Chronic neuropathic pain develops in approximately 40% of people after a spinal cord injury (SCI) and is notoriously difficult to treat. Because of the frequent presence of more than one pain type and the complex mechanisms and symptoms associated with pain in individuals with SCI, a thorough evaluation is important. This review includes an overview of the most recent guidelines for evaluating and classifying pain, suggestions for standardizing outcome measures for clinical use, and a review of the positive and negative evidence for pharmacologic and nonpharmacologic interventions to consider when treating individuals with SCI and chronic neuropathic pain.
Key points
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Chronic neuropathic pain after a spinal cord injury (SCI) is common and difficult to treat in many patients. The evaluation and proper diagnosis of the pain conditions of patients with SCI are especially important in this patient group in order to make informed treatment decisions.
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The use of validated assessment tools and questionnaires in clinical practice can help the physiatrist track outcomes when new treatment approaches are embarked on and offer an avenue for enriched discussion with, and evaluation of, patients in pain.
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Although studies of the long-term efficacy of pharmacologic agents for pain management in patients with SCI and neuropathic pain are lacking, strong support for the safety and efficacy of pregabalin does exist. Gabapentin, amitriptyline, and duloxetine have less support but may be effective in some patients.
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Even fewer clinical trials exist for nonpharmacologic treatment strategies, such as massage, acupuncture, and transcutaneous, spinal, and transcranial stimulation, although survey studies show that persons with SCI and chronic pain are receptive to such therapies and often report good outcomes.
Introduction
The presence of chronic pain in patients with spinal cord injury (SCI) is the rule, not the exception, with most studies estimating that approximately 70% of individuals with SCI have persistent pain that does not subside with time. The impact that chronic pain has on emotional function, activities of daily living, and quality of life in those patients with SCI is well documented.
Chronic pain after SCI is most commonly either nociceptive or neuropathic in nature. The mechanisms and treatment approaches for nociceptive pains are typically more easily identified than those for neuropathic pains; although the prevalence of chronic neuropathic pain in persons with SCI is lower (approximately 40% ) than for nociceptive pains, it is generally rated as more severe.
The possible symptoms and signs for neuropathic pain are shown in Box 1 . An individual with neuropathic pain may exhibit all or only a few of these components of neuropathic pain. Typically, a patient will complain of spontaneous burning pain that is continuously present and may be accompanied by dysesthesias often described as tingling or pricking. He or she may also describe electric shock–like or stabbing sensations that are intermittent and may or may not be provoked by stimulation. Some patients will also describe being especially sensitive in the area of neuropathic pain, referring to pain that is induced by light touch or moderate thermal stimuli (ie, allodynia) and to particularly severe pain elicited by normally mild nociceptive stimuli (ie, hyperalgesia).
Spontaneous pain
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Burning, pricking
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Nonpainful sensations (tingling, itching)
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Continuous
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Intermittent/paroxysmal
Evoked pain
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Allodynia
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Hyperalgesia
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Tactile
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Thermal
Neuropathic pain is generally identified by its spontaneous pain characteristics, which may include all or some of the qualities listed. Exaggerated pain provoked by tactile or thermal stimuli is present in many, but not all, cases of neuropathic pain.
Much research has been devoted to understanding the mechanisms of neuropathic pain and investigating the efficacy of several treatment options so that most patients who develop this type of pain might realize the reduction or elimination of pain. Although neuropathic pain caused by SCI shares some mechanisms with neuropathic pain of other origins, several treatments that have been shown to be effective in other patient groups, particularly those with peripheral neuropathic pain, have been less effective for individuals with SCI.
Suggestions for the proper evaluation of patients with SCI who have pain; for treatment approaches, both pharmacologic and nonpharmacologic; and for monitoring the efficacy of treatments in patients with pain are presented in this review. Definitions for the pain terminology used can be found in Box 2 .
Pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage
Nociceptive pain: Pain that arises from actual or threatened damage to non-neural tissue and is caused by the activation of nociceptors
Neuropathic pain: Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system
Spontaneous pain: Pain that is not evoked by a known stimulus
Evoked pain: Pain that is caused by an external stimulus
Allodynia: Pain caused by a stimulus that does not normally provoke pain
Hyperalgesia: Increased pain from a stimulus that normally provokes pain
Dysesthesia: An unpleasant abnormal sensation, whether spontaneous or evoked (can include allodynia or hyperalgesia)
Introduction
The presence of chronic pain in patients with spinal cord injury (SCI) is the rule, not the exception, with most studies estimating that approximately 70% of individuals with SCI have persistent pain that does not subside with time. The impact that chronic pain has on emotional function, activities of daily living, and quality of life in those patients with SCI is well documented.
