Spinal Cord Injury–Related Neuropathic Pain




Abstracts


Spinal cord injuries are relatively uncommon yet potentially devastating in their impact upon a person’s life and ability to function. Spinal cord injury–related neuropathic pain is a complex chronic complication that is difficult to quantify or for a patient to describe but potentially serious in its implications. This chapter details the approach to diagnosis and treatment of spinal cord injury–related neuropathic pain. Treatments discussed include rehabilitation and physical medicine options, medication management, and interventional treatments.




Keywords

Central pain, Gabapentin, Neuropathic pain, SCI, Spinal cord injury

 




Introduction


Spinal cord injury is a relatively uncommon injury. Spinal cord injuries are often divided as being either traumatic or nontraumatic and complete or incomplete. SCI is categorized according to the international standards for neurological classification of spinal cord 18 injury (ISNCSCI) colloquially referred to as the ASIA (American Spinal Injury Association) examination. The ASIA scale involves listing the caudal most normal level of neurologic examination in three categories—motor strength, pinprick sensation, and light touch sensation with the superior most intact level considered the overall level of the spinal cord injury. The ASIA scale further classifies the severity of the injury from A to E. A implies a complete injury, B is a sensory incomplete injury, C is a motor incomplete injury, D is a motor incomplete injury with at least half of tested muscles below the level of injury being antigravity or stronger, and E is a fully recovered spinal cord injury. Spinal cord injuries are often complicated by neuropathic pain, with an estimated prevalence of approximately 50% of patients.


Diagnostic Criteria


Patients with a spinal cord injury often present with complex multifactorial pain complaints that are difficult to describe or differentiate. Multiple attempts at classifying spinal cord injury–related pain have been made. Twenty-nine systems of classification were catalogued by Hicken et al. More recently the Spinal Cord Injury Pain Task Force of the International Association for the Study of Pain (SCIP-IASP) proposed a new pain classification based on previous work by Cardenas and Bryce-Ragnarsson. The SCIP-IASP classification divides pain into three tiers. The first tier separates pain types into nociceptive pain, neuropathic pain, other pain, or unknown pain. Tier two then divides each of those categories into further subdivisions. Nociceptive pain is divided into musculoskeletal pain, visceral pain, and other nociceptive pain, and then each of those categories are divided into the etiology or primary pain source in the tier 3. Neuropathic pain is divided into spinal cord injury at level pain, below level pain, and other neuropathic pain, and each one of these is divided into the contributing pain sources in tier 3. Other pain and unknown pain do not have a tier 2 subtype and are listed in tier 3 by primary pain source or pathology subtype ( Fig. 17.1 ).




Fig. 17.1


International spinal cord injury pain (ISCIP) classification.

From Bryce TN, Biering-Sørensen F, Finnerup NB, et al. International spinal cord injury pain classification: part I. Background and description. Spinal Cord . 2012;50(6):413–417. http://dx.doi.org.easyaccess2.lib.cuhk.edu.hk/10.1038/sc.2011.156 ; with permission.


Neuropathic pain has proven difficult to define and quantify, and this is particularly challenging in spinal cord injury. In 2008 the Special Interest Group on Neuropathic Pain of the IASP proposed a grading system of definite, probable, and possible neuropathic pain. Definite neuropathic pain would require a pain distribution consistent with injury to the peripheral nervous system (PNS) or central nervous system (CNS) of the previous or current injury, disease affecting the PNS or CNS, and abnormal sensory signs within the body area corresponding to the injured parts of the CNS or PNS along with diagnostic tests that confirm the lesion, or disease in these structures. This definition was unsatisfactory for spinal cord–injured patients and additional criteria were proposed that include:



  • 1.

    Onset of pain within 1 year following spinal cord injury.


  • 2.

    No primary relation to movement, inflammation, or local tissue damage.


  • 3.

    Hot, burning, tingling, pins and needles, sharp, shooting, squeezing, cold, electric, or shock-like quality of pain.



