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Treatment Options in Neuropathic Pain

Jacintha S. Cauffield, Pharm.D., BCPS
President and Clinical Pharmacy Consultant
GeM Integrative Pharmacotherapy, Inc., Jupiter, FL


Pain is one of the most common reasons for a patient to seek medical care. An estimated 50 million patients suffer from chronic nonmalignant pain, or pain of greater than 3 months’ duration that is not related to cancer.1 Pain results in a staggering 40 million physician office visits per year, accompanied by approximately 4 billion lost work days, $65 billion in lost work productivity and $3 billion in over-the-counter analgesics.2 Above all, it results in a dramatically decreased quality of life for the patient who experiences it. In a 1997 Gallup poll, 73% of people feared inadequate pain relief at the end of life. In a separate poll, 69% of cancer patients stated they would consider suicide if they felt their pain was inadequately controlled.3

Characterized by sensations of burning, electricity, extreme cold, numbness and tingling, neuropathic pain has numerous etiologies.
Although it may occur with cancer, neuropathic pain is a common type of chronic, nonmalignant pain. Diabetic neuropathy approaches 50% in most diabetic populations, many with painful symptoms.4 The incidence of herpes zoster is 125 in 100,000 in the general population, and it rises to 400 in 100,000 in octogenarians.5 Optimizing pain relief is crucial to helping a patient regain control of his or her life. Because pharmacotherapy plays a prominent role in treating neuropathy, it is also a perfect opportunity for the pharmacist to be involved.

Pathogenesis

Etiologies: Neuropathic pain has many different etiologies (see TABLE 1). The common underlying mechanism is nerve injury or dysfunction. According to the "gate control" pain theory, injury to peripheral nerves or nerves descending from the spinal cord results in disinhibition of the nerve’s impulses at the spinal cord "gate," which results in pain. Mechanosensitivity, spontaneous activity and increased responsiveness to both beta-adrenergic agonists and sympathetic chain stimulation also contribute to the pain. Neuropathic pain due to diabetes, HIV, and vitamin deficiencies all involve peripheral nerves.5 Other neuropathic pain is centrally mediated, such as post-stroke central pain syndrome, spinal cord injury, and multiple sclerosis.6

Table 1
Common Etiologies of Neuropathic Pain

Alcohol
Diabetes mellitus type 1 and 2
Eosinophilia-myalgia syndrome
Guillain-Barre syndrome
Heavy metals
Arsenic
Lead
Mercury
Thallium
HIV/AIDS
Malignant tumor-related
Medications
amiodarone
aurothioglucose
cisplatinum
dapsone
d4T (stavudine)
ddC (zalcitabine)
ddI (didanosine)
disulfiram
FK 506
hydralazine
isoniazid
metronidazole
nitrofurantoin
paclitaxel
phenytoin
vincristine
Monoclonal gammopathies
Multiple sclerosis
Post-stroke central pain
Postherpetic neuralgia
Traumatic
Carpal tunnel syndrome
Cervical or lumbar radiculopathy
Complex regional pain syndrome
Spinal cord injury
Stump pain

Trigeminal neuralgia
Vasculitis
Vitamin B6 megadosing
Vitamin deficiencies (B12, B1, B6, E)
Source: References 5-10


Medications can also result in neuropathies, sometimes with associated pain. Isoniazid and hydralazine induce neuropathy by depleting pyridoxine. Ironically, megadoses of pyridoxine also cause neuropathy. Other medications have reversible dose-related effects. These include amiodarone, statins, dapsone, nucleoside analogs, paclitaxel and vincristine. A dose-dependent neuropathy is associated with cisplatin, but may not resolve and possibly worsen with drug discontinuation.7,10 Nitrofurantoin induces a dose- and total body load-independent neuropathy, although patients with renal insufficiency (CrCL <60 mL/min) are at an increased risk. It can become severe, irreversible and fatal, particularly if nitrofurantoin therapy is continued.11 Phenytoin- or disulfiram-induced neuropathies have a delayed onset of months to years.7