Chronic pain after SCI is most commonly either nociceptive or neuropathic in nature. The mechanisms and treatment approaches for nociceptive pains are typically more easily identified than those for neuropathic pains; although the prevalence of chronic neuropathic pain in persons with SCI is lower (approximately 40% ) than for nociceptive pains, it is generally rated as more severe.
The possible symptoms and signs for neuropathic pain are shown in Box 1 . An individual with neuropathic pain may exhibit all or only a few of these components of neuropathic pain. Typically, a patient will complain of spontaneous burning pain that is continuously present and may be accompanied by dysesthesias often described as tingling or pricking. He or she may also describe electric shock–like or stabbing sensations that are intermittent and may or may not be provoked by stimulation. Some patients will also describe being especially sensitive in the area of neuropathic pain, referring to pain that is induced by light touch or moderate thermal stimuli (ie, allodynia) and to particularly severe pain elicited by normally mild nociceptive stimuli (ie, hyperalgesia).
Spontaneous pain
- •
Burning, pricking
- •
Nonpainful sensations (tingling, itching)
- •
Continuous
- •
Intermittent/paroxysmal
Evoked pain
- •
Allodynia
- •
Hyperalgesia
- •
Tactile
- •
Thermal
Neuropathic pain is generally identified by its spontaneous pain characteristics, which may include all or some of the qualities listed. Exaggerated pain provoked by tactile or thermal stimuli is present in many, but not all, cases of neuropathic pain.
Much research has been devoted to understanding the mechanisms of neuropathic pain and investigating the efficacy of several treatment options so that most patients who develop this type of pain might realize the reduction or elimination of pain. Although neuropathic pain caused by SCI shares some mechanisms with neuropathic pain of other origins, several treatments that have been shown to be effective in other patient groups, particularly those with peripheral neuropathic pain, have been less effective for individuals with SCI.
Suggestions for the proper evaluation of patients with SCI who have pain; for treatment approaches, both pharmacologic and nonpharmacologic; and for monitoring the efficacy of treatments in patients with pain are presented in this review. Definitions for the pain terminology used can be found in Box 2 .
Pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage
Nociceptive pain: Pain that arises from actual or threatened damage to non-neural tissue and is caused by the activation of nociceptors
Neuropathic pain: Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system
Spontaneous pain: Pain that is not evoked by a known stimulus
Evoked pain: Pain that is caused by an external stimulus
Allodynia: Pain caused by a stimulus that does not normally provoke pain
Hyperalgesia: Increased pain from a stimulus that normally provokes pain
Dysesthesia: An unpleasant abnormal sensation, whether spontaneous or evoked (can include allodynia or hyperalgesia)
Patient evaluation overview
Comprehensive Evaluation of Patients in Pain
It has often been suggested that patients with chronic pain need to be evaluated and treated with several factors in mind, including the potential cause of pain; the severity of pain; the functional limitations caused by pain; and the history, psychology, behavior, and cultural characteristics of the patients. Considering the complexity of health, social, and psychological issues that patients with SCI face, this global approach is especially important. In order to best select and evaluate treatments, therefore, the clinician should include several assessments, targeting different domains of the pain experience, and not concentrate only on the reduction of pain intensity when determining treatment efficacy in patients.
