penetrate deep into the spinal cord. Repetitive stimulation of the C fibers results in prolonged discharge or spontaneous activity of the neuron in the dorsal horn of the spinal cord. This sensitization leads to release of excitatory amino acids such as glutamate. Glutamate is a neurochemical that can attach itself to the N-methyl-D aspartate (NMDA) receptor site and further excite other neurons. It follows that agents that are NMDA-receptor antagonists, such as ketamine, dextromethorphan, and memantine, could block this excitation. Sensitization in the dorsal horn eventually leads to increased activity of neurons or hyperexcitability of the nerves and a decrease in the pain threshold. An increased number of adrenergic receptors can develop along the length of the C fibers, resulting in increased sensitivity and an increase in sympathetically mediated pain signals. Agents that prevent reuptake of catecholamines at these receptor sites, such as tricyclic antidepressants (TCAs), are effective in preventing pain signal transmission. Nerve injury in the periphery also can result in the release of inflammatory neuropeptides, substance P, and prostaglandins. Another mechanism of pain transmission is the continuous electrical discharge along the nerve fiber resulting in "ectopic" activity. These electrical discharges continue to fire, generating impulses even in the absence of stimulation or injury and are related to an increase in the number of sodium channels. Sodium channels facilitate sodium influx, enabling continuation of the action potential or electrical impulse to travel along the nerve pathway. Anticonvulsant agents are useful in blocking these channels. Ectopic discharges also occur in the cells at the dorsal root and lead to hyperactivity of the neurons in the spinal cord.

Economic, Human, and Societal Costs

Neuropathic pain is costly. Individuals affected by neuropathic pain are oftentimes high users of the health care system as they search for relief from persistent suffering. Much of the available cost data defines costs relative to chronic pain in general so that costs attributable to neuropathic pain are contained with those numbers. The American Pain Society conducted a survey demonstrating that most people with chronic/persistent pain had been experiencing their pain for more than 5 years, and one third described the pain as the "worst ever." Many sufferers had to visit multiple physicians to achieve only partial relief from their pain.5 Direct and indirect costs of persistent pain, including neuropathic pain, are derived from economic, human, and societal components. The economic burden relates to direct medical costs and productivity loss in the workplace. Chronic pain sufferers may become unemployable or remain underemployed. The National Institute for Occupational Safety and Health estimates that chronic pain costs $100 billion annually in lost workdays, medical expenses, and other benefit costs.6 In terms of human costs, living with chronic pain affects patients' day-today ability to function. Physical and mental problems include difficulties in sleeping, impaired concentration, and decline in cognitive abilities. Pain contributes to disruption of sleep patterns, which can foster irritability, leading to enhanced sensitivity to pain, and the patient becomes caught up in a vicious cycle. Anger, fear, depression, and anxiety are common and may lead to suicidal ideations, attempted suicide, or successful suicide.

Neuropathic pain is also responsible for societal burdens. The patient with neuropathic pain becomes isolated because of the loss of functioning, and the impact on the family can strain relationships. For these reasons, patients benefit from a multidisciplinary approach to treatment. Team members such as a psychiatrist, psychologist, social worker, occupational and physical therapist, nurse, pharmacist, and physician are integral to treating the patient holistically.

Diagnosis of Neuropathic Pain: The Role of the Pharmacist

Neuropathic pain can be misdiagnosed and treated as musculoskeletal pain. When the diagnosis of neuropathic pain is overlooked, the patient may be treated inappropriately, leading to months or even years of mismanaged chronic persistent pain and decreased function. The pharmacist can assist in the recognition of this condition, which manifests in heterogeneous symptoms (Table 2).

Figure

It can be difficult for the patient to separate the neuropathic pain from other chronic pain, particularly if there is tissue damage. In addition, patients may be unfamiliar with the terminology to describe this type of pain, or do not think this complaint is important enough to share with the physician, adding to the difficulty in diagnosing this type of pain. Patients may find it difficult to describe the pain and complain of exaggerated responses to slightly painful stimuli. The pain may present months after the initial nerve injury. Common questions that pharmacists may face include, what is neuropathic pain, and why do I experience this type of pain? What is the difference between nerve and muscle pain, and is this type of pain serious? Can nerve pain have a variety of symptoms, and can it affect my sleep? Can nerve pain be cured?

