Current Trends in Neuropathic Pain Treatments with

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Aug 16, 2004 - controlled trials, which are reported here if they had been published ... Future research will have to apply new approaches (eg, .... the physiological electrical activities of ascending neu- ..... In a pilot study by Lynch and colleagues,62 20 ..... A randomised, double blind, placebo controlled crossover study.
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Current Trends in Neuropathic Pain Treatments with Special Reference to Fibromyalgia By Martin Offenbaecher, MD, MPH, and Manfred Ackenheil, MD

Needs Assessment

Accreditation Statement

The Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide Continuing Medical Education for physicians. The Mount Sinai School of Medicine designates this Continuing Medical Education activity for a maximum of 3.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Credits will be calculated by the MSSM OCME and provided for the journal upon completion of agenda. It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States.

Neuropathic pain is a common and underestimated symptom of a heterogenous group of conditions with a high prevalence. Despite this growing importance, clinical trials often give no convincing results. Recently there have been a number of well designed studies which show some short-term benefits in these syndromes.

Target Audience Neurologists and psychiatrists

Learning Objectives At the end of this activity, the participant should be able to: • List the most common pain phenomena in neuropathic pain syndromes. • Describe the action of tricyclic antidepressants, the most commonly used drug treatment in chronic neuropathic pain syndomes. • List a number of alternative drugs (other than anticonvulsants, opioids, or N-methyl-D-aspartate antagonists) evaluated in the neuropathic pain trials. • Appraise the results of recent drug trials in neuropathic pain syndromes.

To Receive Credit for This Activity Read this article, and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME quiz found on pages 327 and 328. To obtain credits, you should score 70% or better. Termination date: April 30, 2007. The estimated time to complete this activity is 3 hours.

ABSTRACT Neuropathic pain and fibromyalgia are prevalent diseases which have major consequences on healthcare resources and the individual. From the clinical point of view neuropathic pains represent a heterogeneous group of aetiologically different diseases ranging from cancer to diabetes. Patients with fibromyalgia also display clinical features common in neuropathic pain suggesting that there might be some overlap. The mechanisms responsible for symptoms and signs in both diseases are still unknown. Recently, there have been numerous reports of various pharmacological treatments of neuropathic pain and fibromyalgia with often disappointing results.

Most of the studies were of short duration, had high attrition rates, and displayed other methodological problems. Some compounds had high rates of adverse effects which makes it often difficult for the patients to tolerate the treatment, especially in the long-term. At present, the best options for medication treatment are tricyclic antidepressants in lower dosage than usual in psychiatric disorders and a wide range of anticonvulsants. Opioids are sometimes recommended but have been found to have minor efficacy. Recently, there have been more controlled trials, which are reported here if they had been published between 2002 and 2004. Various compounds have been tested in different studies. Treatment of fibro-

Dr. Offenbaecher is research assistant in the Department of Medical Psychology and Dr. Ackenheil is professor of psychiatry and clinical pharmacology in the Department of Psychiatry both at the University of Munich Medical School. Disclosure: The authors do not have an affiliation or financial interest in any organization that might pose conflict of interest. This article was submitted on August 16, 2004, and accepted on February 28, 2005. Please direct all correspondence to: Martin Offenbaecher, MD, MPH, Department of Medical Psychology, University of Munich, Goethestrasse 31, 80336 München, Germany; E-mail: [email protected]. Volume 10 – Number 4 © MBL Communications Inc.

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Review Article cohort with PNDs included patients with various disorders, such as back and neck pain with neuropathic involvement, causalgia, and diabetic neuropathy. In comparison with matched control subjects, patients with PNDs were much more likely to have other chronic comorbidities, such as osteoarthritis, depression, and coronary heart disease. They also had substantially higher healthcare charges (almost three-fold). Although ~75% of PND patients had received pain-related medications, relatively few were using antiepileptic drugs or tricyclic antidepressants (TCAs) despite their potential efficacy in the treatment of neuropathic pain. Use of opioids and nonsteriodal anti-imflammatory drugs, on the other hand, was widespread, with >50% of PND patients receiving the former. One explanation of these differences in healthcare charges and drug use could be the higher frequency of comorbidities. However, it is still unclear whether these disorders might not be treated optimally in clinical practice. Haythornthwaite and colleagues6 reviewed the literature concerning the psychosocial disease consequence in neuropathic pain. The authors found that among these conditions, pain is associated with significant reductions in quality of life (QOL), including changes in mood and physical and social functioning. They further concluded in their review that consistent with the literature on chronic pain, depression is a significant factor associated with poorer adjustment.

myalgia, which has many features in common with depressive symptoms, became the focus of interest. New promising studies with dual serotonin-norepinephrine reuptake inhibitors (duloxetine and milnacipram) and a newer antiepileptic drug (pregabalin) are in progress. Future research will have to apply new approaches (eg, using a mechanism based classification of neuropathic pain and carrying out studies in populations with the same symptom but not necessarily the same disease) in order to find effective treatments for these common and often debilitating diseases. CNS Spectr. 2005;10(3):285-297 INTRODUCTION According to the International Association for the Study of Pain (IASP),1 pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. It is also described in terms of such damage. On the website of the IASP further definitions of specific pains related to the nervous system are given1: • Neuropathic pain: Pain initiated or caused by a primary lesion or dysfunction in the nervous system • Neurogenic pain: Pain initiated or caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral or central nervous system (CNS). • Central pain: Pain initiated or caused by a primary lesion or dysfunction in the CNS. EPIDEMIOLOGY AND ECONOMIC IMPLICATION OF NEUROPATHIC PAIN SYNDROMES Neuropathic pain, or pain associated with disease or injury to the peripheral or CNS, is a common symptom of a heterogenous group of conditions, including diabetic neuropathy, trigeminal neuralgia, postherpetic neuralgia, and spinal cord injury (Table 1).2 The true prevalence of neuropathic pain is largely unknown. Current estimates suggest that ~1.5% of the general population in the United States may be affected.3 This figure is probably underestimated4 because there might be a neuropathic component in the pain experienced by patients with cancer, degenerative diseases, or neurologic conditions that has so far gone unnoticed. Since these conditions are most prevalent in the aging population and this population is increasingly growing neuropathic pain will place progressively demand burden on healthcare resources and the individual. Using a large US health insurance claims database Berger and colleagues5 compared patients with painful neuropathic disorders (PND) with age- and gender-matched group without PNDs in respect to healthcare costs, comorbidities, and drug use. The Volume 10 – Number 4 © MBL Communications Inc.