Establishing a Diagnosis of Neuropathic Pain in SCI
Chronic pain conditions can result from several causes; signs and symptoms of the same underlying pathophysiology may differ from patient to patient, thus, establishing that a patient’s reported pain is neuropathic in nature is not always straightforward. The criteria for determining a diagnosis of neuropathic pain were proposed by the Special Interest Group on Neuropathic Pain (NeuPSIG) of the International Association for the Study of Pain (IASP) in 2008. This group of experts suggested a grading system of definite , probable , and possible neuropathic pain. According to their published criteria, a definite neuropathic pain diagnosis would require (1) a pain distribution consistent with injury to the peripheral nervous system (PNS) or the central nervous system (CNS), (2) a previous or current injury or disease affecting the PNS and/or CNS, (3) abnormal sensory signs within the body area corresponding to the injured part of the CNS or PNS, and (4) a diagnostic test confirming a lesion or disease in these structures. Based on these definitions, almost any pain reported at and/or below the neurologic level of injury in a person with SCI would qualify as a neuropathic pain. This general definition of neuropathic pain could be especially problematic for pains located at the level of injury, in which sensory dysfunction (requirement [3] of the aforementioned definition) could be present in an area where either or both nociceptive and neuropathic mechanisms underlie the pain report. Taking this into account, Finnerup and Baastrup added additional criteria for neuropathic pain specifically for persons with SCI: (1) onset of pain within 1 year following SCI; (2) no primary relation to movement, inflammation, or other local tissue damage; and (3) hot-burning, tingling, pricking, pins-and-needles, sharp, shooting, squeezing, cold, electric, or shock-like quality of pain.
Based on these criteria, a determination of a probable neuropathic pain diagnosis can be made by a careful examination and interview of patients with SCI, which can be assisted by using validated self-report measures, some of which are specifically targeted toward neuropathic pain characteristics ( Table 1 ; also see “Tools for Diagnosis and Evaluation of Neuropathic Pain” section later). Additionally, the presentation of select stimuli to evaluate positive or negative sensory signs (ie, hyposensitivities or hypersensitivities) in areas where spontaneous pain is reported will yield further insight.
| Type of Assessment | Measurement Tool | Description |
|---|---|---|
| Neuropathic Pain Questionnaire | 12 items assessing the presence and severity of different qualities of pain and sensations associated with neuropathic pain; includes 2 affective aspects (unpleasant, overwhelming); sensitivity = 66%, specificity = 75% |
| Pain-DETECT | 9 items regarding symptoms associated with neuropathic pain; 2 items regarding presence of evoked sensations; ≥19 = neuropathic pain likely; ≤12 = neuropathic pain unlikely; sensitivity = 85%, specificity = 80% | |
| ID Pain | 6 items used to discriminate between neuropathic and nociceptive pain; >3 = likely presence of neuropathic pain | |
| Leeds Assessment of Neuropathic Symptoms and Signs | 7 items: 5 self-report symptoms and 2 physical assessments for brush allodynia and pinprick hyperalgesia; ≥12 = neuropathic pain likely; sensitivity = 85%, specificity = 80% | |
| Douleur Neuropathique en 4 questions | 10-item questionnaire and assessment; 7 self-report items of the presence of specific pain qualities associated with neuropathic pain and 3 physical examination items for decreased sensitivity to touch and pinprick and allodynia to brushing; >4 = likely neuropathic pain; sensitivity = 83%, specificity = 90% | |
| Numerical rating scale | 0–10 scale, where 0 typically means no pain and 10 is typically defined as the most intense pain imaginable; patients must choose a number to represent the intensity of their pain |
| Visual analog scale | 10-cm horizontal line is presented to patients, with “no pain” as an anchor at the left end and “the most intense pain imaginable” as an anchor on the right end of the line; patients are instructed to estimate pain intensity by marking on the line the place where pain intensity falls | |
| Verbal rating scale | Patients choose a word/phrase to indicate pain intensity: no pain, slight pain, mild pain, moderate pain, severe pain, extreme pain, the most intense pain imaginable | |
| Neuropathic Pain Scale | 1 item to rate overall intensity of pain; 6 items to assess the intensity of separate qualities of pain (eg, burning, sharp, itchy); 1 item to assess temporal aspects of pain; 1 item to rate unpleasantness of pain; and separate ratings for the intensity of surface and deep pain |
| Neuropathic Pain Symptom Inventory | 10 items for rating the intensity of different qualities or evoked aspects of pain; 2 items to evaluate temporal aspects of pain; 5 subscale scores can be calculated as well as a total score | |
| Interference subscale of the Brief Pain Inventory–short form | 7 items to rate regarding the interference of pain on activities, sleep, mood, and relationships; a revised version for patients with disability has been published |
| Life Interference subscale of the Multidimensional Pain Inventory | Assesses activities of daily living and social aspects (relationships with family, friends) regarding the impact that pain has on the satisfaction or enjoyment of each activity/relationship; a revised version for use with patients who have SCI has been published | |
