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Address reprint requests to: M. Sam Chong, MD, Department of Neurology, King's College Hospital, Mapother House, De Crespigny Park, London, SE5 9AZ, UK
Affiliations
Department of Neurology, King's College Hospital, London, and The Medway Hospital, Gillingham, Kent, UK
Currently, no consensus on the optimal management of neuropathic pain exists and practices vary greatly worldwide. Possible explanations for this include difficulties in developing agreed diagnostic protocols and the coexistence of neuropathic, nociceptive and, occasionally, idiopathic pain in the same patient. Also, neuropathic pain has historically been classified according to its etiology (e.g., painful diabetic neuropathy, trigeminal neuralgia, spinal cord injury) without regard for the presumed mechanism(s) underlying the specific symptoms. A combined etiologic/mechanistic classification might improve neuropathic pain management. The treatment of neuropathic pain is largely empirical, often relying heavily on data from small, generally poorly-designed clinical trials or anecdotal evidence. Consequently, diverse treatments are used, including non-invasive drug therapies (antidepressants, antiepileptic drugs and membrane stabilizing drugs), invasive therapies (nerve blocks, ablative surgery), and alternative therapies (e.g., acupuncture). This article reviews the current and historical practices in the diagnosis and treatment of neuropathic pain, and focuses on the USA, Europe and Japan.
is a common symptom of a heterogeneous group of conditions, including diabetic neuropathy, trigeminal neuralgia, post-herpetic neuralgia and spinal cord injury.
The true prevalence of neuropathic pain is largely unknown because of the lack of proper epidemiologic studies. Current estimates suggest that around 1.5% of the general population in the US may be affected,
since there can be a neuropathic component in the pain experienced by patients with cancer, degenerative diseases, or neurologic conditions (such as Parkinson's disease) that has so far gone unnoticed. These conditions are most prevalent in the aging population; since the size of this population is increasing worldwide, it is inevitable that neuropathic pain will place a progressively demanding burden on healthcare resources. Thus, there is a need to reassess neuropathic pain and its treatment.
This paper explores the similarities and differences between historical and current practices for the clinical management of patients suffering from neuropathic pain around the world, with particular focus on the US, Europe and Japan.
Diagnosis
While the history of pain research is long, dating back centuries, it was not until the International Association for the Study of Pain (IASP) was founded in 1973 that attention focused on the causes and treatment of neuropathic pain. The IASP published its first list of pain terms in 1979.
However, neuropathic pain was not included in the list until 1994, when it was then defined as ‘pain initiated or caused by a primary lesion or dysfunction in the nervous system’ (Table 1).
This very broad definition encapsulates the concept that, when a nerve becomes damaged, changes within the neural pathways can result in chronic pain even in the absence of a continuing stimulus. Although this theory has now gained general acceptance, it was initially a revolutionary idea that repudiated the Cartesian model of nociception and pain. Thus, neuropathic pain is categorically different from nociceptive pain, which results from activation of nociceptive sensory axons by noxious stimuli. Nociceptive pain is usually finite, localized, and subsides with healing or removal of the noxious substance. The characteristic symptoms of neuropathic pain are described in more detail elsewhere in this supplement.
Table 1A Selecion of Pain Terms Plus Definitions From the Published IASP List of Pain Terms
An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such
Allodynia
Pain due to a stimulus which does not normally provoke pain
Causalgia
A syndrome of sustained burning pain, allodynia, and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes
Central pain
Pain initiated or caused by a primary lesion or dysfunction in the central nervous system
Dysesthesia
An unpleasant abnormal sensation, whether spontaneous or evoked
Hyperalgesia
An increased response to a stimulus which is normally painful
Hyperpathia
A painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold
Neuralgia
Pain in the distribution of a nerve or nerves
Neuropathic pain
Pain initiated or caused by a primary lesion or dysfunction in the nervous system
Neuropathy
A disturbance or pathologic change in a nerve; in one nerve, mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse and bilateral, polyneuropathy
Nociceptor
A receptor preferentially sensitive to a noxious stimulus or to a stimulus which would become noxious if prolonged
Noxious stimulus
A noxious stimulus is one which is damaging to normal tissues
Paresthesia
An abnormal sensation, whether spontaneous or evoked
Peripheral neuropathic pain
Pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system
The separation of stimulus from symptom is partly responsible for the difficulties in diagnosing neuropathic pain. If the IASP definition is strictly applied, the clinician needs only to demonstrate nerve damage or dysfunction in a patient experiencing pain to make the diagnosis of neuropathic pain. However, nerve damage and/or dysfunction may manifest itself as negative symptoms (sensory loss) as well as positive symptoms (e.g., paresthesia, hyperalgesia). Although the sensitivity of the IASP definition is potentially high, the specificity is low, since not all patients with nerve damage experience neuropathic pain. This may lead to a situation in which a patient with nerve damage and coincidental pain from another source is misdiagnosed with neuropathic pain and subsequently mistreated. Conversely, neuropathic pain may be under-diagnosed when the signs and symptoms of neural dysfunction are not recognized.
