Treatment Options for Peripheral Neuropathy

Management of Symptoms of Peripheral Neuropathy

If the cause of the peripheral neuropathy cannot be determined or if the underlying cause of the neuropathy cannot be resolved, therapy focuses on managing the symptoms. There is not one adequate, predictable, and specific treatment to control established neuropathic pain. However, there are a variety of medications available to manage the pain at least partially. Some of the medications may take several weeks to reach their maximal potential and may be effective for some patients but not for others. Therefore, attainment of adequate pain control requires a good working relationship with the health care team as well as time and patience.

Currently, there are no standard guidelines available for the treatment of peripheral neuropathy. Clinical trials to identify effective treatments have been inconclusive for several reasons including:

  • Medications are considered effective even if only a small number of subjects experience limited pain relief.
  • People with peripheral neuropathy want pain relief without side effects from the medication which is unrealistic. Since results from clinical trials often involve subjective evaluation of a treatment efficacy, results are not very accurate or reliable.
  • The response to placebo ("sugar pill") treatment in clinical trials is significant and can be seen in up to 30-50% of patients.

Most clinicians consider successful treatment to result in a 30-50% reduction in pain, which is usually significantly less than patient expectations. Treatment of peripheral neuropathy is typically a combination of various modalities as any single modality is usually insufficient. Some of the treatment options that clinicians have found to be effective include:

  • Adopting healthy living habits
  • Drug therapy
  • Physical and/or occupational therapy
  • Surgical therapy

Adopting Healthy Living Habits

Clinicians agree that adopting a healthy lifestyle is important in the ongoing management of peripheral neuropathy. While lifestyle changes may not affect the pain directly, they improve the overall health of the patient and thus reduce some of the physical and emotional effects of the pain. According to the National Institute of Neurological Diseases and Stroke (NINDS), some of these measures include:

  • Maintaining optimal weight
  • Eating a healthy diet with attention to adequate vitamin intake

  • Following an exercise program approved by the physician as it may help to:

    • reduce cramps associated with peripheral neuropathy
    • prevent muscle wasting in weakened or paralyzed limbs
    • increase muscle strength

  • Meticulous daily foot care

  • Use of appropriate, supportive shoes
  • Limit alcohol consumption
  • Stop smoking

Drug Therapy

In general, drug therapy for peripheral neuropathy is individualized for each patient and depends upon a number of factors that your doctor will take into consideration such as your past and present medical history, extent of pain, other medications that you may be taking, presence of other serious comorbid conditions (such as kidney disease, liver disease) and history of drug allergies. Many of the drugs used to treat peripheral neuropathy are used "off-label", meaning that they are approved by the U.S. Food and Drug Administration (FDA) for the treatment of other specific conditions (not for peripheral neuropathy) but have been shown over time to be effective also for the treatment of peripheral neuropathy. Recently, two drugs, an anticonvulsant called pregabalin (Lyrica) and an antidepressant called duloxetine (Cymbalta) received FDA approval for the treatment of neuropathic pain associated with diabetic neuropathy (see below for details).

The major classes of drugs currently used to treat peripheral neuropathy include:

  • Antidepressants
  • Anticonvulsants
  • Antiarrhythmics
  • Narcotic analgesics
  • Non-narcotic analgesics
  • Other drugs
  • Topical agents

Antidepressants

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are the most widely studied class of drugs regarding treatment for neuropathic pain. Examples include:

  • Amitriptyline (Elavil)
  • Nortriptylene (Aventyl, Pamelor)
  • Desipramine (Norpramine)
  • Imipramine (Janimine)

Tricyclic antidepressants work by inhibiting the reuptake (reabsorption) of three neurotransmitters associated with mood: serotonin, norepinephrine and dopamine. They also relieve pain. Tricyclic antidepressants are generally considered effective for spontaneous pain and hyperalgesia (increased sensitivity to pain).

There is evidence that the efficacy of different TCAs is similar but that individuals may respond slightly better to one drug over the others. If patient response is not sufficient with one TCA, the physicians may prescribe a different TCA until one is found that is effective. In studies evaluating the use of these drugs for diabetic neuropathy, approximately one-third of patients achieved a 50% reduction of pain. Efficacy of TCAs does not appear to be related to the quality of the pain (e.g. stabbing, or burning).

