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Painful Sensory Neuropathy - A Rational Approach to Diagnosis and Treatment
By: Howard Aaron Aronow, M.D.
This article concentrates on a rational approach to the diagnosis and pharmacologic treatment of HIV-associated DSPN. It is a simplified "how-to" designed to assist physicians and other primary health care providers of HIV-positive patients.
The most frequent and debilitating complaint that our HIV-infected patients present with what is commonly called Painful Sensory Neuropathy. It also is referred to as Peripheral Neuropathy and Distal Symmetrical Peripheral Neuropathy (DSPN).
The diagnosis is actually fairly straightforward. The patient will complain of the insidious onset of, first, numbness and paraesthesias involving the feet that progressively gets worse over weeks to months and spreads up the legs. The numbness is then accompanied by a burning, electrical, jabbing, freezing or lancinating type of pain. This pain tends to be worse at night and can be so severe as to be triggered by bedclothes moving against the legs. It rarely involves the upper extremities and is predominantly sensory. In the few cases involving the upper extremities, classic dictum is that the shaded stocking deficit (incomplete sensory loss that is worse distally that decreases, thus shades, as it moves more proximally up the leg) has extended to or above the knees before there is any glove type deficit (incomplete sensory loss that is worse distally as it moves more proximally) in the hands. Any significant weakness of the extremities should alert the examiner of an alternative diagnosis.
On examination, there is a mostly symmetrical shaded stocking deficit to primary sensory modalities, including touch (both dull and sharp), temperature, and vibratory sensation to a 128 Hz tuning fork. Deep tendon reflexes are usually preserved at the knees, but severely diminished or absent at the ankles. Preservation of ankle jerks (Achilles reflexes) or briskness of these reflexes should again alert the examiner to an alternative diagnosis and usually indicates that the pain and sensory loss is due to spinal cord disease, commonly referred to as Vacuolar Myelopathy, which is the most frequently associated HIV syndrome of spinal cord injury. This syndrome is usually manifest by lower extremity spasticity, urinary frequency, constipation, and in the male patient, sexual impotence. There may be proximal weakness and, again, deep tendon reflexes in the lower extremities are brisk and may be pathological with associated clonus and bilateral Babinski responses. When there is significant diffuse weakness, along with loss of all reflexes, then the diagnosis is usually that of a Demyelinating Polyneuropathy. When this is acute, it is known as Guillain-Barré Syndrome. When it is more slowly progressive and chronic, it is known as Chronic Inflammatory Demyelinating Polyneuropathy (CIDP).
It is crucial that the examiner be able to differentiate amongst these diagnoses because treatment is different for each of these entities and, especially because Guillain-Barré and CIDP can be life-threatening when these syndromes involve compromise to accessory respiratory muscles. These Demyelinating Polyneuropathies require confirmation by delayed late responses in nerve conduction velocity testing (delayed or absent H and F reflexes). Spinal fluid analysis by lumbar puncture (LP) may reveal a lymphocytic pleocytosis (elevation of white blood cells), which would be indicative of an inflammatory response. These conditions are treated with high-dose Intbravenous Gamma globulin, with or without Plasmapheresis, which is meant to quell an auto-antibody attack against the myelin coating of peripheral nerves.
Vacuolar Myelopathy may require confirmation by performing Magnetic Resonance Imaging (MRI) scans of, at minimum, the thoraco-lumbar spinal cord to see the termination of the spinal cord, but may also require MRI of the cervical cord, especially if there is any question of upper extremity involvement. These scans should be normal or at least show no evidence of mass lesion, hemorrhage or infection. Additionally, LP may reveal a lymphocytic pleocytosis or may be relatively acellular and may have an elevated protein. Current quantitative HIV RNA PCR on spinal fluid (spinal fluid viral load) is often positive. There should be no evidence of other infection such as CMV. In other words, CMV PCR should be negative. Treatment of Vacuolar Myelopathy should consist of highly active anti-retroviral therapy (HAART) that includes at least two drugs to which the patient's virus is sensitive and that cross the into the central nervous system (CNS). These include AZT/Combivir, Zerit, Viramune, and Sustiva. They also may include Abacavir and Amprenavir, but there is limited data regarding the efficacy of these latter two agents. It is known that Abacavir gets into the CNS, but preliminary studies did not reveal great benefit in its treatment of HIV-associated CNS disease, which includes dementia and myelopathy. While Amprenavir is still experimental, it is the only protease inhibitor that significantly crosses the blood-brain barrier and achieves high levels in the CNS.