Signs and Symptoms

Several features of neuropathy distinguish it from other types of pain (see TABLE 2). Pain is delayed in onset after the injury occurs. Patients often describe their pain as "electrical" or "burning." Other descriptors include feelings of extreme cold, "like frostbite," despite an absence of temperature changes upon physical exam. Patients with diabetic neuropathy or Guillain-Barre syndrome sometimes experience numbness, tingling, or "needles and pins" sensations. Pain descriptors vary between patients, and don’t reliably identify the etiology. Pain may worsen with activity or with wearing clothes over the affected area, or may have a daily pattern.5
A neuropathy diagnosis involves signs of sensory dysfunction on physical examination accompanied by correlating evidence of nervous system injury. There may be motor dysfunction as well. Patients often develop secondary myofascial pain. Negative findings on diagnostic tests do not rule out neuropathic pain.

Certain physical examination techniques help to identify abnormal sensory perceptions. Patients may have allodynia, a painful response to a typically nonpainful stimulus. Allodynia is elicited by brushing the affected area with a fingertip or cotton swab, or by thermal stimulation with a cold or warm object. Patients sometimes experience hyperpathia, an exaggerated pain response to a minor painful response, such as pinpricks. The pain tends to increase with repeated exposure, may spread outside of the contacted area (summation), and may include painful after-sensations.5

Neuropathic pain clearly can impact a patient’s ability to carry out his or her activities of daily living (ADLs). Increased pain during the night interferes with sleep. The patient may have difficulty ambulating without feeling pain. Handling eating utensils or tools may cause pain. The patient may guard an affected painful limb, limit social activities, or develop depression.1,5 Pain relief is important to improve the patient’s quality of life.

Treatment Goals

While the first goal of therapy is to relieve pain, goals should be realistic. Patients often hope for a "cure," but this is not always possible. Complete pain relief may not be achieved with treatment. A more realistic goal is to decrease pain to a tolerable level. Successful treatment should improve ADLs. This includes improved ability for patient self-care, and increased ability to socialize. Specific goals should include activities the patient wishes to resume with pain relief. Effective treatment usually combines nonpharmacologic methods with medication.

Nonpharmacologic Management

Nonpharmacologic techniques are usually used as an adjunct to medication. Transcutaneous electrical nerve stimulation (TENS) is frequently used to augment pharmacotherapy. Skin electrodes applied on the skin near the affected nerve endings are used to transmit mild electrical impulses in an effort to block transmission of pain signals to the brain.5 Acupuncture has been used for diabetic neuropathy with some success.12 Other techniques include physical therapy, occupational therapy, biofeedback, relaxation therapy, meditation, and hypnosis.5

Pharmacologic Management

Pharmacotherapy is the mainstay for treating neuropathic pain. Medication from several different drug classes are used to treat neuropathic pain, including topical agents, tricyclic antidepressants, anticonvulsants, and nonopioid analgesics (see TABLE 3 and TABLE 4). The common underlying mechanism of action is reduction of neuronal hyperexcitability, either peripherally or centrally. In a sense, the nerve impulses are blunted. Carbamazepine is currently the only medication that carries an FDA- approved indication for neuropathic pain, specifically for trigeminal neuralgia. Clinical trials give some guidance on agent selection, but they do not predict which agent will relieve an individual patient’s pain. Patients should be informed of the need for sequential drug trials to determine the optimal agent for treating their neuropathic pain.

Table 2
Signs and Symptoms of Neuropathy

Symptoms
Pain descriptors:
Electric
Burning
Icy cold
Frostbite
Aching
Tingling
Needles and pins
Onset of pain delayed after injury
Signs
Sensory dysfunction
May or may not have muscular dysfunction
Allodynia (pain from normally nonpainful stimulation, e.g., touching with finger, cotton swab, warm or cold objects)
Hyperpathia (exaggerated pain to minor stimulus, such as pin prick, that increases with each exposure)
Source: Reference 5