When assessing the patient, various bits of information should be obtained. Pharmacists can assess patients for pain in a primary care/ambulatory care practice as part of the vital signs package, pain being the 5th vital sign, and upon follow-up to determine therapeutic effect of interventions, which are primarily pharmacologic. The pharmacist should review all the components of pain assessment, such as the onset/duration of pain, location, quality, intensity, aggravating or relieving factors, and emotional factors contributing to or the result of pain. Certain key terms used to describe the pain are specific to neuropathic pain, including burning, tingling, electric shock-like, shooting, radiating, or statements such as "it feels like I am walking on broken glass." For example, diabetic neuropathy has been described as pins and needles in the feet, legs, or hands. Descriptions of constant, stabbing, and electric shock-like sensation can be representative of PHN. Other associated characteristic descriptions of neuropathic pain are related to the unique physiology of this type of pain. The patient may say that even the bed sheets hurt. Such patients may be suffering from allodynia associated with the neuropathic pain. Allodynia is the perception of pain to a greater degree than would be expected considering the pain stimulus. More specific diagnosis by the physician may reveal the underlying cause of the neuropathy. See Table 3 for diagnostic testing performed by the physician.

Figure

Patients suffering with chronic pain/neuropathic pain usually have a long history of seeking treatment, because the relief achieved is usually only partial. Patients should be questioned as to the current and prior attempts to manage their own pain, and what treatment or strategy was successful and what was not. Treatment strategies include pharmacologic treatments, alternative treatments such as chiropractic and acupuncture, and coping strategies. It is useful to explore the patient's history of medical problems relative to surgeries and accidents; psychosocial history such as job stressors, unemployment, compensation issues; family history focusing on interpersonal dynamics; and psychological effects of the persistent pain on mental status and emotions to get a comprehensive picture of the patient. The patient's functional baseline should also be assessed as it relates to the patient's work, family activities, care for the house and other family members, and the ability to participate in sports or hobbies.

Neuropathic pain in the diabetic patient can be thought of as the forgotten symptom, being lost in the myriad of other higher-priority medical problems. The pharmacist can conduct baseline and periodic assessment of the patient's reported pain by using the visual analog scale or the numeric rating scale (NRS) along with the neuropathic pain scale (NPS) and by performing a filament examination of the feet. The NPS might help the clinician to identify distinct pain symptoms and target specific treatment depending on the quality of the pain reported. The scale focuses on adjectives that have been shown to be associated with neuropathic pain. In the NPS scale, the patient is asked to measure intensity, severity, and qualities such as sharp, hot, dull, cold, sensitive, itchy, deep pain, or surface pain.7

The physician will perform the neurologic examination and possibly order various diagnostic studies to assist in the assessment of the patient's pain. The neurologic exam begins with sensory testing for touch, pain, temperature, and vibration. The patient will also be assessed for pain perception—allodynia is assessed with a nonpainful stimulus, and hyperalgesia is assessed with pinpricks. Muscle strength, coordination, and gait pattern can be observed as an indication of limitations imposed by nerve pain, which can compromise the skeletal structure over time. Additional diagnostic studies such as x-ray, computed axial tomography (CAT) scan, or magnetic resonance imaging (MRI) can be ordered to rule out medical problems that could be treated, leading to a resolution of the pain complaint. Underlying causes of nerve pain include diseases such as acquired immune deficiency syndrome (AIDS), diabetes, cancer, or shingles. Peripheral neuropathy may be associated with diabetes, renal failure, chemotherapy, amyloidosis, infections such as HIV, PHN, nerve entrapment, amputation, or ischemia. Central neuropathy follows an injury to the CNS secondary to trauma, malignancy, inflammation, vascular problems, cerebrovascular accident, or multiple sclerosis.

Laboratory and serologic analysis may also be used to rule out medical problems. Electromyography and nerve conduction velocity tests have limitations in that these do not necessarily assess the specific function of the small nerve fibers and the C fibers involved in the pathophysiology of neuropathic pain.

The Pharmacist's Plan of Care

The pharmacist's plan of care involves a discussion of the expectations and goals of treatment. A clear understanding of the treatments ordered can be reviewed along with the schedule for monitoring therapies and laboratory follow-up. Because neuropathic pain takes a chronic course, it is usually only partially responsive to treatments. The pain more than likely will not be totally eradicated, so the patient needs to be counseled about setting realistic expectations and achievable goals. Questions to consider include "What are the functional abilities the patient hopes to achieve, such as the ability to ambulate? What will be the overall quality of life the patient hopes to achieve?"