Once the examiner has excluded these more dangerous diagnoses, along with the classic history and examination, then the diagnosis of DSPN is easy. It requires a trained examiner, a 128 Hz tuning fork, and a reflex hammer. DSPN is often one of the most difficult and frustrating painful conditions for any health care provider to treat. By definition, it is an axonopathy, which means that the actual distal nerve segments are damaged. The most common causes of DSPN worldwide include diabetes mellitus, alcoholism, and HIV Disease. The diagnostic work-up for DSPN must include testing for and exclusion of toxic-metabolic abnormalities and neurosyphilis. These tests consist of a B12 level, a folate level, a thyroid panel (which includes thyroxin level and thyroid stimulating hormone level [TSH]), and RPR (syphilis serology - rapid plasma reagen) or VDRL (syphilis serology - venereal disease research laboratory). Nerve conduction velocities and electromyography, while confirming the diagnosis, are rarely necessary and are often too painful for the patient with DSPN to endure. When the history reveals exposure to heavy metals, such as what might be experienced by pesticide workers, lead reclamation workers, industrial and house painters, gardeners and landscapers, and chemists, then urine testing for lead, arsenic, and mercury should be performed. If these are elevated, then chelation therapy is indicated. Obviously, cessation of alcohol and consideration of diabetes and, in the known diabetic, strict glucose control is crucial to the treatment of DSPN.
In the HIV-infected patient, specific medications are well-known to contribute to or directly cause DSPN. These include the commonly referred to "D" drugs: the nucleoside analogues ddI (Videx), ddC (Hivid), and d4T (Zerit), and the prophylactic agent against PCP, Dapsone. Other drugs that commonly cause DSPN include the Vinca alkaloid chemotherapeutic agents such as Vincristine and Vinblastine, which are often used to treat Kaposi's Sarcoma (KS) and lymphoma, the two main tumors associated with HIV. It may be necessary to reduce the doses of these medications or eliminate them from the treatment regimen when the DSPN is severe. It is more likely that the medication or medications known to cause DSPN that are most temporally related to its symptoms are the cause of the DSPN rather than medications previously tolerated. For example, if a patient has been taking Zerit for a relatively long period of time without symptoms and Videx is added, then Videx is more likely to be the cause of the DSPN and its dose should be lowered on it should be discontinued. When two or more drugs known to cause DSPN are initiated at approximately the same time, then it may be difficult to discern which medication is causing the problem and, in fact, any and all of the medications may be contributing. The decision as to whether or not to lower the dose or discontinue any potentially toxic medication should be based on several factors. These include the importance of the particular medication in treating the condition and how opposed the patient is to continuing the medication. Often, when the pain is minimal or is being adequately controlled, the patient will be amenable to continuation of the potentially toxic medication. This is especially true when the medication is working to treat tumors such as KS or lymphoma or, with regard to HAART, the patient has achieved undetectable HIV viral load and is feeling well, aside from having painful feet.
In patients with markedly compromised immune systems (CD4+ < 50), concomitant CMV infection must be considered, as up to 20% of individuals with significant pain in this category will have CMV. Additionally, DSPN easily can be differentiated from the condition known as CMV Polyradiculomyelopathy in that, in this condition, there is significant weakness, especially to the lower extremities, as well as marked bowel and bladder dysfunctions, and it is almost always associated with a known, poorly treated or resistant CMV infection. The treatment for CMV infection is, at minimum, one anti-CMV drug, such as Gancyclovir, but, in the case of possible resistance, two drugs are usually necessary, such as Gancyclovir and Foscarnet.
