Unmet Needs in the Management of Neuropathic Pain

Transcription

1 S12 Journal of Pain and Symptom Management Vol. 25 No. 5S May 2003 Neuropathic Pain: From Mechanisms to Treatment Strategies Unmet Needs in the Management of Neuropathic Pain Norman Harden, MD and Mitchell Cohen, MD Rehabilitation Institute of Chicago (N.H.), Chicago, Illinois, and Pain Medicine (M.C.), Jefferson Medical College, Philadelphia, Pennsylvania, USA Abstract Neuropathic pain is a challenging condition to treat. It is heterogeneous in nature and largely resistant to treatment with commonly prescribed analgesics. Current management strategies fail to achieve adequate or satisfactory pain relief in a high proportion of patients. The four main reasons that treatments for neuropathic pain fail are: inadequate diagnosis and a lack of appreciation of the mechanisms involved; insufficient management of comorbid conditions; incorrect understanding or selection of treatment options; and the use of inappropriate outcomes measures. These unmet needs in the current management of neuropathic pain are reviewed in this article. The review focuses on the need for a methodical and mechanistic approach to diagnosis, and a flexible, interdisciplinary approach to treatment of neuropathic pain conditions, in order to improve pain relief and quality of life in patients with neuropathic pain. J Pain Symptom Manage 2003;25:S12 S U.S. Cancer Pain Relief Committee. Published by Elsevier. All rights reserved. Key Words Neuropathic pain, antiepileptic drug, oxcarbazepine, comorbidity, pain diagnosis, pain management Address reprint requests to: Norman Harden, MD, Rehabilitation Institute of Chicago, 1030 N. Clark Street 320, Chicago, IL 60677, USA. Introduction Neuropathic pain can be defined as pain related to abnormal processing in either the peripheral or central nervous systems following injury to neural tissues. Most nerve damage does not lead to clinically important neuropathic pain; however, in some cases, even small degrees of nerve injury can precipitate severe pain. 1 Studies have demonstrated that neuropathic pain can result in substantial reductions in patients health-related quality of life. 2,3 In addition, comorbid conditions, such as depression, are common complications of chronic pain, and further contribute to increased impairment and disability in patients daily activities. 4,5 Neuropathic pain is recognized as a challenging condition to treat. 6 Symptoms vary considerably among patients and are largely resistant to treatment with commonly prescribed analgesics. 7 However, with appropriate therapy, a significant proportion of patients will experience meaningful pain reduction and improved quality of life. Unfortunately, available data suggest that the clinical management of neuropathic pain is often inadequate. In one recent Scandinavian study, 7% of patients with spinal cord injury were found to be receiving treatment with drugs considered effective against neuropathic pain (antidepressants or antiepileptic drugs [AEDs]). 8 This study was a postal survey of outpatients attending a special U.S. Cancer Pain Relief Committee /03/$ see front matter Published by Elsevier. All rights reserved. doi: /s (03)