NEUROPATHIC PAIN FROM THE CLINICAL POINT OF VIEW From the clinical point of view neuropathic pains represent a heterogeneous group of aetiologically different diseases ranging from cancer to TABLE 1. CLASSIFICATION OF NEUROPATHIC PAIN BY ETIOLOGY AND ANATOMICAL LOCALIZATION7 Periphery

Spinal

Brain

Neuropathies Traumatic nerve injury Plexus avulsion Amuptation Neuralgia Compression HIV infection Polyradiculitis

Multiple sclerosis Spinal injuries Myelopathies Ischaemic lesions Syringomyelia Chordotomy Cancer compression

Syringobulbia Stroke Multiple sclerosis Parkinson’s disease

HIV=human immunodeficiency virus. Offenbaecher M, Ackenheil M. CNS Spectr. Vol 10, No 4. 2005.

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Review Article diabetes.7 They also differ with respect to location; disorders may exists anywhere between the peripheral receptor and the brain. Despite the heterogeneity in etiology and anatomical location, neuropathic pains share certain characteristics. Classically, patients with neuropathic pain complain of spontaneous pains (those that arise without detectable stimulation) and evoked pains (abnormal responses to stimuli). Spontaneous pains can be continous, steady, and ongoing or paroxysmal, episodic, and intermittent.8 Otto and colleagues9 evaluated the frequency of pain phenomena and signs in painful polyneuropathy of mixed causes and compared the symptomatology in patients with signs of increased small fibre response with that in patients with signs of deafferentation. The most common pain phenomena were deep aching pain (88%) and pain on pressure (69%) follwed by pain paroxysms (59%) and pain on light touch (31%). In this study,9 >50% of the patients could be classified with decreased input from afferent small nerve fibres, whereas 40% of the patients could not be classified in one of the two groups indicates that several different mechanisms may often be present in the individual patient. The mechanisms responsible for these symptoms and signs in neuropathic pain are not yet settled. While it is generally accepted that neuronal hyperexcitability is a key phenomenon in neuropathic pain conditions, it is unclear whether this is of peripheral or central origin or a combination of both.

developement in terms both of defining targets and describing which patients are likely to benefit. Hansson 13 has a somewhat restricted opinion about the value of a mechanism-based classification system. He stressed that researchers and clinicians lack operational criteria for translating clinical symptoms and signs into distinct pathophysiological mechanisms. Due to this shortcoming in unravelling detailed pain mechanisms from the clinical examination, researchers and clinicians are currently not in the position to extrapolate and to draw firm conclusions from clinical phenomenology and pathophysiological mechanisms in animals. Neuropathic pain syndromes are characterized by chronic, stimulus-independent pain sensation accompanied by hyperalgesia/allodynia and paresthesia. Patients with fibromyalgia display such features, suggesting that there may be some overlap in clinical characteristics. The clinical overlap is supported by Martinez-Lavin and colleagues.14 They evaluated fibromyalgia patients and patients with rheumatoid arthritis with a specially developed questionnaire for neuropathic pain. The authors found a high prevalence of associated sensory disturbances in fibromyalgia patients, which supports the notion that fibromyalgia might be a neuropathic pain syndrome. Both conditions also share many common biological processes.15 In addition to these similar clinical and pathophysiological characteristics fibromyalgia has the ineffective response to many analgesics in common with neuropathic pain syndromes. FIBROMYALGIA: A SPECIFIC DISORDER WITH FEATURES OF NEUROPATHIC PAIN? In contrast to the localized neuropathic pain syndromes, fibromyalgia is characterized by chronic widespread pain and further symptoms such as fatigue, sleep abnormalities, and psychological distress with a prevalence of 2% in western countries. 16 Fibromyalgia predominantly affects middle-aged women and prevalence seems to increase between 60 and 79 years of age.16 The diagnosis is based on 1990 recommendations of the American College of Rheumatology (ACR) classification criteria17 including the history of widespread pain and excess tenderness in at >11 of 18 tender points at specific anatomic sites. Frequently depressive symptoms are dominant and many patients fulfill the criteria of major depression or other affective disorders. Genetic and molecular genetic studies18,19 show an association to depression. Common biological factors, such as abnormalities of hormone secretion and shortened rapid eye movement

NEUROPATHIC PAIN FROM A BASIC SCIENCE POINT OF VIEW As Jensen 7 pointed out, the traditional classification of neuropathic pain has been of limited help in the search for a rational treatment of patients with neuropathic pain. Woolf and colleagues10 have recently advanced a more fundamental mechanism based classification. Woolf and colleagues10 and Jensen and Baron11 propose that pain symptoms, mechanisms, and syndromes should form a new hierarchy that does not involve traditional dichotomies such as malignant/nonmalignant or acute/chronic. This classification for clinical syndromes might generate testable hypotheses for selecting treatments which interact with specific mechanisms.10,12 A mechanism-based classification would also suggest carrying out a study on a population with the same symptom but not necessarily the same disease and would have implications for clinical drug Volume 10 – Number 4 © MBL Communications Inc.