Patients with neuropathic pain frequently develop comorbidities such as insomnia, depression, and anxiety. The pharmacist assessing the patient for insomnia should ask the following questions:

The pharmacist should also review sleep hygiene in general, including napping patterns during the day. All of these efforts will contribute to improved sleep patterns and decreased fatigue and drowsiness the next day, contributing to a better quality of life. Depression and anxiety can be assessed using standard self-rating scales and by checking for the presence of symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, Revised Fourth Edition (DSM-IV-R). Such symptoms include feelings of guilt or lack of self-worth, isolation from family and friends, crying spells, lack of appetite, weight loss, waking early in the morning, difficulty in concentrating, irritability, and feelings of fatigue. Symptoms of anxiety include excessive worry about events or activities where the individual cannot control these feelings, restlessness and feeling edgy, fatigue, trouble concentrating, irritability, insomnia, increased muscle tension. In depression and anxiety, the symptoms are considered severe enough to impair the patient's ability to work or impair social, family, or personal relationships.

Current Treatments

Treatments for neuropathic pain cover a wide range of options reflecting the multidisciplinary nature of care for the patient (Table 4). Treatments include psychological management of the chronic pain through stress management, relaxation, biofeedback, cognitive behavioral techniques, and counseling by a psychologist or psychiatrist. In addition, multiple agents are offered as pharmacologic treatment of neuropathic pain. Often these agents are used in combination, with continued evaluation for efficacy being a crucial element of the management process. Patients may respond poorly to any single agent or a combination of agents. Finding the effective treatment is often a challenging and labor-intensive journey.

Figure

Pharmacologic Agents

A number of pharmacologic agents are available for the treatment of neuropathic pain (Table 5). First-line agents include TCAs, gabapentin, topical lidocaine, opioids, and tramadol.8 Pharmacotherapy is considered not only for pain management but also to treat common comorbidities such as depression and anxiety. The TCAs and antidepressants exhibiting the mixed mechanism of serotonergic and adrenergic reuptake blockade are more effective for the treatment of neuropathic pain than the selective serotonin reuptake inhibitors. Clinical trials of TCAs have demonstrated efficacy in DPN, although the drugs are not FDA-approved for this indication. Clinical trials have evaluated amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline. In these combined clinical trials of approximately 300 people participating in the active-therapy group, approximately one third of the patients received a 50% reduction in pain.8 In general, dosing may be initiated at 10 mg to 25 mg at bedtime with weekly increments of 25 mg to a target dose of 150 mg daily. Pharmacists are well aware of the side-effect profiles of TCAs, such as dry mouth, constipation, increase in appetite and weight gain, urinary retention, and somnolence. The tertiary amines, such as desipramine and nortriptyline, may be preferred over amitriptyline, because they are better tolerated by the patient. Serious risks, especially in the elderly, are cardiac conduction disturbances and orthostatic hypotension.9

Figure

Gabapentin is FDA-approved for PHN and is used extensively off-label for diabetic neuropathy and other neuropathies. The effectiveness of gabapentin in the treatment of DPN and PHN has been demonstrated in 2 large placebo-controlled, randomized, double- blind clinical trials.10,11 Doses used in these studies ranged from 900 to 3600 mg daily given in 3 divided doses. Pain relief was generally achieved early in therapy and at doses above 1800 mg per day. In another study, pain scores of patients with diabetic neuropathy decreased from an average of 6.5 NRS to 4.0, with effective doses ranging from 1800 to 2400 mg.12 In addition, a review has summarized the evidence for gabapentin in treatment of PHN.13 The reviewers found 2 randomized, placebo-controlled, parallel-group, multicenter clinical trials demonstrating the efficacy of gabapentin in PHN at doses of up to 3600 mg/day. The drug is renally excreted, so there is little to no opportunity for potential drug interactions. The common adverse effects of gabapentin are somnolence, fatigue, and lack of coordination. This necessitates slow titration of the dose to effective levels. From clinical experience, an appropriate trial to assess pain relief, titrate, and balance side effects will take at least 2 to 4 weeks. Even after this time period, patients most likely will have some residual pain.

The topical lidocaine patch is FDA-approved for postherpetic pain. The patch may be applied locally to relieve pain for a period of 12 hours and then removed. Several randomized clinical studies have demonstrated the efficacy of the patch in the treatment of PHN.14-16 The patch was well tolerated with only mild redness reported at the site of application.

