Case Presentations Case 1. A 67-year-old woman, a grade school teacher, complained of exacerbating pain. She had been diagnosed with non-insulin-dependent diabetes mellitus 12 years ago, noted numbness and tingling in her feet for the first time five years ago, and first experienced pain three years ago. The pain had gotten progressively worse and more constant. The patient described it as a burning ache that was exacerbated by walking. Sleep had become particularly difficult, since she was kept awake by any touch from the bed coverings. The pain was also interfering with her work. Stimulation with vibration and pinprick revealed sensory deficits; light stimulation with a cotton-tipped applicator revealed hyperalgesia. Treatment with gabapentin was begun, and after the dose was titrated to therapeutic levels over two weeks, her pain markedly improved. Transient sedation was managed by decreasing the dose for two days; the dose was then increased again. Because her insomnia decreased only partially, nortriptyline was added to the regimen. As a result, her sleep was improved and the pain further alleviated. Case 2. A 47-year-old man had been diagnosed with insulin-dependent diabetes mellitus six years earlier. A small business owner, he had been very active until six weeks before to his visit to a pain clinic, when he experienced sudden onset of severe right-sided trunk pain. The pain extended from his back to his front and was been so severe that he had been unable to sleep between the time of onset and presentation at the clinic. He described the pain as sharp and lancinating, and complained of notable hypersensitivity to the touch of clothing. He was very distraught, pleading for help. "I need to sleep!" he said. The general medical and neurologic examinations were normal except for hyperalgesia along the right T10 and T11 dermatomes. A diagnosis of diabetic ischemic radiculitis was made and treatment with morphine was begun. The dose was briskly titrated to 10 mg every four to six hours. After a few days, the formulation was changed to long-acting morphine, 30 mg tid. The patient's sleep improved markedly. After a stable dose of morphine had been achieved, treatment with desipramine was begun, and the dose was increased to 50 mg per day. Six months later, after his pain started to abate, all of the analgesics were tapered and withdrawn. Pathophysiology The pathophysiology of diabetic neuropathy has two major aspects: 1) interneuronal accumulation of byproducts of abnormal sugar and fat metabolism, and 2) ischemia in the blood vessels that supply the peripheral nerves. However, since not every patient with diabetic neuropathy has pain, there are additional pathophysiologic processes that are not yet fully understood. We do know that although most of the damage of nonpainful diabetic neuropathy occurs in the axon, in diabetic neuropathic pain the entire neurologic pathway is perturbed. Animal models of so-called traumatic neuropathic pain have demonstrated sensitization of both the injured peripheral axon and the central nervous system (CNS). Sensitized peripheral nerves show overexpression of sodium channels and certain types of adrenergic receptors, whereas affected central nerves demonstrate increased sensitivity of the N-methyl-D-aspartate (NMDA) receptors (the so-called glutamine-activated receptors) as well as alterations in opiate and other neuropeptide receptors. Those pathways are currently the subject of intensive research, and in future may become an avenue for therapy. Sensitization appears to reflect a cascade of events that follow injury to peripheral nerves. The injured nerves appear to be unable to heal themselves, perhaps because of a genetic predisposition. In the CNS, neuropathic pain involves a phenomenon known as windup--that is, an increasing response to an unchanging pain stimulus. The mechanism by which windup develops is very complex and probably includes not only increased sensitivity to ascending signals (in part because of substance P, a so-called neuromodulator that strengthens the pain signal) but also dysfunction of the descending inhibitor system. Endogenous opiates become less effective, so the body's higher pain-modulating centers such as the brainstem do not exert as much pain inhibition. When speaking with patients, I use an analogy with the telephone system to explain the development of neuropathic pain: Normal pain is like a telephone call that originates in a peripheral nerve and travels through the CNS (the switchboard) and the cerebral hemispheres, where the conscious mind "picks up the receiver" and gets the message about what is wrong. In neuropathic pain, the peripheral nerve is injured, short circuits, and then overwhelms the switchboard with messages until it too short-circuits. Now the phone rings constantly, but when the receiver is picked up, nobody is on the line, just the noise of neuropathic pain. As with other diabetic complications, tight control of blood sugar levels can help slow or stop the progression of neuropathy. In rare cases, the first manifestations of painful diabetic neuropathy paradoxically occur with the initiation of insulin treatment, when the patient starts to achieve good glycemic control. Moreover, once painful neuropathy develops, it usually assumes a life of its own; it may progress independently of the diabetes. In some patients, the pain resolves as the neuropathy progresses. Many times, however, the neuropathic pain keeps pace with the advancing neuropathy, moving from the feet to the knees and thighs. Diagnosis Pain assessment is a crucial aspect of managing painful diabetic neuropathy. Taking a history of the pain itself is the first step. Where is the pain? What does it feel