Therefore, the diagnostic work-up in patients with suspected neuropathic pain must include a detailed medical history and review of systems, in addition to a comprehensive physical and neurologic examination.
The medical history provides insight into the onset, location, and distribution of the pain (since this often matches the degree of neural lesion), and the possible association of the pain with trauma (e.g., surgery or current diseases). In addition, the quality of the pain should be recorded using pain descriptors (e.g., shooting, burning, aching) provided by the patient. Since the diagnosis of neuropathic pain rests heavily on the demonstration of sensory abnormalities in the area innervated by the suspected damaged nerve, a thorough clinical examination should be performed to determine the presence and extent of sensory deficits, using a range of instruments (e.g., warm and cold metal rollers for temperature sensation, a camel hair brush for touch sensation, and a pin for pain sensation).
A recently introduced assessment tool—the Neuropathic Pain Scale (NPS)—has been developed based on descriptors that specifically define the most common qualities of neuropathic pain.
The NPS is an easily administered tool that provides a reproducible appraisal of the type of symptoms experienced by the individual patient, which may eventually allow the clinician to tailor treatment according to the patient's symptoms. While it remains to be determined whether use of this scale contributes to improvements in diagnosis or clinical management of neuropathic pain, validation of national versions of this scale appear indicative of its potential clinical use.
Other scales specific to the assessment of neuropathic pain are also under development (e.g., the Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale).
The classification of neuropathic pain is a complex matter, for which guidelines exist. The traditional approach classifies neuropathic pain according to the underlying cause (e.g., painful diabetic neuropathy, trigeminal neuralgia, post-herpetic neuralgia or spinal cord injury), as well as the presumed location of the nerve injury (peripheral or central).
Again, a detailed medical history and examination are prerequisites for this system. In addition, it is important to stratify the various drugs used to treat neuropathic pain according to their putative anti-neuralgic mechanisms of action.
Beydoun A. Symptomatic treatment of neuropathic pain: A focus on the role of anticonvulsants. Medscape CME Circle Lecture 2001. http://www. medscape.com/.
This mechanistic stratification is discussed in detail elsewhere in this supplement.
Treatment Strategies
Historically, the earliest treatment strategies for neuropathic pain were invasive in nature. By applying the Cartesian model for pain, it was hoped that blocking neural transmission, either temporarily using local anesthetics or permanently by surgical nerve ablation, would alleviate pain. These techniques were particularly favored in the treatment of chronic pain associated with amputations or wounds suffered by soldiers during the great wars. In 1916, Leriche suggested that vasomotor changes seen in patients with peripheral nerve damage might indicate an association between pain and abnormal vascular stimulation: this led to the use of periarterial sympathectomy in an attempt to alleviate pain. However, none of these therapies was found to be consistently successful.
Currently, there are several treatment strategies for managing neuropathic pain, including both invasive and non-invasive therapies (Fig. 1). Published guidelines exist for the treatment of neuropathic pain in general (Fig. 1),
However, these recommendations are usually based on anecdotal evidence or clinical trials showing efficacy of a therapy in some patients with a particular causative condition for their neuropathic pain. In addition, many of these early trials randomized small numbers of patients and were often poorly designed.
Fig. 1Algorithm for the treatment of neuropathic pain (GABA-B-gamma aminobutyric acid-B). Reproduced with kind permission.13
One of the simplest forms of non-invasive treatment for pain is transcutaneous electrical nerve stimulation (TENS). This has been used since the 1960s, following the development of the gate control theory of pain transmission by Melzack and Wall.
The technique is based on the interaction between small and large afferent fibers, which converge on the dorsal horn neurons before projecting to higher centers, and is a useful adjunctive treatment that is virtually free from adverse effects.