| Beck Depression Inventory | 21 items scored on a 0–4 scale, with higher scores indicating greater depressive symptoms; scores ≥17 are considered borderline, or worse, clinical depression |
| Spielberger State-Trait Anxiety Inventory | 20 items are rated to evaluate state anxiety and 20 items are rated to evaluate trait anxiety | |
| Hospital Anxiety and Depression Scale | 7 items evaluate anxiety and 7 items evaluate depression; can be used to evaluate the extent of anxiety and depressive symptoms in patients | |
| Pain Catastrophizing Scale | 13 items each rated on a 5-point scale to evaluate the extent the individual engages in catastrophic thinking with regards to pain; a total score and 3 subscale scores (rumination, magnification, helplessness) can be calculated | |
| Patient Global Impression of Change | Typically one question is used that is suited to the situation (eg, Compared with the time before you started this medication, how would you rate your condition now?); response categories are provided ranging from very much improved to very much worse |
SCI Pain Taxonomy
It is important to note that most patients with SCI have more than one persistent pain problem, so differentiating between a patient’s pains, with respect to location, quality, and factors that increase or decrease the pain, is particularly important for comprehensive pain management. This necessity is evident in the International Spinal Cord Injury Basic Pain Dataset (ISCIBPD) and the International Spinal Cord Injury Pain (ISCIP) Classification, which require that each pain that an individual experiences is evaluated separately in order to best define a patient’s pain profile.
The ISCIP Classification, published in 2012, is an attempt by international experts in the SCI and pain community to develop a consensus classification scheme so that research and clinical efforts are not confused by differences in nomenclature or criteria. The ISCIP Classification consists of a 3-tiered structure, with the first tier differentiating nociceptive , neuropathic , other , and unknown pain. In accordance with the IASP’s definitions, the ISCIP Classification identifies nociceptive pain as pain that is caused by the activation of nociceptors and neuropathic pain as pain that is caused by a lesion or disease of the somatosensory nervous system. The ISCIP defines other pain as pain that does not have an identifiable cause attributable to nociceptive or neuropathic mechanisms and is unrelated to SCI onset but that has been defined (eg, fibromyalgia, complex regional pain syndrome type I). Unknown pain types are those pains for which nociceptive , neuropathic , or other cannot be reasonably assigned.
It is recognized in the ISCIP Classification that a pain located in the same or overlapping areas can be classified as having more than one component (eg, nociceptive and neuropathic) based on the presenting signs and symptoms as well as imaging diagnostics. The primary reason for identifying different types of pains using a consensus classification scheme is so that the principal mechanisms causing the pain may be identified and studied and, thus, treatment approaches can be better selected and evaluated.
Types of Neuropathic Pain in Patients with SCI
In addition to establishing a probable diagnosis of neuropathic pain, it is further helpful to determine whether the pain is located in the region above, at, and/or below the level of injury and whether it is likely to be peripheral or central in nature. Identifying these features of pain can aid in choosing viable treatment options.
Tier 2 of the ISCIP Classification further divides the tier 1 classifications of nociceptive pain and neuropathic pain. The tier 2 subcategories for neuropathic pain are at-level SCI pain, below-level SCI pain, and other neuropathic pain (not directly related to the SCI). The descriptions for and examples of each of these subcategories can be found in Table 2 . The identification of the source of the pain and/or the underlying pathologic condition(s) is recommended as the tier 3 level of classification, if possible. The tier 3 classification would necessarily be influenced by imaging and additional diagnostic tests and would further guide the clinician in selecting management strategies.
| Tier 2 Subcategory of Neuropathic Pain in SCI | Description/Criteria | Example Pathologic Condition(s) or Source of Pain/Tier 3 |
|---|---|---|
| At-level SCI pain |
|
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| Below-level SCI pain |
|
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| Other neuropathic pain |
|
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Tools for Diagnosis and Evaluation of Neuropathic Pain
As mentioned previously, it is particularly important in persons with SCI to determine whether more than one pain is present and to ask patients to identify characteristics of each pain separately. Based on the published guidelines for the evaluation of pain both in patient groups with mixed causes of neuropathic pain and specifically in patients with SCI-related neuropathic pain, the global evaluation of pain characteristics should include pain intensity, temporal aspects of pain, pain qualities, impact of pain on activities of daily living and quality of life, and the psychological state of the person in pain.