Topical Agents: Topical agents offer the advantage of local relief without systemic toxicity. Capsaicin cream, which contains an extract of chili peppers, is sometimes used to treat neuropathic pain. It may act on unmyelinated primary afferent nerves by depleting substance P, a peptide thought to be involved in pain transmission. Depletion requires repeated and consistent use of capsaicin. The most common side effect is a burning sensation that decreases with consistent use. Pain relief with capsaicin cream in clinical trials has been inconsistent. Two trials of its effects on diabetic neuropathy were either negative or only slightly effective. Two trials in postherpetic neuralgia had conflicting results. A fifth trial in polyneuropathy had negative results.5,13 Lidocaine is also used topically, particularly in the newly approved patch form, with modest effects in the treatment of postherpetic neuralgia.13

Antidepressants: Both tricyclic antidepressants and serotonin reuptake inhibitors are used to treat neuropathic pain. Tricyclic antidepressants (TCAs) are considered first-line agents for all neuropathies except trigeminal neuralgia.5 Numerous clinical trials demonstrate the safety and efficacy of TCAs when used to treat either diabetic neuropathy or postherpetic neuralgia.13-15 Amitriptyline was the first tricyclic used to treat neuropathy, and it is still widely prescribed. Amitriptyline also has a high incidence of anticholinergic side effects. This can lead to delirium in elderly patients and should be avoided in that population. Desipramine and nortriptyline, which have the least anticholinergic activity of the TCAs, are equally efficacious substitutes.16-18 The pain-relieving properties of TCAs occur independently of their effect on mood.5

Like cisapride and the class IA antiarrhythmics quinidine and procainamide, TCAs have proarrhythmic effects, including an increased risk for torsade de pointes. Patients should have a baseline ECG, with a repeat after achieving a therapeutic dose. The greatest risk for developing arrhythmias occurs with a QRS >100 ms or a prolonged QTC (greater than or equal to 440–470 ms). Other risk factors include congestive heart failure with an ejection fraction <35%, active ischemic heart disease, and bundle branch block. TCAs should also be avoided in patients with closed-angle glaucoma, benign prostatic hypertrophy, uncontrolled seizure disorder, and bipolar disorder.5 TCAs can be used in patients who have hemi-block or first-degree heart block.19

Serotonin specific reuptake inhibitors (SSRIs) have less consistent effects on neuropathic pain. Fluoxetine decreased pain secondary to diabetic neuropathy, but only in depressed patients.18 Conversely, paroxetine was comparable to imipramine for relieving diabetic neuropathy-related pain, independent of mood.20 In one study citalopram was more effective than placebo for decreasing diabetic neuropathic pain.21

Venlafaxine is gaining interest as a potential treatment for neuropathic pain, because it combines the norepinephrine-reuptake inhibiting effects of TCAs with the serotonin-reuptake inhibiting effects of the SSRIs, without the anticholinergic side effects. The clinical literature is currently limited to two case reports of decreased pain—one associated with low back radicular pain and the other involving diabetic neuropathy.22,23 The most common side effects of venlafaxine include increased blood pressure and/or hypertension, irritability, insomnia, nausea, vomiting and constipation.

Table 3
Benefit-Risk Analysis of Agents Used to Treat Neuropathic Pain

Medication Number of Patients Needed to Treat (NNT)
for Efficacy/Adverse Effects
Painful/Diabetic
Neuropathy Postherpetic Neuralgia Peripheral
Nerve Injury Trigeminal Neuralgia
Tricyclic antidepressants
Amitriptyline
Desipramine 2.4/4.9
2.0/9.7
3.4/20 2.3/6
2.3/6.2
1.9/4.8 2.5/ND
2.5/ND
— —
—
—
SSRIs
Paroxetine
Citalopram 6.7/ND
2.9/ND
7.7/ND —
—
— —
—
— —
—
—
Phenytoin 2.1/9.5 — — —
Carbamazepine 3.3/1.9 — — 2.6/3.4
Gabapentin 3.7/1.8 3.2/3.4 — —
Lamotrigine — — — 2.1/ND
Mexiletine 10.0/6.3 — — —
Baclofen — — — 1.4/ND
Tramadol 3.4/ND — — —
Oxycodone — 2.5/ND — —
Source: References 15,21,22,26,27,30-32,37