Figure

Historically, opioids have not been a widely accepted treatment for patients with neuropathic pain. In the elderly, however, opioids may actually be the best choice to treat moderate-to-severe pain because this age group does not tolerate other agents well, and clinical trials indicate opioid efficacy in the treatment of neuropathic pain. One study demonstrated effective use of opioids in 81 patients with central or peripheral neuropathic pain using either a low-or high-dose regimen of levorphanol.17 The investigators assessed patients for pain relief and quality-of-life indicators, demonstrating improvement in 1 month. The quality-of-life indicators include ability to ambulate, mood, general activity level, ability to work, quality of relationships, sleep patterns, and overall enjoyment of life.

Oxycodone has been evaluated in both PHN and DPN. In a study of 50 PHN patients receiving oxycodone, patients reported relief of steady pain, spontaneous pain, and allodynia in this randomized, double-blind, crossover trial.18 The efficacy of timereleased oxycodone has also been studied in DPN in a multicenter 6-week study of 159 patients.19 Oxycodone CR was effective in treatment of neuropathy as measured by overall average daily pain intensity and rating in subject diaries on a numeric rating scale.

Although few studies have been published reviewing the efficacy of methadone in the treatment of persistent neuropathic pain, the author's clinical experience has been favorable. An understanding of the pathophysiology of neuropathic pain and the ability of methadone to antagonize the NMDA receptor site are clinically demonstrated in pain relief reported by patients. In patients on high doses of morphine (>300 mg daily) who remain unresponsive to this treatment, conversion to methadone is an option. Careful titration and respect for the long and variable half-life of this compound is essential. The elderly patient with neuropathic pain may respond to very low doses, such as 5 mg daily at bedtime.

The reluctance to use opioids in chronic pain patients is in part related to the fear of the potential for abuse. Clinicians should be educated as to the low potential for abuse of opioids in patients who have no history of substance abuse, and in patients who have a positive history for abuse the use of agreements and ongoing rehabilitation counseling are useful. Adverse effects include constipation and cognitive and psychomotor impairment. It is recommended that medication be taken on a regular schedule with additional doses ordered for breakthrough pain. Agents should be slowly titrated to the effective dose, and the patient should be prescribed a prophylactic stool softener with a mild laxative to avoid constipation during chronic opioid therapy.

The last of the agents recommended as first-line treatment for neuropathic pain is off-label use of tramadol. This agent was evaluated in a multicenter study in patients with diabetic neuropathy. The average daily dose required for pain relief in this study of 131 patients was 210 mg.20 The daily effective dose ranged between 100 and 400 mg. When using this weak mu opioid receptor agonist, which is an inhibitor of norepinephrine and serotonin reuptake, consideration must be given to its potential for abuse and side effects such as dizziness, headache, somnolence, anxiety, nausea, and constipation. Precipitation of seizures is a concern at higher doses. Potential drug interactions with drugs having similar affinity for receptor sites, such as monoamine oxidase inhibitors, TCAs, and selective serotonin reuptake inhibitors should be kept in mind.

Considered second-line treatments, anticonvulsant agents are frequently used in combination with a first-line treatment option. These agents are not FDA-approved for the treatment of neuropathic pain with the exception of carbamazepine for trigeminal neuralgia. Trials have been published on lamotrigine use in diabetic neuropathy, HIV-associated neuropathy, trigeminal neuralgia, and central poststroke pain. A trial involving 92 patients with HIVassociated neuropathy showed that lamotrigine was more effective than placebo in relieving pain. The dose given was 400 to 600 mg in divided doses twice daily.21 Lamotrigine, however, does not appear to be useful in the treatment of neuropathic pain as a result of central poststroke pain. Adverse effects commonly included dizziness, unsteadiness, drowsiness, and rash. Rash is a significant concern if the starting dose is too high or the titration too fast. Overall, results remain inconclusive as to lamotrigine's efficacy in the treatment of neuropathic pain.22 Carroll and colleagues reviewed case reports and studies on the role of topiramate in the treatment of DPN.23 The drug is usually well tolerated with slow dose titration initiated at low doses. Difficulty with concentration, speech hesitancy or word finding difficulties, somnolence, and fatigue are the most commonly reported adverse effects. Researchers found 400 mg daily to be an effective dose, with effective dose ranging from a minimum of 50 mg/day to a maximum effective dose of 600 mg/day. It may be necessary to assess effectiveness over a period of 3 to 12 weeks, and weight loss can be troublesome. The drug, as with lamotrigine, does not appear to be useful in poststroke pain. A wide variety of anticonvulsants are used to treat neuropathic pain without large, double-blind, placebo-controlled, randomized trial evidence to support their use. These include oxcarbazepine, zonisamide, valproate, tiagabine, and levetiracetam. Published trials are needed to provide evidence-based support for their use in the treatment of neuropathic pain.

