Medical Approach to the Management of Neuropathic Pain
Originally Published in The Siegel Rare Neuroimmune Association Newsletter
Volume 7 Issue 2
Joanne Lynn MD
The Ohio State University MS Center
Adapted from a presentation at the 2006 Rare Neuroimmunologic Disorders Symposium
This article focuses on the medical treatments for neuropathic pain. I am not a pain specialist or an anesthesiologist. I am a neurologist in an MS clinic; my experience derives from treating people with neuropathic pain who come to our clinic. I am going to describe the types of pain and clinical manifestations of neuropathic pain, the various ways that pain neurons respond to injury and how different medications may modulate the pain pathways. Finally, I will describe the first and second line medications that we use for the management of neuropathic pain.
We have more information about neuropathic pain in MS patients than we do from any of the other neuroimmunologic diseases. From various surveys of large MS clinic populations, 45% to 55% of patients report that they have some sort of pain syndrome. In the past, it was believed that pain was not a symptom of MS. This is obviously not the case. A large survey with 1672 respondents was administered to determine the pain syndromes that were found with MS (Archibald, et al. 1994). Trigeminal neuralgia was reported by 2% of the patients. This is one of the most difficult pains; a stabbing, lancinating pain in the face, which may be triggered by speaking or chewing. We sometimes have to admit people to the hospital who have flares of trigeminal neuralgia, because they cannot eat or stay hydrated. Lhermitte’s sign was reported by 9% of the MS patients in this survey. This is an electric feeling that spreads down the body when you bend your head forward. Dysesthetic pain was reported by 18.1%. Back pain was identified by 16.4%. Back pain may or may not be directly related to the MS. Painful tonic spasms were reported by 11% of the patients. Sometimes people with spinal cord disorders experience spasms of the hand or leg which occur as constant or intermittent contractions and can be very painful.
Dr. Douglas Kerr has reported from his experience at the Johns Hopkins Transverse Myelitis Center that during the acute phase, 80-94% of patients have numbness, paresthesias or band-like dysesthesias (Krishnan, et al. 2004). Kerr also indicates that pain or dysesthesias are the most debilitating long-term symptom in approximately 40% of TM patients (Kerr 2001, in Griffin and McArthur, Current Therapy in Neurologic Disease).
There are different types of pain. Nocioceptive pain is caused by activation of pain receptors from injuring tissue. The causes can be somatic, such as from a skin burn, muscle tear or pulled ligament or from visceral structures, such as infection of the gall bladder, bowel obstruction and distention. Neuropathic pain is different from nocioceptive pain. Neuropathic pain is from injury or dysfunction in the nervous system and can occur in the peripheral or the central nervous system. Within the nervous system, the injury starts sending off abnormal signals interpreted as “I’m experiencing pain” even though there is no discernable active tissue damage.
There are a number of different neuropathic pain sensations or experiences. Dysesthesias are spontaneous unpleasant sensations which occur without a clear cause. For instance, it might feel as though you are being stabbed by a knife, but you are not. Allodynia refers to pain perception produced by a normally non-noxious stimuli, such as lightly brushing the skin. Hyperpathia or hyperalgesia refers to prolonged or exaggerated pain from a pinprick or other lightly painful stimulus. For instance, when I am doing a neurological exam and touch the skin with a pin that might evoke a sensation that is briefly, transiently uncomfortable, for someone with this type of pain, it might cause a spreading or prolonged painful feeling.
When we are treating someone with pain, it is important for us to try to determine the cause. It is helpful when patients give these issues some thought so that they come to their appointments being able to describe their pain. During our assessment, we want to know the location of pain. We want to identify the character of the pain; is it stabbing, burning, hot, cold, ripping, squeezing? We are seeking some descriptive words for the pain. If a person says that it is “bad” pain or that it is “painful all over;” that information is less helpful for us in determining the cause of the pain. We are interested in the pain’s intensity and the temporal pattern; is it acute or chronic. We also want to know if there are exacerbating or ameliorating factors; what kinds of things make it better or worse.
This is a list of common neuropathic pain syndromes or causes:
- Painful diabetic neuropathy
- Post-herpetic neuralgia
- Spinal cord injury
- Complex regional pain syndrome
- Multiple Sclerosis
- Trigeminal Neuralgia
- Post-stroke pain
- HIV-related pain
People with diabetes get peripheral nerve disease. They can experience burning and pain that can be so difficult that they do not even want the sheets to touch their feet. This type of pain is very common, because diabetes is so common. People that have herpes zoster or shingles may also develop the pain syndromes that occur acutely with the shingles outbreak or may follow the recovery. Both diabetic neuropathy and post-herpetic neuralgia are so common and so standard that they are most often used as neuropathic pain syndrome models to study drug treatments. Many of the drugs that I present in this article were studied in the context of these diseases. These drugs are not studied in disorders that are rare, such as in TM or in MS. Pain is common in TM and MS, but it is difficult to study, because people have such a wide variety of characteristics associated with their pain. Spinal cord injury pain could include TM. People with strokes can have pain from injuries to the spinal cord or higher pain pathways or centers.