Anticonvulsants: Anticonvulsants are considered second-line therapy for most neuropathies. Carbamazepine, phenytoin, gabapentin and lamotrigine are all used to treat neuropathic pain. Inhibition of sodium channel blocking activity by agents such as carbamazepine, phenytoin, and lamotrigine is a proposed mechanism of treating neuropathic pain.15 Although carbamazepine is still used, phenytoin has produced mixed results in clinical trials.15 It has fallen out of favor due to its effects on cognition. It may also cause neuropathy when used over a period of years.7,8 Neither valproic acid nor clonazepam has been well-studied for effects on neuropathic pain, but available data suggest lack of efficacy.5
Carbamazepine: Carbamazepine is considered first-line therapy for trigeminal neuralgia. Clinical trials suggest its efficacy for treating diabetic neuropathy, but results are mixed for postherpetic neuralgia.5,13,15 Some evidence supports the use of plasma concentrations to reach an effective dose. In a study of 31 patients with polyneuropathies due to postherpetic neuralgia, trigeminal neuralgia, phantom-limb pain or reflex sympathetic dystrophy, the average plasma level needed to give 50% pain relief was 9.5 mcg/mL.24

The most common side effects of carbamazepine are dizziness, giddiness and dyspepsia. These symptoms are dose-related, and can be minimized by starting with low doses.11 Carbamazepine carries a black box warning for blood dyscrasias, including agranulocytosis and aplastic anemia. Both of these side effects are idiosyncratic. Postmarketing studies suggest a 5- to 8-fold increase in risk for blood dyscrasias in patients taking carbamazepine. The incidence is still low at 6/100,000 for agranulocytosis and 2/100,000 for aplastic anemia, and is highest within the first three months of therapy. In 7% of patients, the white blood cell count (WBC) can drop up to 25%, as low as 4,000/mm3. This decrease usually reverses within the first four months of therapy. Risk for agranulocytosis may be increased in patients with a low normal WBC. A complete blood count (CBC) can be monitored either according to the package insert or in one of two other ways. If the patient’s CBC, reticulocyte count and serum iron are within normal limits at baseline, the CBC can be monitored 2–4 weeks after starting therapy and then periodically (approximately every 3–6 months) thereafter. If the CBC reveals a low normal WBC (less than or equal to 4,500/mm3), then the CBC should be monitored every two weeks for the first three months. If the WBC count drops below 3,000/mm3, or the absolute neutrophil count (ANC) is *1,000/mm3, the dose should be tapered and/or stopped based upon a risk-benefit analysis. Because carbamazepine is also associated with the syndrome of inappropriate ADH secretion (SIADH) and hepatotoxicity, a SMA 7 and liver function tests should be obtained at baseline, and periodically thereafter.11,25

Anticonvulsant agents are considered second-line therapy for most neuropathies.

Gabapentin: Until recently, evidence for treating neuropathies with gabapentin was based on anecdotal information or case studies. However, objective evidence from randomized, double-blind trials is available. Gabapentin is more effective than placebo at reducing diabetic neuropathy and postherpetic neuralgia-associated pain.26,27 In a comparative trial, a nonsignificant trend favored amitriptyline over gabapentin for decreasing pain in 22 patients with diabetic neuropathy. The authors pointed out that they would have needed to enroll 260 patients in order to detect a 33% difference in pain relief at 80% certainty at an alpha factor of 0.5. Incidence of adverse effects was similar between the two groups.28 The most common side effects associated with gabapentin are asthenia, headache, dizziness and somnolence.11 Ironically, gabapentin has been reported to induce polyneuropathy.29 Until large, well-designed comparative clinical trials are available, gabapentin should be reserved as a second- or third-line agent.

Off-Label Drug Uses

Off-label drug use applies to medications that have FDA-approved indications but are also used for non-approved indications. Use may be appropriate, but data sufficient to gain an additional indication is either lacking, and/or the manufacturer may not have an interest in expanding the medication indications. Only a few medications used to treat neuropathic pain have FDA approval for the indication. There are a couple of exceptions. Carbamazepine is approved for trigeminal neuralgia, and both capsaicin cream and the Lidoderm patch is approved for treating pain associated with postherpetic neuralgia. Analgesics, including NSAIDs, opioids, and tramadol, are used to treat neuropathic pain, although none of them carry an indication for treating neuropathic pain. The rest of the agents are used off-label to treat neuropathic pain.