Other Treatments

The patient suffering from neuropathic pain may have impaired functioning contributing to declining social function, isolation, and a diminished quality of life. To address these issues, nonpharmacologic strategies can be recommended, such as physical/occupational therapy and rehabilitation, group support therapy with other patients with chronic pain, cognitive behavioral therapy, interventional therapies, and intrathecal analgesic drug delivery. The pharmacist can assist the patient in accessing the health care system for physical therapy to help with neuromuscular rehabilitation and a possible transcutaneous electrical nerve stimulation (TENS) trial. The occupational therapist is helpful in transitioning an individual from a loss of function to functional, possibly employable, status. Cognitive behavioral therapy consists of meditation, relaxation, and attention- diversion techniques. Assisting the patient to normalize sleep routines emphasizes sleep hygiene methods and limiting caffeine consumption. In addition, the patient can develop an exercise routine with the help of the multidisciplinary pain team members. Finally, interventional treatments can be suggested for those who are unresponsive to other approaches. Examples of interventional treatments are sympathetic nerve blocks, implantable technologies, or chemical/ physical neurolysis. Local anesthetics and corticoid nerve blocks may be used to afford the patient some function while other strategies are being identified. Nerve blocks are temporary, and efficacy is controversial as few placebo-controlled trials have been conducted.24 Finally, intrathecal drug delivery can be considered. Intrathecal pharmacotherapy is delivered using opioids, clonidine, baclofen, or local anesthetics for those patients who have intractable pain and require long-term treatment. Individuals who suffer unmanageable adverse effects from other treatments yet require chronic therapy and have responded positively to a trial are candidates for intrathecal drug delivery.

New and Emerging Treatments

Duloxetine has received FDA approval for treatment of depression and subsequently for DPN. The drug is a serotonin and norepinephrine reuptake inhibitor similar to venlafaxine. Two 12-week trials evaluated the efficacy of duloxetine in DPN.25,26 The average age of the participants was 60 years, mean duration of diabetes was 11 years, and duration of DPN was 4 years. In total, between the 2 trials, nearly 800 individuals participated. Duloxetine significantly reduced pain compared with placebo at doses of 60 mg QD or BID. The higher dose was not found to be superior to the daily dose, however. Potential adverse effects, in order of prevalence, included nausea, dry mouth, constipation, insomnia, dizziness, and somnolence. Duloxetine is metabolized through the cytochrome P-450 1A2 and 2D6 enzyme systems, requiring the pharmacist to review for potential drug interactions with enzyme inhibitors such as ciprofloxacin, cimetidine, or paroxetine. Duloxetine is itself an inhibitor of the 2D6 enzyme system, and this may affect metabolism of TCAs, phenothiazines, and propafenone. Clinically significant adverse drug interactions as yet have not been reported. It is recommended that the drug not be given to patients with renal impairment, specifically those with creatinine clearance <30 mL/min.

Pregabalin has received FDA approval for neuropathic pain associated with DPN and PHN. It is pharmacologically similar to gabapentin but has a faster onset of action and shorter titration period. Although the mechanism of action is not completely understood, the target site is the calcium channel. Researchers have completed three 12-week trials for each indication.27-29 Positive response to the drug was observed within the first week of treatment. In one of the studies, it was reported that the drug was well tolerated with early improvement.28 Clinically important improvement was defined as >50% reduction in pain score as compared with baseline equivalent or a reduction of 3 points on the NRS. Response was not always significant with the 150-mg strength. The 600-mg dose, given in 2 or 3 divided doses, produced a more significant pain improvement.

Pregabalin is 2.4 times more potent than gabapentin and has an improved side-effect profile. Differences in bioavailability allow for a shorter titration schedule to effective dose. Safety was shown in studies involving more than 9000 patients with the most common side effects reported as dizziness, somnolence, dry mouth, peripheral edema, blurred vision, and weight gain. The drug will be marketed in late 2005. The Drug Enforcement Adminstration (DEA) has reviewed the drug and has classified pregabalin as a C-V drug. Clinical experience will be needed to evaluate its place in therapy.

NMDA receptors play a key role in the sensitization of central pain pathways in neuropathic pain. Antagonists at this receptor have been developed and tested, but most of the compounds display poor side-effect profiles. Memantine shows promise as an analgesic in animal models of pain. A clinical program sponsored by the manufacturer is under way to study the use of memantine in neuropathic pain.

