Ley Tributaria

Medical treatment is first-line therapy for neuropathic pain syndromes. It is the character of the prominent pain symptoms that drives therapeutic decision making, and the efficacy of drugs against neuropathic pain has been discovered serendipitously through clinical observation, usually after the drugs have been marketed for other indications. While pain researchers and pharmaceutical companies search for new ligands with molecular specificity, most of the effective treatments in current clinical use have activity at multiple sites within the pain pathways.

The good news is that multiple medications have proven effective against neuropathic pain in blinded, placebo-controlled clinical trials. The bad news is that none of these medications is effective in all patients, and we do not yet know how to predict who will be improved by which medication. Because of these limitations, it is often necessary to try several different medications before identifying the optimal agent and dosage for a particular patient. This sequential process should be explained to the patient to ensure that expectations for the extent and timing of relief are appropriate.

In general, the medication, or class of medications, judged most likely to be effective should be tried first, raised to an adequate level, and monitored for efficacy and side effects. Only if the primary analgesic is ineffective at the maximally tolerated dose should it be discontinued and replaced with a second agent. The four major classes of medications for treating neuropathic pain syndromes are tricyclic antidepressants (TCAs), anticonvulsants, opioid analgesics, and topical agents.

1. Tricyclic antidepressants

Historically, the TCAs have been the mainstay of medical therapy for neuropathic pain. They are well studied and widely prescribed. There is strong evidence of efficacy in diabetic neuropathy and PHN. Initially, the tricyclic antidepressants were thought to be most effective for persistent ongoing pain. More recent studies demonstrate their efficacy for lancinating pain and allodynia as well. Despite this, patients rarely obtain complete relief and frequently are unable to tolerate the side effects of TCAs.

The TCAs increase serotonergic and noradrenergic activity by interfering with their removal from the synaptic cleft. They have substantial sodium channel blocking activity and affect many other transmitters and receptors as well. Imipramine, amitriptyline, nortriptyline, and clomipramine are balanced in their reuptake of serotonin and norepinephrine, whereas desipramine is more selective for norepinephrine and tends to be associated with fewer side effects (see Chapter 11, table 1). In fact, affinity for histaminergic, cholinergic, and adrenergic receptors varies with each agent. This spectrum of receptor affinities accounts for the variability of analgesia and side effects described by patients. Caution is needed in patients with cardiovascular disease and closed-angle glaucoma. A full description of these drugs can be found in Chapter 11 and in Appendix VIII.

Starting doses range from 10 to 25 mg, usually given at bedtime. Choosing the initial dose depends on the patient's age and concerns about side effects. Elderly patients or those on complicated regimens should begin at the lowest dose. Tolerability and degree of relief guide the process of weekly dose escalation in 10- to 25-mg increments. It is important to proceed slowly in the early phase of titration as the anticholinergic side effects (constipation and dry mouth) may prompt

susceptible patients to discontinue the medication prematurely. Most patients experience pain relief in the range of 30 to 100 mg/day. If at the upper end of this range significant relief is not attained, other therapies should be tried. Occasional patients require doses from 150 to 250 mg/day.

2. Anticonvulsants

A full description of these drugs can be found in Chapter 10. (i) Sodium channel blockers

First-generation sodium channel blocking anticonvulsant drugs, such as carbamazepine and phenytoin, have long been the preferred drugs for the treatment of lancinating pain. This parsing of treatment by symptom has not been supported by more recent trials. The most effective use of these first-generation agents is in trigeminal neuralgia where carbamazepine markedly reduces pain in approximately 75% of patients. Significant pain relief for patients with diabetic neuropathy has been demonstrated in controlled trials, but second-generation anticonvulsants (e.g., gabapentin) are favored because their side effects are more tolerable. Regardless of the diagnosis, the analgesic dose response varies greatly among patients.

The initial dosage for sustained-release carbamazepine in adults is 200 mg once daily. After a 1-week period to allow induction of hepatic enzymes, slow titration to a daily dose of approximately 400 mg twice daily should follow. The therapeutic range is usually between 800 and 1200 mg/day. For the central syndromes,

carbamazepine has been more extensively studied. If effective, it is usually in the dosage range used for treatment of seizures. Blood count and liver and renal function must be monitored.

(ii) Gabapentin

The relatively benign side-effect profile of gabapentin (Neurontin) is propelling it to a first-option treatment for neuropathic pain in spite of the fact that it is not approved by the U.S. Food and Drug Administration for this indication. Unlike earlier anticonvulsants, gabapentin causes few drug–drug interactions and less CNS dysfunction. Tolerability allows for the high-dose therapy that is often necessary for significant pain relief. With no need to monitor levels or enzymes, this drug is relatively easy to use. Gabapentin has a broad range of effectiveness for sensory and affective pain qualities in the treatment of PHN and diabetic neuropathy.

approximately 900 mg three times daily. Most responders report significant relief in the dose range of 2,100 mg to 3,600 mg daily. Dizziness and mild sedation are common. Edema of the extremities is the most frequent specific side effect.

3. Opioids

Although traditionally opioids have been avoided in the treatment of neuropathic pain, in patients who do not respond to nonopioid adjuvant therapy, opioids are an important alternative. These agents may offer the most disabled patients relief when all other drugs and modalities have been ineffective. The basis of the traditional avoidance of opioids was twofold: (a) the belief that they were not effective and (b) the fear of addiction. The efficacy of opioids in chronic neuropathic pain has been demonstrated prospectively in several blinded placebo-controlled trials. Unfortunately, they are not helpful for all patients, and often a trial is necessary to determine efficacy. The risk of addiction is a real though exaggerated concern. Patients with chronic pain rarely develop opiate addiction, except when there is a prior history. The use of opioids in chronic nonmalignant pain is discussed in detail in Chapter 30.