2 Vol. 25 No. 5S May 2003 Unmet Needs in the Management of Neuropathic Pain S13 ist rehabilitation center for spinal cord injury in western Denmark, with data available for 330 patients. In contrast to the finding that so few patients were being prescribed AEDs or antidepressants, 43% of the respondents were found to be receiving conventional analgesic therapy (opioids or nonsteroidal anti-inflammatory drugs). Survey of utilization patterns of tricyclic antidepressants (TCAs) in a US multidisciplinary pain clinic found that patients were commonly receiving suboptimal doses. 9 This retrospective review of 1145 patient charts found that only 12% of the 282 patients treated with TCAs were prescribed appropriate doses. Therefore, it is not surprising that a recent US survey of 88 spinal cord injury patients found that the majority of respondents were dissatisfied with the treatment they were receiving for their pain. 10 Overall, there seem to be four main reasons that treatments for neuropathic pain fail: inadequate diagnosis and appreciation of the mechanisms involved; inadequate management of comorbid conditions; incorrect understanding or selection of treatment options; or use of inappropriate outcome measures. This review outlines areas where improvements are required in the current management of neuropathic pain, with a particular focus on pharmacotherapy and management of comorbid conditions. Factors Contributing to Suboptimal Management of Neuropathic Pain Diagnosis Many doctors, including primary care physicians and non-pain specialists (such as diabetologists or neurologists), will encounter patients with neuropathic pain. However, misdiagnosis or a lack of understanding of pain mechanisms by non-specialists is recognized to be a problem throughout the world. In one recent Japanese study involving a total of 6,472 outpatients with diabetes, 85% of patients were found to have neurologic symptoms, yet only half of these patients were identified as suffering from diabetic neuropathy by attending physicians. 11 In contrast, due to a superficial approach to diagnosis, some patients may be being treated for neuropathic pain even though they do not have it. Despite the fact that the number of dedicated pain clinics is increasing worldwide, only a relatively small proportion of patients are referred to pain specialists. Results of a UK study of 703 patients suffering from neuropathic pain found that most (79%) had suffered pain for more than one year before being referred to a pain clinic. 12 This delay may have a detrimental effect on the clinical management and longterm outcomes of these patients, since most had not received appropriate therapy prior to referral. Indeed, fewer than 25% of patients had previously received an adequate trial of antidepressants and only 14% of patients had been appropriately treated with AEDs before attending the pain clinic. Similarly, results of a US study of referral patterns for patients with facial pain (including trigeminal neuralgia) found that patients had seen approximately five different physicians prior to referral to a pain clinic. 13 The variability in referrals to pain clinics may result from difficulties in accurately diagnosing neuropathic pain, 14 such as the use of outdated pain classification systems. In addition, some non-neurologic pain conditions can closely resemble painful neuropathies in symptoms. 15 The precise mechanisms underlying neuropathic pain have yet to be identified, 6,16,17 but several independent pathophysiologic mechanisms in both the peripheral and central nervous systems are thought to be responsible for spontaneous and evoked pains in peripheral neuropathies; 16 these are discussed in more detail elsewhere in this supplement. However, although distinct pathophysiologic mechanisms appear to lead to specific symptoms (e.g., dynamic mechanical allodynia or cold hyperalgesia), these mechanisms and symptoms may change during the course of disease, 16 further complicating the process of accurate diagnosis. The relationships between mechanisms and symptoms are complex (Table 1) 6 and can operate together in a single disease entity (e.g., post-herpetic neuralgia) or in a single patient; it is also not unusual for there to be more than one diagnosis in any particular case. To improve the accuracy of diagnosis, studies are currently ongoing to determine the value of using an additional hierarchically structured system that classifies pain on the basis of: symptoms; symptoms plus signs; symptoms plus signs plus mechanisms; and symptoms plus signs plus mechanisms plus pharmacologic analysis (to determine if a particular symptom can be modulated by a drug with a specific action). 6 By improving diagnostic procedures, it may be possible to dissect out the various elements

3 S14 Harden and Cohen Vol. 25 No. 5S May 2003 Unmet Clinical Needs Table 1 Relationship Between Pathophysiologic Mechanisms and Neuropathic Pain Symptoms Examples One mechanism may produce several symptoms One symptom may be due to several mechanisms One disease may have one or several symptoms Sensitized C-nociceptors may produce ongoing and evoked pain Touch allodynia results from central and peripheral sensitization Diabetic neuropathy may be associated with paroxysms, aching pain and allodynia of neuropathic pain present in individual patients and target rational drug therapy to the relevant pathophysiologic mechanisms that are generating the pain. 16 In doing so, the drugs used to treat neuropathic pain could be stratified into three categories, according to their putative antineuralgic mechanisms of action: sodium channel modulators hypothetically targeting peripheral sensitization and/or ectopic/ ephaptic activity (e.g., phenytoin, carbamazepine, oxcarbazepine (Triceptal, Novartis International AG, Basel, Switzerland), tricyclic antidepressants [TCAs]); calcium flux modulators, operating at the level of the dorsal horn (e.g., oxcarbazepine, carbamazepine, gabapentin, N-methyl-D-aspartate antagonists, and substance-p blockers); and drugs that enhance descending inhibition via their action on serotonin, norepinephrine and opioid transmission (e.g., TCAs, selective serotonin re-uptake inhibitors, serotonin and norepinephrine re-uptake inhibitors, and opioids). A mechanistic approach to treatment, employing these putative drug actions against putative pain generators, is discussed in more detail elsewhere in this supplement. Comorbid Conditions Behavioral and psychiatric comorbidities are very common in patients with neuropathic pain, and may be a consequence of delayed diagnosis or mistreatment. In particular, depression, anxiety disorders, and sleep disorders are more common among patients with chronic or neuropathic pain than in the general population and may be accompanied by substance abuse, abnormal illness behavior and adaptation to chronic illness. A recent review of epidemiologic data on psychiatric comorbidity has indicated that, in all studies, most chronic pain patients had major psychiatric diagnoses. 18 Although discrepancies exist among studies, some have reported a prevalence rate of almost 100% for depression in patients with chronic pain. 18 Therefore, depression may be a consequence, rather than a cause, of chronic pain. Moreover, insomnia is also a common comorbid condition, as pain is generally more severe at night, and 50 70% of patients with pain suffer sleep disturbances. 19,20 Overall, pain may be the most common cause of secondary sleep disturbance. 21 In general, although it is recognized that treatment of comorbidities can lead to improvements in pain and quality of life, the degree of improvement has tended to be suboptimal. Treatment Treatment for neuropathic pain is generally selected on the basis of data from randomized, controlled studies in patients with diabetic polyneuropathy, post-herpetic neuralgia or trigeminal neuralgia. 22,23 However, one of the reasons that treatments for neuropathic pain fail is that they tend to be used in a uniform fashion across the patient population, regardless of individual patients symptoms or syndromes. 24 Unfortunately, due to the heterogeneous nature of neuropathic pain, even within a single etiologic diagnosis, results from these trials cannot always be successfully extrapolated to other syndromes. Treatments may act preferentially or selectively on some components of the studied etiologic diagnosis, rather than producing global and uniform analgesic effects, pointing to the necessity of conducting a thorough evaluation of patients presenting with neuropathic pain. 24 For example, amitriptyline has been shown to be effective in the treatment of diabetic polyneuropathy, 25 but not in HIV-related painful neuropathy. 26 Clinical experience suggests that most of the drugs in current use may be effective against multiple pain components, although these effects have not been confirmed in controlled clinical trials. In fact, very few good studies have