The ISCIPBD tool may be useful to provide the clinical team with a standardized pain evaluation form to start with. This form includes the patient’s report regarding the impact of pain on sleep, mood, and activities; identification of areas of the body where pain is present; pain intensity ratings; classification of pain; onset of pain; and whether or not medications are currently used for pain.
Several recommended measures for assessing overall functioning in patients with pain are outlined later and included in Table 1 . A battery of these questionnaires should be considered by the clinical team regardless of whether a patient is participating in a clinical trial, as these validated questionnaires can help to better understand the impact that pain has on the life of the patient and provide standardized baseline assessments that may be used for comparison during follow-up visits, particularly when a new treatment approach is being embarked on.
Screening tools for diagnosing neuropathic pain
Several screening tools have been developed by different groups as a way to initially identify patients that may have neuropathic pain. They are listed and described in Table 1 . The use of these tools provides an easy way to initially identify patients that may have neuropathic pain, but they fail to identify about 10% to 20% of persons who would be diagnosed with neuropathic pain based on a pain specialist’s diagnosis. These screening tools all ask patients to describe their pain in terms of qualities that have long been associated with neuropathic pain and 2 (Leeds Assessment of Neuropathic Symptoms and Signs, Douleur Neuropathique en 4 questions [DN4] ) also include an assessment component (measurement of evoked sensations) that should be carried out by the examiner. No recommendation was made by the NeuPSIG of the IASP as to which specific neuropathic pain screening tool should be used, but a systematic review regarding neuropathic pain in SCI recommended the DN4, as it has evidenced high sensitivity (89.9%) and specificity (82.9%).
For a diagnosis of neuropathic pain, it is required that the pain be located in an area of sensory disturbance. Therefore, a proper neurologic examination (ie, International Standards for Neurologic Classification of Spinal Cord Injury ) is critical to identify whether the pain is in an area affected by the spinal cord lesion; classification at the tier 2 level (at, below, other) in the ISCIP Classification terminology also requires the establishment of the level of injury.
Quantitative sensory testing (QST) has recently been endorsed as a complementary tool to the clinical examination for obtaining additional information regarding the functional status of the somatosensory system. A few studies have shown that results from QST vary with treatment effects and can be used to predict the treatment outcome. However, universally accepted standards for performing QST in the clinical setting do not currently exist, making the use of QST for diagnostic purposes premature.
Tools for capturing the severity and characteristics of neuropathic pain
The most common, and recommended, tool used to evaluate pain intensity for research or clinical purposes is the numerical rating scale (NRS). The visual analog scale (VAS) and the verbal rating scale are also often used. In order to obtain a picture of the severity of a patient’s pain, it is recommended that patients are asked to rate the intensity of their pain when it is at its worst, at its least, and on average.
Evaluating the components of neuropathic pain, including the spontaneous, continuous, intermittent, and evoked aspects, may yield additional insights regarding possible treatment choices and the effect of treatments on each component separately, as they may be the result of independent mechanisms that are differentially affected by the treatment. The Neuropathic Pain Scale and the Neuropathic Pain Symptom Inventory (NPSI) (see Table 1 ) were created to assess the severity and temporal aspects of common symptoms of neuropathic pain. The NPSI has been recommended in both the NeuPSIG’s guidelines and in the review by Calmels and colleagues, which was specifically geared toward SCI-related neuropathic pain.
Tools to evaluate the impact of pain on physical function
The effect that neuropathic pain has on the ability to perform activities of daily living in persons with SCI should be evaluated separately from the effects that are caused by limitations in motor function. The Brief Pain Inventory (short form) interference subscale is frequently used for this purpose, although it includes one item (interference with walking ability) that is not appropriate for most patients with SCI. It has been endorsed by several groups and can be used to track the extent of disability caused by neuropathic pain across different time periods, so that the impact a pain management strategy has on physical function can be assessed.
Tools for evaluating emotional function
The preexisting psychological state of a patient in pain has been shown to be an indicator of the success of particular treatment approaches. Thus, it is prudent to evaluate depression, anxiety, and pain coping style in patients with SCI and neuropathic pain. By asking only general questions about the presence of psychological concerns, an examiner may overlook clinically significant symptoms of psychological distress. Therefore, the use of validated screening assessments and questionnaires may assist with treatment decisions and referrals, if necessary.
