J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811 jcem.endojournals.org 4803pliance with treatment resulting in a general worsening of 2009. She had been admitted to an eating disorder clinicthe condition. Patients with chronic neuropathic pain re- from February 2009 through April 10, 2009. She had beenport poor physical health and mental conditions com- on an insulin pump that she had manipulated to controlpared with those with other causes of chronic pain even her weight and was subsequently placed on an injectableadjusting for pain intensity (3). Diabetic neuropathy pain combination of short- and long-acting insulin, Lantus (40is a difficult-to-manage clinical problem. It is often asso- U in the morning) and NovoLog (1 U for every 15 g ofciated with mood and sleep disturbances, and patients carbohydrate for meals and snacks and 1 U for every 50with diabetic neuropathy pain are more apt to seek med- mg/dl of her blood glucose greater than 100 mg/dl). Onical attention than those with other types of diabetic neu- this regimen, her blood glucose levels averaged 100 to 220ropathy. Two population-based studies showed that neu- mg/dl without hypoglycemic episodes. Within 2–3 monthsropathic pain is associated with a greater psychological of this therapy, she developed intractable pain and wasburden than nociceptive pain (4) and is considered to be referred for consultation. The pain was burning and ach-more severe than other pain types. Early recognition of ing with tenderness bilaterally in the feet and the legs, aspsychological problems is critical to the management of well as in the hips. A rheumatologist had diagnosed fibro-pain, and physicians need to go beyond the management myalgia and prescribed Gabapentin [100 mg twice dailyof pain per se if they are to achieve success. Patients may (BID), 200 mg at bedtime (HS) for 2 wk, increased to 200 mgalso complain of decreased physical activity and mobility, three times a day for 1 week, and then increased to 300 mgincreased fatigue, and negative effects on their social lives. BID and 600 mg at bedtime]. This had no real impact on theProviding significant pain relief markedly improves qual- pain. She was very distressed and tearful, was confined toity-of-life measures, including sleep and vitality (5). Be- bed, and was unable to sleep. Advil two to three times per daycause of its complexity, the presentation of pain poses a eased the pain slightly. Her last hemoglobin A1c was 9.0.diagnostic dilemma for the clinician who needs to distin- She had exercised regularly, including Pilates, beforeguish between neuropathic pain arising as a direct conse- the pain occurred, but she stopped because of pain. Shequence of a lesion or disease of the somatosensory system had an eye exam in the fall of 2008, and there was noand nociceptive pain that is due to trauma, inflammation, evidence of retinopathy. Her urine specimen contained noor injury. It is imperative to try to establish the nature of protein and was negative for ketones. She had developedany predisposing factor, including the pathogenesis of the grand mal seizures controlled with lamotrigine 150 mgpain, if one is to be successful in its management. Man- daily (QD). She denied stress or phobia, although she hadagement of neuropathic pain requires a sound relationship some difficulty with heights. She attended college andbetween patient and physician, with an emphasis on a lived at home with her parents. Her family history revealedpositive outlook and encouragement that there is a solu- an older sister who suffered from some degree of anxiety;tion, using patience and targeted pain-centered strategies her mother had Hashimoto thyroiditis and also had rheu-that deal with the underlying disorder rather than the matoid arthritis, for which she was treated with Enbrel andusual “Band-aid” prescription of drugs approved for gen- methotrexate in small doses. Her father is disease free. Hereral pain, which do not address the disease process. The maternal grandmother had Hashimoto thyroiditis with di-inciting injury may be focal or diffuse and may involve abetes, and her grandfather had a myocardial infarction. Onsingle, or more likely, multiple mechanisms such as meta- the paternal side, there was a history of lung cancer. Thebolic disturbances encompassing hyperglycemia, dyslipide- patient smoked a pack of cigarettes a day for 5 yr, but quit inmia, glucose fluctuations, or intensification of therapy with November 2008. She did not consume alcohol or use illegalinsulin. On the other hand, the injury might embrace