Originally Published in The Siegel Rare Neuroimmune Association Newsletter
Volume 4 Issue 2
October 2001

John T. Farrar, MD, MSCE
Departments of Anesthesiology, Neurology, and Epidemiology, the Center for Clinical Epidemiology and Biostatistics, the University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania.
Correspondence: John T. Farrar, MD, MSCE Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, 423 Guardian Drive, Blockley Hall, Room 816, Philadelphia, Pennsylvania.

Abstract

Neurologists have the option of choosing from among numerous drugs and drug classes when treating neuropathic pain. The challenge, therefore, lies not in having limited options for treatment, but in the art of practicing medicine, i.e., of identifying neuropathic pain and empathizing with the patient without the benefit of either an objective test or a complete understanding of pain pathophysiology, and providing the best evidence-based options for therapy. The International Association for the Study of Pain definition of pain – a sensory and emotional experience, signaling actual or potential tissue damage – illustrates the dual nature, both objective and subjective, of this condition. The neurologist’s unique understanding of the complex interactions that occur in the nervous system can provide a significant contribution to the care of patients with pain.

Additionally, we must remember that many patients, unable to quantitatively describe their pain and witnessing the medical community’s lack of codified remedies, leave the physician’s office thinking that the practitioner views their pain, even when incapacitating, as psychosomatic. An equally important role of the practicing neurologist, therefore, is to acknowledge the patient’s experience of pain without attempting to validate its source. This article includes strategies for approaching a neuropathic pain patient, useful methods to treat the whole patient, and a discussion of why a holistic approach is important. An overview of the pharmacotherapies available for the treatment of neuropathic pain and their role in treating the whole patient is also provided.

Copyright 2001 Galen Publishing, LLC. First published in the September 2001 issue of Advanced Studies in Medicine, New Developments in the Management of Migraine and Neuropathic Pain (Volume 1, Number 6: 241-247), www.ASIMCME.com.

Treating neuropathic pain means treating the neuropathic pain patient by first understanding what the patient is experiencing. This can be difficult, as there are no empirical tests for pain. Yet, the pain is completely real to the patient, and may even be incapacitating. The primary role of the physician is to make the appropriate diagnosis and focus treatment on the most important features of the patient’s pain as reported by the patient. This should always include the presumed underlying pathophysiologic mechanism but must also focus on other contributing factors, some of which may be more amenable to treatment than the primary process.

What Is Pain?

The International Association for the Study of Pain (IASP) defines pain as: “The unpleasant sensory and emotional experience of actual or potential tissue damage or an experience expressed in such terms.”¹ Since pain is both a sensory and an emotional experience (i.e., it affects the whole person), the whole person must be treated. The degree of pain intensity can be affected by the patient’s attitude and perceptions of his surroundings. A broken toe will seem less painful if injured on the way to the airport to start one’s vacation than if this takes place on the way to an Internal Revenue Service audit. Similarly, a cancer patient with back pain will experience a lessening of pain when assured by the physician that the pain is not indicative of metastasis or recurrence of the cancer. In fact, the use of environmental factors for managing pain intensity, known as distraction therapy, is widely used by practitioners and patients to help patients perform daily activities in spite of pain and other discomforts. The popularity of distraction therapies is the result of its demonstrated effectiveness in both the laboratory and the clinical setting.²

Despite the exponential growth of our knowledge about the brain in recent years, we do not yet understand the intricate pathophysiological mechanisms of neuropathic pain. We do, however, know that the brain, through the production of hormones and direct nerve connections from the brain to the pain fibers, is capable of far more control over the pain system than was previously thought. Yet since we have not identified a means to specifically harness this descending control system, a physician’s best hope for providing effective treatment is to present patients with the various pain-management strategies and to support them in their search for the one or ones that work, remembering that efficacy is subjective and patient specific, much like in the treatment of psychiatric illness. Similarly, the success of treatment can be assessed only by individual patients reporting on changes in their symptoms.

The IASP definition of pain also includes the phrase “actual or potential tissue damage or an experience expressed in such terms.” Acute pain is experienced immediately upon injury and notifies the individual of tissue damage. Neuropathic pain is caused by nerve damage proximal to the sensory nerve endings in the skin. Neuropathic pain has no protective or predictive value, because it persists long after tissue (i.e., nerve) damage has occurred. In essence, the lack of a specific measure of tissue damage does not preclude the sensation of pain.