Recommendations for the assessment of psychological function in patients with chronic pain include the following: Beck Depression Inventory, Spielberger State-Trait Anxiety Inventory, Hospital Anxiety and Depression Scale, and the Pain Catastrophizing Scale (see Table 1 ).
It may not be practical to use all of the assessments and questionnaires identified here in the clinical setting. However, the administration of a selection of these measures to patients on the initial evaluation can assist the clinician in his or her decision making regarding the best strategies for pain management. In addition, follow-up using the same questionnaires can provide a concrete and less biased way of evaluating treatment efficacy compared with a general question of how patients are doing.
Pharmacologic treatment options
The treatment of neuropathic pain conditions is notoriously difficult, and neuropathic pain after SCI is especially refractory to treatment. Many of the pharmacologic approaches that have been tested for SCI pain were first shown to be effective for peripheral neuropathic pain conditions and, thus, may not target the primary mechanisms responsible for SCI-associated neuropathic pain. Even those pharmacologic treatments that have been shown to provide effective relief or reduction in pain for many individuals with SCI are found by other individuals either to not provide sufficient relief or to produce side effects that are intolerable. An overview of the pharmacologic agents that show the most promise for treating neuropathic pain in persons with SCI are listed in Table 3 . Evidence for the efficacy of these medications, and others, is reviewed in the following text.
| Medication | Typical Dosage Range (Per Day) | Common Side Effects | Special Considerations |
|---|---|---|---|
| Anticonvulsants | |||
| Gabapentin | 400–3600 mg | Somnolence, dizziness, diarrhea, constipation, peripheral edema, asthenia, weight gain, dry mouth |
|
| Pregabalin | 150–600 mg | Somnolence, dizziness, peripheral edema, asthenia, dry mouth, constipation |
|
| Antidepressants | |||
| Amitriptyline | 125–150 mg | Dry mouth, orthostatic hypotension, constipation |
|
| Venlafaxine | 150–250 mg | Nausea, headache, sedation, dizziness |
|
| Duloxetine | 60–120 mg | Somnolence, nausea-vomiting, dizziness, confusion, headache |
|
| Opioids | |||
| Tramadol | 100–400 mg | Somnolence, dry mouth, dizziness, sweating, constipation, nausea |
|
Anticonvulsants
Anticonvulsant, or antiepileptic, medications include a variety of pharmacologic agents. The general mechanism of anticonvulsants is to prevent excessive neuronal firing, which seems to be a common link between epileptic seizure disorders and chronic neuropathic pain; but the specific mechanisms of action differ considerably among the agents within this class of drugs.
Anticonvulsants are used by many patients with neuropathic pain after SCI. Gabapentin and pregabalin are generally considered first-line agents for the treatment of SCI-associated neuropathic pain and have been the most studied anticonvulsants in patients with SCI.
Pregabalin, whose mechanism of action is similar to that of gabapentin, has been shown to be effective in 2 large (n>100) placebo-controlled multisite clinical trials in patients with SCI and neuropathic pain. The average reduction in pain across these studies was 1.92 and 1.66 on a 0 to 10 rating scale, respectively, with a number needed to treat (NNT) (for a 50% pain reduction) of approximately 7 in both studies. A smaller study (n = 40), which included patients with central neuropathic pain of different causes (approximately 50% were subjects with SCI), further supports the efficacy of pregabalin, showing a reduction in pain rating of 2.5 during the 4-week trial. Based on evidence from these studies, pregabalin was recently approved by the Food and Drug Administration specifically for its use in patients with SCI and neuropathic pain, after having been previously approved for neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia.
Gabapentin has shown efficacy in reducing pain intensity in patients with neuropathic pain after SCI in small clinical trials (n<30), with an additional study reporting significant decreases in “unpleasant feelings” in subjects treated with gabapentin compared with subjects randomized to placebo (with trends for reductions in pain intensity and burning feeling). A retrospective chart review and an observational study additionally support the efficacy of gabapentin in patients with SCI. However, Rintala and colleagues found gabapentin to be no more effective than amitriptyline or an active placebo (diphenhydramine) in a blinded crossover trial of 38 subjects.