auto- drugs. She had not been exposed to heavy metals, organo-immune mechanisms, neurovascular insufficiency, deficient toxins, or other toxins. She was not intolerant to cold orneurotrophism, oxidative and nitrosative stress, and inflam- constipated and had no voice change or hair loss.mation (6). Because pain syndromes in diabetes may be focalor diffuse, proximal or distal, acute or chronic, each has its Physical examinationown pathogenesis, and the treatment must be tailored to the Physical exam revealed an alert and oriented individualunderlying disorder if the outcome is to be successful. who, although tearful, communicated well. She had no pig- mentation change and no dry or brittle hair. She had a fewThe Case psoriatic lesions at the back of her head, but not elsewhere. Head, eyes, ears, nose, and throat were within normalWe first saw the patient—a 24-yr-old female with poorly limits. She had no lymphadenopathy. Her chest and lungscontrolled type 1 diabetes for the past 6 yr and an eating were clear. There were no breast masses. Her heart wasdisorder with anorexia/bulimia syndrome— on May 19, normal without murmurs. Her abdomen was soft, non-
4804 Vinik Approach to Pain Management in Diabetes J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811TABLE 1. Examination: bedside sensory tests Sensory modality Nerve fiber Instrument Associated sensory receptors Vibration A␤ (large) 128-Hz tuning fork Ruffini corpuscle mechanoreceptors Pain (pin prick) C (small) Neuro-tips Nociceptors for pain and warmth Pressure A␤, A␣ (large) 1 and 10 g monofilament Pacinian corpuscle Light touch A␤, A␣ (large) Wisp of cotton Meissner’s corpuscle Cold A␦ (small) Cold tuning fork Cold thermoreceptorstender, and without masses. Her musculoskeletal system tein microalbumin, 12.8 g/ml; TSH, 1.329 U/ml; glu-was intact. She had good dorsalis pedis and posterior tibial cose, 253 mg/dl (elevated); blood urea nitrogen, 18 mg/dl;pulses. Application of pressure to her feet caused her to creatinine, 0.5 mg/dl; electrolytes, within normal limits;scream in agony. She weighed 120.4 pounds and was 5 feet serum glutamic oxaloacetic transaminase, 19; serum glu-11 inches tall. Her body mass index was 16.7 kg/m2. Her tamic pyruvic transaminase, 25; alkaline phosphatase, 64;waist was 26 inches and hip measurement was 34 in, with a calcium and magnesium, within normal limits; estimatedwaist-hip ratio of 0.766. Supine blood pressure was 119/78 glomerular filtration rate, 59 ml/min; antinuclear factormm Hg with a pulse of 94 bpm, sitting blood pressure was antibodies, negative; C-reactive protein, 0.1; sedimenta-125/82 mm Hg with a pulse of 107 bpm, and standing blood tion rate, 12; glutamic acid decarboxylase antibody, 4.7pressure was 109/78 mm Hg with a pulse of 81 bpm. (elevated); and gastric parietal cell antibodies, 1.6. Serum protein electrophoresis revealed no gammopathy, and noNeurological examination motor or sensory nerve antibodies were detected; acetyl- Cranial nerves were intact. Her pupils were large, re- choline receptor antibodies in serum and antinuclear fac-acted to light, and accommodated poorly suggesting au- tor were negative. Serum folate and B12 were normal.tonomic dysfunction. She had no evidence of muscle Urine porphyrins and urine heavy metals were negative.weakness. Handgrip dynamometry was at the 10th per- Serum angiotensin-converting enzyme was normal. Lyme,centile bilaterally. All her reflexes were present, and upper HIV, and hepatitis screening tests were all negative.limb sensation was entirely intact. In the lower limb, she Neuronal cells were incubated in culture with her se-had a reduction of prickling pain perception to 15 cm on rum. With control pooled human serum, 100,000 cellsthe right and 22 cm on the left, but she had marked hy- increased to 871,250 by the fourth day; with her serum,peralgesic and hyperesthetic soles of her feet. Vibration 100,000 cells fell to 11,250 by the second day and fellperception was intact, there was some slight loss of joint further to zero by the third and fourth days. There was noposition, but perception of 1- and 10-g monofilament was recovery of these cells, indicating that her serum wasintact. Her total neuropathy scores were 5 on the right and highly toxic to neuronal cells in culture and indicative of6 on the left, which indicated a mild degree of peripheral an autoimmune response (8).neuropathy (7). The use of simple clinical tools is illus-trated in Table 1. Clinical ConsiderationsLaboratory studies My impressions were that this young woman had type 1 A quantitative sensory