Once all of these other entities and contributing factors to DSPN have been considered and addressed, or, in the cases where there are no contributing factors apart from HIV itself, the treatment becomes one of best controlling the HIV infection and the chronic pain. There are many different classes of drugs which neurologists and pain specialists use to treat the chronic pain associated with DSPN. These include antidepressants (primarily tricyclics), anticonvulsants/antiarrhythmtics, and opiates.
The exact choice of a tricyclic antidepressant anti-pain medication should depend on the amount of associated sedation necessary to treat insomnia or anxiety and should include specific indications for the drug. For example, in patients with extreme insomnia, medications that are relatively sedating, such as Amitriptyline (Elavil) and Sinequan (Doxepin), have marked anticholinergic side effects, which include induction of sleepiness, dry mouth, and occasionally urinary retention and constipation. For those that require some sedation, Nortriptyline (Pamelor) may be beneficial. In those that cannot tolerate the sedating side effects of these medications, Desipramine (Norpramine) has the east anticholinergic side effects of this group and would be indicated. In patients that have panic and anxiety disorder, the use of Imipramine (Tofranil) may be useful to treat both pain and panic/anxiety. The anticonvulsant Carbamazepine (Tegretol) is tricyclic-like in its chemical structure and may also be beneficial in treating painful neuropathy. Tegretol also is approved to treat bipolar affective disorder and may be quite useful in bipolar patients with pain. Because Tegretol has a higher propensity for inducing granulocytopenia (lowering white blood cell count), blood counts must be monitored more carefully during its administration.
The exact dosing of the tricyclic medications is identical across the entire class and usually will begin with 25 mg of a single nighttime dose, which can be advanced over the course of 1-2 weeks to 75 mg, as tolerated, and may be higher with appropriate drug level monitoring. The dose of Tegretol starts out at one 200 mg tablet daily and, over the course of the first two weeks, is advanced to 200 mg three times daily. Of caution is that Tegretol interacts with Ritonavir (Norvir), and the dose of Tegretol usually has to be reduced by one-half or more in order to avoid serious toxicity. The appropriate response and dosing is monitored by blood levels and cessation or diminution of pain. For Tegretol, blood counts should be performed twice weekly for the first two weeks, weekly thereafter for the first month, and then, if the patient's blood counts are stable, the levels and complete blood counts may be monitored monthly. Therapeutic levels for Tegretol range from 6-12 mg/dL. In debilitated patients, elderly patients or patients with history of cardiac arrhythmia, appropriate cardiac clearance should be obtained, which at minimum includes an electrocardiogram to rule out an obvious arrhythmia. In rare instances, the tricyclic medications can induce arrhythmias, which are usually tachy-arrhythmias. Again, significant side effects from tricyclic medications include dry mouth, sedation, and may include urinary retention and constipation. These side effects are usually minimized by the gradual advancement of dose, although dry mouth may be persistent. Patients may be instructed to chew gum or carry hard candies during the day and to keep a glass of water at the bed stand during the night to alleviate this symptom.
Of the selective serotonin reuptake inhibitors (SSRI), both Paroxetine (Paxil) and Nefazodone (Serzone) have undergone limited trials for the treatment of chronic pain. They may be useful as adjunct therapy when an activating antidepressant is indicated. Citalopram (Celexa) in limited series has shown benefit in treating both depression and pain. It is the newest of the approved SSRIs and has limited drug-drug interactions, making it safer to use in patients on HAART.