Other anticonvulsants that may be prescribed for neuropathic pain after SCI generally have little or no support for their efficacy in the literature. Levetiracetam was found to provide no significant improvement in pain intensity compared with placebo in a randomized crossover controlled trial in subjects with SCI and neuropathic pain. Similarly, valproate and lamotrigine did not produce significant effects compared with placebo in randomized controlled trials, although subgroup analyses did show significant pain reduction with lamotrigine in subjects with SCI who had incomplete lesions (n = 12). Additionally, carbamazepine did not confer any protective effect for the development of neuropathic pain in newly injured patients with SCI ; this medication has not been tested in a clinical trial in patients with established chronic neuropathic pain after SCI. The potential effectiveness of anticonvulsants when combined with other pharmacologic treatments has some support in the literature (see “Combination therapies”), but these effects have not been confirmed by a double-blind randomized controlled trial in patients with SCI-associated neuropathic pain.
Antidepressants
It has been suggested that the analgesic effects of certain antidepressant drugs on neuropathic pain rely on different mechanisms of action than those that are related to their antidepressant effects. This finding is attributable to the fact that the doses needed for pain relief are generally subclinical for producing antidepressant effects, and analgesic effects can be seen weeks before improvement in depressive symtpoms. Tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most common antidepressant agents used by those with SCI-associated chronic pain.
The relative popularity of amitriptyline, a TCA, for the treatment of neuropathic pain after SCI is likely because of its proven effectiveness in patients with other neuropathic pain conditions (eg, diabetic neuropathy, postherpetic neuralgia), though it is suggested that amitriptyline provides sufficient relief in only a minority of these patients (approximately 25% ). TCAs have been suggested as first-line agents for neuropathic pain (not specific to SCI) by experts in the field and may be effective in select patients with SCI-related neuropathic pain if side effects are tolerable. Two double-blind controlled studies of amitriptyline for pain relief specifically in persons with SCI did not find significant reductions in pain with treatment, although a subgroup analysis in one of the studies showed a significant reduction of pain in those subjects who also had depressive symptoms.
SNRIs are relatively recent additions to the neuropathic pain arsenal, and their potential utility as a treatment for neuropathic pain in SCI is largely based on clinical trial results and anecdotal success in other neuropathic pain conditions. Duloxetine has been shown to be an effective analgesic in several controlled trials in diabetic peripheral neuropathy, with an NNT of approximately 5 in this patient population. A recent study of duloxetine in patients with severe chronic central neuropathic pain (71% SCI) showed a trend ( P = .05) for significantly greater improvement in VAS scores for pain intensity for the group administered 8 weeks of 60 to 120 mg/d compared with the group administered placebo. Additionally, the Patient Global Impression of Change (PGIC) was significantly different between the groups, with those subjects in the duloxetine arm reporting greater improvement of their situation at the end of the study ( P = .014).
Venlafaxine has shown efficacy for reducing pain in a few controlled trials in patients with pain associated with polyneuropathy, both for patients with diabetes-associated neuropathy and for patients with other causes of neuropathy. Based on the positive results seen for venlafaxine and duloxetine, and their relatively modest side-effect profiles, they have been recommended as first-line treatments for neuropathic pain in general ; but clinical trials of venlafaxine in patients with SCI-associated neuropathic pain have not yet been published.
Opioids
Tramadol is the only orally administered opioid that has been tested in a randomized controlled trial in persons with SCI and neuropathic pain. In this study, subjects were persons with chronic SCI (average 14.6 years after injury) who had chronic neuropathic pain at or below the level of injury for at least 6 months. After a 4-week intervention of either tramadol (100–400 mg/d) or placebo, the subjects in the tramadol arm had a significantly greater reduction of pain than those in the placebo arm. However, 43% of subjects who began treatment on tramadol withdrew from the study before the end of the 4-week treatment period because of adverse side effects compared with 17% of the subjects administered placebo. The efficacy of tramadol in other neuropathic pain patient populations has also been supported in placebo-controlled studies. Tramadol may be a viable treatment option for those patients with SCI-associated neuropathic pain that is refractory to first-line treatments and for whom the adverse events are tolerable.