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Review Article latency at sleep, support the view that basic pathophysiological mechanisms such as low serotonin (5-HT) and noradrenalin (NA) in brain structures are involved. The treatment of choice with classical TCAs is a further hint for close relationship.

these reports have been reviewed in good articles. 7,20–22 Most of the drugs have been found by serendipity. TCAs, antiepileptic drugs (AEDs), and some opioids are options. They all are only in a part of the patients helpful and so far there is no convincing evidence for a specific treatment. We are referring in this article to old treatment strategies, mostly not evidence based and to newer studies published in between 2002 and 2004. TCAs have been used for a long time and are the most frequently prescribed drugs for the treatment of chronic neuropathic pain and fibromyalgia, although these drugs have been found effective more by chance than by clinical trials. TCAs are as well effective on pain, sleep disorder, and asthenia but less in doses tested on depressive symptoms of fibromyalgia. The daily doses of amitriptyline in this indication does not exceed 50 mg. For the treatment of depression the doses is considerably higher. Five studies23-27 evaluated the efficacy of amitriptyline in comparison to placebo in patients with fibromyalgia. Globally, all these studies showed superior efficacy of active substances. All TCAs increase 5-HT and/or NA neurotransmission directly or indirectly in the brain and they change intracellular signal transduction, leading to altered gene expression that results in changes of neuroplasticity.28 Additionally, they effect other transmitter systems, including histamine, acetylcholine, and glutamate. Important to their analgesic properties in the lower dosage29 their effect as ion channel blockers. Based on hypotheses related to the molecular mechanism responsible for neuropathic pain, especially the neurons hyperexcitibilty and corresponding molecular changes, which have many factors in common with epilepsy and bipolar disorders, AEDs have been used for the treatment of neuropathic pain. Carbamazepine and phenytoin were the first AEDs used in controlled clinical trials.30 In comparison with a TCA (amitriptyline), carbamazepine, which is still the treatment of choice for trigeminal neuralgia, was less effective.7 The use of these older AEDs is often complicated by pharmacokinetic factors and frequent adverse effects. Therefore, many other AEDs, such as oxcarbamazepine, lamotrigine, valproic acid, gabapentin, and topiramate, have been recommended for the treatment of neuropathic pain. It is beyond the scope of this article to describe in detail the different studies and aspects. AEDs represent an important treatment option for neuropathic pain. However, recommendations should be based on controlled clinical trials.

REFLECTIONS ON PATHOPHYSIOLOGY Therapeutic management of chronic neuropathic pain and related disorders like fibromyalgia is relatively complex since no curative treatment has yet been found. Since the main symptom of fibromyalgia is diffuse and chronic pain that consists of hyperalgesia (increased sensitivity of a painful stimulus) and allodynia (pain provoked by a normally painless stimulus). Thus, suppression of nociception in the periphery is not the goal, the target of treatment is more central, mainly in the spinal cord and the brain. In addition to the improvement of pain, sleep, depression, and anxiety have to be treated as well because they interfere with pain. The pathophysiological mechanisms of this complex symptomatology can be schematically related to neurons that ascend to brain structures such as thalamus and amygdala and descending fibres that modulate the synapses of ascending neurons on the level of the spinal cord. Sodium, potassium, and calcium channels regulate the physiological electrical activities of ascending neurons. Glutamate interacting with N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole4-propionic acid receptors and neurokinin (NK) -like substance P interacting with NK receptors are promoting pain, whereas opioids and NA and 5-HT are inhibiting these ascending neurones on the level of the spinal cord. This may explain why, in disorders such as depression, with low 5-HT and NA, a lower threshold for pain is observed. Furthermore, it has to be considered that chronic neuropathic pain syndromes are chronic disorders with memory effects similar to those in epilepsy or bipolar disorders that may play a substantial role. Pharmacotherapy remains the mainstay of neuropathic pain management. Since nociception is not important for chronic neuropathic pain, analgesics only play a minor role. Drugs used to treat neuropathic pain can be broadly categorized into agents interacting with the ascending neurons like sodium and calcium channels blockers, NMDA and NK receptor antagonists, or drugs that enhance descending inhibitory fiber activity (eg, TCAs). PRINCIPAL PHARMACOLOGIC AGENTS Recently, there have been numerous reports of pharmacologic treatments of neuropathic pain and fibromyalgia. According to our current knowledge

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Review Article CLINICAL STUDIES IN NEUROPATHIC PAIN PUBLISHED BETWEEN 2002 AND 2004 Treatment directed against neuropathic pain has previously almost exclusively been based on an etiological or anatomical classification of these pains. Current treatments of neuropathic pains rarely result in elimination of pain,31-33 and with the present strategy it has only been possible to reduce a fraction of the single patients pain phenomena. We carried out a literature search on PubMed using the keywords “neuropathic pain” and “therapy.” The search was limited to articles published between January 2002 and December 2004, all adults >19 years of age and randomized clinical trials. From the retrieved papers, a selection was made based on a predefined set of inclusion and exclusion criteria. Included were randomized controlled trials on patients with neuropathic pain syndromes. Toxicity, dose-finding, and no drug studies were excluded. We excluded articles published in abstract form or published in languages other than German or English. To collect information about the studies the following criteria were examined: study design; the disease studied; drug class; the number of patients randomized; the number of drop-outs; the duration of study; the occurrence of adverse events; and whether the drug was superior to the control intervention.