Patients with neuropathic pain may also report fatigue, difficulty in concentrating, depression, and insomnia, and the severity of these symptoms may seem disproportionately high relative to the initial injury. Again, the most effective approach is to acknowledge the patient’s discomfort and make a commitment to treat the pain. The hope gained from knowing that the physician will attempt to treat one’s pain provides an effective distraction.

Types of Pain

The 3 types of pain (somatic, neuropathic, and visceral) are often co-occurring or comorbid as a mixed syndrome, so treating the neuropathic component may only treat part of the patient’s symptoms. Most pain patients, especially those with chronic pain, have a mixed syndrome (neuropathic and somatic pain). Unlike somatic pain, which comes from specialized nerve endings and warns of tissue damage, neuropathic pain comes directly from nerve dysfunction and does not imply ongoing damage. It is important for physicians to explain this distinction to patients, who will be reassured when they learn that their pain does not signal continuous damage and may not be the harbinger of a more serious illness.

A common example of this mixed somatic/neuropathic syndrome is compression of a small nerve in the spine (neuropathic), which leads to muscle spasm (somatic). The body responds to the pain of compression by protecting the area through spasms, which create muscle pain in the area as well as other inflammatory responses. While the patient feels the muscle pain, the underlying pathology can be neuropathic. In treatment, therefore, residual pain after treating somatic pain should be considered an indication of possible neuropathic pain, even if the symptomatic features of the neuropathic pain are not predominant.

There are several neuropathic pain syndromes, outlined in Table 1, that are the result of ectopic generators, nerve trunk pain, microenvironmental changes, central alterations, and changes in the balance of nociceptor and nonnociceptor fibers. At this time, it is not yet possible to determine which of these factors specifically cause an individual’s neuropathic pain. However, all of these factors can result in sensory loss, paresthesias (positive numbness or tingling), dysesthesias (painful or unpleasant burning, tingling or electric shock phenomenon), hyperesthesia (increased perception of mildly painful stimuli), hyperpathia (subthreshold stimuli producing pain), or allodynia (nonpainful stimuli producing pain).

Table 1. Common Types of Neuropathic Pain

Examples of peripheral neuropathic pain

• Carpal tunnel syndrome
• Complex regional pain syndrome
• Human immunodeficiency virus (HIV) sensory neuropathy
• Meralgia paresthetica
• Painful diabetic neuropathy
• Phantom limb pain
• Postherpetic neuralgia
• Postthoracotomy pain
• Trigeminal neuralgia
• Radiculopathy

Examples of central neuropathic pain

• Central poststroke pain
• HIV myelopathy
• Multiple sclerosis pain
• Parkinson’s disease pain
• Spinal cord injury pain
• Syringomyelia

Examples of cancer-associated neuropathic pain

• Chemotherapy-induced polyneuropathy
• Neuropathy secondary to tumor infiltration or nerve compression
• Phantom breast pain
• Postmastectomy pain
• Postradiation plexopathy and myelopathy

Reprinted with permission from A Clinical Guide to Neuropathic Pain. Galer BS, Dworkin RH, eds. Minneapolis, MN: McGraw-Hill Healthcare Information; 2000.

Treating Neuropathic Pain

Pain is a central nervous system (CNS) phenomenon, and neuropathic pain can be thought of as a loss of normal control in the nervous system, not unlike epilepsy.³ However, because we cannot tell which mechanism is the predominant cause, treatment is currently based on assumptions about the type of input, not which transmitter, is out of balance. It has been demonstrated that the way in which pain is perceived and evaluated by patients affects their mood. Chronic pain has been shown to beget depression; conversely, depression can make chronic pain seem worse.⁴

Sections of the thalamus and the sensory cortex are the primary areas of the brain where neuropathic pain is perceived.⁵ Two of the primary descending pain control systems come from the hypothalamus and the periaqueductal gray matter, and are mediated by several neurotransmitters including the noradrenergic and serotonergic systems.^6-8 Some of the first-line pharmacotherapies for neuropathic pain target these systems.⁹ The noradrenergic system may also be involved in the control of pain in situations of severe danger (e.g., running into a burning building to save a child). Nociceptive nerve endings signal the pain but the brain does not register the pain. These are short-lived mechanisms that last only for the duration of the emergency but may be the same mechanisms at work during distraction therapy (i.e., shutting down the nociceptive primary afferent fibers).