4. Topical agents

The introduction of topical therapies in the form of patches, creams, and gels is a promising advance in the treatment of peripheral polyneuropathies and PHN. These are applied to painful skin and act locally at the peripheral sites of pain generation. The absence of systemic side effects and drug interactions make these treatments an important option. Capsaicin, a substance P depleter occurring in chili peppers, has had limited adoption because of its intolerable side effect, a local burning

sensation. Lidoderm, a topical formulation of 5% lidocaine, has proved safe and effective in early, well-designed trials in patients with neuropathic pain. Lidocaine gels, ointments, or sprays can be helpful for patients with pain affecting mucous membranes, allowing them to engage in specific activities such as chewing, defecation, sexual activity, or use of tampons or pads during menstrual periods. Because systemic absorption can occur, serum levels may need to be monitored.

5. Adjunctive treatments

The chronicity of neuropathic pain states creates significant disability. An interdisciplinary approach to the care of these patients should address the psychosocial burdens and functional impact of living with chronic pain. Supportive psychotherapy can be helpful to patient and family alike. Behavioral therapy encourages safely increasing physical activity. Cognitive approaches foster ways of thinking about pain that are less negative and self-defeating. Physical and occupational therapies address the loss of strength, decreased range of motion, and abnormal muscle tone. Physical and occupational therapies maximize functional gains and minimize secondary problems associated with disuse. For example, interventions such as placing a cardboard box under the covers of a patient with allodynia of the feet can prevent a secondary sleep disorder.

6. Invasive options

(i) Neuraxial catheter treatments and stimulators

Invasive methods of pain treatment should be considered for the management of neuropathic pain states refractory to medical therapy. The most common interventions are epidural and intrathecal drug delivery systems and dorsal column spinal cord stimulators. In general, these techniques require a long-term commitment on the part of the patient and pain specialist and consideration of possible, but infrequent, surgical complications. Infusion pumps of morphine,

hydromorphone, and baclofen have all shown analgesic benefit in several case series, but the variety and range of implantation techniques, drugs, and protocols for infusions have precluded conclusive validation with outcome studies. In patients with opioid-responsive pain, infusion pumps may offer a long-term, alternative route of administration that minimizes dose-limiting side effects.

Spinal cord stimulation over the dorsal pathways has been shown to be effective for diverse chronic pain states over the past 30 years. The evidence supporting the use of dorsal column stimulators is not limited to neuropathic pain states and the mechanism of pain relief is not well understood. Chronic precentral and central motor cortex electrical stimulation, for post-stroke pain and deafferentation syndromes are used in the most advanced centers. Recent technical advances have been

promising, but further clinical studies are needed. Peripheral stimulation of individual injured peripheral nerves is a technique with success rates significantly higher than most other medical and surgical options.

(ii) Decompressive neurosurgery

Select patients with well-defined lesions may benefit from surgical exploration and decompression. This is well accepted for patients with carpal tunnel syndrome, but unfortunately underutilized for patients with similar problems elsewhere in the body. The relatively benign nature of these procedures, which do not involve cutting or injuring the involved nerves, must be emphasized. Pain relief after lysis of connective tissue bands compressing peripheral nerves has been described at multiple locations in the body.

(iii) Ablative neurosurgery

These procedures are performed far less frequently now than in the past. In most cases, this is good, because cutting nerves does not usually relieve the pain, but in a very few instances, these options ought to be considered. These procedures should be performed only by those with subspecialty training in neurosurgical

management of pain. Patients in whom these procedures are probably underutilized include those with advanced disease and limited life expectancy. For them, the risks of inadvertent damage to motor or autonomic pathways may be acceptable to achieve good pain control for their remaining time. Transection of the pain pathways of the spinal cord can be performed by a skilled neurosurgeon percutaneously under fluoroscopic guidance. Cutting nerves that innervate areas of neuropathic pain, while a seemingly attractive option, has been shown through a century of clinical practice to be generally ineffective, and it can in fact worsen neuropathic pain. Unfortunately, one still sees patients treated with neurectomies who present with severe and complex neuropathic pain syndromes.

VII. CONCLUSION

Whereas neuropathic pain was considered a distinct entity associated with specific diagnoses such as diabetic peripheral neuropathy, PHN, and trigeminal neuralgia, it is now considered an integral part of many chronic pain syndromes, including CRPS, cancer pain, and even low back pain (under certain conditions). It is certainly the most challenging type of pain we treat in the pain clinic, and the most difficult to understand. It is a prominent focus of attention for clinicians and researchers who together are attempting to unravel its mechanisms and improve the specificity and efficacy of its treatments. Neuropathic pain is ubiquitous in pain practice and worthy of an intensive effort to help its unfortunate victims and to overcome the shortcomings in its treatment.

SELECTED READINGS

1. Backonja MM, Galer BS. Pain assessment and evaluation of patients who have neuropathic pain. Neurol Clin 1998;16:775–790. 2. Devinsky O, Feldmann E. Examination of the cranial and peripheral nerves. New York: Churchill Livingstone, 1988.

3. Galer BS. Painful polyneuropathy. Neurol Clin 1998;16:791–812.

4. Hans G, Davar G. Recent advances in the pharmacology of nerveinjury pain. Neurol Clin 1998;16:951–966. 5. Stewart JD, ed. Focal peripheral neuropathies, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000. 6. Dejerine J, Roussey G. Le syndrome thalamique. Rev Neurol 1906; 14:521–532.

26 Complex Regional Pain Syndromes

The Massachusetts General Hospital Handbook of Pain Management

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