Why Does Peripheral Neuropathy Cause Pain?

Steven Scherer, M.D., Ph.D.
William N. Kelley Associate Professor of Neurology
The University of Pennsylvania Medical Center
Philadelphia, PA 19104-6077

(Editor’s note: This information was presented as part of Dr.Scherer’s presentation at the CMTA patient/family conference at the University of Pennsylvania Medical School.)

Peripheral nerves are a collection of nerve fibers that originate from many different kinds of neurons. Motor fibers originate from motor neurons that are located in the spinal cord. Sensory axons originate from neurons that are located outside the spinal cord in large clusters called ganglia. The ganglia that contain the sensory neurons for the leg are located in the low back region (called the lumbar and sacral levels); those for the arm are located in the neck (called the cervical region). Each of these ganglia contains many thousands of sensory neurons.

Every sensory neuron has two ends. One end is connected to a tissue in the body (a piece of skin, muscle, bone, etc.), and the other end is connected to the spinal cord. Under normal circumstances, sensations are generated only upon stimulation of the end of the nerve fiber that is in the body. Then sensory nerve fibers relay this information to the spinal cord, and cells in the spinal cord, in turn, relay this information to the brain. There are many kinds of sensory neurons.

This is why we can perceive so many different sensations. All of us can appreciate many of these sensations, such as heat, cold, light touch, pin prick, vibration, and movements of the hairs on our skin. Other sensations are less obvious, such as our ability to determine movements of our arms and legs. Each kind of sensation, including pain, is conveyed to the spinal cord by certain kinds of sensory neurons.

So what does this have to do with pain? It is likely that some kinds of neuropathy damage the sensory fibers that convey pain, causing them to be hyperactive even in the absence of stimulation. In other words, damaged "hyperactive pain fibers" trick the brain into perceiving a painful stimulus even though none is present. The hyperactive fibers may not even be properly connected to their tissue, thereby accounting for why people can experience pain in their numb feet or legs.

It should be clear that not all pain is caused by neuropathy, even in people who have peripheral neuropathy. The pain of arthritis and headache, for example, are conveyed, but are not caused, by sensory fibers. Even the pain caused by one of the foot deformities caused by neuropathies is not caused by damaged sensory fibers; the sensory fibers are merely conveying the information to the spinal cord. Conversely, not all people who have peripheral neuropathy have painful symptoms. Pain is a common symptom in some kinds of neuropathy, such as diabetic neuropathy, in which small sensory fibers may be disproportionately affected. Among people who have inherited neuropathy, pain is much less frequent in the demyelinating forms than in the axonal forms affecting small sensory fibers.

The principles of treating painful peripheral neuropathies.

If neuropathy causes pain that is diminishing the quality of life, then this symptom should be treated. In my view, to manage pain effectively, there has to be a partnership between the patient and the physician. The patient needs to understand their pain—when it occurs, how well the drugs work, the side effects of the medications (particularly how troubling they are)—and communicate these things to the physician. The physician needs to know the medications and the relevant information about them—their duration, common side effects, potential interactions with other drugs, and whether a patient has other complicating medical problems—and communicate these things to the patient.

The goal is maximize the patient's quality of life. In practical terms, the patient should take the amount of medication that effectively manages the pain, but that does not cause unacceptable side effects. In the ideal case, the patient would be pain-free without any side effects. In the worst case, the patient has intolerable side effects at a dose that produces no pain relief whatsoever. In the typical case, however, there is a dose of a medication that provides some pain relief but that also causes some side effects. It should be clear that only the patient can know whether a medication works and whether it has acceptable side effects.

Medications for treating painful peripheral neurpathies.

Many medications have been reported to work for painful peripheral neuropathies. A few have been studied in rigorously conducted clinical trials, such as desipramine for painful diabetic neuropathy. Several more have been reported to be effective for painful neuropathy, including other kinds of pain syndromes such as post-herpetic neuralgia or trigeminal neuralgia. I am not aware of any studies that have specifically examined treating pain in inherited neuropathies. Regardless of the medication, the logic is the same:

• Introduce one medication at a time. Changing the doses of two medications simultaneously makes it difficult to determine which medication is responsible for any given effect (especially a side effect).
• Use a gradually escalating dose of one medication until either good pain relief is obtained or intolerable side effects occur. This is the key concept; too often I have seen patients who have been taking potentially effective medications but at dose that neither help the pain nor cause significant side effects.
• If one medication fails, try another one.