like? Patients may have more than one type of pain, and the history helps the physician determine whether a particular pain is neuropathic or nociceptive (arising from activation of pain receptors in response to an identifiable noxious stimulus). Rate the severity of the pain, using a quantifying scale. Finally, ask whether the pain has changed over time, perhaps in response to previous treatments. Neuropathic pain can have different components: 1) ongoing pain that is continually present regardless of what the patient does or does not do; 2) spontaneous paroxysms of pain that appear suddenly in the absence of any identifiable stimulus; 3) hyperalgesia, in which the patient experiences marked pain from an external stimulus that normally causes little or no pain. Another important point to explore is the personal impact of the pain. It has been well established, especially from studies in cancer patients, that as pain increases in intensity, it has an increasingly significant effect on the patient's life. Moderate pain disrupts sleep; severe pain can impair aspects of function, such as walking, that healthy persons take for granted. Prolonged pain can affect a patient's mood and relations with others. Many chronic pain sufferers complain of being short-tempered; they habitually snap at their spouse and children and then feel guilty. How patients cope with the pain and their functional status are elements in treatment planning. If the chief complaint is not "I hurt" but "I can't sleep because of the pain," that becomes an important guide to selecting therapy. The physical examination in a patient with painful neuropathy differs from the usual neurologic examination. With the traditional approach, the examiner focuses on deficits; here one must also look for positive sensory phenomena, such as hyperalgesia. The patient's feet may be numb but also painful. For example, a patient may not be able to perceive a light touch or vibration, but on pinprick testing may cry out and jerk the limb away. Alternatively, the patient may feel nothing on the pinprick test, but find it unbearable to have a cotton ball dragged gently across the skin. In the latter case, the patient typically has difficulty in sleeping because of pain from the weight of the bed coverings. The presentation may differ not only from patient to patient, but also from time in the same patient. Whether because of the nervous system's response to the continuing insult of diabetic neuropathy or evolution in pain pathophysiology, the clinical picture of painful neuropathy can change completely in as little as six months. A patient who used to tolerate pinprick but not light touch may find pinprick excruciating and light touch painless, or vice versa. Indeed, change in status over time is the rule rather than the exception and should not be mistaken for malingering. Treatment Options At present, the only treatment that addresses the underlying cause of painful diabetic neuropathy is improved control of blood sugar levels, although it should be remembered that this addresses the cause of the neuropathy, not of the pain. Investigators have attempted treatment with a nerve growth factor to facilitate repair of injured nerves; however, after treatment, hyperalgesia developed in many subjects. The nerves repaired but were hypersensitive to otherwise normal stimuli. In the absence of a curative therapy, clinicians must turn to pharmacologic and nonpharmacologic tools that provide symptomatic pain control. Pharmacologic therapy includes tricyclic antidepressants, narcotic analgesics, anticonvulsants, and antiarrhythmics. Tricyclic antidepressants have long been a standard treatment for chronic pain. They can perform double-duty in these patients, who often become depressed as pain persists. Unfortunately, tricyclic antidepressants have only modest efficacy, and their use is limited. First, dose titration takes a long time. Second, these agents have a very narrow therapeutic window; beyond a certain dose, most patients experience intolerable adverse effects such as sedation, urinary retention, orthostatic hypotension, or cardiac arrhythmias. In contrast, narcotic analgesics or newer anticonvulsants do not have a dose ceiling. Higher doses of these agents are more likely to cause side effects but will not cause organ damage. Narcotic Analgesics. The use of narcotic analgesics for treatment of neuropathic pain is controversial. There is no evidence that nonsteroidal anti-inflammatory drugs or other nonnarcotic analgesics have much effect on neuropathic pain, and for a long time it was held that opioids are also ineffective. In fact, that is usually true if these agents are given at standard doses. In higher doses, opioids can relieve neuropathic pain. A recent Canadian study by Peter Watkins and associates demonstrated that controlled-release oxycodone effectively relieved postherpetic neuralgia when given in doses of 40 to 60 mg per day (Figure 1). That is a relatively small dose; many patients with neuropathic pain need much larger doses (in some cases, the equivalent of several hundred milligrams of morphine per day). The larger doses are achieved over weeks and months. The choice of a particular opioid depends on price, ease of use, and whether the patient previously had an adverse reaction to an agent in this class. Anticonvulsants. Antiepileptic drugs have been used as adjuvant analgesics for neuropathy, although enthusiasm for this class of agents has largely been limited to carbamazepine as a treatment for trigeminal neuralgia. Studies of carbamazepine in patients with diabetic neuropathy have been few in number, and their positive results did not translate into wider clinical use of the drug. The availability of