Perhaps the greatest development in the treatment of pain associated with DSPN has been the introduction of Gabapentin (Neurontin). This medication has been approved by the FDA in the United States for the treatment of adjunct therapy in specific seizure disorders, but is soon to be approved for the treatment of many severely debilitating neuropathies, including DSPN associated with diabetes, post-herpetic neuralgia (after-shingles pain), and trigeminal neuralgia, also known as Tic Deloreau (severe facial pain). Neurontin currently is in clinical trials for these conditions and for DSPN associated with HIV. While the exact mechanism of action is not entirely understood, Neurontin works to ameliorate pain via a completely independent neurotransmitter pathway known as GABA (Gamma Amino Benzoic Acid). Because Neurontin is metabolized by a separate enzymatic reaction in the liver, it does not interact with any other medications and therefore is very safe. Its main side effect consists of sedation, which usually subsides after an initial two week induction phase. The dosing can start as high as one 300 mg capsule three times daily and, after one week, can be escalated to two 300 mg capsules three times daily. Doses as high as 1200 mg three times daily have been safely used but, in our experience, most adults with DSPN respond at somewhere between 300 mg three times daily and 900 mg three times daily. The medication should be taken with food, if possible, to avoid any gastrointestinal upset, and, if patients are overly sedated, it is available in as little as 100 mg capsules and the dose escalation can be modified in these individuals.
Another anticonvulsant in the GABA family that currently is being studied for painful DSPN is Lamotrigine (Lamictal). Its exact mechanism of action is probably similar to Neurontin, but specifics remain unknown. The dosing is more tedious because it is more sedating than Neurontin and optimal doses of 100 mg twice-daily can take over a month to attain. The standard starting dose is 25 mg twice daily and it is increased by 25 mg at each dose per week. In our experience, when patients fail to respond to Neurontin, they generally will not respond to Lamictal; however, if they have intolerable side effects to one of these agents, the other agent may still be beneficial. For both Neurontin and Lamictal, it is not necessary to monitor drug levels. Nonetheless, for Lamictal, periodic monitoring of blood counts and serum chemistries is indicated.
Valproate (Depakote) is an anticonvulsant that is membrane stabilizing and has been approved to treat, in addition to seizures, bipolar affective disorder and migraine headaches for prophylaxis. Depakote has been used to treat chronic pain and may be especially useful when any of these other conditions are present. The standard dosing of Depakote is 250 mg once daily to start, with escalation of dose every three days by 250 mg until a dose of 500 mg twice daily is achieved. Side effects of Depakote may include mild sedation and nausea, but it is generally well-tolerated. The standard anti-migraine prophylaxis dose is 500 mg twice daily and, at this dose, monitoring of levels generally is not necessary. When one uses doses higher than this, the therapeutic drug range is 50-100 mg/dL. Depakote should be used with caution in patients with severe liver disease, as it can cause liver dysfunction and hyperammonemia (elevated serum ammonia levels). In patients requiring high doses of Depakote, monthly monitoring of drug levels, liver function tests, and serum ammonia levels may be necessary.
The oral anesthetic, Lidocaine-like drug Mexiletine (Mexetil) also has shown benefit in the treatment of DSPN-associated pain. It is contraindicated in any patient with a known cardiac arrhythmia. Side effects may include anxiety and it may be helpful in people for whom a stimulant would be beneficial. It has been studied extensive in diabetic painful neuropathy and we find it particularly useful in HIV-infected patients who are diabetic. The typical dose is 150 mg taken three times daily and the dose can be escalated as high as 150 mg taken five times daily.
In patients with considerable anxiety and/or muscle spasm, Clonazepam (Klonopin) may be a useful adjunct medication. The starting dose of Klonopin usually is .5 mg taken two or three times a day, but in patients with extreme insomnia, it may be given as a single nighttime dose of 1 or more mg. It carries with it the same possibility of development of tolerance as all the benzodiazepines. Klonopin generally is not used as a solitary agent to treat pain. Likewise, the antispasmodic agent Baclofen (Lioresal) can be useful as adjunct therapy for chronic pain. The starting dose of Lioresal is 5 mg (of the 10 mg tablet) taken three times daily and escalated to 1 tablet taken three times daily after one week. The primary side effect, as expected, is sedation. Doses can be escalated as high as 25 mg three times daily. The alpha-2 adrenergic agent Clonidine (Catapres) also can be beneficial in patients requiring high doses of narcotic analgesics (see below), especially if the individuals are hypertensive. Catapres is available in pill and patch forms. The starting dose is .1 mg daily for the pill form and the patch is .1 mg changed weekly.