Treatment Strategies

Although the science of treating neuropathic pain is still young, there are drugs and combination therapies from several different disease areas that can be used. Some of the treatment modalities are, in fact, also used for somatic pain, but some agents are CNS specific.

First-line therapy for neuropathic pain is analgesics, followed by neuroactive agents. There are several classes of adjuvant analgesics that are effective, including antidepressants, anticonvulsants, antispasm agents, local anesthetics, and a2-adrenergic agonists. In general, neuroleptics have not proven to be effective. Of note, a large number of complementary or alternative therapies have been suggested for the treatment of pain. However, they require further evaluation before specific recommendations can be made.

Antidepressants

Amitriptyline is one of the oldest and most commonly used tricyclic antidepressants (TCAs) for post-herpetic neuralgia (PHN) and diabetic neuropathy.^10-12 This drug exerts both noradrenergic and serotonergic uptake inhibition, believed to be the cause of both its analgesic activity and its association with mood elevation. Amitriptyline is also associated with significant anticholinergic side effects that cannot be tolerated in some patients, including cardiac arrhythmias in elderly patients, urinary retention, and dry mouth. Nortriptyline has been shown in controlled clinical trials to be as effective in postherpetic neuralgia as amitriptyline but with far fewer side effects.¹³ The side effects most common with TCAs include dry mouth, somnolence, weight gain, constipation, and memory impairment. Less common side effects include urinary retention, orthostatic hypotension, cardiac arrhythmias, and blurred vision.

The selective serotonin reuptake inhibitors (SSRIs) are also frequently used in chronic pain patients, although they do not appear to have direct analgesic properties. With fewer side effects and effective anti-depressant effects, they are helpful in addressing the psychological sequelae of chronic pain that reinforce and exacerbate the perceived level of pain. SSRIs such as citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline cause far fewer side effects than TCAs. Other antidepressants that also affect norepinephrine reuptake or the noradrenergic system include bupropion, maprotiline, mirtazepine, nefazodone, trazodone, and venlafaxine. Venlafaxine, in particular, has shown benefit in treating neuropathic pain in recent case reports.^14-17 SSRIs have few serious side effects but can cause somnolence, changes in weight, and some memory impairment.

Antiepileptic Drugs

Antiepileptic drugs (AEDs), are useful in the treatment of neuropathic pain and migraine. The mechanism of action of AEDs in neuropathic pain is not well understood. Their effect on cellular activity appears to include modulation of ion channels or alterations in transmitter production, release, uptake, and/or breakdown. Their effect on neuronal activity, also poorly understood, includes suppression of paroxysmal discharges, reduced neuronal hyperactivity, and suppression of aberrant discharges. AEDs act both centrally and peripherally.^18,19

First-generation AEDs were carbamazepine, phenytoin, and valproic acid. Carbamazepine was initially used to treat trigeminal neuralgia (TN) and was the “gold standard” for treatment of TN for many years. Second-generation AEDs include gabapentin, lamotrigine, levetiracetam, oxcarbazepine (a metabolite of carbamazepine), tiagibine, topiramate, and zonisamide. In general, the second-generation AEDs have the advantage of a much improved side-effect profile.

Because each AED works, presumably, by a different mechanism, each one tends to be effective only in a subgroup of patients, as has been shown with gabapentin in the treatment of PHN and diabetic neuropathy.^20,21 This should not discourage the use of AEDs in treating neuropathic pain, because they can be extremely effective in that specific subgroup, however, it makes it all the more important for physicians to carefully manage patient expectations, avoid raising hopes, and promote compliance with an appropriate trial of therapy. Several drugs may need to be tried before the desired results are seen and results will vary among patients, even those suffering from the same underlying disease. For example, among 3 patients with similarly caused damage to the nervous system, the resulting neuropathic pain may be due to the sodium channel in one patient, the calcium channel in another, and a different channel in a third.

