We now have an appreciation that neuropathic pain is associated with structural and functional changes of the peripheral and central nervous system. These changes can lead to the generation and maintenance of chronic pain conditions with its associated disability. While biologic mechanisms play a role in the perception of pain, it is also important to recognize that psychological and environmental factors are important. Recognition of these factors will allow the physician to better (1) treat the recently injured patient, (2) identify the “at risk” patient, and (3) refer the intractable chronic pain patient to the appropriate resources. A full assessment of the patient is required to determine the best approach in any given case.
Therapy for chronic pain ranges from single modality approaches for the straightforward patient to comprehensive interdisciplinary care for the more challenging patient. Therapeutic components such as pharmacologic, interventional, psychological and physical have been found to be most effective when performed in an integrated manner. All therapies are focused on the goal of functional restoration rather than merely the elimination of pain and assessment of treatment efficacy is accomplished by reporting functional improvement. Typically, with increased function comes a perceived reduction in pain and increased perception of its control. This ultimately leads to an improvement in the patient’s quality of life and a reduction of pain’s impact on society.
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American Medical Association (AMA). Guides to the Evaluation of Permanent Impairment, Fifth Edition. 2001: 566, 578.
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Flor, H., T. Fydrich, et al. (1992). "Efficacy of multidisciplinary pain treatment centers: A meta-analytic flow." Pain 49(2): 221-230.
Gatchel, R. J. and D. Bruga (2005). "Multidisciplinary Intervention for Injured Workers with Chronic Low Back Pain." SpineLine (Sept/Oct): 8-13.
Guzman, J., R. Esmail, et al. (2001). "Multidisciplinary rehabilitation for chronic low back pain: systematic review." British Medical Journal 322(7301): 1511-6.
Hanson, R. and Gerber, K. “Table2.1: Contrasting Pain Models” Coping with Chronic Pain: A Guide to Patient Self-Management. New York, NY, Guilford Press. 1993:30.
Linton, S. (2000). “A review of psychological risk factors in back and neck pain.” Spine 25 (9): 1148-56.
Mackey, S. C. and F. Maeda (2004). "Functional imaging and the neural systems of chronic pain." Neurosurg Clin N Am 15(3): 269-88.
Medical Board of California, Guidelines for Prescribing Controlled Substances for Pain,http://www.medbd.ca.gov/pain_guidelines.html Merskey, H. and N. Bogduk (1994). Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. Seattle, WA, IASP Press.
Turk, D. and A. Okifuji, “Chapter 2 Pain Terms and Taxonomies of Pain” in Loeser JD. Bonica’s Management of Pain, 3rd edition. Philadelphia, PA, Lippincott Williams and Wilkins:19.
Siddall P. J. and Cousins, M. J. Persistent pain: a disease entity. Journal of Pain Symptom Management. 2007; 33(2 Suppl): S4-S10.
Part 2 – Pain Interventions and Treatments: All of the following (listed alphabetically) are adapted from ODG except where indicated by “[DWC]”.
Acetaminophen See Medications for Acute Pain
Actiq® Not recommended for musculoskeletal pain. Actiq (oral transmucosal fentanyl citrate), a fast-acting highly addictive "lollipop" painkiller, is indicated only for the management of breakthrough cancer pain in patients with malignancies who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. See Opioids.
Acupuncture [DWC] See Section 9792.24.1 of the California Code of Regulations, Title 8, under the Special Topics section. This section addresses the use of acupuncture for chronic pain in the workers’ compensation system in California.
Anticonvulsants See Anti-epilepsy drugs (AEDs)
Antidepressants for chronic pain Recommended as a first line option for neuropathic pain, and as a possibility for non-neuropathic pain, with duration of about 4-6 weeks required to effectively measure treatment outcome. Have caution regarding sedation with the tricyclics and some other medications due to increased risk of accidents. (Feuerstein, 1997) (Perrot, 2006) Analgesia occurs within a few days and at a lower dose than the antidepressant effect. (Saarto-Cochrane, 2005) Assessment of treatment efficacy should include not only pain outcomes, but also an evaluation of function, changes in use of other analgesic medication, sleep quality and duration, and psychological assessment. (See also Comorbid psychiatric disorders.) It is recommended that these outcome measurements should be initiated at one week of treatment. (Perrot, 2006) (Schnitzer, 2004) (Lin-JAMA, 2003) (Salerno, 2002) (Moulin, 2001) (Fishbain, 2000) (Taylor, 2004) (Gijsman, 2004) (Jick-JAMA, 2004) (Barbui, 2004) (Asnis, 2004) (Stein, 2003) (Pollack, 2003) (Ticknor, 2004) (Staiger, 2003) For more detailed recommendations, see Antidepressants for neuropathic pain and Antidepressants for non-neuropathic pain.