Ziconotide, derived from the venom of a marine snail, can be administered intrathecally as an analgesic for severe chronic pain in those who are intolerant or refractory to other treatments. The drug is approved for use only in appropriate programmable microinfusion pumps either implanted or worn externally for short-term treatment. The mechanism of action is theorized to be a calcium-channel blocker at the primary afferent nerve terminal in the dorsal horn. Use will be specialized, due to its complex method of administration. Side effects such as nystagmus, ataxia, sedation, and hallucinations may further limit its use.30 Capsaicin transdermal patch is being developed for treatment of neuropathic pain. The patch is applied daily for 1 hour to achieve sustained pain relief. Phase 2 trials are ongoing for PHN and diabetic neuropathy.30 GW-1000 (Sativex) is a cannabis extract containing delta-9-tetrahydrocannabinol similar to dronabinol and marijuana. GW-1000 has been approved in Canada for management of neuropathic pain associated with multiple sclerosis. It is administered as an oral spray for use under the tongue or inside the cheek. In the United States, GW-1000 is considered a Schedule I drug by the DEA, so importation is currently illegal.31

Medication Therapy Management for Persistent Neuropathic Pain

The pharmacist can play a significant and meaningful role in the management of patients with pain and especially the complex patient presenting with persistent neuropathic pain. The core elements for medication therapy management (MTM) service32 can be applied to the patient suffering from pain.

1. Performing or obtaining necessary assessments of the patient's health status: The pharmacist should assess for pain as the fifth vital sign and specifically by using instruments such as the NPS. Pharmacists can conduct foot inspection and filament testing in the diabetic patient. Patients may have difficulty describing neuropathic pain; therefore it is important to provide specific adjectives describing neuropathic pain in your pain quality assessment. Assess the impact pain has on daily function and quality of life.

2. Formulating a medication treatment plan, including counseling the patient on expectations regarding medication therapy: The treatment plan should provide an explanation of appropriate goal setting. The patient should understand that pain that is long-standing may not respond completely to treatments. Patients need to set goals where they can manage residual pain. The treatment plan, with provider approval, should include a moderate exercise program. Support should be solicited from family and friends to prevent social decline and isolation.

3. Monitoring and evaluating patient response to therapy, including safety and effectiveness: Monitoring, especially in the first few days of dosage changes or initiation of new agents, is crucial to the titration process in treating pain. The pharmacist should closely follow patients in order to achieve optimum benefits from the regimen prescribed while minimizing and addressing adverse events or other complications as they arise.

4. Performing a comprehensive medication review to identify, resolve, and prevent medication-related problems, including adverse events related to other medications in addition to the pain management regimen and how these interrelate: The individual suffering from neuropathic pain is frequently treated with rational polypharmacy designed to treat the pain and other associated symptoms such as anxiety, depression, and spasm. A prospective drug regimen review by the pharmacist on the patient's first visit is essential to optimizing treatment.

5. Documenting the care delivered and communicating information to other care providers: The patient may have multiple providers, including the physician, physical therapist, psychologist, and others involved in the treatment of the chronic pain. The pharmacist is often a hub of information for these members of the health care team, and he or she should act as a central communicator.

6. Educating the patient on the understanding and appropriate use of medications: Medications used in the treatment of neuropathic pain frequently are prescribed off-label, and patient information sheets are not useful in this setting. Anticonvulsant drugs, some of the opioids, and TCAs are all used off-label for the treatment of neuropathic pain. The pharmacist should take extra time to explain these offlabel medications to the patients.

7. Providing information, support, and resources to enhance patient adherence: The patient with neuropathic pain is frequently using a complex regimen of medications not only for the treatment of pain but also for the treatment of other comorbidities. Nonadherence is a risk in such patients. Pharmacists are specialists in counseling patients on medication use and adherence and can improve patient adherence through appropriate counseling.

8. Coordinating and integrating MTM services within the broader health care management services brought to the patient: The pharmacist can educate patients and families in general about nerve pain, explain its pathophysiology in simple terms, provide education on the wide variety of treatment options, and refer the patient to other members of the multidisciplinary team as necessary.