4 Vol. 25 No. 5S May 2003 Unmet Needs in the Management of Neuropathic Pain S15 Table 2 Issues in the Use of Combination Therapy for the Treatment of Neuropathic Pain The frequent need for two or more drugs to control chronic pain The frequent need for at least one drug therapy for psychologic non-pain suffering The frequent need for at least one drug therapy for side effects of core therapies The need for a sound pharmacodynamic/ pharmacokinetic basis for the use of more than one drug from a particular class The need for critical review of the use of three or more drugs for any single indication The need to beware of additive and synergistic effects and drug interactions been conducted and many suffer from a number of shortcomings in methodology (see Outcomes section). Combination therapy with two or more drugs should be considered in the treatment of neuropathic pain in the event of a partial response to monotherapy. 27 For example, it may be logical to add a serotonergic drug to a sodium channel blocker to complement the analgesic effects in the neuroaxis. A number of practical guidelines should be considered in relation to the use of combination therapy in neuropathic pain (Table 2). Basic research in animal models of neuropathic pain and human clinical trials have led to the accumulation of solid evidence that a number of pathophysiologic and biochemical changes take place in the nervous system, at a peripheral or central level, as a result of injury or disease. The many similarities between the pathophysiologic phenomena observed in some models of epilepsy and neuropathic pain have provided the rationale for the inclusion of AEDs in the symptomatic management of neuropathic pain disorders. 28,29 Consequently, AEDs are considered to be one of the mainstays for the treatment of pain in polyneuropathy. 30 However, there are limiting factors when using AEDs in the treatment of neuropathic pain, including: uncertainty as to which symptoms will be responsive, optimum dosage, and tolerability in patients with pain when compared with patients with epilepsy. Recently, new AEDs with more favorable side-effect profiles have been tested in controlled clinical trials for the treatment of neuropathic pain, including painful diabetic neuropathy and post-herpetic neuralgia. The results of these trials, together with advances in the understanding of neuropathic pain pathophysiology, have provided the basis for a re-evaluation of some of the traditional paradigms that have guided therapy for chronic pain. 31 The efficacy and tolerability of oxcarbazepine in neuropathic pain is discussed elsewhere in this supplement. Treatment of neuropathic pain and comorbid conditions often requires the use of combination therapy. 7 Although combination therapy may improve therapy and minimize side effects, it is also labor intensive, as medications generally need to be started at low doses and titrated to achieve effect. 7 In addition, combination therapy may be associated with a number of problems, such as drug-drug interactions, complex dosing regimens and increased risk of side effects, which indicate the need to use a rational approach. Combination therapy alone may be insufficient to provide complete pain relief. The use of non-pharmacologic treatments, such as physiotherapy, psychotherapy or complementary techniques, may also be required on an empiric basis, though there are no noteworthy, evidence-based studies specifically evaluating these techniques in neuropathic pain. Some studies suggest that cognitive behavioral therapy is effective in reducing pain experience and improving positive behavior expression, appraisal, and coping in individuals with chronic pain. 32 In addition, relaxation techniques, such as progressive muscle relaxation, controlled breathing, guided imagery techniques, and hypnosis, may further help the patient to cope with their pain. 33 In the absence of definitive evidence, it is often prudent to develop interdisciplinary teams to complement pharmacotherapy in selected patients. 34 Outcomes Use of inappropriate outcome measures in clinical trials can lead to difficulties in detecting the clinical benefit of therapies. Most studies have simply not been sufficiently powered to detect either the presence or absence of small treatment effects using traditional pain measures. New techniques, such as time series analysis, have provided cost-effective alternatives for analysis of data; however, these have not received much support from the US Food and Drug Administration.