Antidepressants for neuropathic pain Recommended as a first-line option for neuropathic pain, as indicated below. Tricyclic antidepressants are recommended over selective serotonin reuptake inhibitors (SSRIs), unless adverse reactions are a problem. Caution is required because tricyclics have a low threshold for toxicity, and tricyclic antidepressant overdose is a significant cause of fatal drug poisoning due to their cardiovascular and neurological effects. Tricyclic antidepressants have been shown in both a meta-analysis (McQuay, 1996) and a systematic review (Collins, 2000) to be effective, and are considered a first-line treatment. (Namaka, 2004) (Dworkin, 2003) (Gilron, 2006) (Wolfe, 2004) This class of medications works in both patients with normal mood and patients with depressed mood when used in treatment for neuropathic pain. (Sindrup, 2005) Indications in controlled trials have shown effectiveness in treating central post-stroke pain, post-herpetic neuralgia, painful diabetic and non-diabetic polyneuropathy, and post-mastectomy pain. Negative results were found for spinal cord pain and phantom-limb pain, but his may have been due to study design. (Finnerup, 2005) Tricyclics have not been found to be effective for HIV-related neuropathy. A second class of antidepressants documented to be effective in controlled trials include selective serotonin and norepinephrine reuptake inhibitors (SNRIs), with examples being venlafaxine (Effexor®) and duloxetine (Cymbalta®), but there is some controversy regarding the doses of venlafaxine required to inhibit noradrenaline reuptake. (Blier, 2007) This class of medications has been shown to be effective for painful polyneuropathy (both diabetic and non-diabetic). (Sindrup, 2005) Bupropion (Wellbutrin®), a second-generation non-tricyclic antidepressant (a noradrenaline and dopamine reuptake inhibitor) has been shown to be effective in relieving neuropathic pain of different etiologies in a small trial (41 patients). (Finnerup, 2005) While bupropion has shown efficacy in neuropathic pain there is no evidence of efficacy in patients with non-neuropathic chronic low back pain. (Katz, 2005) The use of selective serotonin reuptake inhibitors (SSRIs), a class of antidepressants that inhibit serotonin reuptake without action on noradrenaline, is controversial based on controlled trials. (Finnerup, 2005) (Saarto-Cochrane, 2005) It has been suggested that the main role of SSRIs may be in addressing psychological symptoms associated with chronic pain. (Namaka, 2004) Regardless of the antidepressant chosen, the effect of this class of medication in combination with other medications has not been well researched. (Finnerup, 2005) The “number needed to treat” (NNT) methodology (calculated as the reciprocal value of the response rate on active and placebo) has also been used to calculate efficacy of the different classes of antidepressants. (Sindrup, 2005) Overall, the NNT for amitriptyline (a tricyclic antidepressant) was 2 (1.7 to 2.5). (Saarto-Cochrane, 2005) For peripheral neuropathic pain (excluding HIV) the NNT for tricyclics is 2.3 (2.1-2.7) versus SSRIs of 6.8 (3.4-4.4, studied in painful diabetic polyneuropathy). For the SNRI venlefaxine in painful polyneuropathy using on the dose level of 150 to 250 mg/day), the NNT was 4.6 (2.9-10.6). The NNT for the above trial of 41 patients for Bupropion was 1.3 (1.6-2.1). (Finnerup, 2005) The results of the Saarto-Cochrane study are slightly different than the others mentioned as they grouped SSRIs and SNRIs into one category. Side effects of antidepressants as well as drug-drug interactions play a role in their selection for patients with chronic pain. Tricyclics are contraindicated in patients with cardiac conduction disturbances and/or decompensation as well as those patients with epilepsy. They create anticholinergic side effects of dry mouth, sweating, dizziness, orthostatic hypotension, fatigue, constipation, and problems with micturition. (Finnerup, 2005) To minimize side effects, it is suggested that titration should be slow and based on the patient’s response. (Namaka, 2004) For medications like amitriptyline, the starting dose may be as low as 10-25 mg at night, with increases of 10-25 mg once or twice a week up to 150 mg/day. The Saarto-Cochrane review suggests a trial of SSRIs if a patient is unable to tolerate atypical antidepressants, but it must be remembered that they grouped SSRIs and SNRIs into one category. Using the data presented by Finnerup and Sindrup, a better alternative choice may be a SNRI or Bupropion.