novel antiepileptics renewed interest in this class of agents, especially since some have few side effects. My work has focused on gabapentin, which has been used in Europe for epilepsy for more than a decade and was approved for that disorder in the United States in the early 1990s. Reports that gabapentin relieves neuropathic pain soon appeared and triggered interest in a controlled trial. The Gabapentin Diabetic Neuropathy Study Group performed a randomized, double-blind, placebo-controlled trial of gabapentin monotherapy in 165 patients with painful diabetic neuropathy. The study found that gabapentin relieved pain and sleep interference and improved mood and some aspects of quality of life (Figures 2 and 3). Even before the publication of that study, gabapentin was used more frequently to treat pain than to treat epilepsy, probably because chronic pain is a more common problem. In the study, treatment with gabapentin was initiated at 900 mg a day and the dose was titrated weekly to 1,800, 2400, and finally 3,600 mg a day. In clinical practice, titration can proceed much faster; I have gone up to 3,600 mg or higher within two weeks. The need for slower titration should always be kept in mind when the patient has renal disease, as many do. However, gabapentin is very forgiving in this respect; if adverse effects occur, they are uncomfortable rather than dangerous. The range of effective doses is wide. Some of my patients responded to as little as 300 mg a day, while others required 4,500 mg a day or more--one patient needed 6 gm a day. It is usually evident within a few days whether gabapentin will be efficacious. Once an effective dose has been achieved, most patients can continue to take that dose. Perhaps 25% of patients will need dose adjustment. In some patients, the effectiveness of gabapentin diminishes within a few months or weeks, even if the dose is increased. The loss of efficacy may be due to the evolution of the disease or the development of tolerance. Antiarrhythmics. The oral antiarrhythmic mexiletine is occasionally given to patients whose pain is not well controlled with other medications. If mexiletine is selected, serum levels should be monitored. Intravenously administered lidocaine is used in specialized pain clinics under the same circumstances. Nondrug Therapy. Nonpharmacologic pain management is an important element of overall treatment. It is typically directed by auxiliary health services. Specially trained psychologists can teach techniques for coping with pain; physical therapists can demonstrate exercise programs that are good for general well-being as well as for pain management. Selecting Treatment In a patient with newly diagnosed painful diabetic neuropathy, my choice of treatment depends on the pain assessment. If the pain is mild to moderate and is causing prominent sleep disturbance, a tricyclic antidepressant is my first choice, since these agents restore sleep. I tend to use nortriptyline rather than amitriptyline, especially in anxious or elderly patients, because nortriptyline relieves depression, induces and maintains sleep, and has less adverse effects than amitriptyline. In patients with moderate to severe pain gabapentin is an excellent choice, because it can be titrated more quickly than the tricyclic antidepressants. Opioids, which can be titrated even more quickly, are a logical choice for patients with severe and breakthrough pain. I consider treatment to be successful if the patient experiences a moderate decrease in pain or improved function, or both. Complete elimination of pain is rare, if not impossible, with currently available drugs. For that reason, patient education is an important part of management. The physician should point out the limitations of therapy from the start, so that patients will have realistic expectations. Most patients need more than one class of medication. For example, it is not unusual for a patient in my clinic to be taking gabapentin, extended-release oxycodone, and nortriptyline. Gabapentin can alleviate sharp, shooting paroxysms of pain and much of persistent pain; however, touch sensitivity and ongoing pain may be severe enough to warrant an opioid. Meanwhile, a tricyclic antidepressant may be required to manage anxiety, depression, and sleep disturbance. The physician needs to be cognizant of the effects and side effects of the different medications involved, and to approach treatment logically. Try one medication at a time to see what works. If it works, stay with it; if it does not, discontinue it. If an agent resolves one component of the problem, continue it and add another agent that should alleviate another component of the problem. Selected Reading Backonja M et al: Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial. JAMA 280:1831, 1998 Kingery WS: A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 73:123, 1997 Low PA, Dotson RM: Symptomatic treatment of painful neuropathy (editorial). JAMA 280: 1863, 1998 Max MB et al: Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 326:1250, 1992 McQuay H et al: Anticonvulsant drugs for management of pain: A systematic review. Br Med J 311:1047, 1995 Oskarsson P, Ljunggren JG, Lins PE: Efficacy and safety of mexiletine in the treatment of painful diabetic neuropathy. Diabetes Care 20:1594, 1997 Stracke H et al: Mexiletine in the treatment of diabetic neuropathy. Diabetes Care 15:1550, 1992 Watson CPN, Babul N: Efficacy of oxycodone in neuropathic pain: A randomized trial in postherpetic neuralgia. Neurology 50:1837, 1998 HOME | CURRENT ISSUE | PAST ARTICLES | GENETICS SERIES CAPSULE & COMMENT | CME | CLASSIFIED ADVERTISING | ABOUT US Copyright (C) 1999. The McGraw-Hill Companies. All Rights Reserved E-mail Privacy Notice