Many additional definitions and subcategories of neuropathic pain have been proposed, including provoked and unprovoked. Multiple questionnaires have been developed in the attempt to ascertain the quality of neuropathic pain. These include the Leeds Assessment of Neuropathic Pain Scale, the Neuropathic Pain Questionnaire, and the DN4 Questionnaire. Bryce et al. have proposed a novel pain questionnaire that would be easy to administer or may even be self-administered by the patient.


Course


Neuropathic pain is generally reported by patients with spinal cord injury within the first 3 months to a year after injury, although it could develop over the course of the first 2 years. The neuropathic pain typically does not abate, although rest, physical activity, and alcohol, as well as medication, have been found to be alleviating factors, whereas stress, anxiety, fatigue, weather changes, and cold ambient temperatures were found to be aggravating factors. The severity of neuropathic pain is difficult to quantify, but the Neuropathic Pain Scale and the Neuropathic Pain Symptom Inventory have been used for this purpose. Pain has been reported to be worse at night than during the day. There are conflicting reports of whether pain is worse with tetraplegia rather than paraplegia. Some of the ambiguity relates to the multifactorial nature of spinal cord injury–related pain. No correlation has been found between pain and the complete or incomplete nature of the injury. Lack of pain at the initiation of acute inpatient rehabilitation has been correlated to lower long-term pain levels. It has been proposed that levels of neuropathic pain can be predicted based upon sensory testing by evaluating the difference between light touch and pinprick scores on the AISA evaluation.


Differential Diagnosis


Neuropathic pain as related to spinal cord injury is often difficult to differentiate from spasticity. Patients may use the term spasm when referring to a pain sensation and report pain when intending to mean spasm. The patient’s complaints should be explored carefully during the acquisition of history, teasing out the nature and setting of the pain and whether spasms are actually observed versus the patient perceiving the sensation of spasm without visual confirmation of spasmodic movement. Central neuropathic pain must also be differentiated from peripheral nerve injury or lesions that may be superimposed upon the central spinal cord injury, such as peripheral compressive neuropathies and inflammatory neuropathies. Often neuropathic pain fluctuates throughout the day. However, pain that is progressively worsening or changing acutely in a previously stable patient should be concerning for a new underlying pathology, such as syrinx formation, soft tissue injury, occult fracture, heterotopic ossification (HO), or other new pathology, that may or may not be related to the spinal cord injury. Exacerbation of neuropathic pain and spasticity can also be a symptom of physiologic stress, such as infection or irritation (i.e., renal and gall bladder calculi), or psychologic stress, including somatization of mood disorders.


Diagnostic Testing


The role of diagnostic testing in the evaluation of neuropathic pain as related to spinal cord injury is limited to excluding alternative diagnoses and to confirming the underlying spinal cord pathology. Radiography is useful in the evaluation of occult fracture and HO. This modality would be appropriate in the setting of exacerbation of pain with physical findings of new edema, redness, bony abnormality on palpation, or change in passive range of motion of a joint. The finding of HO lags on X-ray imaging, as the abnormal bone mineralizes and would better be diagnosed by MRI or nuclear imaging. Ultrasound imaging is useful in the evaluation of abdominal and retroperitoneal organ dysfunction, as persons with spinal cord injuries may not exhibit the typical patterns of pain associated with pathology of these organs. Calculus formation in the gall bladder and urinary system may be increased in those with spinal cord injuries. Ultrasound imaging is also useful in diagnosing disorders of the circulatory system, including deep vein thrombosis and vascular claudication. Computed tomography (CT) scans can be used to better visualize osseous and organ structures discussed in regards to X-ray and ultrasound imaging, albeit with an increased level of ionizing radiation. Diagnostic musculoskeletal ultrasound imaging is emerging as a useful modality in diagnosing peripheral nerve lesions in spinal cord–injured patients because electromyography and nerve conduction velocity studies are often difficult to interpret in the setting of an upper motor neuron lesion. Diagnostic musculoskeletal ultrasound imaging could also be used to evaluate musculoskeletal pathologies that mimic neuropathic pain. The role of electrodiagnostic testing is to exclude secondary diagnoses such as entrapment neuropathies and to evaluate potential comorbid disease entities such as plexopathies and peripheral polyneuropathies. Imaging of the spinal cord does not correlate with pain severity but may reveal a new diagnosis. Should syrinx be suspected, MRI is the test of choice for diagnosis. CT myelogram may be used for those who cannot undergo MRI evaluation. Evidence of syrinx on CT myelogram has predictive value. However, absence of syrinx on a CT myelogram does not rule out its presence. Diagnostic testing to evaluate pain at the level of injury and below has been attempted with quantitative sensory testing. In a few controlled studies, it has been shown to be useful in predicting the treatment outcome but is not standardized nor routinely used in clinical practice. Electroencephalogram and functional imaging find markers of pain by detecting a decrease in cortical activity in the frontal areas, but these tests are not in common clinical usage.