The FDA recognizes physician off-label use of medications. However, without FDA approval, dissemination of off-label use is difficult. Off-label uses, along with appropriate use or prescribing activity, can’t be listed on the drug package insert. Physicians, pharmacists and other health professionals may therefore not know or understand the appropriate conditions of the off-label use. This can be detrimental to both patients and their providers. There is a definite need to develop guidelines or recommendations regarding off-label uses and the provision of appropriate information.
Source: Based on reference 41

Lamotrigine: Lamotrigine shows promise for decreasing pain associated with trigeminal neuralgia.15,30 However, it was no better than placebo when used to treat other types of neuropathic pain.31 The side effect of most concern is skin rash, including Steven-Johnson’s syndrome. To avoid this, therapy should be initiated with low doses and titrated slowly to a therapeutic dose.11 Until more clinical information is available, lamotrigine should be reserved for use only after other, more commonly used therapies are exhausted.


Antiarrhythmics: Certain antiarrhythmics, such as the anticonvulsants listed above, have sodium-blocking activity.15 Low-dose IV lidocaine is sometimes used for temporary pain relief from peripheral nervous system injuries, including diabetic neuropathy and postherpetic neuralgia. It is also used as a diagnostic agent to discern neuropathic pain from idiopathic, myofascial, and central pain. IV lidocaine is also used to predict response to mexiletine. Both lidocaine and mexiletine are contraindicated in patients with liver failure, Adams-Stokes syndrome, significant ventricular conduction defects, second- or third-degree heart block, or who are allergic to amide-type anesthetics. IV lidocaine also should be avoided in patients with systolic congestive heart failure and an ejection fraction <35%. IV lidocaine therapy requires constant monitoring of the patient’s ECG and blood pressure to decrease the risk for seizures and arrhythmias. If the patient develops drowsiness, cognitive impairment or dysarthria, the infusion must be stopped immediately.5,11 The most common side effects of mexiletine are nausea, vomiting, dyspepsia, dizziness, tremor and ataxia.11 Mexiletine mildly decreases pain associated with traumatic mononeuropathy, but has mixed results when used to treat diabetic neuropathy.5,13,15 Neither mexiletine nor amitriptyline was effective for treating HIV-associated neuropathy.32 Due to its risk for side effects and uncertain effects on neuropathic pain, mexiletine should be reserved for use after more conservative therapies have failed.
Analgesics: Analgesics are not first-line agents for treating neuropathic pain. Relief of neuropathic pain with nonsteroidal anti-inflammatory drugs (NSAIDs) is variable. Opioid treatment of neuropathic pain has been controversial over the past 10–15 years. Opioids were thought to be ineffective for treating neuropathic pain, but evidence is mounting for the use of opioids in patients who have failed other modalities. In addition, novel analgesics such as tramadol may offer new options in treating neuropathies.
NSAIDs: Neuropathic pain relief from NSAIDs has varied widely with the type of neuropathy and agent used. Ibuprofen and sulindac both offer some pain relief from diabetic neuropathy.13,33 Conversely, piroxicam has no effect on lumbosacral radicular pain, and single-dose ibuprofen failed to relieve postherpetic neuralgia pain.13
Tramadol: Interest in tramadol for treating neuropathic pain stems from its inhibition of norepinephrine reuptake and release of serotonin, similar to the tricyclic antidepressants. Its active metabolite, (+) M1, also binds to the mu-opioid receptor. Only a few small clinical studies have examined tramadol’s efficacy on neuropathic pain. In one study of 34 patients with polyneuropathy of varying etiologies, tramadol was superior to placebo at reducing both ongoing and touch-evoked pain.34 It was also superior to placebo at decreasing pain and improving social functioning in patients with diabetic neuropathy.35 No trials comparing tramadol to more established medications currently exist. The most common side effects of tramadol are somnolence, constipation, and headache.11,35 Tramadol should be avoided in patients with a history of seizures or substance abuse. In addition, there is a risk for serotonin syndrome if given with other serotonergic agents, such as SSRIs, MAO inhibitors, and triptans.11
Opioids: A small body of evidence suggests that opioids may relieve neuropathic pain in a select population of patients. Opioid analgesia appears to be dose-dependent and related to serum levels when used to treat neuropathic pain.13 Intravenous fentanyl is more effective than placebo at reducing neuropathic pain, regardless of etiology.36 Controlled-release oxycodone may decrease pain and allodynia associated with postherpetic neuralgia when given at doses of 20–60 mg/day.15,37 Conversely, codeine is not effective at reducing postherpetic neuralgia symptoms. Morphine has also been used to treat nerve injuries, with mixed results.13 In general, neuropathic pain relief with opioids remains controversial. Neuropathic pain may be less responsive to opioids than other types of pain, and often requires the addition of one of the previously discussed agents to provide relief.