The medications that work for the pain of neuropathy fall into a few groups:

Tricyclics (e.g, amitriptyline/elavil, nortriptyline, desipramine/norpramin). These drugs were originally used as anti-depressants, typically at much higher doses than are used for treating painful neuropathies. They probably work by blocking norepinephrine receptors. They are usually taken once a day, an hour or so before sleep, as they are slowly metabolized (thus taken once/day) and often cause some degree of drowsiness/sedation (and thus are taken before sleep). The drowsiness is often a useful side effect when pain interferes with sleep. One typically starts with a low dose (25 mg or even 10 mg) and "builds up" the dose until either a good effect has been achieved or there are intolerable side effects (typically 50-100 mg). Beside drowsiness, a dry mouth and cognitive side effects are common (and there are other side effects, too). It is important to know that the tricyclics typically take 2-4 weeks to reach their full effectiveness against pain, and that the severity of the side effects often diminishes over time.

Neurontin (gabapentin). This medication is not approved for the treatment of chronic pain, but is probably more widely used for this reason than for the treatment of its approved indication, epilepsy. It was designed to be long-lasting mimic of a neurotransmitter, GABA. Neurontin comes in 100, 200, and 300 mg capsules; these are taken every 6-8 hours (the dose to be determined by its efficacy and side effects!). Cognitive changes are the most common side effect. In my experience, Neurontin works less reliably than do the tricyclics.

Narcotics. The keys for using narcotics are matching the duration of action to the duration of pain, and letting the patient figure out the dose that provides adequate pain relief with acceptable side effects. There are a few kinds of long acting narcotics:

• MS Contin (the active ingredient is morphine; 15, 30, 60, 100 mg tablets); works for about 12 hours.
• Oxycontin (the active ingredient is oxycodone; 10, 20, 40 mg tablets); works for about 12 hours.
• Duragesic patches (the active ingredient is fentanyl; comes in 10cm2/2.5 mg, 20cm2/5.0 mg, 30cm2/7.5 mg, and 40cm2/10 mg size patches); works for 2-3 days/patch.

There are many kinds of short acting ones. (I often use the regular form of oxycodone, which lasts 3-4 hours.) I typically ask patients to use both long acting narcotics on a regular schedule (usually every 8 hours) to treat the constant pain, and use a short-acting one for "break-through" pain (the episodes of pain that are not "covered" by the long-acting narcotic. When pain is worse during a particular time of the day (late afternoon to early evening), I recommend using oxycodone (for 2-3 hours of relief) or oxycontin/MS contin (for 8 hours of relief), depending on the duration of that period. Like tricylics, narcotics cause drowsiness, and have other side effects, too (constipation, for one). Tricyclics and narcotics often work well together for pain relief (tricyclics "potentiate" the pain relief of narcotics).

Tegretol (carbamazepine). This medication is not approved for the treatment of chronic pain, but is probably more widely used for this reason than for the treatment of its approved indication, epilepsy. Tegretol works by blocking voltage-gated sodium channels. In my experience, Tegretol works only sometimes. Tegretol comes in 100 and 200 mg tablets that are taken every 6 hours. A sustained released form (Tegretol XR) comes in 100, 200, and 400 mg tablets; these are taken every 12 hours.

Anti-inflammatories. There are basically two kinds of anti-inflammatory medications—corticosteroids (these are different than the performance-enhancing "steroids" used by atheletes) and non-steroidal anti-inflammatory drugs (NSAIDs).

Prednisone, prednisolone, and decadron are examples of corticosteriods. These drugs are used for the long-term treatment of some chronic inflammatory conditions, but are more commonly used for short-term conditions. Corticosteroids should not be used to treat painful neuropathies, unless the underlying cause of the neuropathy is an inflammatory condition.

There are many NSAIDs, including the following:

• Aspirin, including Ecotrin. Aspirin or other salicylates are an active ingredient in many combination medications, including Excedrin, Disalcid.
• There are many newer NSAIDs - Anaprox/naproxen, Clinoril, Daypro, Feldene, Indocin/indomethacin, Lodine, Motrin/ibuprofen, Naprosyn, Orudis, Relafen, Tolectin, Toradol/ketoprofen, Voltaren.
• The newest NSAIDs are the COX1 inhibitors. (Vioxx has been removed from the market, however, and Celebrex has a number of potentially harmful side effects.)

Aspirin, and NSAIDs are not effective for the treatment of the pain of neuropathy, but they do work on radicular pain (caused by "pinched nerves") as well as arthritis, tendonitis, and a host of other conditions.