5 S16 Harden and Cohen Vol. 25 No. 5S May 2003 Until recently, outcome measures in clinical trials of drug treatments for peripheral neuropathic pain consisted of pain intensity and relief measures. The intensity of ongoing and evoked pain, for example, has been assessed using a visual analog scale (VAS). These measures do not adequately reflect the patients suffering or the therapeutic ratio of a treatment. 2 The subjective nature of pain and poor patient recall can complicate the measurement of outcomes in neuropathic pain. For example, it can be difficult for patients to measure pain relief on a VAS when they cannot adequately recall what the baseline level of pain felt like. Also, while physicians may find 50% pain relief on a VAS to be a convenient outcome measure, patients may find a return to normal daily activities to be a far more relevant indicator of treatment success. The subject of what constitutes a clinically meaningful reduction in pain has been discussed further in the literature. 35,36 Subjective measures may be important in determining meaningful pain reduction; however, it may be unwise to rely on this outcome alone. Overall, it may be necessary to use both subjective measures and objective, functional outcomes to determine the true, meaningful, pain-relieving capabilities of a treatment. Hence, pain intensity, reduced work status, interference with home or leisure activities, side effects of drug treatment, and comorbid symptoms all contribute to the multidimensional impairment of health-related quality of life for patients with neuropathic pain. 2 Outcome measures in the study of chronic pain should reflect the Bio-Psycho-Social phenomena of this condition. In view of these issues, the use of realistic, validated, and defined measures are required. This differs from the day-today situation for the clinician who is exposed to pragmatic n of one empiric situations, where outcomes may be easier to measure since the patients themselves will determine what, to them, is meaningful relief. Conclusions Despite a significant increase in our understanding of neuropathic pain syndromes over recent years, the clinical management of patients with this condition remains challenging. Many patients are not receiving optimal therapy, with very few patients achieving complete pain relief. In order to provide optimal pain relief for patients, current treatment strategies need to address the multifactorial nature of this condition, including its heterogeneity and the presence of comorbid conditions. This requires a methodical and mechanistic approach to diagnosis, and a patient, flexible, interdisciplinary approach to treatment. References 1. Farrar JT, Portenoy RK. Neuropathic cancer pain: the role of adjuvant analgesics. Oncology (Huntingt) 2001;15: , Meyer-Rosberg K, Burckhardt CS, Huizar K, et al. A comparison of the SF-36 and Nottingham Health Profile in patients with chronic neuropathic pain. Eur J Pain 2001;5: Meyer-Rosberg K, Kvarnstrom A, Kinnman E, et al. Peripheral neuropathic pain a multidimensional burden for patients. Eur J Pain 2001;5: Gallagher RM, Verma S. Managing pain and comorbid depression: a public health challenge. Semin Clin Neuropsychiatry 1999;4: Clark MR, Heinberg LJ, Haythornthwaite JA, et al. Psychiatric symptoms and distress differ between patients with postherpetic neuralgia and peripheral vestibular disease. J Psychosom Res 2000;48: Jensen TS, Gottrup H, Sindrup SH, et al. The clinical picture of neuropathic pain. Eur J Pharmacol 2001;429: Orza F, Boswell MV, Rosenberg SK. Neuropathic pain: review of mechanisms and pharmacologic management. Neuro Rehabilitation 2000;14: Finnerup NB, Johannesen IL, Sindrup SH, et al. Pain and dysesthesia in patients with spinal cord injury: A postal survey. Spinal Cord 2001;39: Richeimer SH, Bajwa ZH, Kahraman SS, et al. Utilization patterns of tricyclic antidepressants in a multidisciplinary pain clinic: a survey. Clin J Pain 1997;13: Murphy D, Reid DB. Pain treatment satisfaction in spinal cord injury. Spinal Cord 2001;39: Kawano M, Omori Y, Katayama S, et al. A questionnaire for neurological symptoms in patients with diabetes cross-sectional multicentre study in Saitama Prefecture, Japan. Diabetes Res Clin Pract 2001;54: Davies HT, Crombie IK, Macrae WA. Why use a pain clinic. Management of neurogenic pain before or after referral. J R Soc Med 1994;87: Turp JC, Kowalski CJ, Stohler CS. Treatmentseeking patterns of facial pain patients: many possi-

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