Neuropathic pain

We must be able to differentiate Neuropathic pain from pain associated with an infection, trauma, suturing pain, or extraction pain. These are not pains invoked by a neuropathic mechanism. Neuropathic pain involves nerves, or neurogenic pain (including damaged peripheral nerves, ie. damage during a local nerve block injection, or if you nick a nerve during surgery). Neuropathic pain involves some dysfunction of the nervous system, including both the central and autonomic (particularly the sympathetic) nervous systems. Sometimes the pain occurs as a sharp, shooting or burning pain; “burning mouth/ burning lip” syndrome is often linked to neuropathic pain. This occurs usually in the absence of tissue damage.


Other labels for neuropathic pain include: reflex dympathetic dystrophy (RSD), diabetic neuropathy, central pain syndromes (ie. something is wrong in the thalamus or a pain relay center, often the only tx is for a neurosurgeon to interrupt neurothalamic tracts surgically), trigeminal and postherpetic neuralgia. Very frequently in diabetic pts, especially type I insulin dependent diabetics, diabetic neuropathy occurs, this alters your pt’s pain perception considerably.



Complex Regional Pain Syndrome (CPRS) is a new emphasis on the way to define chronic pain syndromes, the old term was “causalgia”.


Type I: pain is disproportionate to the event that is provoking the pain, it is more severe. A term such as hyperalgesia can be used to describe it, and should be in your pt record (don’t just write mild or moderate or severe).
Type II: pain is exaggerated, but there is also continuing pain. Not the type of acute pain that will last a few days, but continuing pain as in low back pain (one of the most frequent reasons a pt goes to an MD).


Hyperalgesia is an increase in the intensity and interpretation of a normally painful stimuli. The pain is mediated by the CNS, either C-fibers, A-delta fibers, or NMDA receptors.


When there is injury, we get inflammation from the release of prostaglandins, and we treat this with an NSAID or peripherally acting agent. However, when we have chronic pain it involves the neurons. Clearly because there is a neuronal pathway, giving agents to alter the neuronal firing may be successful in treating the pain. This includes many of the anti-convulsives, or anti-epileptics. These drugs do have an accepted role as adjuncts in this kind of pain, because we’re dealing with neurons that are firing extensively. In sympathetic mediated pain (SMP) there is something wrong with the sympathetic nervous system, and the release of catecholamines, particularly norepinephrine, at nerve endings triggers a particular type of pain. It can be treated by sympatholytics, to block the sympathetic outflow. Chronic pain with complex mediators involves other parts of the nervous system also, maybe the limbic system (heavily mediated by seratonin) where the interpretation and emotional aspect of pain resides. Obviously, using drugs designed to alter norepinephrine in the CNS, including the tricyclic antidepressants (TCAs), the anti-convulsants, and trans-electrical nervous stimulation (TENS, in which a device stimulates nerves blocks the gates of pain pathways, usually used for pts with intractable pain who do not respond to drugs). So there are a very diverse array of strategies available depending on the strategy of your diagnostic skills.


Notice that there are quotation marks around “analgesics” because the drugs listed here are not truly analgesics, but are commonly used as adjuncts in treating pain. These include the Tricyclic Antidepressants (TCAs), of which Amitriptyline, and Desipramine and Imipramine are common. Dr. Inesi will cover these more specifically later this quarter. The TCAs were originally designed to be used by psychiatrists to counter depression, but because they affect norepinephrine reuptake, they can be used to treat neuropathic problems. They are not used alone, but as adjuncts.


Another class is the anticonvulsants, including Carbamazepine (Tegretol), which used to be widely used in dentistry for facial pain syndromes. It has been declining in popularity because it promotes bone marrow depression with chronic use. Because of this, if Tegretol is to be used for chronic pain, it is essential to moniter the pt’s blood chemistry.


Local anesthetics, including Mexiletine (an antiarrhythmic drug) can be used as an adjunct in treating chronic pain syndromes.


The neuroleptics are very popular in Europe, less so here in the USA. These are drugs that interrupt many of the sensory pathways, having nothing to do with norepinephrine, or dopamine or glutamate, (we don’t understand the mechanism) but they are not likely to be used in dentistry.


The controversy is substantial with regard to the muscle relaxants. When dealing with chronic myofacial pain syndrome, there is a perception that the facial muscles are contracting and maybe a muscle relaxants would help… much of the evidence shows that for these syndromes muscle relaxants are no better than placebos.


Corticosteroids may only help if there is an inflammatory cause of pain. These drugs are devoid of analgesic actions, but can help with pain because of their anti-inflammatory action.


Sympatholytic drugs (Prazosin and Phenoxybenzamine) are alpha blockers and probably have no use, but we should add to the list Clonidine (Catapres). Clonidine is a central acting sympatholytic drug, having a significant effect on the alpha-2 receptor and as a result there is interference with sympathetic outflow.


The antidepressants are used in the management of depression, but as used in dentistry to deal with chronic pain syndromes we deal mostly with the TCAs (amytriptyline and nortriptyline are the prototypes). The TCAs are old agents, 40-50 years. They do produce anti-depressant effects that can help if a pt is depressed over their pain. Side effects include the fact that they are powerful anti-muscarenic drugs, like atropine. So we see severe xerostomia, bladder dysfunction, and constipation. If a person is taking these drugs chronically for acute pain, rampant caries is associated with the TCAs. The Serotonin Specific Reuptake Inhibitors (SSRI) will be discussed later, but the prototype is Prozac. SSRIs block serotonin reuptake, are better tolerated compared to the TCAs, but there is little evidence that they are any better than placebos. There are anecdotal reports of efficacy, but no serious studies have been done to quantify their effects as analgesic adjuncts (not to be confused with these drugs effectiveness at fighting depression, at which they are very effective).


