BEHAVIOR
June 1, 2001

Pain Free: Modern Drugs and Neuropathic Pain

Howard L. Fields, M.D., Ph.D.

Dr. Fields is Professor of Neurology and Physiology, and Director, Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco.

In the past three years, Dr. Fields has served as a consultant for Neurogen and Endo Pharmaceuticals, and has served on the Speakers' Bureau for Pfizer, Abbott and Merck.

During the last millenium, mankind made revolutionary advances in relieving pain. Treatment progressed from non-treatments, such as "biting the bullet," to alcohol and crude opium-based drugs, to the development of safe modern opioids, or narcotic-based painkillers, and a wide range of general and local anesthetics. At least in the developed world, most everyone has found pain relief, at one time or another, from one of these drugs.

Yet despite all our advances, there is one type of pain which, until recently, could not effectively be controlled by modern medicine — neuropathic pain.

Usually chronic and often devastating, neuropathic pain is the result of damage to the body's nervous system. The two most common causes are diabetes ("diabetic neuropathy") and herpes zoster ("postherpetic neuralgia" or "shingles"), an infection of the nerves by the same virus that causes chickenpox. Both cause excruciating pain.

What Does Neuropathic Pain Feel Like?
Although neuropathic pain is highly variable and is felt very differently by different people, doctors can easily distinguish it from other causes of pain. There is usually some abnormality of skin sensation in the painful area and sufferers usually describe neuropathic pain as strange, unfamiliar, often as a burning sensation. It can have a sharpness or a brief shooting quality, as well as a sensation that is described as tingling, crawling, electrical.

Frequently, there is a long delay between the actual nerve injury and the appearance of pain; in fact, it is not unusual for the pain to begin at about the time a person is beginning to recover physically.

Treating Neuropathic Pain
The main problem with treating neuropathic pain is that the standard array of non-narcotic analgesics [acetaminophen, aspirin, non-steroidal anti-inflammatory agents (NSAIDs and cyclooxygenase 2 inhibitors)] have little effect on neuropathic pain. Recently, however, several different classes of drugs have been developed that do help people suffering from neuropathic pain. These are:

Antidepressants

TCAs
Tricyclic antidepressant drugs, or TCAs, are the most extensively studied treatments for neuropathic pain. The most commonly prescribed TCA is amitriptyline. While effective, this drug does have significant side effects, including a type of low blood pressure called orthostatic hypotension. Other side effects include urinary retention, memory loss, heart problems and drowsiness. Because of these significant and potentially serious side effects, doctors normally start patients on a very low dose and increase the dosage slowly.

Desipramine, another TCA, appears to be almost as effective as amitriptyline in most studies, but with fewer side effects and significantly less drowsiness.

SSRIs
For most types of neuropathic pain, selective serotonin reuptake inhibitors (SSRIs) are significantly less effective than TCAs, although the SSRI, paroxetine, has been reported to help pain caused by diabetic neuropathy. On the other hand, SSRIs have virtually none of the side effects of desipramine or amitriptyline, and are non-sedating, that is, they don't cause drowsiness. An added benefit of SSRIs is that they are very effective at treating the depression and anxiety that sometimes afflict those with chronic pain.

Newer Drugs
Though still under study, one of the newer generation antidepressants, venlafaxine (sold under the brand name Effexor®), is a promising drug for neuropathic pain control. Like the SSRIs, venlafaxine is safer than TCAs but acts in a similar way to TCAs and, thus, seems to be more effective than other SSRIs for pain relief.

Anticonvulsants
Anti-seizure drugs, phenytoin (Dilantin®) and carbamazepine (Tegretol®), are effective in treating pain caused by a cranial nerve disorder called trigeminal neuralgia (also known as tic doloreux). Unfortunately, most of these drugs do not seem to help with other types of neuropathic pain. An exception is gabapentin (Neurontin®), which does appear to be effective against a broad spectrum of neuropathic pains, including postherpetic neuralgia18 and diabetic neuropathy.1 Many pain specialists are now using gabapentin as a first line drug for neuropathic pain because it is safe and has few unpleasant side effects other than sedation.

Anesthetics and Antiarrhythmics
The local anesthetic lidocaine, given I.V., brings significant relief to those suffering from postherpetic neuralgia19 and some other neuropathic pain syndromes.

Certain drugs designed to treat irregularities of heart rhythm ("anitarrhythmics") work in a similar way to lidocaine and are being used to treat some types of neuropathic pain. These drugs include tocainide (Tonocard®) and mexiletine (Mexitil®). Mexiletine is less toxic and has been shown to be effective for pain caused by diabetic neuropathy6 and other neuropathic pains. Currently, it is used as a third line drug after TCAs and gabapentin. The main side effect of these drugs is gastrointestinal problems, although these can be managed with antacids or other "upset stomach" medications.

Opioids, or Narcotics
We live in a culture in which opioid, or narcotic, drugs are associated with moral, political and legal controversy. Until recently, there was wide disagreement, even among pain experts, over whether opioid painkillers should be given to those with chronic neuropathic pain.

Recent studies, however, have made it clear that opioids can safely relieve many types of neuropathic pain. These drugs include morphine, fentanyl, oxycodone and tramadol. As effective as they are, the potential risk for addiction or abuse is something that both doctors and patients need to keep in mind. Anyone starting on opioids should be very careful to follow their doctor's instructions and use the drugs exactly as directed.

Topical Medications
Topical medications, a category of drugs designed to be applied externally, rather than injected or swallowed, are most commonly used in cases of postherpetic neuralgia.

One example is capsaicin extracts. Found naturally in peppers and other members of the deadly nightshade family, capsaicin14 is commercially available in two forms, Zostrix® and Zostrix-HP® While some studies have found it somewhat effective, many patients stop using it before it begins to work because capsaicin can produce a burning sensation.

A more useful topical medication for neuropathic pain, especially for shingles, is the local anesthetic lidocaine (see above). Available in patch form under the brand name Lidoderm®, it is very safe and convenient. And the lidocaine patch has the added benefit of providing a barrier which helps protect an area of hypersensitive skin.

Treatment Plan
The ideal in medicine is to treat the cause of a disease rather than its symptoms. Unfortunately, for patients with painful nerve injuries, this is often not possible.5 The majority of patients require some type of medical pain management.

Depending on the individual case, the first step is to try the topical local anesthetic patch, Lidoderm®. If local treatments do not work, doctors generally move on to one of the tricyclic antidepressants (TCAs). If these are not effective, or if there is a problem with side effects, the next step is to try gabapentin, sometimes in combination with a TCA. If patients still have significant pain, doctors may then prescribe antiarrhythmics.

Finally, if all other options have been tried and failed, the last resort is to give patients the milder opioid, tramadol. If that does not work, then the more powerful opioids are used, often in combination with a TCA or other drug.

While neuropathic pain is often difficult to treat, new medicines and better approaches are now available. Research in this field is active and promises to provide further improvements in the near future.

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