Table 4
Drug Interactions of the Agents Used to Treat Neuropathic Pain

Agent Interacting Medication Adverse Reaction
TCAs anticholinergic agents (antihistamines) Additive effects
Monoamine oxidase (MAO) inhibitors Hypertensive crisis, seizures, can be fatal
CNS depressants (barbiturates, alcohol, benzodiazepines, opioids, valerian, kava-kava) Possible additive effects

sympathomimetics (amphetamines, cocaine, norepinephrine, epinephrine) Additive sympathetic activity, can be fatal

CYP2D6 inhibitors (cimetidine, quinidine, fluoxetine, paroxetine) May cause toxic symptoms

SSRIs serotonergic agents (venlafaxine, TCAs, dextromethorphan, trazodone, tramadol, meperidine, selegiline, triptans, lithium, buspirone, pentazocine) Serotonin syndrome



MAO inhibitors Hypertensive crisis, seizures, can be fatal
benzodiazepines SSRIs inhibit metabolism, may cause oversedation, toxicity
antipsychotics Severe extrapyramidal symptoms refractory to conventional treatments
carbamazepine SSRIs can increase serum concentrations, toxicity
venlafaxine

SSRIs Serotonin syndrome
carbamazepine (CBZ) fluoxetine, erythromycin, verapamil Increased serum concentrations, toxicity
anticonvulsants (phenytoin, phenobarbital, valproic acid, primidone) CBZ can decrease serum levels and efficacy; valproic acid can increase CBZ epoxide levels, cause toxicity
doxycycline CBZ increases doxycycline clearance, decreases efficacy
gabapentin
antacids Can decrease gabapentin bioavailability by 20%
lamotrigine valproic acid Skin rash, Stevens-Johnson syndrome, (TEN) toxic epidermal necrolysis if lamotrigine is dosed too high or rapidly
lidocaine antiarrhythmics May have additive or proarrhythmic effects
cimetidine, propranolol Can cause lidocaine toxicity
mexiletine cimetidine Variable effects, patient should be monitored
fluoroquinolones (ciprofloxacin) May decrease hepatic clearance through CYP1A2, cause toxicity
CYP inducers (phenytoin, carbamazepine, phenobarbital, rifampin) Can decrease mexiletineconcentrations, efficacy

theophylline Mexiletine can increase theophylline concentrations, cause toxicity
antiarrhythmics May have additive or proarrhythmic effects
tramadol SSRIs (sertraline, paroxetine) Serotonin syndrome
CNS depressants (barbiturates, alcohol, benzodiazepines, TCAs, valerian, kava-kava) Possible additive effects

opioids May cause withdrawal in patients taking opioids, dependence in patients with a
history of opioid dependence
NSAIDs anticoagulants May increase INR, risk of GI
bleed when given with warfarin
digoxin May increase serum digoxin concentrations, cause cardiotoxicity
lithium NSAIDs increase serum concentrations, can cause toxicity
diuretics, cyclosporine May increase renotoxicity
opioids CNS depressants (barbiturates, alcohol, benzodiazepines, TCAs, valerian, kava-kava)
Possible additive effects
MAO inhibitors When given with meperidine, fentanyl, can cause serotonin syndrome
serotonergic agents (SSRIs, venlafaxine, TCAs, dextromethorphan, trazodone, tramadol, selegiline, triptans, lithium, buspirone) Serotonin syndrome when given with meperidine or fentanyl

baclofen CNS depressants (barbiturates, alcohol, benzodiazepines, TCAs, valerian, kava-kava) Possible additive effects