reducing several pain variables, a disability measure, and improving QOL compared with active placebo. Nausea and constipation were significantly more common in the oxycodone CR group (35% and 28%). However, it has to be noted that of the initial 204 screened patients only 45 were randomized. Of these, 22% withdrew after randomization to oxycodone CR and 24% withdrew after randomization to placebo, citing inadequate pain control, leaving only 36 patients in the evaluable population. This restricts generizability of the results. In a study by Attal and colleagues,36 21 patients suffering from post-stroke or spinal cord injury pain were randomly assigned to either intravenous (IV) morphine, or placebo. The authors found no significant difference between the groups in spontaneous pain ratings. Most of their patients subsequently dropped out before 3 months due to insufficient pain relief, side effects, or both. Only three patients switched to oral morphine and experienced persistent pain relief after 1-year follow-up. In a randomized, double-blind, placebo-controlled crossover study by Morley and colleagues,37 19 patients with a diverse range of chronic neuropathic pain syndromes were evaluated. All patients received methadone or placebo for 7 days each. Methadone resulted in a significant better outcome in three pain measures compared with placebo. Seven patients withdrew from the study because of adverse events. In a non-randomized, single blind, and placebocontrolled study38 with 17 muliple sclerosis patients suffering from central pain only a minority of patients responded to IV morphine and at only high doses. The authors do not recommend IV morphine for routine use in muliple sclerosis patients with central pain. Rowbotham and colleagues 39 compared low strength with high strength levorphanol in 81 patients suffering from neuropathic pain. The authors found a significant higher reduction of pain in the high strength group, but in many patients pain relief is not achieved or there are intolerable side effects. Dextrometorphan, an NMDA antagonist, which is metabolized to dextrophan has therapeutic effects on neuropathic pain as well. Interestingly this depends on the pharmakokinetic metabolism. Extensive metabolizer of dextrometorphan have better therapeutic responses, indicating that dextrophan is the therapeutic agent. Morphine and other analogues are of limited value in most of the neuropathic pain states. Only in diabetic peripheral neuropathy oxycodone has a positive effect on pain. A special role has tramadol

WHAT WERE THE RESULTS? One hundred fifty-nine papers were retrieved. After applying our inclusion and exclusion criteria 29 articles remained (Table 2).34-39,42-64 These 29 studies tested 21 different drugs in 11 diseases (Table 2). In the following section we will report our findings according to the different drug classes. OPIOIDS In a study by Gimbel and colleagues,34 159 patients with painful symmetrical distal polyneuropathy were treated with oxycodone continuous release (CR) or with placebo for >6 weeks. In the treatment group, patients had a significant greater pain relief compared with the placebo group, but almost all patients taking oxycodone CR (96%) reported opioid-related side effects (eg, constipation, somnolence, nausea, dizziness, and other symptoms). Forty-five diabetic patients with painful sensory neuropathy were enrolled in a randomized, doubleblind, crossover study by Watson and colleagues.35 The patients received either oxycodone CR 10 mg or active placebo (benztropine) for 4 weeks. Oxycodone CR was significantly more effective in

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Review Article which already has been proposed as an antidepressant. This unique agent combines opiate receptor agonist activity with NA reuptake inhibition, and recent research has suggested that it also has agonist activity at the 5-HT receptor.40,41 Due to this dual action it seems to have some value in the treatment of chronic neuropathic pain and can be recommended for treatment attempts.

15 patients with posttraumatic neuropathic pain received either dextromethorphan 270 mg or placebo on two separate occasions. A single dose of the drug resulted in a significant 30% reduction of pain 4 hours after administration. The effect diminished after 2–3 hours. Most patients (76%) experienced one or more mild to moderate adverse effects, such as light-headedness and drowsiness. The authors concluded that adverse effects seem to be dose-related and this may limit further use of dextromethorphan.

N-METHYL-D-ASPARTATE ANTAGONISTS ANTAGONISTS Kvarnström and colleagues42 examined IV ketamine and lidocaine in 12 patients with long lasting peripheral neuropathic pain in a randomized double blind crossover manner. A significant reduction in mean pain measured with a visual analog scale was only registered between ketamine and placebo. The clinical usefullness is however, limited by disturbing side effects which were mainly somnolence, lightheadedness, paraesthesia and others. Jorum and colleagues 43 compared the effect of IV ketamine, alfentanil (active placebo) and placebo in a double-blind, placebo-controlled, balanced crossover study. Twelve patients suffering from neuropathic pain syndromes received in a random sequence all three treatments once as a bolus and infusion. Significant and marked reductions of hyperalgesia to cold were seen following afentanil and ketamine. Both also significantly reduced ongoing pain and mechanical hyperalgesia. Since in this study all three treatments were applied in one day and the main outcome were changes in thermal thresholds, no firm conclusion can be made on the long-term effect of afentanil and ketamine and the clinical usefullness of these substances. Seventeen patients with painful diabetic neuropathy took part in a study by Amin and colleagues44 receiving either IV amantadine or placebo in a double-blind, crossover fashion. Pain scores were reduced significantly in the IV amantadine group but the effect only lasted for 1 week postinfusion. The study by Wallace and colleagues45 using a glycine antagonist in 63 patients with neuropathic pain of mixed origin in order to reduce pain failed to show a positive effect in comparison with placebo. Sang and colleagues46 evaluated in a randomized, double-blind, active-placebo trial dextromethorphan and the NMDA receptor antagonist memantine in patients with diabetic neuropathy and postherpetic neuralgia. After a treatment period of 9 weeks no comparison with placebo reached statistical significance. In a placebo-controlled, double-blind, randomized crossover study by Carlsson and colleagues,47