Severe side effects associated with AEDs include hepatotoxicity (carbamazepine and valproate), Stevens-Johnson syndrome (lamotrigine, phenytoin, and zonisamide), aplastic anemia (carbamazepine), and teratogenicity (carbamazepine, valproate, and possibly others). Mild and more common side effects include dizziness and ataxia, somnolence, cognitive impairment, nausea/vomiting, and weight gain. However, topiramate has been associated with weight loss in some people, which may be an advantage in treating overweight or obese patients with neuropathic pain. Also, topiramate, levetiracetam, and gabapentin do not appear to cause hepatotoxicity.²² Hepatotoxicity and anemia can be particularly problematic in treating pain in cancer patients.

Opioids

Opioids may be effective at very high doses and can offer dramatic relief for some patients treated at these levels. Patients often report that lower doses take the edge off their pain, but substantial relief may require very high does. Like other drugs used for neuropathic pain, opioids can be effective in a select subgroup of patients. Although their use has sparked controversy due to the potential of abuse by patients who are addiction prone, it is rare for a chronic pain patient to develop a true addiction. As with the other neuroactive medications, opioids should be used on a case-by-case basis, and the drugs should be discontinued if they are ineffective or if the side effects cannot be tolerated. Patients who may be candidates for high-dose opioid therapy are probably best served by a referral to a chronic pain clinic.

Topical Therapies

Topical therapy (patches or creams) can be useful for patients who have small areas that are hyperesthetic. Patches that protect the area against impact or friction and reduce sensory inputs from the area are available, with or without lidocaine. Capsaicin cream may be effective, but the patient often experiences pain at the site of application like that typically associated with eating hot peppers. This pain often abates after 3 or 4 uses, but if the patient stops regular use, the “hot pepper response” returns and tolerance needs to be rebuilt. These therapies are short acting and many of them are difficult to apply.^23-27

Physical Therapy

Physical therapy is important for neuropathic pain management because active people heal and adapt faster.^28-30 Because muscle spasms can add significantly to a patient’s pain, it is vital that muscles be kept active and loose. Training tight muscles or muscles that are in spasm (a common cause of trigger points) to relax can substantially improve a patient’s level of function. In addition, patients must maintain muscle tone and the support that muscles provide, because loss of tone and support can lead to other problems such as back instability and tight, painful joints. However, as patients begin to improve and increase their activity, they may initially request more pain medication to offset the pain related to the activity. This is a reasonable request and should be fulfilled, because renewed activity serves the primary purpose of treatment for pain: to help patients return to a more normal lifestyle. In fact, if the newly active patient requests additional medication for this purpose, the pain treatment has been a success.

Psychological Therapy

Psychological therapy should always be part of the pain-management process. Chronic illnesses, especially those associated with neuropathic pain, can cause severe psychological distress, often leading to depression, so neurologists must actively address the psychological aspects of the patient’s condition and be prepared to make referrals for appropriate psychological services.⁹ It is important to reassure the patient that they are not imagining or overreacting to their pain, and that you are encouraging them to get appropriate help and that you understand the difficulty of their situation.

Several therapies can benefit patients by helping them to understand the mind-body connection and take control of the pain, rather than allowing the pain to control them. These include yoga, acupuncture, biofeedback, relaxation techniques, hypnosis, imagery, and a host of other meditative techniques. In addition to the positive psychological effects of such therapies, there is growing evidence, taken from experiments in animals and brain imaging studies, that patients can increase endogenous endorphin levels and influence the brain’s pain-control system.^31-35 As with the pharmacotherapeutic interventions, we cannot predict which method will work for a particular patient, so again, the therapy must be matched to the patient’s lifestyle and needs.

Neurolytic Techniques

Neurolytic techniques, either neurosurgical or anesthesiological, are generally not helpful, except in some patients who have less than a 12-month life expectancy, because the pain often returns. Pain is resilient; it often finds another way around externally imposed blocks. It is important to realize that the nerve cell body for peripheral sensory nerves is in the dorsal root ganglion, near the spinal cord. One of many possible theories is that if a peripheral nerve is cut during surgery, the central pain system continues to function and adapts to the fact that no signal is being sent from the cut nerve. This may result in sensitivity to any response being increased to the point that when a signal comes in (i.e., from a different nerve), the response to the signal is picked up much more acutely. It has been demonstrated that nerves will try to grow back after being severed, although often in an aberrant manner, such as neuromas.^36,37 Another theory about the etiology of neuropathic pain is that there is aberrant cross-stimulation between these neurons resulting in painful discharges.