Pharmacotherapy remains the mainstay of neuropathic pain management. Since neuropathic pain may be partially or completely unresponsive to primary analgesic treatments, medical therapies for neuropathic pain tend to involve adjuvant analgesics (ie drugs whose primary indication is not analgesia), such as antiepileptic drugs (AEDs), antiarrythmics and antidepressants. Adjuvant analgesics used to treat neuropathic pain can be broadly categorized into membrane stabilizing agents, which inhibit ectopic discharges on damaged neural membranes (e.g., AEDs), and drugs that enhance dorsal horn inhibition (e.g., antidepressants) (Fig. 1).
Early clinical trial results suggested that antidepressants might have a direct analgesic action; however, many of these trials were uncontrolled or complicated by the presence of an adjuvant pain-relieving drug.
More recent clinical trials have clearly demonstrated that antidepressants directly alleviate pain in a proportion of patients with neuropathic pain, though pain relief may be incomplete and some patients are totally unresponsive to this treatment.
The most effective antidepressants used to treat neuropathic pain are the tricyclic antidepressants, which have been used to manage neuropathic pain for over 30 years.
Unfortunately, tricyclic antidepressants are often associated with treatment-limiting adverse effects. The newer antidepressants, such as the serotonin selective re-uptake inhibitors, are better tolerated but appear to be less efficacious than the tricyclic antidepressants.
Beydoun A. Symptomatic treatment of neuropathic pain: A focus on the role of anticonvulsants. Medscape CME Circle Lecture 2001. http://www. medscape.com/.
The first published trial of an AED for the treatment of neuropathic pain was in 1942, when Bergouignan used phenytoin to treat patients with trigeminal neuralgia, on the basis that the condition resembled the neuronal hyperexcitability seen in some epilepsy models.
Different AEDs may act via different mechanisms, but most drugs in this class possess some ability to reduce neuronal hyperexcitability by inhibiting sodium channels. The mechanisms of action of AEDs in neuropathic pain are discussed further elsewhere in this supplement. As with the antidepressants, the main problem with using AEDs is their tolerability profile: adverse effects include dizziness and sedation and these tend to be worse with the older generation AEDs.
Again, the evidence for the effectiveness of most AEDs in neuropathic pain comes from anecdotal evidence and a few trials of patients with specific causative conditions.
Generally, the current evidence on efficacy does not support the use of one drug over another. The selection of a particular drug may depend on the experiences of the clinician and the patient, as well as expected side effects. In addition, more than one drug may be necessary to optimize pain control. Unfortunately, existing data on combination drug therapy for neuropathic pain are even more inadequate; management of neuropathic pain by combined drug treatment is entirely empirical and the guiding principle is to choose drugs according to their additional therapeutic effects rather than their adverse effects.
Invasive Therapies
The range of neurosurgical techniques used to treat neuropathic pain has increased over time, and includes nerve modulation (e.g., dorsal column stimulation) as well as neural ablation.
Numerous ablative surgical techniques to destroy nerves have been described, including nerve avulsion or section, dorsal rhizotomy, spinal dorsal root entry zone lesions, spinothalamic tractotomies, thalamotomies, cingulotomy, frontal lobotomy, and even destruction of the primary sensory cortex. However, these treatments are generally not recommended as they cause more damage to the nervous system, which can intensify the neuropathic pain. Furthermore, none of these surgical techniques has been found to be uniformly successful in treating patients with neuropathic pain. Indeed, there are many examples in the literature of patients who have undergone surgical therapies to treat pain (e.g., due to nerve injury, trigeminal neuralgia, amputation, or post-herpetic neuralgia), only to find that surgery has exacerbated their original pain.
An invasive treatment regimen that is supported by some clinical evidence, and a fairly convincing rationale, is spinal cord dorsal column stimulation. As with TENS, this technique attempts to modulate rostral nociceptive transmission in the spinal cord by stimulation of the large diameter nerve fibers. Success depends on patient selection, and it is generally accepted that patients also suffering some ischemic pain are particularly suited to this method of treatment.
The major advantage of this technique is that nerves are not deliberately damaged. Similarly, clinical evidence supports the use of microvascular decompression in providing relatively good long-term outcome for patients with trigeminal neuralgia.
in: Zakrewska J.M. Harrison S.D. Assessment and management of orofacial pain. Pain research and clinical management series; Vol. 14. Elsevier Science,
Amsterdam2002
Temporary nerve blocks achieved by injection of local anesthetic (e.g., lidocaine), are still sometimes used, though efficacy is controversial and few placebo-controlled trials of this therapy have been performed.
The available data clearly indicate that approaches to the clinical management of neuropathic pain vary according to whether the patient is being treated by a pain specialist or by a non-specialist. While non-specialists tend to treat individual symptoms, pain specialists are more likely to select a drug therapy that is targeted towards the mechanisms that are presumed to be causing pain in an individual patient or the anti-neuralgic mechanisms of various drugs.