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NEWER ANTIEPILEPTIC DRUGS Simpson and colleagues48 evaluated lamotrigine for the treatment of pain in human immunodeficiency virus-associated sensory neuropathies. In this doubleblind study, patients were stratified into those patients who received antiretroviral therapy (ART) and those patients that did not receive ART. The patients were then randomized. Ninety-two patients were receiving ART and 135 were not. Analysis after an 11-week treatment period using the Gracely Pain Scale, the primary outcome measure, revealed no difference in the total cohort or in the subgroups. However, in some of the secondary outcome measures, lamotrigine was more effective in patients receiving neurotoxic ART, but not more effective than placebo in patients who were not receiving ART. Finnerup and colleagues49 investigated the effect of lamotrigine in patients with spinal cord injury pain and signs of neuronal hyperexcitability. Twenty-two patients received in a randomized, double-blind, crossover study lamotrigine and placebo for 9 weeks each. The authors found no statistically significant effect of lamotrigine in the total sample. In some secondary outcome measures (spontaneous pain and evoked pain in the area with spontaneous pain) in patients with incomplete lesions, however, lamotrigine was superior to placebo. They concluded that their findings may indicate that different mechansisms may underlie spinal cord pain and emphasize the need for a mechanism-based classification of patients with neuropathic pain. In a study by Sabatowski and colleagues,50 238 patients with postherpetic neuralgia were randomized to receive either placebo, pregabalin 150 mg, or pregabalin 300 mg for 8 weeks. In this trial the treatment group showed statistically significant and clinical improvement in the endpoint pain score and other outcome variables compared with placebo. However, a substantial proportion of the pregabalin group (83%) experienced one or more side effects, such as dizziness, somnolence, peripheral oedema, headache, and dry mouth.

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Review Article In the double-blind, crossover study by Bone and colleagues,51 14 patients with phantom limb pain were treated with gabapentin and placebo for 6 weeks. The authors found no significant difference in all outcome parameters. Serpell and colleagues52 conducted a double-blind, randomized, placebo-controlled, multicentre 8-week study using gabapentin in patients with a variety of neuropathic pain syndromes. It is interesting to note is that the authors used a novel study design that was symptom-based rather than syndrome-based. In total, 307 patients were randomized to receive either gabapentin or placebo. The primary outcome variable (mean pain diary score for the last 7 days) decreased by 1.5 (21%) in gabapentin-treated patients, compared with 1.0 (14%) in the placebo group (P=.048). There were also significant differences in other outcomes such as in some domains of the short form of the McGill Pain Questionnaire and the 36-item Short Form. However, the authors noted that the clinical benefits of gabapentin were apparent early in the treatment and faded away after 7 and 8 weeks, respectively (no significant difference between gabapentin and placebo in mean daily pain). Gabapentin was well tolerated in this study and the most common adverse events (dizziness and somnolence) were usually mild to moderate and occurred early in treatment. In the multicenter, double-blind, placebo-controlled study by Caraceni and colleagues.53 One hundred twenty-one patients suffering from neuropathic pain due to cancer were randomized. Gabapentin was titrated from 600 mg/day to 1,800 mg/day in addition to stable opioid dose and given for 10 days. In an intent-to-treat analysis the primary outcome measure, the global pain score, was significantly lower in the gabapentin compared with the placebo group (4.6 versus 5.4). Among the associated neuropathic symptoms, dysaesthesias were less severe in the treatment group. Although the authors found a significant benefit of gabapentin as an adjuvant to opioids they considered the information as of limited clinical value. Levendoglu and colleagues54 performed a doubleblind, placebo-controlled, crossover clinical trial with 20 patients with complete traumatic spinal cord injury and neuropathic pain. In this trial gabepentin up to 3,600 mg/day reduced the intensity as well as the frequency of pain, and some neuropathic pain descriptors and improved QOL significantly. However, the statistical test (Wilcoxon signed rank test) does not seem to be appropriate in a repeated measurement situation. The authors found—comparable with other studies evaluating gabapentin—a high incidence (65%) of side effects in the treatment group.

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Thienel and colleagues55 investigated the efficacy and tolerability of topiramate in patients with painful diabetic polyneuropathy. They performed three randomized, double-blind, placebo-controlled trials at 195 centers. The trial design included a 7-week baseline phase and a treatment phase (18 weeks in one study and 22 weeks in two studies). In the treatment phases patients received either one of three different doses of topiramate (in total 1,269 patients) or placebo (384 patients). In the topiramate arm, only 47% completed the study. These large studies did not find the drug to be significantly more effective than placebo in reducing pain scores in patients with painful diabetic polyneuropathy. VARIOUS COMPOUNDS In the add-on study by McCleane,56 cholecystokinin (CCK) 2 antagonist L-365 or a placebo was given to 44 patients who were receiving morphine for chronic neuropathic pain. However, the aim of this investigation to show whether the co-administration of this compound augments the analgesic effect of morphine was not met. CCK 2 antagonist was not superior to placebo. Lynch and colleagues57 administered adenosin in a double-blind, placebo-controlled manner to 23 adenosin responders who had experienced a >30% response in an open trial. The primary finding in this study was that the infusion of a low dose of adenosin led to a significant reduction in spontaneous pain and hyperalgesia in individuals with neuropathic pain of various etiologies. Eisenach and collegues58 studied seven patients with chronic neuropathic pain in a double-blind, placebo-controlled, crossover design. The patients received on two occasions intrathecal adenosine or IV adenosine or saline. Intrathecal but not IV adenosine reduced areas of allodynia significantly (25%). However, pain was not affected by adenosine by either route. Backache lasting 6 hours was observed in five of the seven patients receiving intrathecal adensione. The authors concluded that the role for intrathecal adenosine is very limited for the treatment of neuropathic pain. Ametov and colleagues59 investigated the efficacy of alpha lipoic acid (ALA) in a randomized, double-blind trial. One hundred twenty patients with symptomatic diabetic sensomotor polyneuropathy received daily infusions for 5 days/week of active drug or placebo for 14 treatments. ALA improved significantly symptoms such as pain and several other neuropathic end points compared with placebo. Due to its safety profile, the authors conclude that this