Antidepressants for non-neuropathic pain Recommended as an option in depressed patients with non-neuropathic pain, but effectiveness is limited. Non-neuropathic pain is generally treated with analgesics and anti-inflammatories. There have been 25 controlled trials that have studied the use of antidepressants for fibromyalgia, including 3 meta-analyses. Except for good results found with duloxetine and fibromyalgia (Arnold, 2005), the results generally show limited effectiveness on only a minority of patients for this condition, and most of these studies evaluated tricyclics. (Perrot, 2006) (Moulin, 2001) There appears to be a large placebo effect of this class of medications in treatment of this condition. Four reviews have studied the treatment of low back pain, and tricyclic antidepressants were found to be slightly more effective than placebo for the relief of pain. A non-statistically significant improvement was also noted in improvement of functioning. No studies have specifically studied the use of antidepressants to treat pain from osteoarthritis. (Perrot, 2006) In depressed patients with osteoarthritis, improving depression symptoms was found to decrease pain and improve functional status. (Lin-JAMA, 2003) In guidelines recommended by Perrot it was suggested that antidepressants may be prescribed as analgesics in non-depressed patients, with the first-line choice being tricyclics initiated at a low dose, increasing to a maximally tolerated dose. They also suggested that trials of newer classes of antidepressants should only be initiated if tricyclics proved to be ineffective, if the patient was unable to tolerate side effects, or they were contraindicated.
Antiepilepsy drugs (AEDs) Anti-epilepsy drugs (AEDs) are also referred to as anti-convulsants. Recommended for neuropathic pain (pain due to nerve damage), but not for acute somatic pain. (Gilron, 2006) (Wolfe, 2004) (Washington, 2005) (ICSI, 2005) (Wiffen-Cochrane, 2005) (Attal, 2006) (Wiffen-Cochrane, 2007) (Gilron, 2007) (ICSI, 2007) There is a lack of expert consensus on the treatment of neuropathic pain in general due to heterogeneous etiologies, symptoms, physical signs and mechanisms. Most randomized controlled trials (RCTs) for the use of this class of medication for neuropathic pain have been directed at postherpetic neuralgia and painful polyneuropathy (with diabetic polyneuropathy being the most common example). There are few RCTs directed at central pain and none for painful radiculopathy. (Attal, 2006) The choice of specific agents reviewed below will depend on the balance between effectiveness and adverse reactions. See also specific drug listings below: Gabapentin (Neurontin®); Pregabalin (Lyrica®); Lamotrigine (Lamictal®); Carbamazepine (Tegretol®); Oxcarbazepine (Trileptal®); Phenytoin (Dilantin®); Topiramate (Topamax®); Levetiracetam (Keppra®); Zonisamide (Zonegran®); & Tiagabine (Gabitril®)
Outcomes: A “good” response to the use of AEDs has been defined as a 50% reduction in pain and a “moderate” response as a 30% reduction. It has been reported that a 30% reduction in pain is clinically important to patients and a lack of response of this magnitude may be the “trigger” for the following: (1) a switch to a different first-line agent (TCA, SNRI or AED are considered first-line treatment); or (2) combination therapy if treatment with a single drug agent fails. (Eisenberg, 2007) (Jensen, 2006) After initiation of treatment there should be documentation of pain relief and improvement in function as well as documentation of side effects incurred with use. The continued use of AEDs depends on improved outcomes versus tolerability of adverse effects. AEDs are associated with teratogenicity, so they must be used with caution in woman of childbearing age.