We often talk about different kinds of neuropathic pain qualities in describing the sensations. The pain can be steady; often described as burning, hot or sometimes cold. It may be paroxysmal shock-like or stabbing. It may be pain to touch (allodynia). It can be deep, aching pain. Often the pain is the most difficult at night.
There are non-pharmacologic treatments of pain. We rely on physical therapists to help with modalities, such as application of heat and cold and gradual, graded therapeutic exercise. We may use acupuncture and transcutaneous nerve stimulation. If pain is difficult to manage, we may need to look into sleep quality and management of depression. Every pain syndrome is made worse by depression. We need to treat the associated depression which is found in high percentages of people with chronic pain. Psychological approaches are important non-pharmacologic treatments of pain. These may include cognitive therapies, such as relaxation and imagery hypnosis, biofeedback, behavioral therapy and music and art therapy.
I am going to provide an overview of the pharmacologic treatments for neuropathic pain. To many patients, the long list of medications is baffling and frustrating. Some people just do not want to try any more drugs. It is important to understand the different types of medications and why we are trying these as treatments for neuropathic pain.
Optimally, management of neuropathic pain would be guided by knowledge of the underlying problem and its resultant mechanisms of pain production. For instance, if you had stabbing pain, it would be great if we knew exactly where in the nervous system the malfunctioning circuit was located, what specific neurotransmitter system was dysfunctional and what drug would fix the problem. That is just not the way it is for almost all of the pain syndromes. The pain results from multiple processes and we have not been able to define them with a sufficient degree of detail or specificity. We have very little information about the specific sites or mechanisms of dysfunction for various pain syndromes.
Wherever nerves are injured or in the normal appreciation of pain, pain receptors trigger electrical impulses of nerve fibers. That information then enters the spinal cord and the neuron releases a chemical neurotransmitter – often glutamate. Glutamate activates second order neurons that carry pain signals to the thalamus and other areas in the brain and brainstem where pain appreciation is modulated and controlled.
What do we know about the mechanisms of neuropathic pain? Nerve fibers bring pain information, for instance, from limbs or from skin and there are several different kinds of sodium channels that are needed for firing of these nerve fibers. One type of Na+ channel is found only on nocioceptive (carrying information about pain) sensory neuron fibers. If you have damage to that type of nerve, it can cause an increase in the numbers of sodium channels. That increase in sodium channel density impacts the function of the nerve with resultant hyper-excitability and spontaneous or recurrent nerve discharge or sensitization. The nerve can start to fire on its own, without a stimulus and it can feel like stabbing or a shock. You might also get recurrent nerve discharges. For example, it might be set off once by being bumped and then it keeps going off. The whole system becomes sensitized to the point where it will fire off more easily; there is a lower threshold to fire caused by this kind of injury.
We have some drugs that modulate this sodium channel activity and help neuropathic pain. Some of these are anti-seizure medicines, such as carbamazepine (Tegretol®), oxcarbazepine, and Lidocaine. Some are tricyclic antidepressants, such as phenytoin (Dilantin®), topiramate (Topamax®), and lamotrigine (Lamictal®).
There are two subunits of voltage gated calcium ion (Ca++) channels that are upregulated on the dorsal root ganglion (on the nerve fibers) and spinal cord dorsal horn neurons (spinal cord neurons) after injury. If the function or number of these channels is abnormal, it can be associated with allodynia; a stimulus that would not normally be painful becomes painful. Both gabapentin (Neurontin®) and pregabalin (Lyrica®) bind to these subunits and inhibit the high voltage Ca++ channels. There are other medications that also bind to Ca++ channels.
Nerve damage can produce excitatory neurotransmitters and chemicals (peptides) which may cause central sensitization in the spinal cord and brain pathways for pain. These nerve injuries may also cause damage (toxicity) to descending pain control pathways that inhibit pain (inhibitory neurons that use neurotransmitters, such as norepinephrine – NE, dopamine – DA, serotonin – 5-HT and endogenous opioids). If the systems that control our pain appreciation pathways are damaged, then there will be increased problems with pain. There are medications that can increase the activity of the inhibitory neurotransmitters to help decrease pain perception.