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Review Article drug appears to be a useful ancillary treatment for the symptoms of diabetic polyneuropathy. Yuen and colleagues60 evaluated in a double-blind randomized, placebo-controlled and a two-period crossover study design the effects of isosorbide dinitrate (ISDN) spray in 22 diabetic patients. After 4 weeks overall neuropathic pain and burning sensation was significantly reduced in the ISDN group. In a double-blind placebo-controlled, crossover study by Brill and colleagues,61 seven patients with postherpetic neuralgia (PHN) received once magnesium sulphate or placebo as an infusion. There was a significant difference in pain scores after 30 minutes. Five out of seven patients reported complete pain relief after the magnesium infusion and none after the saline infusion. However all of the patients reported that the pain had come back a few days later. The authors concluded that although the sample size was small, magnesium clearly reduced PHN pain for a short period of time. In a pilot study by Lynch and colleagues, 62 20 patients with neuropathic pain of different origin were included. The study design consisted of a 2-day, randomized, double-blind, placebo-controlled, 4-way crossover trial of topical amitriptyline, ketamine, a combination of both, and placebo. The result was that there was no significant difference from placebo for any treatment in the outcome measures used. In a randomized, double-blind, placebo-controlled, crossover trial, Svendsen and colleagues63 evaluated the effect of the cannabinoid dronabinol at a maximum dose of 10 mg/day in patients with MS and central neuropathic pain. They included 24 patients in this study. The mean outcome measure (median spontaneous pain intensity in last week) was significantly lower in the cannabinoid group compared with the placebo group. Also the median pain relief score was significantly higher. Almost all patients (96%) receiving dronabinol experienced side effects such as dizziness, tiredness, headache, myalgias, etc. The authors concluded that dronabinol has a modest but clear and clinically relevant analgesic effect in MS patients with central pain. They recommend that this substance should be available for patients whose central pain is not sufficiently treated with alternative drugs such as AEDs, antidepressants, or opioids. Meier and colleagues64 performed a randomized, placebo-controlled, crossover study in patients with peripheral neuropathic pain syndromes. Fifty-eight patients were included and received either a lidocaine 5% patch or a vehicle patch onto the painful area for 12 consecutive hours. In patients using the

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lidocaine patches ongoing pain and allodynia was reduced significantly during the first 8 hours after application and over a period of 7 days. STUDIES IN PROGRESS There are preliminary studies in neuropathic pain and fibromyalgia with very promising results. Pregabalin belongs to the class of AEDs, which modifies intracellular calcium levels and decreases norepinephrine (NE), 5-HT, and dopamine secretion. It improves diabetic neuropathy and seems to be effective in fibromyalgia patients.65,66 Another group of drugs are newer antidepressants (duloxetine and milnacipram) which inhibit NE and 5-HT reuptakte more specifically than the classic antidepressants, meaning that they have almost no effect on other transmitters and therefore have more favorable side effects. The results of these studies67,68 were reported at the 2004 Myopain Congress in Munich, Germany. Kamata and colleagues68 evaluated the efficacy of milnacipram, a novel serotonin-norepinephrine reuptake inhibitor, in a series of five patients with chronic pain of mixed origin. Four out of five patients experienced a pain reduction between 42% and 86% during a 12-week treatment period. In a phase II study reported at Collegium Internationale Neuro-Psychopharmacologicum Paris in 2004,69 milnacipram was used in 125 patients with fibromyalgia. The authors administered milnacipram either four times daily or twice daily. They found that the latter was better tolerated and resulted in significant improvements of several outcome variables such as pain (37% reported a 50% reduction), fatigue, stiffness, and physical functioning. Overall, 273 adverse events were reported of which 49% were mild, 38% moderate, and 13% severe. In a congress report by Susman, 70 results of a study by Detke was presented. Detke investigated duloxetine in patients with diabetic neuropathy. Duloxetine is a potent and balanced dual reuptake inhibitor of both 5-HT and NE, possessing comparable affinities in binding to NE and 5-HT transport sites, in contrast to most other dual-reuptake inhibitors.67 The authors enrolled 457 patients with diabetic neuropathy to receive placebo or three different doses of duloxetine in a 12-weeks, multicentre, double-blind study. The 60 mg and the 120 mg dose were significantly more effective in reducing 24-hour pain. In the highest dose, patients displayed more side effects, such as nausea, somnolence, dizziness, and increased appetite. This clinical results provided evidence that duloxetine 60 mg/day and duloxetine 60 mg BID is effective

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Review Article in the treatment of pain associated with diabetic neuropathy. These positive results of duloxetine on pain were further supported by a currently pub-

lished study by Goldstein and colleagues. 68 Data from 3 different studies investigating primarily the effect of duloxetine on mood in patients with

TABLE 2. LIST OF STUDIES ACCORDING TO THE DRUG AND THE INVESTIGATED DISEASE Number of patients in the study/ drop-outs (%)