Beydoun A. Symptomatic treatment of neuropathic pain: A focus on the role of anticonvulsants. Medscape CME Circle Lecture 2001. http://www. medscape.com/.
The available data clearly indicate that patients treated in specialized pain clinics are more likely to receive therapies with proven efficacy for the treatment of neuropathic pain than those treated in non-specialist clinics.
One study of 379 patients newly referred to a German pain clinic, 18% of whom had a diagnosis of neuropathic pain, found that 74% obtained pain relief of more than 50% compared with baseline on their new treatment plan.
Notably, these patients had suffered from pain for a mean of 8 years and had seen an average of 8 different physicians prior to referral to the pain clinic.
National Issues
Management of neuropathic pain syndromes can, in some cases, be handled by the specialist pain physician; however, a multidisciplinary approach is often required, encompassing education and physical, occupational and behavioral therapy. Use of pragmatic, functional restoration algorithms is common (Fig. 2) and pharmacotherapy is generally only used when this approach fails.
Fig. 2Example of the type of functional restoration algorithm typically used for the management of patients with neuropathic pain in the USA. Reproduced with kind permission.27
In many countries, the use of ‘complementary’ or ‘alternative’ therapies is not uncommon. For example, in the USA, a telephone survey of 77 patients who were suffering from chronic pain due to spinal cord injury found that 40% of the patients had tried one or more ‘alternative’ approaches, most commonly acupuncture, to manage their pain.
In Japan, tolerability is considered the most influential factor when choosing therapy and, consequently, monotherapy is generally prescribed, particularly by non-pain specialists. Most drugs currently used for neuropathic pain in Japan have good tolerability but low efficacy; for example, vitamin B12 and aldose reductase inhibitors are often prescribed for painful diabetic neuropathy. Pain specialists usually aim to treat intractable pain with drugs that cause neural blockade.
Off-label prescribing is not permitted in Japan. Clinical trials of drugs for neuropathic pain are conducted in specific conditions, leading to an indication for that particular condition if successful, but not for neuropathic pain in general. Consequently, in contrast to the situation in Europe and the USA, tricyclic antidepressants are rarely used for the treatment of neuropathic pain, with the exception of evening doses for the relief of nocturnal symptoms. Tricyclic antidepressants and newer AEDs are more commonly used for the treatment of neuropathic pain in Europe.
The clinical efficacy of different treatment options may be compared by calculating the number-needed-to-treat (NNT), i.e., the number of patients that must be treated with a given drug in order to obtain at least a 50% reduction in pain severity in a single patient.
Although the NNT can also be determined for 25% or 75% pain relief, 50% pain relief is commonly used because it is an easily understood concept and is generally accepted to be indicative of a relevant clinical effect. Only placebo-controlled trials can be used to calculate the NNT, since a correction for placebo responders is included in the formula. Figure 3 shows the NNT for a number of different drugs commonly used in the treatment of neuropathic pain, calculated from results of placebo-controlled trials in different neuropathic pain conditions.
However, in the absence of direct head-to-head trials, it appears that comparison of NNT is the best indicator of comparative efficacy currently available.
At present, there is no consensus concerning the optimal therapeutic strategy for neuropathic pain and its comorbid conditions. Reasons for this include the relatively recent recognition of neuropathic pain as a condition in its own right, difficulties in establishing unequivocal diagnoses, and the scarcity of well-designed, large clinical trials to evaluate the efficacy of drugs for treating neuropathic pain. Since there is no systematic or mechanistic approach to neuropathic pain management, treatment strategies are generally based around anecdotal evidence and data from a few clinical trials. As a result, a patient may receive several therapies before pain relief is obtained. Thus, historically, there has been an empirical approach to the management of neuropathic pain. More recently, it has been suggested that clinicians should concentrate more on the mechanisms underlying the symptoms of neuropathic pain, and use this as a basis for the treatment approach. This will hopefully result in more rational and improved strategies for managing patients suffering from this condition.
Acknowledgements
The authors would like to thank Professor Troels Jensen for his help in writing this article.
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Beydoun A. Symptomatic treatment of neuropathic pain: A focus on the role of anticonvulsants. Medscape CME Circle Lecture 2001. http://www. medscape.com/.
in: Zakrewska J.M. Harrison S.D. Assessment and management of orofacial pain. Pain research and clinical management series; Vol. 14. Elsevier Science,
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