Neuropathic Pain

NEUROPATHIC PAIN

Neuropathic pain includes pain associated with diabetic neuropathy, causalgia, phantom limbs, postherpetic neuralgia, stroke, spinal cord injury, and multiple sclerosis. Cancer pain and chronic low back pain may have prominent neuropathic compo-nents. Neuropathic pain tends to be paroxysmal and sometimes lancinating with a burning quality, and is usually associated with hyperpathia. Mechanisms of neuropathic pain are reviewed earlier.

Because neuropathic pain is often difficult to treat, multiple therapeutic modalities may be nec-essary. Treatment options include anticonvulsants (eg, gabapentin, pregabalin), antidepressants (tri-cyclic antidepressants or serotonin-norepinephrine reuptake inhibitors), antiarrhythmics (mexiletine), α₂-adrenergic agonists (clonidine), topical agents(lidocaine or capsaicin), and analgesics (NSAIDs and opioids). Of note, tricyclic antidepressants may have significant anticholinergic side effects that may limit their tolerability. Secondary amines, such as nortriptyline or desipramine, may have less severe or fewer anticholinergic side effects than tertiary amines such as amitriptyline or imipramine. Spi-nal opioids may be very effective for some patients. Sympathetic blocks are effective in selected disor-ders . Spinal cord stimulation may be effective for patients who do not tolerate or respond to other treatments.

Diabetic Neuropathy

Diabetic neuropathy is the most common type of neuropathic pain encountered in practiceand is a major cause of morbidity. Its pathophysi-ology is poorly understood but may be related to microangiopathy and to abnormal activation of metabolic (polyol) pathways and glycation of pro-teins as a consequence of chronic hyperglycemia. Diabetic neuropathy may be symmetric (general-ized), focal, or multifocal, affecting peripheral (sen-sory or motor), cranial, or autonomic nerves.

The most common syndrome is peripheral polyneuropathy, which results in symmetric numb-ness (“stocking-and-glove” distribution), pares-thesias, dysesthesias, and pain. The pain varies in intensity, may be severe, and is often worst at night. Loss of proprioception may lead to gait distur-bances, and sensory deficits can lead to traumatic injuries. Isolated mononeuropathies affecting indi-vidual nerves may lead to wrist or foot drop or to cranial nerve palsy. Mononeuropathies typically have a sudden onset and are reversible, lasting a few weeks. Autonomic neuropathy typically affects the gastrointestinal tract, causing diarrhea, delayed gastric emptying, and esophageal motility disorders. Orthostatic hypotension and other forms of auto-nomic dysfunction are common.

Treatment of diabetic neuropathy is symp-tomatic and directed at optimal glycemic control to slow progression. Acetaminophen and NSAIDs are usually ineffective for moderate to severe pain. Risks associated with opioids limit their use in the treatment of this condition. Adjuvant drugs play a major role. The combination of an antiepileptic drug and a tricyclic antidepressant may be particu-larly effective.

Sympathetically Maintained & Sympathetically Independent Pain

Complex regional pain syndrome (CRPS) is a neuropathic pain disorder with significantautonomic features that is usually subdivided into two variants: CRPS 1, formerly known as reflex sympathetic dystrophy (RSD), and CRPS 2, formerly known as causalgia. The major difference between the two is the absence or presence, respectively, of documented nerve injury. Signs, symptoms, patho-physiology, and response to treatment are quite similar. Previously, this condition was thought to represent sympathetically maintained pain, but there is recent evidence that in some cases the pain may be sympathetically independent.

CRPS is a largely underdiagnosed condi-tion affecting at least 50,000 patients a year in the United States alone. It affects individuals from childhood to late adulthood and may occur more commonly in females. Patients frequently present with burning neuropathic pain having components of hyperalgesia and allodynia. The autonomic ner-vous system may be involved, exemplified by alter-ations in sweating (sudomotor changes), color, and skin temperature, and by trophic changes in the skin, hair, or nails. Decreases in strength and range of motion in the affected extremity may be present. CRPS may develop after minimal injury, although the most common initiating events are surgery, fractures, crush injuries, and sprains.

The pathophysiology of CRPS 1 and 2 is prob-ably multifactorial, involving both the sympathetic nervous system and the central nervous system. There may be changes in the cutaneous innervation after a nerve injury, along with changes in central and peripheral sensitization. Genetic, inflammatory, and psychological factors may all play roles. Causal-gia (which means burning pain), first identified in injured veterans of the American Civil War, typically follows gunshot injuries or other major trauma to large nerves. The pain often has an immediate onset and is associated with allodynia, hyperpathia, and vasomotor and sudomotor dysfunction. It is exacer-bated by factors that increase sympathetic tone, such as fear, anxiety, light, noise, or touch. The syndrome has a variable duration that can range from days to months or may be permanent. Causalgia commonly affects the brachial plexus, particularly the median nerve, and the tibial division of the sciatic nerve in the lower extremity.

Patients with CRPS often respond to sympa-thetic blocks, but a multidisciplinary therapeutic approach must be utilized to avoid long-term func-tional and psychological disability. Some patients recover spontaneously, but if left untreated other patients can progress to severe and irreversible functional disability. Sympathetic blocks and intra-venous regional sympatholytic blockade are equally effective; these blocks should be continued until either a cure is achieved or the response plateaus. The blocks facilitate physical therapy, which plays a central role and which typically consists of active movement without weights and of desensitization therapy. Many patients require a series of three to seven blocks. The likelihood of a cure is high (over 90%) if treatment is initiated within 1 month of symptom onset and appears to decrease over time with therapeutic delay.

Some patients benefit from transcutaneous electrical nerve stimulation (TENS) therapy. Spi-nal cord stimulation can be particularly effective in both acute and chronic settings. In the acute phase of treatment, there is increasing interest in placing tunneled epidural catheters for infusion therapy, or percutaneous electrodes for extended trials of spinal cord stimulation, in order to help patients tolerate physical therapy. Many patients benefit from sur-gical implantation of peripheral nerve stimulators placed directly on the larger injured nerves.

For sympathetically maintained pain, oral α-adrenergic blockers, such as the nonselectivephenoxybenzamine or the α₁-selective prazosin, may be beneficial. Caution is advised because of the risk of orthostatic hypotension with these agents, and dosage should be increased gradually. Anticon-vulsant and antidepressant medications may also be beneficial.

Surgical sympathectomy in patients with chronic symptoms is frequently disappointing, resulting in only transient relief and in some cases a new, alternate pain syndrome. Recent research suggests that patients with pain refractory to prior medical or procedural therapies may respond to intravenous infusions of ketamine in a monitored setting.