Duration of study

Study drug superior to placebo as measured with the primary outcome parameter

Finnerup et al (2002)49 Spinal cord injury with neuropathic pain

30/27%

9 weeks

No

Simpson et al (2003)48 HIV-associated painful sensory neuropathies

227/24%

11 weeks

No

Anticonvulsants

Disease

Lamotrigine

Gabapentin Bone et al (2002)51

Phantom limb pain

19/26%

6 weeks

No

Serpell et al (2002)52

Mixed neuropathic pain

307/23%

8 weeks

Yes

121/27%

10 days

Yes

20/0%

18 weeks

Yes*

238/20%

8 weeks

Yes

1,653/43%

22 weeks

No

19/15%

3 weeks

Yes

63/11%

3 weeks

No

Traumatic peripheral nerve or root lesion

12/0%

1 day

Yes

Posttraumatic neuropathic pain

12/0%

1 day

Yes

44/18%

9 weeks

No

15/13%

1 day

Yes

Caraceni et al (2004)53 Neuropathic pain due to cancer Levendoglu et al (2004)54

Spinal cord injury with neuropathic pain

Pregabalin Sabatowski et al (2004)50

Postherpetic neuralgia

Topiramate Thienel et al (2004)55 Diabetic peripheral neuropathy NMDA Antagonists Amantadine Amin and Sturrock (2003)44

Diabetic peripheral neuropathy

Glycine Wallace et al (2002)45 Mixed neuropathic pain (diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, peripheral nerve injury) Ketamine and lidocaine Kvarnström et al (2003)42 Ketamine Jorum et al (2003)43

Dextromethorphan and memantine Sang et al (2002)46

Diabetic neuropathy and postherpetic neuralgia

Dextromethorphan Carlsson et al (2004)47 Posttraumatic neuropathic pain

(continued on page 294)

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Review Article

(continued from page 293)

TABLE 2. LIST OF STUDIES ACCORDING TO THE DRUG AND THE INVESTIGATED DISEASE Number of patients in the study/ drop-outs (%)

Duration of study

Study drug superior to placebo as measured with the primary outcome parameter

Poststroke or spinal cord injury pain

22/32%

3 weeks

No

Neuropathic pain due to multiple sclerosis

14/0%

1 day

No

Mixed neuropathic pain (focal nerve injury, postherpetic neuralgia, spinal cord injury, central pain, multiple sclerosis)

81/29%

8 weeks

Yes†

Diabetic peripheral neuropathy

159/28%

6 weeks

Yes

Watson et al (2003)35 Diabetic peripheral neuropathy

45/20%

4 weeks

Yes

18/37%

20 days

Yes

Neuropathic pain (not further specified)

52/25%

3 days

No‡

Mixed neuropathic pain

23/0%

1 day

Yes

7/0%

1 day

No

120/2%

14 days

Yes

22/8%)

4 weeks

Yes

7/0%

1 day

Yes

20/0%

2 days

No

24/0%

3 weeks

Yes

58/0%

1 week

Yes

Opioids

Disease

Intravenous morphine Attal et al (2002)36 Kalman et al (2002)

38

Levorphanol Rowbotham et al (2003)39 Oxycodone Gimbel et al (2003)34 Methadone Morley et al (2003)37

Neuropathic pain (not further specified)

Various drugs Cholecystokinin 2 antagonist McCleane (2003)56 Intravenous adenosine Lynch et al (2003)57

Eisenach et al (2003)58 Neuropathic pain (not further specified) Alpha Lipoic Acid Ametov et al (2003)58 Diabetic peripheral neuropathy Isosorbide dinitrate spray Yuen et al (2002)60

Diabetic peripheral neuropathy

Intravenous magnesium Brill et al (2002)61

Postherpetic neuralgia

Topical amitriptylin and ketamine Lynch et al (2003)62

Posttraumatic neuropathic pain

Dronabinol Svendsen et al (2004)63 Neuropathic pain due to multiple sclerosis Lidocaine 5% patches Meier et al (2003)64

Peripheral neuropathic pain

*

Statistical test not adaquate. Therefore, the result has to be interpreted with caution. In this study high-dose levorphanol was superior to low-dose levorphanol. A placebo was not included in the trial. ‡ It was investigated whether the study drug enhances the effect of morphine. HIV=human immunodeficiency virus; NMDA=N-methyl-D-aspartate. †

Offenbaecher M, Ackenheil M. CNS Spectr. Vol 10, No 4. 2005.

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Review Article major depression were analysed concerning painful symptoms, a secondary outcome in these studies. The authors found that compared to placebo, duloxetine reduces significantly painful physical symptoms in these patients. Crofford and colleagues68 investigated the efficacy and safety of pregabalin in 529 patients with fibromyalgia. In this multicenter study three different doses of pregabalin 150 mg, 300 mg, and 450 mg were compared with placebo over an 8-week period. They authors found in the highest pregabalin dose a significant pain reduction (change from baseline of two points on a visual analog scale). Additionally, other outcome (eg, sleep quality, fatigue, and health-related QOL) improved as well. However, a high proportion of the patients reported side effects such as dizziness, somnolence, headaches, and others.