test done on May 12, 2009, diabetes for 6 yr, a seizure disorder, and anxiety, withshowed normal vibration perception, touch/pressure, claustrophobic panic disorder. She was an anorexic bu-warm and cold thermal perception, indicating that her limic and was using an insulin pump to allow her to adjustsomatic nervous system was intact. the insulin doses down so that she could lose weight. When A cardiac autonomic function test revealed an expira- placed on a regular insulin regimen, monitored in an in-tion/inspiration ratio of 1.14, a Valsalva ratio of 1.05, and stitution, she could no longer do this and within a fewa 30:15 ratio of 1.05. This very abnormal result indicated weeks of the intensification of insulin developed a severe,autonomic nerve dysfunction. The QTc interval was highly sensory form of neuropathy with autonomic man-425 msec on electrocardiogram, which was normal. She ifestations, classic of the insulin neuritis syndrome. Shehad a sinus tachycardia syndrome of 100 bpm and ap- had a long family history of autoimmune disease, and herpeared to have slight left atrial enlargement, but no serum was highly toxic to neurons in culture, suggestingother abnormalities. the possibility of autoimmune disease. Neuropathic pain Vitamin D level was 10.7 ng/ml, which is inordinately is not uncommon. A population-based survey of 6000low. The remainder of the biochemistries were: urine pro- patients treated in family practice in the United Kingdom
J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811 jcem.endojournals.org 4805reported 6% prevalence of pain predominantly of neuro- duction. Pain is deep seated and gnawing in quality, “likepathic origin (9). Similarly, a large population-based study a toothache” in the foot, or “a dog gnawing at the bonesin France showed that 6.9% of the population had neu- of the feet,” or “feet feel as if they are encased in concrete.”ropathic pain (4). Interestingly, in a Dutch population sur- In contrast, the nociceptive pain of arthritis does notvey of more than 362,000 people, younger people with have these qualities. It is localized to the joints; fasciitis ispain tended to be mostly women, but with advancing age localized to the fascia; entrapment produces pain in a der-the gender differences disappeared. Perhaps a little recog- matome, and claudication is made worse by walking. Ar-nized fact is that mononeuritis and entrapments were three thritic pain starts with morning stiffness and improves astimes as common as diabetic peripheral neuropathy the day wears on (18).(DPN), and fully one third of the diabetic population has It is noteworthy that one third of patients with diabetessome form of entrapment (10), which when recognized is have some form of entrapment. In contrast with thereadily amenable to intervention (11). Even more salutary mononeuropathies, the condition begins gradually and isis the mounting evidence that even with impaired glucose made worse with repeated minor trauma or history oftolerance, patients may experience pain (12–14). As a cor- occupational exposure. The sensory disturbance oftenollary, patients presenting with painful neuropathy have does not reflect the nerve distribution, and the pain canimpaired fasting glucose or impaired glucose tolerance, exceed the area of sensory innervation leading to incorrectand about 50% of the time, they are overweight and have diagnosis. Nerve conduction velocity is required to showautonomic dysfunction (12). Even in the absence of ele- impairment of conduction across the site of entrapment.vated fasting blood glucose (Ͻ100 mg/dl), pain may be the Evaluation of pain intensity is essential for monitoringpresenting feature of the metabolic syndrome and coseg- response to therapy. There are a number of symptom-regates with elevated triglycerides and a low high-density based screening tools, such as: Nerve Total Symptomlipoprotein-cholesterol (15). Indeed, a risk factor for neu- Score-6, Brief Pain Inventory, Quality of Life Diabeticropathic pain in diabetic and nondiabetic populations is Neuropathy, Short Form-36, Visual Analog Scale for Painan impairment of peripheral vascular function (14, 16). Intensity, Neuro-QOL, and Norfolk Neuropathy Symp- toms Score (7). With the visual analog scale, the patient marks the intensity of their pain on a scale from 0 –10, al-The Clinical History lowing an assessment of the response to intervention. Simul- taneously, the patient should complete a quality of life toolHistory taking is becoming an obsolete art. Without it, ar- such as the Norfolk QOL-DN (17), which permits