MAO inhibitors Can cause CNS depression, hypotonia
clonidine CNS depressants (barbiturates, alcohol, benzodiazepines, TCAs, valerian, kava-kava) Possible additive effects

agents that can cause bradycardia (beta-blockers, cardiac glycosides, diltiazem, guanethidine, or verapamil) Can cause complete AV nodal block (verapamil), hypotension, hypertensive crisis if switch from clonidine to beta-blocker
NSAIDs, sympathomimetics Decrease antihypertensive effects
diuretics, antihypertensives, hawthorn Additive hypotension
ketamine CNS depressants (barbiturates, alcohol, benzodiazepines, TCAs, skeletal muscle relaxants, H1-blockers, valerian, kava-kava) Increases risk of developing respiratory depression
Levothyroxine, thyroid hormones Hypertension, tachycardia
dextromethorphan Serotonergic agents (SSRIs, venlafaxine, TCAs, trazodone, tramadol, selegiline, triptans, lithium, buspirone, MAO inhibitors) Serotonin syndrome

Source: Reference 11



Other Agents: Baclofen is used as a first-line agent to treat trigeminal neuralgia, with or without anticonvulsants. Baclofen blocks both presynaptic and postsynaptic GABA B receptors, which are concentrated in the spinal cord on the primary afferent neurons. This decreases the response of nerves to electrical stimulation and other pain stimuli. It may also inhibit the release of substance P. The most common side effect is drowsiness, which is partially avoidable by starting with a low dose and titrating slowly.38

Transdermal clonidine has been used with mixed results to treat diabetic neuropathy. Oral clonidine may have some benefits when used to treat postherpetic neuralgia, but should be reserved for use only after more conservative treatments have failed.13

Ketamine, an N-methyl-D-aspartic acid (NMDA) receptor antagonist, has garnered increased interest for treating neuropathic pain in the past decade. New evidence suggests that NMDA receptors play a role in mediating neuropathic pain. In a comparative trial, ketamine, but not morphine, relieved continuous and lancinating pain, and allodynia in postherpetic neuralgia.39 Most studies done to date used short-term infusions of ketamine. Long-term parenteral use of ketamine can lead to painful indurations at the site of injection and psychomimetic effects. Ketamine is chemically related to phencyclidine (PCP), and causes sedation, slowed reaction times and hallucinations with long-term use. For this reason, it not currently recommended for use in chronic non-malignant pain.13

Dextromethorphan is also an NMDA antagonist. It has been used with some success to decrease pain in patients with diabetic neuropathy. It does not appear to have any effect on postherpetic neuralgia, peripheral neuropathies of other etiologies, or central post-stroke pain.15

The Role of the Pharmacist

Pharmacists can play a very important role in the management of patients with neuropathic pain. Many of the medications have significant side effects and drug interactions, so patient education is vital to successful therapy. Interdisciplinary pain clinics often include a pharmacist to help monitor and titrate medications. Because pain is a subjective experience, it is important to set up an accurate evaluation system to track patient progress. This should include pain ratings based on the visual analog scale (VAS). Ratings for the present moment and at its minimum, maximum and average give a representative picture of treatment efficacy, and can be collected by the patients in a daily pain diary. The patient’s ability to perform ADLs should also be monitored. This might include an objective tool, such as the SF-36, or patient-specific goals of activities or ADLs they wish to resume with adequate pain relief. Affect is an important indicator of efficacy and as a screen for depression, anxiety or other mood disorders that might need intervention from a psychiatrist or psychologist.

Conclusion

Neuropathic pain remains a clinical challenge for treatment. Any medication used to treat neuropathy must be weighed for benefits and risks before using. It may take several trials to find an effective medication or combination of medications. Patients may need support throughout the process. Neuropathic pain often requires a combination of medication and nonpharmacologic modalities in order to achieve adequate pain relief.

Issue date: June 2000

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