Side-effects of TCAs can be strong and their overall tolerability is considered poor although they are widely used. Side-effects may outweigh the benefits especially for older people. Adverse effects may include:

  • Dry mouth
  • Dizziness
  • Constipation
  • Drowsiness/sedation
  • Muscle twitches
  • Weakness
  • Nausea
  • Weight gain
  • Urinary retention
  • Cognitive/memory difficulties
  • Increased sweating
  • Decreased libido (sexual drive)

Tricyclic antidepressants are contraindicated in people with various health conditions including:

  • Cardiac arrhythmia (irregular heartbeat)
  • Recent heart attack
  • Congestive heart failure
  • Glaucoma

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are drugs that block the reuptake of the neurotransmitter, serotonin, that is involved in the transmission of nerve impulses. This leaves more serotonin in the brain and improves mood. This class of drugs has also has been found to reduce pain. Clinical trials indicate that they are less effective than TCAs for controlling pain for patients with peripheral neuropathy. For patients who cannot tolerate TCAs, SSRIs may be considered an option.

Examples of SSRI's include:

  • Citalopram (Celexa)
  • Paroxetine (Paxil)
  • Fluoxetine (Prozac)
  • Sertraline (Zoloft)

Adverse effects of SSRI's may include:

  • Somnolence or insomnia
  • Nausea/vomiting
  • Dry mouth
  • Decreased libido and/or impotence

Atypical Antidepressants

Atypical antidepressants are a class of drugs that work by inhibiting the reuptake of serotonin and norepinephrine and are known as SSNRIs (selective serotonin and norepinephrine reuptake inhibitors). Examples include:

  • Duloxetine (Cymbalta) - Approved by the FDA in September 2004, duloxetine (Cymbalta) was the first drug that was specifically approved for the treatment of neuropathic pain associated with diabetic neuropathy. The most common side-effects reported by patients included:

    • nausea
    • somnolence (sleepiness)
    • dizziness - some patients also experienced "hot flashes" together with dizziness
    • reduced appetite
    • constipation

  • Venlafaxine (Effexor) - Venlafaxine has fewer side effects than TCAs. There is some indication that it may be effective for cancer-related neuropathies. There is now an extended release form of venlafaxine which appears to be effective for diabetic peripheral neuropathy. Adverse reactions may include:

    • nausea
    • dizziness
    • fatigue
    • sexual dysfunction
    • dry mouth

  • Bupropion (Wellbutrin) - Some studies indicate that this drug diminishes pain by approximately 30% in some individuals. It is considered to be better tolerated than TCAs. The sustained release form of bupropion was the subject of a clinical trial with patients suffering from several types of neuropathic pain. Approximately 70% of the subjects reported significant pain relief after two weeks with a 30% reduction of pain scores as well as improved quality of life measures. Adverse effects may include:

    • restlessness
    • agitation
    • anxiety
    • insomnia
    • skin rash
    • aching muscles
    • frequent urination
    • weight gain or weight loss
    • dry mouth
    • headache/dizziness

For more information about antidepressants for the treatment of peripheral neuropathy, please click on the following link: http://www.medifocus.com/abstracts.php?gid=NR021&ID=15910402

Anticonvulsants

Anticonvulsant drugs inhibit the sodium channels at the cellular level and prevent the spread of abnormal electric discharges. They also are effective in reducing neuropathic pain. Anticonvulsant medications used for peripheral neuropathy include:

  • Gabapentin (Neurontin) - This drug is a popular first-line treatment for neuropathic pain although the mode of action of this drug is not clear. Some studies involving patients with diabetic neuropathy show significant improvement in pain scores as well as in secondary outcomes (e.g., mood, sleep disturbances) while other studies did not yield such definitive results. Results for nondiabetic peripheral neuropathy are also not uniformly conclusive. Side effects, most commonly dizziness or drowsiness, are considered to be tolerable and better than for many other medications used to treat peripheral neuropathy. In order to minimize sedation or drowsiness, many patients take the larger portion of their daily dose at night before bedtime.