evalua-riving at the correct diagnosis can be hazardous. Pain asso- tion of the impact of the pain on quality of life, anxiety, andciated with a peripheral nerve injury has several distinct clin- depression, known to be accompanying features of DPN.ical characteristics. Neuropathic pain derived from smallnerve fibers is often burning, lancinating, or shooting in qual-ity with unusual, tingling, or crawling sensations referred to The Clinical Examinationas formication. Some describe bees stinging through thesocks, whereas others talk of walking on hot coals. The pain, A careful evaluation of the nature of pain and its exactworse at night, keeps the patient awake and is associated with location and a detailed examination of the lower limbs aresleep deprivation (17). Patients volunteer that they have al- mandatory to ascertain alternate causes of pain (Table 1).lodynia or pain from normal stimuli, such as the touch ofbedclothes, and may have hyperesthesias, increased sensitiv- Laboratory Testsity to touch, or hyperalgesia with increased sensitivity topainful stimuli or even altered sensation to cold or heat. These tests usually done for research: laser-evoked poten-These may be paradoxical with differences in sensation to tials; contact heat-evoked potentials, whereby brain sig-one or other modality of stimulation. Unlike animal models nals evoked by peripheral heat stimulation can be quan-of DPN, the pain is spontaneous and does not need provo- tified and amplitudes and conduction velocities of the slowcation such as a hot plate or laser heat. It is a glove and conducting fibers measured; and quantitative sensory testsstocking distribution. Small fiber neuropathies usually that measure the thresholds for various sensory modali-present with pain in the feet or hands, do not have abnor- ties, such as vibration and heat and cold perception, andmalities in sensation, lack weakness or loss of reflexes, are can be adapted to identifying hypoalgesia and hypoes-electrophysiologically silent, and often lead to the erroneous thesia. Also included are 3-mm skin biopsies to quan-diagnosis of hysteria or conversion reactions. titatively assess the number of nerve fibers present in the Large fiber neuropathy presents with characteristic epidermis. Paradoxically, these are reduced in numberweakness, ataxia, loss of reflexes, and impaired nerve con- in DPN (19 –21).
4806 Vinik Approach to Pain Management in Diabetes J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811Conditions Mimicking Diabetic Neuropathy strategies using the newer antiepileptic agents, which may address the underlying neurophysiological aberrations inThere are a number of conditions that can be mistaken for neuropathic pain, allowing the clinician to increase thepainful diabetic neuropathy: intermittent claudication, in likelihood of effective management (Table 2). The neuro-which the pain is exacerbated by walking; Morton’s neu- pharmacology of pain is also becoming better understood.roma, in which the pain and tenderness are localized to the For example, recent data suggest that ␥-aminobutyricintertarsal space, elicited by applying pressure with the acid, voltage-gated sodium channels, and glutamate re-thumb in the appropriate intertarsal space; osteoarthritis, ceptors may be involved in the pathophysiology of neu-in which the pain is confined to the joints and made worse ropathic pain. Many of the newer agents have significantwith joint movement or exercise and is associated with effects on these neurophysiological mechanisms. Hyper-morning stiffness that improves with ambulation; radic- glycemia may be a factor in lowering the pain threshold.ulopathy, in which the pain originates in the shoulder, Pain is often worse with wide glycemic excursions. Para-arm, thorax, and back and radiates into the legs and feet; doxically, acute onset of pain may appear soon after ini-Charcot neuropathy, in which the pain is localized to the tiation of therapy with insulin or oral agents (22). In con-site of the collapse of the bones of the foot and the foot is trast, it has been reported that a striking amelioration ofhot rather than cold, as occurs in neuropathy; plantar fas- symptoms can occur with continuous sc insulin adminis-ciitis, in which there is shooting or burning in the heel with tration, which may reduce the amplitudes of excursion ofeach step and there is exquisite tenderness in the sole of blood glucose (22). This dichotomy is not well explained.the foot; and tarsal tunnel syndrome, in which the pain There is a sequence in diabetic neuropathy, beginningand