Rehabilitation and Physical Medicine Options


Cognitive behavioral therapies have been postulated as being effective in the treatment of pain. A study consisting of 61 people conducted in four Dutch rehabilitation centers found that a cognitive behavioral program decreased pain intensity, pain-related disability, and anxiety in spinal cord–injured patients. However, the level of decrease in pain was less than predicted and the effect on pain-related disability was only borderline significant. Roosink and Mercier performed a literature review of virtual feedback for pain rehabilitation in spinal cord–injured patients. Seventeen studies were identified, and all were deemed to be of low quality. Although virtual feedback was found to have potential in improving motor function and reducing pain in spinal cord–injured patients, more research was found to be necessary in identifying appropriate patients and developing maximally effective treatment regimens. Transcranial direct current stimulation is an emerging technology that is being explored for the treatment of pain. Studies have yielded conflicting results regarding the efficacy of transcranial stimulation in the treatment of spinal cord injury–related neuropathic pain. These discrepancies may be explained by subject selection and the chronicity of the spinal cord injury in the various studies. A small study found efficacy with exercise in the management of neuropathic pain in spinal cord–injured patients. The use of transcutaneous electrical nerve stimulation (TENS) has been evaluated with inconsistent results. TENS may have improved efficacy in patients with more recent injuries. Patients should be monitored for autonomic dysreflexia if this modality is used. The use of acupuncture has yielded disappointing results. A prospective study by Norrbrink and Lundeberg found a reduction in pain with a course of acupuncture; however, the results were not sustained at 2 months post study. The efficacy of spinal cord stimulators and dorsal root entry zone lesioning have been studied in a very limited fashion in the setting of spinal cord injury, but the results were not encouraging. A small pilot study showed promising results from having patients “virtually walk,” but the sample size was small and the results were mixed. As virtual reality and robotic-aided ambulation become more prevalent, their utility in treating pain will become more apparent.




Medication Options


Topical Medications


Topical medications do not have a significant role in the treatment of neuropathic pain as related to spinal cord injuries because of the diffuse body areas that are usually affected. In a case series, two patients were found to respond well to topical 8% capsaicin patches applied after pretreatment with lidocaine and prilocaine. Although the results were promising, it is difficult to extrapolate from a small study. The subjects in the study were ASIA classification D, which makes it further difficult to extrapolate to a broader range of patients with spinal cord injury. One must also consider the risks of autonomic dysreflexia in a patient with a spinal cord injury.


Antiepileptic Medications


Pregabalin is the only medication approved by the Federal Drug Administration for the treatment of neuropathic pain related to spinal cord injury. Pregabalin affects the voltage-gated calcium channel complexes in the presynaptic terminal. This in turn results in decreased neurotransmitter release and decreased pain sensation. In a study by Carddenas et al., pregabalin was given to 108 patients with 112 placebo matched controls. Almost 80% of treated patients reported improvement of their pain. A study of 137 patients with 12-week follow-up undertaken by Siddall et al. also demonstrated a significant reduction in pain levels. Pregabalin is effective at 100–150 mg/day in divided doses, with a maximal dose of 600 mg/day. Common side effects of pregabalin include somnolence (approximately 30%–40%), peripheral edema in approximately 13%, and dizziness. There are a variety of less frequent, but potentially significant, adverse reactions such as weight gain, abnormalities of thought processing, and suicidal ideation. Pregabalin has also been found to be effective in decreasing secondary issues related to pain, including difficulty sleeping, depression, and anxiety.