  • Pregabalin (Lyrica) - Pregabalin is a new anticonvulsant drug for peripheral neuropathic pain that was approved by the FDA in August 2005. It is a Schedule V controlled substance meaning that it has accepted medical use and has low potential for abuse relative to certain other drugs, but patients must be carefully monitored to prevent drug dependency and abuse. Pregabalin is closely related in both chemical structure and pharmacological action to gabapentin and is indicated for the treatment of neuropathic pain associated with diabetic neuropathy and for the treatment of neuropathic pain associated with post-herpetic neuralgia. Randomized, controlled clinical trials have shown that pregabalin is safe and effective in decreasing neuropathic pain in patients with diabetic neuropathy and also improved mood, sleep disturbances, and overall quality of life. The most common side-effects experienced by patients in clinical trials who were treated with pregabalin included:

    • dizziness
    • somnolence
    • peripheral edema (swelling of the limbs)
    • weight gain

  • Lamotrigine (Lamictal) - Some studies indicate moderate relief for pain related to diabetic neuropathy and HIV-related neuropathy. Side effects are considered minimal and may include:

    • dizziness
    • headache
    • ataxia (loss of coordination)
    • fatigue
    • nausea
    • blurred vision
    • skin rash (mild to severe)

  • Carbamazepine (Tegretol) - This drug has been approved by the FDA for the treatment of trigeminal neuralgia. There is limited data regarding its efficacy for the treatment of peripheral neuropathy. Side effects are frequent and can be very pronounced in the elderly. They include:

    • dizziness
    • nausea/vomiting
    • confusion
    • blurred vision
    • fatigue
    • liver dysfunction
    • leucopenia (reduction in the number of white blood cells)

  • Oxcarbazepine (Trileptal) is an analog of carbamazepine and is usually better tolerated. This drug is used for the treatment of epilepsy. Limited data from small trials indicate that it may improve pain scores for people suffering from diabetic neuropathy.

  • Phenytoin (Dilantin) is an anticonvulsant drug that is used for the treatment of epilepsy. Phenytoin is usually not used as a first line medication for peripheral neuropathy since results from studies are inconsistent. There are some indications that it may be more effective when given intravenously for painful neuropathies. Phenytoin also inhibits insulin production which could be problematic for diabetic patients.

  • Topiramate (Topamax) is an anticonvulsant medication that has been reported to be effective in relieving pain associated with various neuropathies, including diabetic neuropathy, in case reports and small clinical trials

Antiarrhythmic Drugs

  • Mexiletine - Some studies indicate that mexiletine (Mexitil) is effective for painful diabetic neuropathy but results from other studies are conflicting. Side effects may include:

    • nausea/vomiting
    • dizziness
    • tremor
    • headache
    • abnormal liver function

Narcotic Analgesics

  • Oxycodone - This drug is a narcotic and, therefore, carries a high risk of drug dependence. Oxycodone is effective for some types of neuralgia (e.g., postherpetic neuralgia) but data is limited regarding sensory neuropathy. The controlled release form of oxycodone has shown promising results for diabetic neuropathy, with significant improvement in pain levels and sleep quality. The extended-release formulation of oxycodone is preferred for long-term therapy. Doses are titrated slowly until pain relief is achieved. Higher doses of oxycodone yield significant results for some patients with peripheral neuropathy, however, they are also associated with more adverse effects. Side-effects are common and include:

    • nausea/vomiting
    • decreased appetite
    • constipation
    • dry mouth
    • dizziness
    • fatigue
    • increased sweating
    • decreased sex drive
    • muscle twitches
    • seizures
    • changes in breathing
    • allergic reactions

Oxycodone is contraindicated in people with a history of drug/alcohol abuse or patients with chronic obstructive pulmonary disease.