numbness radiate from beneath the medial malle- when A, ␤, and C nerve fiber function is intact and thereolus to the sole and are localized to the inner side of the is no pain. With damage to C-fibers, there is sympatheticfoot. These contrast with the pain of DPN, which is sensitization, and peripheral autonomic symptoms are in-bilateral, symmetrical, covering the whole foot and par-ticularly the dorsum, and worse at night, interfering terpreted as painful. Topical application of clonidinewith sleep. causes antinociception by blocking emerging pain signals at the peripheral terminals via ␣-2 adrenoreceptors (23), in contrast with the central actions of clonidine on blood pressure control. With the death of C-fibers, there is no-Therapeutic Modalities for ciceptor sensitization. A␤ fibers conduct all varieties ofNeuropathic Pain peripheral stimuli such as touch and these are interpretedThe growing knowledge about the neural and pharmaco- as painful, e.g. allodynia. With time there is reorganizationlogical basis of neuropathic pain is likely to have impor- at the cord level and the patient experiences cold hyper-tant treatment implications, including development and algesia and ultimately, even with the death of all fibers,refinement of a symptom/mechanism-based approach to pain is registered in the cerebral cortex, whereupon theneuropathic pain and implementation of novel treatment syndrome becomes chronic without the need for periph-TABLE 2. Treatments for symptomatic diabetic polyneuropathy: dosing and side effects Drug class Drug Dose (mg) Side effects Tricyclics Amitryptyline 50 –150 HS Somnolence, dizziness, dry mouth, tachycardia Nortriptyline 50 –150 HS Constipation, urinary retention, blurred vision Imipramine 25–150 HS Confusion Desipramine 25–150 HS SSRIs Paroxetine 40 QD Somnolence, dizziness, sweating, nausea, anorexia Citalopram 40 QD Diarrhea, impotence, tremor SNRIs Duloxetine 60 QD Nausea, somnolence, dizziness, anorexia Anticonvulsants Gabapentin 300 –1200 TID Somnolence, dizziness, confusion, ataxia Pregabalin 50 –150 TID Somnolence, confusion, edema, weight gain Carbamazepine/oxcarbezepine Up to 200 QID Dizziness, somnolence, nausea, leukopenia Topiramate Up to 400 QD Somnolence, dizziness, ataxia, tremor Opiods Tramadol 50 –100 BID Nausea, constipation, HA somnolence Oxycodone CR 10 –30 BID Somnolence, nausea, constipation, HA Topical Capsaicin 0.075% QID Local irritation Lidocaine 0.04% QD Local irritation Injection Botulinum toxin NoneQID, Four times daily.
J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811 jcem.endojournals.org 4807eral stimulation. Disappearance of pain may not neces- methorphan exerts analgesic efficacy (30). The NMDAsarily reflect nerve recovery but rather nerve death. When receptors play an important role in central sensitization ofpatients volunteer the loss of pain, progression of the neu- neuropathic pain. Their use, however, has not been wide-ropathy must be excluded by careful examination. spread due in part to dose-limiting side effects (31).Adrenergic blockers Antidepressants Initially, when there is ongoing damage to the nerves, Antidepressants are now emerging as the first line ofthe patient experiences pain of the burning, lancinating, agents in the treatment of chronic neuropathic pain (32).dysesthetic type often accompanied by hyperalgesia and Clinical trials have focused on interrupting pain trans-allodynia. Because the peripheral sympathetic nerve fibers mission using antidepressant drugs that inhibit the re-are also small unmyelinated C-fibers, sympathetic block- uptake of norepinephrine or serotonin. This central ac-ing agents (clonidine) may improve the pain. tion accentuates the effects of these neurotransmitters in activation of endogenous pain-inhibitory systems inTopical capsaicin the brain that modulate pain-transmission cells in the C-fibers use the neuropeptide substance P as their neu- spinal cord (33).rotransmitter, and depletion of axonal substance P(through the use of capsaicin) will often lead to amelio- Tricyclic antidepressants (TCA)ration of the pain. Prolonged application of capsaicin de- With the development of newer agents, this class is nowpletes stores of substance P, and possibly other neuro- being used less frequently due to cholinergic side effects oftransmitters, from sensory nerve endings. This reduces or dysautonomia, dry mouth, and fatigue that can be trou-abolishes the transmission of painful stimuli from the pe- blesome. Caution needs to be exercised in patients withripheral nerve fibers to the higher centers (24). Recent ischemic heart disease and arrhythmias. Amitriptylineanalysis of randomized and controlled studies revealed and imipramine should be avoided in elderly patientsthat either a repeated application of low doses of capsaicin because they can exacerbate cognitive impairment andor single application of high doses affords pain relief (25). gait disturbances, predisposing them to falls. Switching to nortriptyline or desipramine may lessen some of theLidocaine anticholinergic effects of amitriptyline. The advantages A multicenter randomized, open-label, parallel-group of TCA are that they can be administered once daily andstudy of lidocaine vs. pregabalin with a drug washout are inexpensive.phase of up to 2 wk and a comparative phase of 4-wktreatment periods of 5% lidocaine (n ϭ 99 vs. pregabalin, Selective serotonin reuptake inhibitors (SSRIs)n ϭ 94) showed that lidocaine was as effective as pregaba- SSRIs inhibit presynaptic reuptake of serotonin but notlin in reducing pain and was free of side effects (26). This norepinephrine, but are not effective.form of therapy may be of most use in self-limited formsof neuropathy. If successful, therapy can be continued Selective serotonin norepinephrine reuptakewith oral mexiletine. This class of compounds targets the inhibitors (SNRIs)pain caused by hyperexcitability of superficial, free nerve There has been much focus on this group of drugs latelyendings (27). in treatment of diabetic neuropathic pain. Duloxetine has been studied in two doses of 60 and 120 mg for its effectsTramadol and N-methyl-D-aspartate (NMDA) of reducing diabetic neuropathic pain and for pain in fi-receptor antagonists bromyalgia. To achieve an outcome of 50% pain relief There are two possible targeted therapies. Tramadol is over 12–13 wk, the number needed to treat was 6 (Tablea centrally acting weak opioid analgesic for use in treating 3). Adverse effects include nausea, constipation, somno-moderate to severe pain. Tramadol was shown to be better lence, decreased appetite, some increase in fasting bloodthan placebo in a randomized controlled trial (28) of only sugar, and dry mouth (34, 35). There do not appear to be6-wk duration, but a subsequent follow-up study sug- any significant cardiovascular risks. Venlafaxine is an-gested that symptomatic relief could be maintained for at other SNRI that has mixed action on catecholamine up-least 6 months (29). Side effects are, however, relatively take. At lower doses, it inhibits serotonin uptake, and atcommon and are similar to other opioid-like drugs. An- higher doses it inhibits norepinephrine uptake (36). Theother spinal cord target for pain relief is the excitatory extended-release version of venlafaxine was found to beglutaminergic NMDA receptor. Blockade of NMDA re- superior to placebo in diabetic neuropathic pain in non-ceptors is believed to be one mechanism by which dextro- depressed patients at doses of 150 –225 mg/d, and when
4808 Vinik Approach to Pain Management in Diabetes J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811TABLE 3. Odds ratios for efficacy and withdrawal, numbers needed to treat (NNT) and numbers needed to harm (NNH) Odds ratio Drug class Efficacy Withdrawal due to adverse effect NNT NNH Tricyclics 22.2 (5.8 – 84.7) 2.3 (0.6 –9.7) 1.5–3.5 2.7–17.0 Duloxetine 2.6 (1.6 – 4.8) 2.4 (1.1–5.4) 5.7–5.8 15.0 Traditional anticonvulsants 5.3 (1.8 –16.0) 1.5 (0.3–7.0) 2.1–3.2 2.7–3.0 Newer generation anticonvulsants 3.3 (2.3– 4.7) 3.0 (1.75–5.1) 2.9 – 4.3 26.1 Opioids 4.3 (2.3–7.8) 4.1 (1.2–14.2) 2.6 –3.9 9.0added to gabapentin there was improved pain, mood, and pal neurons in patients with mesial temporal sclerosisquality of life (37). both enlist activation of NMDA receptors (42, 43), which can be affected by felbamate (39). The evidenceAntiepileptic Drugs (AEDs) supporting the use of AEDs for the treatment of DPNAntiepileptic drugs (AEDs) have a long history of effec- continues to evolve (36). Patients who have failed totiveness in the treatment of neuropathic pain, dating back respond to one AED may respond to another or to twoto case studies of the treatment of trigeminal neuralgia or more drugs in combination (44).with phenytoin in 1942 and carbamazepine in 1962 (38).Principal mechanisms of action include sodium channel Sodium Channel Blockersblockade (felbamate, lamotrigine, oxcarbazepine, topira- Voltage-gated sodium channels are crucial determinantsmate, zonisamide), potentiation of ␥-aminobutyric acid of neuronal excitability and signaling. After nerve injury,activity (tiagabine, topiramate), calcium channel