In order to prevent spurious findings of the efficacy of analgesia studies, which investigate treatment that have frequent side effects, it has been recommended that the experimental design should use a range of doses of the study drug or compare the treatment with an active placebo that also has side effects or to compare one active drug to another.69 Only two studies 35,39 in the group of opioids and AEDs, where side effect are common, followed these recommendations. In the study by Rowbotham and colleagues39 a range of doses was administered while Watson and colleagues35 used benztropine as an active placebo. Neither of the studies included an inactive placebo. All studies were short in duration and did not include follow-ups of the patients. The average duration of the trials in neuropathic pain was 5.5 weeks. In chronic pain conditions this is a problem since there is little data on long-term analgesic efficacy and on the patients ability to tolerate the adverse side effects associated with long term use of the drug. In 10 of the 29 studies37,43,44,47,48,50,56-58,60 pain was the main outcome measure. However, functional and physical measures are equally important in patients with neuropathic pain. These parameters (eg, quantitative sensory testing or QOL), were assessed in the remaining 19 studies. All but one study52 used the traditional approach of classifying the patients with neuropathic diseases not trying to link symptoms to potential pathophysiological mechanisms. As Woolf and colleagues10 suggest a mechanism-based classification of neuropathic pain syndromes would mean carrying out a study on a population with the same symptoms but not necessarily the same disease. This approach may advance our understanding of the treatment of neuropathic pain. Switching from the traditional therapeutic class stratification to one based on putative antineuralgic mechanisms of action would also allow a more rational selection of therapies, and aid evaluation of the additive or synergistic effects of drugs when used in combination. 70 Many studies used a state-of-the-art randomized, doubled-blind, placebo-controlled and crossover in design and were generally executed correctly. Future studies should include a higher number of patients and not only use pain as an outcome but rather include a broader variety of measures, such as disability and QOL. More attention should also be paid to the problem of high attrition rates and clearly studies with longer duration and follow-up periods are warranted. CNS

CONCLUSION Neuropathic pain, including fibromyalgia, has a high prevalence (>2%) in the population. There are different attempts to classify neuropathic pain but there are still many controversies. Theoretically the treatment should be oriented towards pathophysiological consent. Most of the treatments are not based on placebo-controlled clinical trials. However, in clinical practice the most frequently prescribed drugs in chronic neuropathic pain including fibromyalgia are classic TCAs and AEDs, both of them with the wel-known side effects which limit their long-term administration. Recently, the problem has been recognized—there is possible shift from rheumatology to psychiatry—and newer studies have been published or are still in progress. These newer drugs—on the one hand, specific dual NE/5-HT reuptake inhibitors, and on the other hand newer AEDs—are promising in terms of efficacy and fewer side effects. In our review, we found 29 studies investigating different drug classes in various painful neuropathies. The effects of the drugs were different in the drug groups. For example, in the opioid and AED group, eight of 14 studies could demonstrate a superior effect of the drug in comparison with a placebo.34,35,37,39,50,52-54 On average, 15% of the patients dropped out during the study due to side effects or other reasons. Especially in studies evaluating opioids or AEDs the attrition rate was rather high (on average 24% and 23%, respectively). This restricts the internal validity and generizability of the result of these studies.

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Review Article 59. Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 2003;26:770-776. 60. Yuen KCJ, Baker NR, Rayman G. Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray. Diabetes Care. 2002;25:1699-1703. 61. Brill S, Sedgwick PM, Hamann W, Di Vadi PP. Efficacy of intravenous magnesium in neuropathic pain. Br J Anaesth. 2002;89:711-714. 62. Lynch ME, Clark AJ, Sawynok J. A pilot study examining topical amitriptyline, ketamin, and a combination of both in the treatment of neuropathic pain. Clin J Pain. 2003;19:323-328. 63. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ. 2004;329:253. 64. Meier T, Wasner G, Faust M, et ak. Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain. 2003;106:151-158. 65. Sharma U, Iacobellis D, Glessner C. Two studies show pregabalin effectively relieves pain in patients with painful diabetic peripheral neuropathy. Abstract presented at the Annual Meeting of the American Pain Society. November 2-5, 2000; Atlanta, GA. 66. Bryans JS, Wustrow DJ. 3-substituted GABA analogs with central nervous system activity: a review. Med Res Tev. 1999;19:149-177. 67. Kamata M, takahashi H, Sato K, Naito S, Higuchi H. Efficacy of milnacipram for the treatment of chronic pain patients. Poster presented at: Annual meeting of the MYOPAIN congress. July 18-22, 2004; Munich, Germany.

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68. Crofford LJ, Rowbotham MC, Mease PJ, et al. Efficacy of pregabalin for treatment and associated symptoms in patients with fibromyalgia syndrome (FMS). Poster presented at: Annual meeting of the MYOPAIN congress. July 18-22, 2004; Munich, Germany. 69. Psychiatry Congress Reports page [Psychiatry Source web site]. Available at: http:// www.actioncns.com/psychsource/Congress_Reports/Mood_Disorders/article638. htm. Accessed July 26, 2004. 70. Susman E. IDF: Duloxetine Relieves Pain Associated With Diabetic Neuropathy [Doctor's Guide Global Edition Web site]. Available at: http://www.pslgroup. com/dg/2390F2.htm. Accessed July 26, 2004. 71. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, et al. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporter in vitro, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001;25:871-880. 72. Goldstein DJ, Lu Y, Detke MJ, Hudson J, Iyengar S, Demitrack MA. Effects of duloxetine on painful physical symptoms associated with depression. Psychosomatics. 2004;45:17-28. 73. Max MB, Schafer SC, Culnane M, Dubner R, Gracely RH. Association of pain relief with drug side effects in postherpetic neuralgia: a single dose study of clonidine, codeine, ibuprofen, and placebo. Clin Pharmacol Ther. 1988;43:363-371. 74. Beydoun A, Backonja MM. Mechanistic stratification of antineuralgic agents. J Pain Symptom Manage. 2003;25:18-30.

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