Pay attention to the side effects associated with use of the TCAs (of which Amitriptyline is the prototype, and Nortriptyline is secondary). Severe xerostomia, bladder dysfunction, constipation and sedation are common.



What do our esteemed colleagues from the National Institute of Health in Bethesda think about antidepressants for chronic orofacial pain? “Many putative dental and surgical treatments for TMDs have not withstood scientific scrutiny.” The effects of antidepressants on TMJ dysfunction are almost always based on anecdotal accounts and don’t stand up in scientific studies.


It has been found, and published in JAMA (1998), that “neither acupuncure nor amitriptyline (TCA) was more effective than placebo in relieving pain caused by HIV-related peripheral neuropathy.” Until somebody refutes this, this is what we call evidence-based dentistry.


Gabapentin (Neurontin) was developed and approved for the tx of seizures in adults. However, there are increasing reports in the literature that Neurontin is effective in sympathetic dystrophy. It takes from 2 hours to 12 days for pain relief. In neuropathic and myofascial pain, it has been found to decrease the pain associated with post herpetic neuralgia. So this drug is approved as an anti-epileptic drug, but used as monotherapy for post herpetic neuralgia. It’s been effective against migraine headaches as well. Side effects include dizziness, sleepiness, and some motor ataxia and nystagmus, but very minor. The doses must be high, however, sometimes as far as 2-3.6 grams per day… so its not very potent.


Gabapentin is effective in treating shingles pain, quality of life is improved- it is palliative. Gabapentin is effective in the treatment of pain and sleep interference associated with PHN. Mood and quality of life also improve with gabapentin therapy- it is a first-line therapy for these pains.


When a pt has had pain for over a year, over 90% will have persistence of pain in the elderly. So there is an age related incidence of pain. Again, when we’re talking about acute pain, we’ll think of the NSAIDs, peripheral agents, acetaminophen, and the opiate class. When we come to chronic pain, you’re going to go over the line and look at adjuncts; we don’t want pts to be on chronic opiate therapy year after year because of the risks of drug tolerance and dependence.


Gabapentin has been shown to be effective for treating the pain associated with diabetic peripheral neuropathies, which occurs in 45% of patients with diabetes (mostly type I). Gabapentin is effective as monotherapy! That means that you don’t need an analgesic.


The prevalence of neuropathy may be present in up to 60% of diabetics. In non-insulin dependent diabetes mellitus (NIDDM), or type II, the duration of neuropathy will be increased.


When we’re looking at trigeminal neuralgia (TN), it often masquerades as pulpitis, facial pain, cluster headaches, secondary pains associated with tumors, etc. So the differential diagnosis of TN requires some clinical skill and maybe a med consult. If there are orofacial manifestations of that condition, then the issue is choosing the appropriate drugs.


Carbamazepine (Tegretol) is traditionally used to treat TN, and is very effective. However, side effects include blood dyscrasias, agranulocytosis; monitering of blood chemistry is essential.

Phenytoin (Dilantin) is an anticonvulsant drug, can be used alone or in conjunction with other drugs, and is less effective than Tegretol.

Baclofen (Lioresal) acts on the spinal cord pathways and apparently interferes with GABA neurons in the spinal cord, and has fewer side effects but is less effective.


Neurologists can also treat TN by other methods such as glycerol injections, radiofrequency thermocoagulation , and microvascular decompression, but these are things that even neurosurgeons are not inclined to do.


This is an ad for Clonidine HCl. Those of us who remember our pharmacology will remember that Clonidine (brand name Catapres) is a drug used for HTN. It is a central acting alpha-2 receptor agonist… what does this have to do with pain? This drug is very effective because of its alpha-2 agonist activity in the CNS, and manages neuropathic pain well. It is approved for the treatment of neuropathic pain “in combination with epidural opioids, provides enhanced relief of severe neuropathic pain in cancer patients- pain not adequately relieved by opioids alone.” Clearly, this means that anesthesiologists will use this to treat the excruciating pain associated with cancer via intra-thecal injection (into the spinal fluid of the spinal canal).


There are still physicians who prescribe muscle relaxant drugs such as Cyclobensaprine (Flexeril), Methocarbamol (Robaxin), and Carisprodol (Soma) to manage chronic facial pain syndromes. THESE DRUGS HAVE LITTLE EFFICACY IN CHRONIC OROFACIAL OR HEAD PAIN!!!


Although it is effective as an acute muscle relaxant, Diazepam (Valium) in “40 mg or more (muscle relaxant doses) over the long term is unlikely to be efficacious.”


Although I keep telling you that lidocaine is not an analgesic, but a local anesthetic, the fact is that in intractable pain (that doesn’t respond to anything else) lidocaine is approved for treatment. So when nothing seems to work, block the peripheral nerve and then give I.V. lidocaine. This is obviously something out of the realm of general dentists.


One last word about behavioral and relaxation approaches in managing chronic pain. The hard evidence is not there concerning the efficaciousness of relaxation, hypnosis and biofeedback. But, “…data are insufficient to conclude that one technique is more effective than another for a given condition.”

Category: Pharmacology Notes