Gabapentin is structurally similar to pregabalin. Gabapentin affects calcium channels at the neural bouton yielding an inhibitory effect on the neuron by diminishing calcium influx. Together with pregabalin, it is considered a first-line treatment for neuropathic pain related to spinal cord injury. A meta-analysis undertaken by Mehta, McIntyre et al. found eight studies that demonstrate significant neuropathic pain reduction with gabapentin. It is believed that there is no significant difference between the efficacies of gabapentin and pregabalin, although there is a conflicting literature to this point.


Carbamazepine and oxcarbazepine are anticonvulsive drugs that affect voltage-gated sodium channels of the neuron. Oxcarbazepine has improved tolerance and is associated with fewer side effects than carbamazepine. Oxcarbazepine was found to be more effective than pregabalin in constant electrical, burning sensations and prickly paresthesias. In contrast, pregabalin was found to be more effective in the control of electrical shooting–like pain as well as hyperalgesia and allodynia. It has been postulated that different antiepileptic drugs may treat different subsets of the neuropathic pain.


Levetiracetam is a novel antiepileptic medication. It is commonly used in posttraumatic seizure prophylaxis, but it has not been found to have meaningful efficacy in the treatment of spinal cord injury–related neuropathic pain. A Cochrane review in 2014 found no evidence of efficacy of levetiracetam in the treatment of neuropathic pain. Lamotrigine is an antiepileptic drug that acts upon the voltage-gated sodium channel. Lamotrigine has been found to have efficacy in the treatment of neuropathic pain, particularly in the setting of incomplete injury. Valproic acid is a first-generation antiepileptic that acts upon voltage-gated sodium channels, causing a decrease in the firing frequency of neurons and also an increase in the γ-aminobutyric acid concentration of the brain. However, a double-blinded, crossover study found no significant difference in pain control between the treatment and nontreatment groups after 3 weeks. Topiramate is commonly used for migraine headache prophylaxis. Its efficacy in controlling spinal cord injury–related neuropathic pain is weak, as the literature is conflicted.


Antidepressant Medications


Tricyclic antidepressants act upon 5-HT2A receptors yielding an increase in serotonin-norepinephrine concentrations in the CNS. Amitriptyline has been classically used to control neuropathic pain syndromes of various etiologies. There is evidence demonstrating that amitriptyline is effective in the treatment of spinal cord injury pain in the context of depression. Of note, it has been suggested that amitriptyline may increase spasticity in spinal cord–injured patients. Rantala demonstrated the efficacy of amitriptyline in a crossover study with gabapentin and an active placebo, diphenhydramine. Tricyclic antidepressants are associated with anticholinergic side effects, including dry mouth, constipation, cardiac arrhythmia, glaucoma, and urinary retention. Weight gain may be significant. Other tricyclic antidepressants, such as imipramine and nortriptyline, have been found to have less adverse reactions than amitriptyline.


Trazodone is an atypical antidepressant with strong serotonin reuptake inhibition and to a lesser degree norepinephrine reuptake inhibition. In a 6-week, double-blind, placebo-controlled trial, Davidoff et al. found that trazodone was not better than placebo in controlling neuropathic pain in spinal cord–injured patients. Lithium is a mood stabilizer that was studied in China for possible efficacy as a neuroregenerative agent. The study found no benefit in terms of improved function or neurologic outcome as compared with placebo, but pain was reduced with its use. More research into the use of lithium is needed before a recommendation for its use can be made. Selective serotonin reuptake inhibitors are not found to have efficacy in controlling neuropathic pain. Selective serotonin norepinephrine reuptake inhibitors (SSNRIs) are found to have efficacy in the treatment of neuropathic pain, particularly in the setting of concomitant depression. In a study conducted by Vranken, 48 patients received escalating doses of duloxetine or placebo to a maximal dose of 120 mg/day and found a statistically significant decrease in dynamic pain and cold allodynia; however, tactile and pressure pain thresholds did not improve. Only one domain in an SF36 survey (a patient-reported survey of patient health) showed improvement. The Pain Disability Index survey did not show any significant improvement with the addition of duloxetine. The study’s conclusion was to withhold judgment on the efficacy of this medication on central neuropathic pain.