There are three main classes of drugs that we use to treat neuropathic pain: antidepressants, anticonvulsants or anti-seizure drugs, and analgesics, which include opioids. Antidepressants are a well-established older therapy; we have used them for decades. These are the antidepressants that were around before fluoxetine (Prozac®). They were not optimal for the treatment of depression, because of their high side-effect profile. They are good for treating pain, however, because we can use lower doses that are associated with fewer side effects. There are numerous studies which have demonstrated pain relief without an antidepressant effect in many types of neuropathic pain, including diabetic neuropathy, post-herpetic neuropathy, headache, facial pain and low back pain.
The neurotransmitters that are affected by the antidepressants are norepinephrine, dopamine, and serotonin. The tricyclic antidepressants are older medications, such as amitriptyline (Elavil®) and nortriptyline (Pamelor®). These are primarily a combination of serotonin and noradrenaline reuptake blockade. They have some other effects, including peripheral sodium channel blockade and weak NMDA antagonism.
These medications work to inhibit neuropathic pain by blocking the reuptake of one or more of these neurotransmitters. A nerve sends information via a chemical mechanism out to the next adjacent nerve. The information is a pain signal that is interpreted by the brain as, “You are having pain.” The transmission of pain information from one nerve to another can be decreased by slowing reuptake of these neurotransmitters back into the releasing nerve after each nerve firing. This is one mechanism that can inhibit the transmission and perception of pain.
When we treat neuropathic pain with nortriptyline (Pamelor®) and amitriptyline (Elavil®) the guidelines are to start low and increase slowly. There also have to be accommodations for age. If the person is younger than 65, then perhaps start with 25 mg qhs; if older than 65, then start with 10 mg qhs. The dose is also dependent on the person’s weight. If we need to increase the dose, we increase gradually; 10 – 25 mg q 1-2 weeks. We also have to look for various side effects, including glaucoma, urinary obstruction, and asthma. The traditional tried and true method was to keep increasing the drug until pain relief was achieved or the person experienced a significant side-effect. We exercise more care today in watching for the side effects of these medications. The side-effects from tricyclic antidepressants include: dry mouth, constipation, weight gain, urinary retention, tachycardia, and drowsiness. Dry mouth can be helped with sugar free lozenges or artificial saliva. We will discontinue these medications, if there is urinary retention or tachycardia. For drowsiness, we will decrease the dose.
Some of the newer antidepressants have been evaluated as treatments for pain. These are the selective serotonin reuptake inhibitor (SSRI) agents (agents that selectively affect neuron systems with serotonin receptors), including fluoxetine (Prozac®), paroxetine (Paxil®) and sertraline (Zoloft®). The results from studies of the SSRIs in the treatment of painful diabetic neuropathy suggest that these agents are less effective than agents that affect both serotonin and norepinephrine. These drugs are great for the treatment of depression, but are not very effective for neuropathic pain.
Another group of newer antidepressants are serotonin-norepinephrine reuptake inhibitors. Venlafaxine (Effexor®) inhibits both norepinephrine and serotonin at 150 mg/d but not 75 mg/d. It has been effective in pain treatment, but it is not being used as a first line medication. Duloxetine (Cymbalta®) is FDA-approved for the treatment of painful diabetic neuropathy. It has relatively few side-effects, and is also used to treat depression, so it has the benefit of being a two-for-one drug.
There is a group of antidepressants that are norepinephrine-dopamine reuptake inhibitors; two neurotransmitter systems. Bupropion (Wellbutrin®) inhibits both norepinephrine and dopamine reuptake. It has been reported to be effective in the treatment of both peripheral and central pain syndrome. There are a number of medications in this group so there are options. There is a low side-effect frequency, but bupropion can cause weight loss, occasional agitation or insomnia. We make decisions about medications on an individual basis and attempt to match medications with a particular set of issues. For instance, a person might have a problem with sleepiness or insomnia, and we would select the appropriate medication accordingly.
For all antidepressants we should consider the FDA black box warnings for increased risk of suicidality in depressed patients treated with antidepressants. Special attention and consideration in this regard needs to be focused on adolescent and pediatric patients. This really means that we should continue to do what we have always done; when using these drugs for pain, we assess for comorbid depression and suicidality.
The next class of medications for neuropathic pain are the antiepileptic drugs. Gabapentin (Neurontin®) is FDA approved for post-herpetic neuralgia or zoster (for patients in the United States) and for neuropathic pain in general in the United Kingdom. It blocks the sodium channels (Ca++) and inhibits excitatory neurotransmitter release. It may decrease the process of central sensitization resulting in lower thresholds for pain. It has a good side effect profile for most people. There is great variation in how much gabapentin a person can handle; some people cannot handle 900 mg/day, while others are able to tolerate above 3600 mg/day.