Support for the efficacy of oxycodone as an analgesic in patients with neuropathic pain associated with postherpetic neuralgia or diabetic neuropathy is present in the literature. One prospective, observational study lends moderate support for its use in patients with SCI and neuropathic pain, showing significant decreases in VAS ratings of pain intensity and increases in quality of life over the course of a 3-month follow-up period. Only 2 subjects withdrew based on adverse effects; but 33.3% of subjects complained of constipation, the most frequent side effect. Given the low level of evidence provided by this observational study, it is difficult to determine whether oxycodone will prove effective for the treatment of neuropathic pain associated with SCI.
There is some support for the use of opioids administered intravenously for the relief of pain associated with SCI. An early study in 9 patients with SCI pain found that intravenous (IV) alfentanil (μ-opioid agonist) was effective at significantly reducing ongoing pain, allodynia, and wind-up–like pain. Similarly, Attal and colleagues reported that in their sample of patients with central pain (after stroke or SCI), IV morphine (μ-opioid agonist) produced a significantly greater reduction in evoked pain sensations (allodynia) compared with placebo. However, they did not find a significantly greater reduction in intensity ratings of spontaneous pain for morphine compared with placebo. Additionally, those subjects who did report reductions in ongoing pain with IV morphine were more likely to report pain reduction when given oral morphine compared with nonresponders to IV morphine and to continue taking oral morphine when assessed 1 year later.
The effect of intrathecal (IT) or epidural administration of morphine has been reported in the literature, with a randomized blinded study reporting no effect with a single IT injection in 15 patients with SCI ; a study of the pain-relieving effects of lidocaine, morphine, and clonidine in subjects with SCI and refractory pain reported mixed results. Although some subjects obtained substantial pain relief, it was short lived. Given the lack of consistent results across studies, and the short duration of its analgesic effect, injections or infusions of opioids for relief of neuropathic pain after SCI are not recommended as a long-term management strategy.
Cannabinoids
Although survey studies of persons with SCI and chronic pain support the use of cannabinoids for the relief of pain, there is scant literature regarding its efficacy in clinical trials. One small study of dronabinol did not show efficacy compared with an active placebo in patients with SCI pain.
The results from small (n<40) clinical trials in other neuropathic pain patient groups, and in studies with mixed diagnoses that include SCI-related neuropathic pain, generally support the use of cannabis or cannabinoid agents for at least modest reductions in pain intensity and improvements in secondary outcomes (eg, sleep, mood), although one large study (n = 339) reported equivocal results. The efficacy of different doses of tetrahydrocannabinol (THC) for the reduction of neuropathic pain suggests that low doses can confer similar analgesic effects as medium and high doses, and low-dose THC limits the effect of the drug on cognitive decline.
Studies that did report significant effects of cannabinoids on neuropathic pain included both subjects with central neuropathic pain and subjects with peripheral neuropathic pain, whereas the large study that did not show definitive effects of THC compared with placebo was limited to those with central neuropathic pain caused by multiple sclerosis. Given the generally tolerable side-effect profile for low-dose THC, future randomized controlled trials in refractory SCI neuropathic pain are warranted.
N-Methyl-d-Aspartate Antagonists
Ketamine and other N-methyl-d-aspartate (NMDA) antagonists have shown promise for relieving neuropathic pain at lower doses than those inducing anesthesia. Positive results have been shown specifically in persons with SCI and chronic central neuropathic pain, including both single-dose infusions and a trial that included one infusion of ketamine per day for 7 days as an adjuvant to oral gabapentin. A recent study in 13 patients also suggests that ketamine administration during the acute phase of neuropathic pain symptoms (average time since neuropathic pain onset was 10.3 days) may prevent its development into chronic pain. Although interruption of NMDA receptor mechanisms can produce large reductions in neuropathic pain, the route of administration, dosing scheme, and elimination or reduction of unacceptable side effects still need study.
Antispasticity Agents
Antispasticity agents, such as baclofen, are commonly used to suppress spasticity in patients with SCI and have also been shown to significantly reduce musculoskeletal pain after SCI. However, the effect of IT baclofen on neuropathic pain in SCI has little support, and oral baclofen has not been clinically tested for this indication.
Summary
Pharmacologic agents can be effective for the relief of neuropathic pain in some patients with SCI. The agents with the most evidence of efficacy in this patient group are pregabalin, gabapentin, amitriptyline, tramadol, and duloxetine. Other agents can be tried in refractory cases, as response to treatment and acceptability of side effects vary patient by patient.
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