Specifically studied disease states: (also see below for specific drugs)
Painful polyneuropathy: AEDs are recommended on a trial basis (gabapentin/pregabalin) as a first-line therapy for painful polyneuropathy (with diabetic polyneuropathy being the most common example). The other first-line options are a tri-cyclic antidepressant (if tolerated by the patient), or a SNRI antidepressant (such as duloxetine). (Attal, 2006) (Jensen, 2006)
Postherpetic neuralgia: Gabapentin and pregabalin are recommended. (Attal, 2006) (Backonja, 2004)
Central pain: There are so few trials (with such small sample size) that treatment is generally based on that recommended for peripheral neuropathy, with gabapentin and pregabalin recommended. Lamotrigine has been found to be effective for central post-stroke pain (see below for specific drugs), and gabapentin has also been found to be effective. (Backonja, 2004)
Acute pain: Not indicated due to lack of evidence.
Chronic non-specific axial low back pain: There is no evidence to support the use of these medications for this indication.
Treatment of pain associated with osteoarthritis of the hip: Not indicated
Spinal cord injury: Gabapentin is recommended for chronic neuropathic pain. (Levendoglu, 2004)
CRPS: Gabapentin has been recommended (Serpell, 2002)
Fibromyalgia: Gabapentin and pregabalin have been found to be safe and efficacious to treat pain and other symptoms. (Arnold, 2007) (Crofford, 2005) Pregabalin is FDA approved for fibromyalgia.
Lumbar spinal stenosis: Gabapentin produced statistically significant improvement in walking distance, decrease in pain with movement and sensory deficit in a pilot study. (Yaksi, 2007)
Myofascial pain: Not recommended. There is a lack of evidence to demonstrate that AEDs significantly reduce the level of myofascial or acute musculoskeletal pain, or other sources of somatic pain. (Wiffen-Cochrane, 2005) (Washington, 2005)
Postop pain: AEDs may also be an option for postoperative pain, resulting in decreased opioid consumption. (Peng, 2007) (Buvanendran, 2007)
SPECIFIC ANTI-EPILEPSY DRUGS:
Gabapentin (Neurontin®) has been shown to be effective for treatment of diabetic painful neuropathy and postherpetic neuralgia and has been considered as a first-line treatment for neuropathic pain. (Backonja, 2002) (ICSI, 2007) (Knotkova, 2007) (Eisenberg, 2007) (Attal, 2006) It has been given FDA approval for treatment of post-herpetic neuralgia. The The number needed to treat (NNT) for overall neuropathic pain is 4. It has a more favorable side-effect profile than Carbamazepine, with a number needed to harm of 2.5. (Wiffen2-Cochrane, 2005) (Zaremba, 2006) Gabapentin in combination with morphine has been studied for treatment of diabetic neuropathy and postherpetic neuralgia. When used in combination the maximum tolerated dosage of both drugs was lower than when each was used as a single agent and better analgesia occurred at lower doses of each. (Gilron-NEJM, 2005) Recommendations involving combination therapy require further study.
Mechanism of action: This medication appears to be effective in reducing abnormal hypersensitivity (allodynia and hyperalgesia), to have anti-anxiety effects, and may be beneficial as a sleep aid. (Arnold, 2007)
Specific pain states:
Acute pain: There is limited evidence to show that this medication is effective for acute pain, and for postoperative pain, where there is fairly good evidence that the use of gabapentin and gabapentin-like compounds results in decreased opioid consumption. This beneficial effect, which may be related to an anti-anxiety effect, is accompanied by increased sedation and dizziness. (Peng, 2007) (Buvanendran, 2007) (Menigaux, 2005) (Pandey, 2005)
Spinal cord injury: Recommended as a trial for chronic neuropathic pain that is associated with this condition. (Levendoglu, 2004)
CRPS: Recommended as a trial. (Serpell, 2002)
Fibromyalgia: Recommended as a trial. (Arnold, 2007)
Lumbar spinal stenosis: Recommended as a trial, with statistically significant improvement found in walking distance, pain with movement, and sensory deficit found in a pilot study. (Yaksi, 2007)
Side-Effect Profile: Gabapentin has a favorable side-effect profile, few clinically significant drug-drug interactions and is generally well tolerated; however, common side effects include dizziness, somnolence, confusion, ataxia, peripheral edema, and dry mouth. (Eisenberg, 2007) (Attal, 2006) Weight gain is also an adverse effect.