Opioid Medications


Opioid medications are commonly used to treat pain of many etiologies. Although there is controversy regarding the use of opioids in non-cancer-related chronic pain, opioids are commonly used in the treatment of spinal cord injury–related neuropathic pain. In a study of 7447 male veterans with spinal cord injury, 70% were noted to have received opioid medications. A survey study by Cardenas found that 58% of responding patients had a therapeutic trial on opioid medications and that, as a medication class, opioids provided more relief from pain than any other class of oral medication. A study conducted in Spain showed significant benefit in terms of neuropathic pain reduction by opioid medications in spinal cord–injured patients. This finding is consistent with previous research on the role of opioid medications for the treatment of neuropathic pain. The misuse of opioids in the spinal cord–injured population was found to be consistent with that in the general population with chronic pain.


Recommendations for responsible opioid prescribing include the use of “opioid contracts,” obtaining informed consent from the patient, performing random urine drug screens and pill counts, monitoring for aberrant behaviors, consulting with state data banks to minimize the risk of multiple providers prescribing opioids, using abuse deterrent formulations when appropriate, and setting treatment goals based upon functional outcomes. Many of these measures, however, are more difficult to perform with persons with spinal cord injuries. For example, patients performing bladder routines may need catheter kits and nursing assistance to provide a urine drug screen. This patient population may find it difficult to bring in medications for review because of poor dexterity and a fear of theft that they cannot prevent. Often these patients have a reliance on others to dispense medications, which complicates their responsibility for safe storage of medications. Aberrant behaviors and substance abuse may have been the etiology of the spinal cord injury but it does not negate the validity of the new pain syndromes suffered. Patients with spinal cord injuries may travel to distant medical centers, including crossing state lines, for specialized care, a behavior that may be suspicious in other patient populations. Individuals with dysphagia may not be able to use certain sustained-release formulations or abuse deterrent formulations. A variety of screening tools and surveys have been developed with the goal of identifying misuse of opioid medications in the population with chronic pain ; however, they are not well studied in the population with spinal cord injury.


Patients receiving opioid medications should also be monitored for medical side effects, including urinary retention, constipation, somnolence, respiratory depression, depressed testosterone levels, pruritis, mood disorders, and hyperalgesic syndrome. Caution should be exercised when prescribing opioid medications concurrent with benzodiazepine medications, commonly prescribed for the treatment of spasticity.


Tramadol


Tramadol is a unique medication in that it is a weak μ-opioid agonist with weak monoamine reuptake inhibition. Tramadol has been found to be effective in improving at level and below level neuropathic pain in a crossover study performed by Norbrink and Lundeberg.


Cannabinoids


There is an emerging availability and interest in cannabinoid medications for the treatment of pain and spasticity. The body of the literature for the use of cannabinoids in spinal cord injury–related pain is scant, although a small study found no efficacy with the use of dronabinol as compared with active control. Limitations of that study include a small sample size; it also only tested a specific extract of marijuana. There is a growing body of evidence that cannabis has efficacy in the treatment of neuropathic pain and spasticity as related to multiple sclerosis, particularly in its vaporized form. Following the multiple sclerosis literature, further research into the application of cannabis to spinal cord injury patients is warranted.


Miscellaneous Medications


Nonsteroidal antiinflammatory drugs are ineffective in the treatment of neuropathic pain. Their use in the acute phase of spinal cord injury may be contraindicated in the context of recent spine surgery and possible effects on bone healing. Acetaminophen does not have a significant efficacy in neuropathic pain ; however, it is often used to potentiate opioid medications.

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Jun 17, 2019 | Posted by in NEUROLOGY | Comments Off on Spinal Cord Injury–Related Neuropathic Pain

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