Counseling Points for the Patient with Neuropathic Pain

Resources for Pharmacists and Patients

www.theacpa.org The American Chronic Pain Association (ACPA) is raising awareness about neuropathic pain. Pharmacists can facilitate this initiative by identifying patients with neuropathic pain and educating patients and families. A survey sponsored by the ACPA found that neuropathic pain is not well understood by the public.33 The survey was a random sampling of 939 Americans not employed in the medical field. Nearly 34% of the respondents to the telephone survey knew someone with or had the pain described as tingling, pins and needles, burning, or electric shock-like sensations. Only 6% recognized these symptoms as nerve pain. Educating patients can empower them to manage their own pain. The Web site offers support resources such as group support by geographical region.

www.medsch.wisc.edu/painpolicy The University of Wisconsin Web site offers information about pain relief and public policy. The aim is to raise awareness about pain and to ensure adequate availability of pain medications for patient care while minimizing diversion and abuse. The Pain and Policy Studies Group (PPSG) facilitates this mission.

www.pharmacy.duq.edu/div PharmPrac.html Duquesne University Mylan School of Pharmacy has established an interdisciplinary chronic pain team. The Chronic Pain Initiative utilizes the resources of the university to improve the quality of life of those with pain and their family members through an interdisciplinary effort focusing on healing of mind, body, and spirit. The team believes that there is much work to be done in educating not only patients and families, but also health care professionals about pain management. The Chronic Pain Initiative involves students early on in their training as members of the interdisciplinary team model of care. Team members provide support and informational resources for patients, families, and caregivers of those suffering from pain to reintroduce hope into their lives.

www.ampainsoc.org The American Pain Society (APS) is a multidisciplinary organization composed of professionals who are involved in basic research, clinical research, treatment, advocacy, and public policy regarding pain. Resources on the Web site include publications, calendar of events, news, and links to related Web sites.

www.ittakesnerve.org A consumer Web site for the patients and their families who cope with the suffering from neuropathic pain. Information includes how to enjoy life and improve the quality of life despite nerve pain. The site is associated with the American Chronic Pain Association (ACPA).

Conclusion

Neuropathic pain is a chronic disorder associated with much personal suffering, compromised quality of life, and loss of function. The patient is optimally treated by a multidisciplinary team of health care professionals using a combination of therapies such as rational polypharmacy, physical and occupational therapy, and cognitive therapies. The pharmacist plays an integral role on the team treating the patient with neuropathic pain through application of medication management principles in the community or hospital practice setting. These medication management principles can optimize therapeutic outcomes for individual patients.

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

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@ascendmedia.com.

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

1. Neuropathic pain is costly to our health care system and society. Direct and indirect costs are represented by:

  1. Cost of medication.
  2. The patient being in pain and not reporting for work.
  3. The patient in pain reporting to physical therapy for a scheduled appointment.
  4. All of the above

2. Persistent neuropathic pain can lead to which of the following comorbid medical problems?

  1. Multiple sclerosis
  2. Depression
  3. Anxiety
  4. b and c

3. The diagnosis of neuropathic pain is often overlooked because:

  1. The patient is not asked about specific symptoms indicating neuropathy.
  2. The physician quickly diagnoses the pain as musculoskeletal pain.
  3. The patient cannot understand the numeric rating scale.
  4. a and b

4. Which of the following characteristics describes neuropathic pain?

  1. Throbbing headache and eye pain
  2. Deep muscular pain in the shoulder
  3. Burning, tingling, radiating pain down the leg
  4. Itching sensation

5. Peripheral neuropathy may be associated with which of the following etiologies?

  1. Lung cancer
  2. Chemotherapy
  3. Stroke
  4. Abdominal pain

6. Tricyclic antidepressants (TCAs) may be used for the treatment of neuropathic pain. Which of the following is true?

  1. Tertiary amines are the worst-tolerated compounds in terms of side effects.
  2. Dry mouth, constipation, and urinary retention may be troublesome side effects.
  3. The potential for cardiac arrhythmias is of particular concern in the 20-to 40-year-old age group.
  4. The FDA has approved neuropathic pain as an indication for the use of TCAs.

7. The pharmacist can counsel the diabetic patient taking gabapentin for tingling and burning in the feet on which of the following points?

  1. The medicine should be taken in low doses to begin with and then increased.
  2. The patient should perform a daily foot inspection.
  3. The pain may be only partially relieved.
  4. All of the above

8. Relief from pain is not the only measure of therapeutic success in patients suffering from neuropathic pain. What other indicator(s) is (are) measured for treatment success?

  1. Regular sleeping patterns
  2. Complete resolution of pain
  3. Using only one dose of oxycodone daily
  4. None of the above

9. Methadone can be a useful agent in treating which of the following patient(s)?

  1. A patient who is treated with high doses of ibuprofen and remains in pain
  2. A patient who chronically complains of radiating, tingling pain in the arm
  3. A patient who complains of severe back pain due to muscle spasm
  4. A patient who has occasional abdominal pain

10. Patients receiving chronic opioid therapy should be counseled by the pharmacist on the following point(s):

  1. You will become addicted to this medication in several weeks.
  2. Be aware of side effects associated with your medication, such as drowsiness and nausea.
  3. Use a Fleet enema daily to prevent constipation.
  4. Take the medication only when you have severe pain.