  • Levorphanol - Limited data indicates modest pain relief for some types of neuropathic pain (less effective for sensory neuropathy than for other types such as postherpetic neuralgia) but side effects occur frequently and include:

    • itching
    • mood swings
    • confusion
    • weakness

Non-Narcotic Analgesics

  • Tramadol (Ultram) - This drug has properties of narcotics but does not bind to opioid receptors so is less likely to cause dependence or abuse. It has been in use in the United States since 1995. Limited trials indicate that its effect is similar to TCAs or levorphanol for diabetic and other types of neuropathies. Pain relief was significant and overall health and quality of life scores improved. Small studies indicated that this effect may still be seen after 6 months. Some studies reported improvement in spontaneous pain, touch-evoked pain, and allodynia. Tramadol appears to be better tolerated than TCAs. Adverse effects are frequent, mild, and considered tolerable. They include:

    • nausea
    • constipation
    • headache or dizziness
    • somnolence (fatigue, sleepiness)
    • insomnia
    • loss of appetite
    • blurred vision

It is contraindicated for people with hypersensitivity to opiates, a history of alcohol or drug use, or liver/kidney disease. In a small number of people, more serious side effects may occur including seizures, severe skin rash, shallow breathing, or weak pulse.

Mild neuropathic pain may be alleviated by a variety of analgesics available "over-the-counter" such as aspirin, acetaminophen (e.g., Tylenol), or ibuprofen (e.g., Advil; Motrin).

Other Drugs

  • Dextromethorphan is commonly used as a non-prescription cough suppressant. Studies in a limited number of patients indicate a significant improvement in pain scores for patients with diabetic neuropathy who were treated with dextromethorphan. Side effects may include:

    • sedation (up to 70% of patients)
    • memory impairment
    • ataxia (reduced motor coordination)

  • Nerve Block

A nerve block involves the injection of a drug (such as steroids, opioids, or local anesthetics) directly into the area of an affected nerve in an attempt to interrupt the transmission of pain signals to the brain. Although some patients with peripheral neuropathy report relief from pain following a nerve block, most studies indicate that the therapeutic value of the injections is short-lived.

Topical Agents

There are two topical agents that may be used, namely capsaicin and lidocaine patch.

Capsaicin

This topical agent is extracted from chili peppers and depletes substance P from sensory nerves in the skin. Results for neuropathic pain are inconsistent. Efficacy for diabetic neuropathy may be moderate (some report up to 90% reduction on pain scores) with improvement seen in other quality of life parameters including work, sleep, and daily functioning. There are indications that capsaicin is as effective as amitriptyline for reducing pain and improving the quality of life for patients with diabetic neuropathy but without systemic side effects.

Capsaicin is available over-the-counter at a strength of 0.075%. The most common side effect is burning or pain when first administered but this subsides over time. It is important not to rub your eyes after administering capsaicin since contact with the eyes will cause considerable burning and could cause eye damage. Some people have reported coughing, sneezing, or respiratory irritation due to the residue or fumes that remain following the application of capsaicin. These symptoms can be minimized by applying capsaicin in a well ventilated room.

Topical Lidocaine

This drug is available as a patch and is approved by the FDA for treatment of postherpetic neuralgia. It appears to be less effective for other neuropathic pain which usually extends over an area much larger than the size of the patch. It may be beneficial for placement at sites of particularly intense pain.

Other Treatments

Some types of peripheral neuropathy, particularly those related to immunologic etiology, may require other treatment modalities, for example:

  • Guillain-Barre syndrome - treatment includes intravenous immunoglobulin therapy (IVIG) and/or plasmapheresis (partial removal of plasma from the blood which is then returned to the circulatory system) to help hasten recovery and reduce long-term disability.
  • Chronic inflammatory demyelinating polyneuropathy (CIDP) - treatment includes immunotherapy, immunosuppressive agents such as cyclophosphamide, steroids, and/or plasmapheresis.
  • Multifocal motor neuropathy - treatment includes IVIG and immunosuppressive agents
  • Vasculitis related to mononeuropathy multiplex is treated with corticosteroids and other immunosuppressive agents such as cyclophosphamide.