Pregabalin (Lyrica®) is a newer drug that is a presynaptic calcium (Ca++) channel blocker that reduces excitatory neurotransmitter release. It is FDA approved for painful diabetic neuropathy and post-herpetic neuralgia. It comes in 50 and 75 mg tablets and we can give up to 600 mg/day. It can cause sedation and ataxia as you push up. It will be interesting to see how this medication works for some of the pain syndromes that we see in transverse myelitis.
Carbamazepine (Tegretol®) is an older drug that is FDA approved and has been especially effective for the treatment of trigeminal neuralgia, the facial pain seen in MS, and also shock-like pains. Carbamazepine can cause sedation and balance problems. There are other anti-seizure medicines that are not first line drugs; they may not be as good and they are not as well studied. Oxcarbazepine (Trileptal®) is related to carbamazepine and there has been one positive study in painful diabetic neuropathy. Other antiepileptic drugs include Lamotrigine (Lamictal®), a second line drug that has been shown to be effective against neuropathic pain of several different etiologies, including spinal cord injury. Valproate (Depakote®) is useful for migraine prophylaxis and one study has shown a benefit for painful diabetic neuropathy. Multiple toxicities and drug-drug interactions make it a second line drug (Kochar, et al. 2004). There have been no randomized controlled trials for the use of the selective GABA reuptake inhibitor Tiagabine (Gabitril®) for the treatment of neuropathic pain conditions.
There are various topical agents that we use for neuropathic pain. There is the lidocaine patch 5% (Lidoderm®) and Capsaicin, a cream made from the chili pepper. Capsaicin affects pain fibers. It burns when it is initially applied. It may then cause some degeneration of neurofibers, and that may create benefit in the long run. There are also some topical NSAIDs and topical antidepressants that are available.
There are also some miscellaneous agents that have been used for neuropathic pain. Baclofen (Lioresal®) is a GABA-A receptor agonist that is mainly used for the treatment of spasticity. It has also been reported to be effective in treating trigeminal neuralgia. Clonidine has been effective in the treatment of cancer-associated neuropathic pain, but requires study in non-cancer neuropathic pain.
Opioids have generally been underutilized for the treatment of neuropathic pain. In addition to working on opioid receptors, opioids also decrease glutamate receptor activity. Physicians who are not anesthesiologists or pain doctors are typically reticent to use opioids and neurologists tend to be conservative. There have been some studies in the past that have reported that opioids are less effective for neuropathic pain compared to tissue injury (somatic) pain. It is certainly appropriate for a patient with moderate to severe pain who has not responded to other types of treatment and who is willing to accept the discipline of a structured opioid prescription program to use these medications.
Opioids may be associated with tolerance; there may be a need to increase the dose over time to maintain effectiveness. It may also be associated with physical dependence and with unpleasant withdrawal symptoms when stopping the drug. Less often, there may be addiction; drug seeking behavior to satisfy drug craving despite harm. For most people with a pain syndrome, they do not develop addiction or drug seeking behavior when using opioids as a legitimate treatment.
Setting up an opioid prescription program helps to reduce the risk of addiction. Having scheduled appointments on a regular basis reduces risk for abuse. There can be an agreement with the patient that they obtain all of the analgesics or opioids through one doctor and one pharmacy. There can be a written contract that sets limits and may agree to urine testing. Some of the opioids are tramadol (Ultram®), morphine or extended release morphine, oxycodone, fentanyl patch and vicodin or percocet for breakthrough pain.
Finally, I want to discuss combination therapy for the treatment of neuropathic pain. Patients consider a 30% improvement in pain to be significant. In many treatment trials only 1 out of 3 to 4 patients treated will experience moderate improvement. It is difficult to identify the underlying pain mechanisms in a patient. Due to these uncertainties, it is sometimes important to try multiple agents. A common approach used in combination therapy is to start with one drug and titrate up until maximum benefit or intolerable side effects result. In one study (Gilron, 2005), a combination of gabapentin and morphine was found to be more effective than each drug used separately.
It is important for patients to remain hopeful and persistent in their efforts to obtain effective treatment for their neuropathic pain. Fortunately, there are a large number of drugs that are effective for treating neuropathic pain. Finding the appropriate treatments is a great challenge and it is important to have a good partnership with your physician in working through the treatments. It is a trial and error process to find the most useful drug or combination of drugs at the right doses with the least side effects to treat neuropathic pain.