Postherpetic neuralgia – Starting regimen of 300 mg once daily on Day 1, then increase to 300 mg twice daily on Day 2; then increase to 300 mg three times daily on Day 3. Dosage may be increased as needed up to a total daily dosage of 1800 mg in three divided doses. Doses above 1800 mg/day have not demonstrated an additional benefit in clinical studies. (Neurontin package insert)
Diabetic neuropathy (off-label indication) – Gabapentin dosages range from 900 mg to 3600 mg in three divided doses (Backonja, 2002) (Eisenberg, 2007). Gabapentin is 100% renally excreted.
Recommended Trial Period: One recommendation for an adequate trial with gabapentin is three to eight weeks for titration, then one to two weeks at maximum tolerated dosage. (Dworkin, 2003) The patient should be asked at each visit as to whether there has been a change in pain or function. Current consensus based treatment algorithms for diabetic neuropathy suggest that if inadequate control of pain is found, a switch to another first-line drug is recommended. Combination therapy is only recommended if there is no change with first-line therapy, with the recommended change being at least 30%. (TCA, SNRI or AED). (Jensen, 2006) (Eisenberg, 2007)
Weaning and/or changing to another drug in this class: Gabapentin should not be abruptly discontinued, although this recommendation is made based on seizure therapy. Weaning and/or switching to another drug in this class should be done over the minimum of a week. (Neurontin package insert) When to switch to pregabalin: If there is evidence of inadequate response, intolerance, hypersensitivity or contraindications. There have been no head-to-head comparison trails of the two drugs.
Pregabalin (Lyrica®) has been documented to be effective in treatment of diabetic neuropathy and postherpetic neuralgia, has FDA approval for both indications, and is considered first-line treatment for both. This medication is designated as a Schedule V controlled substance because of its causal relationship with euphoria. (Blommel, 2007) This medication also has an anti-anxiety effect. Pregabalin is being considered by the FDA as treatment for generalized anxiety disorder and social anxiety disorder. In June 2007 the FDA announced the approval of pregabalin as the first approved treatment for fibromyalgia. (ICSI, 2007) (Tassone, 2007) (Knotkova, 2007) (Eisenberg, 2007) (Crofford, 2005) Dose adjustment is necessary in patients with renal insufficiency.
Side-Effect Profile: Pregabalin has been associated with many side effects including edema, CNS depression, weight gain, and blurred vision. Somnolence and dizziness have been reported to be the most common side effects related to tolerability. (Tassone, 2007) (Attal, 2006) It has been suggested that this drug be avoided if the patient has a problem with weight gain. (Jensen, 2006)
Diabetic neuropathy – Begin with 50 mg 3 times a day; may be increased in one week based on tolerability and effect to a maximum of 300 mg/day. (Doses up to 600 mg/day were evaluated with no additional benefit and increase in side effects.)
Postherpetic neuralgia - Begin with 50 mg three times a day for one week; may be increased to 100 mg three times a day after one week based on tolerability and effect. Dose may be increased as tolerated after two to four weeks up to 300 mg twice daily (maximum dose 600 mg/day). (ICSI, 2007)
Trial period: There is no established trial period, but the onset of action is thought to be less than 1 week. (Attal, 2006)
Weaning: Do not discontinue pregabalin abruptly and weaning should occur over a one-week period. Withdrawal effects have been reported after abrupt discontinuation.
Lamotrigine (Lamictal®) has been proven to be moderately effective for treatment of trigeminal neuralgia, HIV, and central post-stroke pain; (Backonja, 2002) (Namaka, 2004) (Maizels, 2005) (ICSI, 2005) (Dworkin, 2003) (Wiffen-Cochrane, 2007). It has not been shown to be effective for diabetic neuropathy. Due to side-effects and slow titration period, lamotrigine is not generally recommended as a first-line treatment for neuropathic pain. (Dworkin, 2003) (ICSI, 2007) Furthermore, a recent Cochrane review determined that although there is some evidence that lamotrigine may be effective for HIV neuropathy and post-stroke pain, this drug does not have a “significant place in therapy at present.” This was partly due to the availability of more effect treatments including other AEDs and antidepressants. (Wiffen-Cochrane, 2007)
Side-Effect Profile: Lamotrogine is associated with many side effects, including a life-threatening skin rash, Stevens-Johnson syndrome (incidence 1/1000), and it has been reported that up to 7% developed a skin rash that may be dose-dependent. (Wiffen-Cochrane, 2007) There is a black box warning regarding skin rashes for this medication. The drug should be discontinued at first sign of rash. (Eisenberg, 2007) Other side effects include dizziness, nausea, headache and fatigue.