Summary of Drug Therapy Recommendations for Peripheral Neuropathy

To date, there have been no formal standard guidelines regarding drug therapy for peripheral neuropathy that reflect the addition of Lyrica and Cymbalta which were recently approved for treatment of diabetic peripheral neuropathy by the U.S. Food and Drug Administration. The conclusions of an article appearing in 2003 in the New England Journal of Medicine (Volume 348; pp. 1243-1255, March 26, 2003) were as follows:

  • Gabapentin is a reasonable first-choice for efficacy and tolerability
  • If there is no pain relief or if it is insufficient at the maximum dose, adding a second drug, such as tramadol, is a reasonable choice, beginning at a low dose and raising the dose slowly.
  • If the individual cannot tolerate gabapentin, the initial drug of choice is tramadol.
  • If pain persists, adding a third drug, such as oxcarbazepine, which is as effective and better tolerated than tricyclic antidepressants, is a reasonable choice, starting at a low dose and then slowly increasing the dose.
  • If a combination of three drugs is ineffective, one may wish to try the extended release formulation of a narcotic analgesic, preferably sustained release oral morphine.

Capsaicin can be used at any time since it has no systemic side effects. Some people have found it to be helpful when used in conjunction with prescribed medications.

Physical and Occupational Therapy for Peripheral Neuropathy

Physical Therapy

Regardless of the underlying cause of peripheral neuropathy, physical therapy may be helpful in maintaining strength, mobility, and function of the affected limb(s). Patients with diabetic neuropathy may also benefit from physical therapy, however, they must also rigorously control their blood sugar levels to prevent major fluctuations that can lead to further nerve damage. Some of the objectives of physical therapy include:

  • Maintaining range of motion through progressive stretching.
  • Strengthening muscles including exercising against increasing resistance, use of weights, and isometric exercise

Once a patient has reached a level where range of motion and muscle strength is at optimum function, it is important that they continue with the exercises independently in order to retain the benefit from therapy.

Physical therapists may also recommend:

  • Braces - hand and/or foot braces can help with support if the patient suffers from muscle weakness. Braces also help with improving balance and posture.
  • Splints - splinting temporarily immobilizes a limb or part of a limb and, by doing so, may reduce pain and dysfunction. It also prevents contracture of muscles which could further compress nerves and increase pain. Splints are often used in the treatment of compression mononeuropathies, such as carpal tunnel syndrome.
  • Orthotics (customized foot supports) or orthopedic shoes may improve difficulties with gait as well as prevent foot injuries.

Occupational Therapy

Occupational therapy is instrumental in helping the patient cope with the functional, vocational, and social impact of peripheral neuropathy by:

  • Improving sensory-motor skills
  • Teaching the patient how to avoid exposure to environmental or industrial toxins
  • Teaching self-care activities
  • Teaching the patient safety issues, (e.g., paying more attention to the terrain when walking since falling or tripping may pose a risk for patients with peripheral neuropathy)
  • Teaching the patient to pay attention to issues which involve automatic functions (e.g., learning how to change positions smoothly to avoid a sudden drop in blood pressure and the risk of falling)

Surgery for Peripheral Neuropathy

Surgery may be necessary for certain underlying conditions that may be associated with peripheral neuropathy. For example, if the neuropathy is caused by a condition such as carpal tunnel syndrome or the nerve compression is caused by a ruptured disk or a tumor, surgery may be necessary to resolve the underlying problem and relieve the neuropathic pain. Reconstructive surgery may be required for structural changes that may occur as neuropathy progresses (e.g., Achilles tendon lengthening).

Spinal Cord Stimulation

Spinal cord stimulation (SCS) is a treatment that delivers electrical stimulation to the dorsal column of the spinal cord through a surgically implanted electrode which is connected to an electrical stimulating device. Spinal cord stimulation is usually reserved for treatment of pain in patients with neuropathy who have not responded to conventional treatment. Up to 70% of these patients have reported pain relief one year after initiating treatment with SCS. Spinal cord stimulation appears to be more effective for spontaneous pain than for other types (e.g. allodynia). Studies are being conducted investigating the addition of an intrathecal baclofen pump (medication delivered directly into the spinal fluid) to SCS for patients with various types of neuropathic pain who do not respond to SCS alone.