Experimentally, the agent Human Nerve Growth Hormone (hNGH) is being studied in clinical trials to treat painful DSPN in HIV and is about to be approved by the FDA to treat DSPN associated with diabetes. This medication has to be injected subcutaneously on a daily or three times per week basis and, in some cases, has caused exacerbation of pain. It is promising to note, however, that in many of the diabetics studied, there was objective evidence of regrowth of nerve shown by improvement in nerve conduction velocities. Similar studies are ongoing with regard to the use of hNGH in HIV-associated painful DSPN.
In patients with severe pain, especially in those that show incomplete response to the above-mentioned agents used alone or in combination, it often is necessary to add a narcotic analgesic. When there is episodic breakthrough pain, a short-acting oral narcotic is the drug of choice and can range from Tylenol with Codeine to Vicodin to Percocet to oral Dilaudid. When multiple dosings of these medications are necessary, longer acting narcotic analgesics become necessary. These include Oxycontin, MS Contin or Oramorph, and Methadone. When there is considerable gastrointestinal distress and a long-acting narcotic is necessary, Fentanyl (Duragesic) patches are useful. Doses of all narcotic analgesics must be individualized; however, it is important to note that Tylenol with Codeine, Percocet or Percodan, and Vicodin or Lorcet all contain Tylenol and the daily maximum of these medications in an average-sized adult is six tablets per day due to potential liver toxicity. These medications can be used to treat breakthrough pain in lesser doses in patients who are taking long-acting narcotics or in patients, as stated above, whose pain is only intermittent. However, when a patient requires more than six doses of these daily, the patient should be switched to a long-acting narcotic agent that does not contain Tylenol.
There are many adjunct non-pharmacologic treatments of DSPN that have been found to be beneficial in a subset of patients.
These include acupuncture, biofeedback, chiropractic, physical therapy, psychotherapy and hypnotherapy. Patients can be referred for these modalities based on the patient's wishes and when the primary caregiver believes these will be helpful.
There are some basic principles that any treatment provider must follow when administering to patients with chronic pain. First, remember that pain is entirely subjective and our objective should be to treat the patient and not the health care provider. This means that narcotic analgesics can be used safely when there is a clear diagnosis such as DSPN and health care providers should not be frightened or biased against ameliorating the patient's pain to allow the patient the best quality of life. Second, the health care provider should avoid inappropriate use of any pain management intervention. For example, an intervention is unnecessary if the desired objective can be achieved by simpler means. To illustrate this, a long-acting narcotic such as MS Contin may not be necessary if the patient has not undergone a trial of Neurontin. If a pain management intervention is unsuccessful, in that, for example, the medication is not treating the pain adequately or is causing intolerable side effects, then an alternative intervention must be entertained. Whenever complications or side effects outweigh a treatment benefit, the treatment should be discontinued and a different treatment should be undertaken. Certainly, when the quality of life is diminished because of the therapeutic intervention, other forms of treatment must be considered.
What often is helpful when managing patients with chronic pain who require narcotic analgesics and who may be taking benzodiazepines such as Klonopin is to discuss and insist upon what is known as the "Verbal Pain Contract." This places several responsibilities on the patient. The standard Verbal Pain Contract includes the following mandates:
- Only take what your doctor prescribes. Do not obtain pain medications from any other physician or source.
- Try to use only one pharmacy.
- Do not lose your medication or have it stolen.
- Do not buy pain medication or sell your prescribed medication on the street.
- If the medication is not controlling your pain, tell your doctor and ask for an increase in dose.
- As a courtesy, if you are requiring more medication, call your doctor at least one week in advance for refills and to schedule an earlier appointment to avoid pain, anxiety, and possible drug withdrawal.
- Above all, be honest. Your doctor cannot help you if you do not communicate your needs effectively.
The goal for most patients with painful DSPN is to attain the highest quality of life while remaining functional with regard to activities of daily living. Using various combinations of the treatment modalities discussed in this article usually results in adequate pain control. A realistic goal is to tell patients that pain control may not be complete, but that, at least from a starting point, pain should not be the central focus of every waking minute and that, over time, with multiple therapies, their lives should be pain-controlled and fulfilling.
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