Counterstimulation Techniques

Spinal cord stimulators are generally wires that are inserted through an epidural needle placed in the spinal canal and appear to cause a counterirritation in the affected area. This input to the nervous system of a nonnoxious stimuli appears to reduce the amount of noxious input. Spinal cord stimulators are most useful in unilateral limb disease but can be used bilaterally, and in different areas of the body. Limitations to their use include the lack of clinical trials to support their use in neuropathic pain, a battery life of 5 to 7 years, and the risk for infection. Additionally, the lead of the wire can be covered with fibrose tissue and lose effectiveness over time.^38-40

Peripheral nerve stimulators require a neurosurgeon, preferably a peripheral nerve specialist, to open and examine the damaged nerve. For select patients with well-defined, dramatic mononeuropathies, peripheral nerve stimulators have an 80% to 90% success rate compared with 50% for spinal cord stimulators. However, of those who are successfully treated initially, only about one half will enjoy long-term relief.⁴¹

Transcutaneous electrical nerve stimulation (TENS) involves applying small amounts of electrical stimulation to the skin. TENS has not been shown to be effective in treating neuropathic pain, perhaps because the electrodes are placed on the nerve endings rather than connected directly to the nerve.⁴² Success or failure with a TENS unit does not predict the outcome from other types of stimulators.

Principles of Use

The principles of adjuvant medication use in neuropathic pain treatment are outlined in Table 2.

Table 2. Principles of Adjuvant Medication Use

Examples of peripheral neuropathic pain

• Believe the patients’ report of their pain
• Establish the appropriate diagnosis and treatment of pain
• Choose medication carefully for both effect and side effects
• In drugs that have significant side effects, start at a very low dose to allow accomodation to those side effects
• Increase dose slowly and regularly until effective or side effects become intolerable
• Push to high therapeutic dose if possible
• Watch for and treat side effects
• Try each medication one at a time and allow enough time for results
• All potentially effective medication in a group should be tried
• Polypharmacy is often necessary

Assuring an appropriate diagnosis and treatment are important and first require addressing the problems of the patient as a whole. For example, a previously stable patient who presents with uncontrollable pain may be under the influence of several factors. While it may be true that the underlying disease process that is causing the pain has gotten worse, it is also just as likely that the absorption of previously tolerable drug therapy may have changed, the patient may have become tolerant to the effects of the drugs, or the patient may be experiencing significant personal distress (e.g., divorce, job loss, death of a loved one) that has reduced their tolerance for pain. The second step is to choose the initial medication or any change in medication based on both the desired effects and side effects. Clinicians should try to use the side-effect profile to their advantage. For example, an insomniac patient may do better on a pain treatment with a somnolence side effect, when a majority of the dose is given at night. For medications with significant potential side effects, the treatment should start at a low dose and be titrated up slowly. For newer drugs with less side effects, doses can be started at therapeutic levels. Most important, the dose should continue to be increased until there is a beneficial effect, the patient has too many side effects, or the level being used exceeds the high therapeutic range before deciding whether the treatment is working. Similarly, adequate time should be given to determine the success or failure of treatment.

Because drugs in the same class can work through different mechanisms, all drugs in a class should be tried sequentially in patients with difficult-to-control symptoms. Given the complex set of symptoms involved in chronic pain, polypharmacy is often necessary. If a medication works, it is reasonable to treat any side effects associated with high therapeutic doses when necessary. When possible, side effects should be anticipated and aggressively managed.

Conclusion

In addition to the appropriate use of the myriad pharmacotherapy choices for treating neuropathic pain, perhaps the most important clinical intervention neurologists can offer neuropathic pain patients is empathy, hope, and ongoing support. The importance of this cannot be overstated. Chronic pain inflicts significant sensory and emotional burdens on our patients and both must be addressed to ensure successful outcomes. Most neuropathic pain patients experience some improvement when physicians adopt a holistic approach to treatment.

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