blockade hyperexcitability and spontaneous firing develop at the(felbamate, lamotrigine, topiramate, zonisamide), an- site of injury and also in the dorsal root ganglion cell bod-tagonism of glutamate at NMDA receptors (felbamate) ies. This hyperexcitability results at least partly from ac-or ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic cumulation of sodium channels at the site of injury (45).acid (felbamate, topiramate), and mechanisms of action Carbamazepine and oxcarbazepine are most effectiveas yet to be fully determined (gabapentin, pregabalin, against “lightning” pain (46).levetiracetam) (39). An understanding of the mecha-nisms of action of the various drugs leads to the conceptof “rational polytherapy,” where drugs with comple- Calcium Channel Modulatorsmentary mechanisms of action can be combined for syn- Five types of voltage-gated calcium channels have been iden-ergistic effect. For example, one might choose a sodium tified, and the L- and N-types of channels have a role to playchannel blocker such as lamotrigine to be used with a in the neuromodulation in the sensory neurons of the spinalglutamate antagonist such as felbamate. Furthermore, a cord. Gabapentin and pregabalin are medications that bindsingle drug may possess multiple mechanisms of action, at the ␣ 2 ␦ subunits of the channels. Unlike traditional cal-perhaps increasing its likelihood of success (e.g. topi- cium channel antagonists, they do not block calcium chan-ramate). If pain is divided according to its derivation nels but modulate their activity and sites of expression. Thefrom different nerve fiber types (e.g. A␦ vs. C-fiber), exact mechanism of action of this group of agents on neu-spinal cord or cortical, then different types of pain romodulation has yet to be clearly defined.should respond to different therapies. In addition to providing efficacy against epilepsy, these Gabapentinnew AEDs may also be effective in neuropathic pain. For Gabapentin was significantly superior to placebo in painexample, spontaneous activity in regenerating small-cal- control, beginning at wk 2 and continuing through wk 8, andiber primary afferent nerve fibers may be quelled by so- it significantly reduced sleep interference beginning at wk 1dium channel blockade, and hyperexcitability in dorsal and continuing through wk 8. The most common adversehorn spinal neurons may be decreased by the inhibition of events with gabapentin were dizziness and somnolence (47).glutamate release—two mechanisms of action possessed Gabapentin has the additional benefit of improvingby the AED lamotrigine (40, 41). Clinical trials, how- sleep (47), which is often compromised in patients withever, have not been salutary (5). This was evident in our chronic pain (44). Over the long term, it is known to pro-patient who was being treated with lamotrigine for sei- duce weight gain, which may complicate diabetes man-zures, and lamotrigine was ineffective in relieving pain. agement (48). Combination therapy has been examinedIn addition, the “wind-up” phenomenon caused by using gabapentin and morphine, indicating slight superi-nerve injury and the kindling that occurs in hippocam- ority of the combination (49).
J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811 jcem.endojournals.org 4809Pregabalin Focal neuropathic pain is best treated with diuretics toSeveral randomized, double-blind, placebo-controlled, mul- reduce edema in the canal, splinting, and surgery to releaseticenter studies have evaluated the effectiveness of pregabalin entrapment. Diffuse neuropathies are treated with medi-in a fixed dose with an open-label extension in alleviating cal therapy and in a majority of cases, need multidrugpain associated with DPN. Forty percent of patients receiving therapy. Immune-mediated neuropathies are treated withpregabalin reported at least a 50% reduction in pain, com- iv Ig, steroid, or other immunomodulators.pared with 14.5% of the placebo group (P ϭ 0.001) (50). Secondary measures that improved included a reduc-tion in mean sleep interference scores on the SF-36 Bodily Back to the PatientPain subscale (P Ͻ 0.0001), total SF-MPQ score (P Ͻ Having reviewed the treatment options we return to the0.05), and total mood disturbance and tension-anxiety patient.components of the Profile of Mood States (P Ͻ 0.03) (50). If this was insulin neuritis syndrome, it would simply beIn this respect, the data appear to be not unlike the early a matter of time and would recover spontaneously. How-reports on gabapentin. ever, the patient clearly had an eating disorder, anxiety/ depression, evidence of autoimmunity, and autonomicTopiramate nerve dysfunction. She was started on topiramate 15 mgAlthough topiramate failed in three clinical trials, due to QD for 1 month, increased to 25 mg, and then to 50 mg/d.the use of the wrong endpoint (51), it has been shown to Topiramate has been shown to induce nerve regenerationsuccessfully reduce pain and induce nerve regeneration and also reduces body weight in contrast with gabapentin,(52), and has the added advantage of causing weight loss which causes weight gain. We added NutriNerve (an over-and improving the lipoprotein profile particularly useful the-counter combination of antioxidants) at a dose ofin overweight type 2 diabetic patients. two tablets BID because this contains ␣-lipoic acid, which has been shown to improve autonomic dysfunc-Botulinum Toxin tion (55). Thirdly, she was placed on topical lidodermBotulinum toxin has been tried for trigeminal neuralgia to reduce the allodynia and hyperalgesia. Because of the(53) and has been shown to have long-lasting antinoci- seizure disorder, we endorsed the use of gabapentin andceptive effects in carpal tunnel syndrome with no electro- lamotrigine.physiological restoration (54). June 16, 2009Guidelines Her legs and feet still hurt very badly. She was very weepy, and one could not touch her toes. She had a magnetic reso-Figure 1 is an algorithm that we propose for the manage- nance image done bilaterally of the feet, and this was foundment of painful neuropathy in diabetes. This starts with to be negative for impending Charcot neuropathy. Her heartidentification of neuropathic pain being focal or diffuse. rate had returned toward normal, about 80 bpm. Our impression of the effects of topiramate (25 mg/d), NutriNerve (two pills BID), and a 5% lidoderm patch was that the pain has lessened some, but was still bad at night. In light of the very intense autoimmune response with the ap- optosis of neuronal cells in culture, we resolved to do the following: 1) give her a course of iv Ig at 1.0 g/kg⅐d on con- secutive days (two per week) for 3 wk; 2) increase the dose of topiramate to 50 mg/d and possibly to 100 mg/d; and 3) replace the vitamin D with 50,000 U ergocalciferol every month. July to November 2009 We were making slow progress and decided to give her a course of botulinum toxin into her feet. The pain soon started to improve, and a second course was given in December. October 19, 2009FIG. 1. Treatment algorithm: neuropathic pain after exclusion of Her Lantus was changed to 13 U in the morning and 26nondiabetic etiologies and stabilization of glycemic control. U in the evening. She was also to use Novolog coverage (1
4810 Vinik Approach to Pain Management in Diabetes J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811U for every 12 g of carbohydrate for meals and snacks, said, “We need to go from failure to failure without losingalong with 1 U for every 50 mg/dl of blood sugar Ͼ200 our enthusiasm and ultimately we will succeed….”mg/dl). She is currently covering with 1 U for 10 g ofcarbohydrate and 1 U for every 50 mg/dl blood sugargreater than 150 mg/dl. Acknowledgments She checks her blood sugar “too much”—about 10 –15times daily. The range is usually 70 –140 mg/dl. For the Address all correspondence and requests for reprints to: Aaronpast couple of days, the results have been higher and she Vinik, Department of Internal Medicine, Eastern Virginia Med-is upset. For anxiety/depression, Ativan 1 mg BID was ical School, Strelitz Diabetes Center and Neuroendocrine Unit atincreased to three times daily (TID). Ambien was also in- Norfolk, Norfolk, Virginia 23510. E-mail: firstname.lastname@example.org. Disclosure Summary: A.V. is a consultant for Ansar,creased from 10 to 12.5 mg HS. AstraZeneca, Eli Lilly, KV Pharmaceuticals, Merck, NovartisNovember 16, 2009 Pharmaceuticals, R.W. Johnson Pharmaceutical Research Insti- She was feeling better. Her hemoglobin A1c was 5.5, tute, Sanofi-Aventis, Takeda, and Tercica; and is on the speakers bureau for Abbott, Ansar, AstraZeneca, Bristol Meyer Squibb,down from 8.8 in May 2009. Eli Lilly, GlaxoSmith Kline Beecham, Merck, Novartis Pharma-January 2010 ceuticals, Pfizer Inc., Sanofi-Aventis, and Takeda. Pain had resolved completely. Diabetes control remainedsuperb. The patient had started to reduce the dosages of themedications, and she had returned to doing a full exercise Referencesprogram including Pilates and yoga! Repeat autonomic func-tion tests showed improvement in the autonomic function, 1. 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