11. The treatment plan written for a patient afflicted with neuropathic pain could include which of the following recommendations?

  1. Consult with a psychologist to learn meditation techniques.
  2. Use multiple medications, such as opioids and anticonvulsants.
  3. Consult with a physical therapist for strengthening exercises.
  4. All of the above

12. A variety of anticonvulsants have been used in the treatment of neuropathic pain. Which of the following statements is true?

  1. Anticonvulsants are suggested as first-line treatment options for neuropathic pain.
  2. There is solid evidence-based literature to support the use of lamotrigine in the treatment of neuropathic pain.
  3. Topiramate usually is initiated at a low dose and titrated slowly to a maximum tolerated and effective dose.
  4. Rash is a common adverse effect associated with the use of carbamazepine.

13. Intrathecal drug delivery may be accomplished by using which of the following agent(s)?

  1. Baclofen
  2. Hydrocodone
  3. Celecoxib
  4. None of the above

14. A new drug treatment for neuropathic pain is duloxetine. All of the following statements describe duloxetine except:

  1. The drug should not be administered to a patient whose creatinine clearance is less than 30 mL/min.
  2. The drug is used in the treatment of depression.
  3. The drug is approved for use in the treatment of postherpetic neuralgia.
  4. The drug is associated with the adverse effects of nausea, dry mouth, and constipation.

15. Pregabalin is a new agent used in the treatment of diabetic neuropathy and postherpetic neuralgia. It is closely related to gabapentin. How does pregabalin differ from gabapentin?

  1. Pregabalin is much more potent milligram per milligram than gabapentin.
  2. An increase in the patient's blood pressure is seen with the use of pregabalin.
  3. Pregabalin is prescribed as once-aday dosing.
  4. Pregabalin is extensively metabolized through the cytochrome P-450 enzyme system.

16. The pharmacist can provide medication therapy management (MTM) services to the patient with neuropathic pain in which of the following way(s)?

  1. The pharmacist can assess the impact pain has on the ability of the patient to perform activities of daily living.
  2. The pharmacist can assess the fifth vital sign.
  3. The pharmacist can discuss ways in which the family can support the patient with persistent pain, such as assisting with medication adherence.
  4. All of the above

17. The patient suffering from neuropathic pain is frequently receiving complex medication regimens. The pharmacist's role in providing MTM services includes which of the following?

  1. Assisting the patient in setting and achieving realistic goals with respect to pain
  2. Following up with the patient when a dose of medication is changed to assess therapeutic effect
  3. Telling the patient to abruptly discontinue a medication ineffective for pain control
  4. a and b

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

  1. The pathophysiology of nerve pain in simple terms
  2. Expectations from medication therapy
  3. The use of nonpharmacologic treatment options
  4. All of the above

19. Ziconotide is a new agent for the treatment of neuropathic pain. Which of the following characteristics describes ziconotide?

  1. The drug is derived from the venom of a spider.
  2. The drug is given by the intrathecal route of administration.
  3. The drug is available in both an oral and a sublingual tablet.
  4. The drug is associated with neutropenia in the first 3 months of therapy, and blood count must be monitored.

20. A new agent containing cannabis extract and approved for the treatment of neuropathic pain associated with multiple sclerosis, available in Canada but not the United States, is:

  1. Ziconotide
  2. Pregabalin
  3. Sativex
  4. Duloxetine

CE ANSWER FORM INSTRUCTIONS

TESTING AND GRADING PROCEDURES

1. Each participant achieving a passing grade of 70% or higher on any examination will receive a statement of credit giving the number of CE credits earned. This form should be safeguarded and may be used as documentation of credits earned.

2. Participants receiving a failing grade on any exam will be notified and permitted to take 1 reexamination at no extra cost.

3. All answers should be recorded on the answer form attached. For each question, decide which choice is the best answer, and circle the letter of the response representing your choice.

4. Mail your completed exam form to the following address: Pharmacy Times, 405 Glenn Drive, Suite 4, Sterling, VA 20164-4432.

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Please mail completed forms to: Pharmacy Times CE Department, 405 Glenn Drive, Suite 4, Sterling, VA 20164-4432

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