Dosing Information: (off-label indication) Begin with 25 mg daily; then titrate up by 25 mg to 50 mg every 1-2 weeks up to 400 mg/day; titration must occur slowly and tapering should occur upon discontinuation. (ICSI, 2007)
Carbamazepine (Tegretol®) has been shown to be effective for trigeminal neuralgia (Backonja, 2002) (ICSI, 2007) (Finnerup, 2005) and has been FDA approved for this indication. The NNT for this medication for trigeminal neuralgia has been reported as 2.6. (Backonja, 2002)
Side Effect Profile: Carbamazepine’s use is often limited because of side-effects, (Knotkova, 2007) including ataxia, cognitive decreases (Namaka, 2004), dizziness, somnolence, CNS depression, hyponatremia, nausea and vomiting, skin rashes (rarely Stevens-Johnson Syndrome has been reported) and hematolgic disorders, including agranulycytosis and aplastic anemia. There is a black box warning regarding development of potentially fatal blood cell abnormalities following the use of carbamazepine, and the drug should be discontinued at the first sign of a rash. Pretreatment CBC should be obtained for monitoring purposes; other monitoring parameters include: CBC with platelet count, reticulocytes, serum iron, lipid panel, liver function tests, urinalysis, BUN, serum carbamazepine levels, thyroid function tests, serum sodium; ophthalmic exams (pupillary reflexes). Patient should also be observed for excessive sedation during initial therapy or when increasing dose. Additionally, a long-term effect of weight gain has been reported. This medication also has significant drug-drug interactions. The number needed to treat (NNT) for this medication for overall neuropathic pain is 2.5; while the number needed to harm found in the Cochrane review was 3.7. (Wiffen-Cochrane, 2005)
Trigeminal neuralgia – Begin with 100 mg twice daily with food; increase in increments of 100 mg twice daily as needed as tolerated. Usual dose is between 400-800 mg daily in two divided doses. Maximum dose 1200 mg/day.
Oxcarbazepine (Trileptal®) has demonstrated benefits for treating neuropathic pain, specifically trigeminal neuralgia and diabetic neuropathy (ICSI, 2007).
Side-Effect Profile: Similar side-effect profile to carbamazepine (see above). Generally better tolerated when compared to carbamazepine and fewer drug-drug interactions (ICSI, 2007) Serum sodium should be monitored (i.e., especially during initial three-month period).
Dosing Information: Trigeminal neuralgia (off-label indication) - Titrate as tolerated to effect, using recommended dosage titration schedules. Starting doses of 150 mg to 300 mg twice daily; may be titrated by no more than 600 mg/day at weekly intervals to a maximum of 2400 mg daily. Most patients respond to doses between 900 mg—2400 mg/day. (ICSI, 2007) Dose adjustment is necessary in patients with renal insufficiency; use in patients with severe hepatic insufficiency has not been established.
Other Antiepileptic Drugs
Phenytoin (Dilantin®) has been shown to have limited effectiveness to treat neuropathic pain, except for possible use in acute flares above baseline, and then, given as an IV injection. (Namaka, 2004)
Topiramate (Topamax®) has been shown to have variable efficacy, with failure to demonstrate efficacy in neuropathic pain of “central” etiology. It is still considered for use for neuropathic pain when other anticonvulsants fail. Topiramate has recently been investigated as an adjunct treatment for obesity, but the side effect profile limits its use in this regard. (Rosenstock, 2007)
Levetiracetam (Keppra®), Zonisamide (Zonegran®), and Tiagabine (Gabitril®), are among the antiepileptic drugs (AEDs) most recently approved, while these drugs may be effective for neuropathic pain, the ultimate role of these agents for pain requires further research and experience (ICSI, 2007) (Knotkova, 2007) (Eisenberg, 2007). In the interim, these agents should be used to treat neuropathic pain only when carbamazepine, gabapentin, or lamotrigine cannot be used. (Guay, 2003) In addition, underlying depression and anxiety symptoms may be exacerbated by levetiracetam. (Ettinger, 2007)