Despite the multitude of consequences of spinal cord injury, pain is rated as the most difficult symptom to manage. The literature and evidence basis for treatment for spinal cord injury-associated neuropathic pain are slim.
Approximately 11,000 people will experience a spinal cord injury in the United States each year, with over half of those between the ages of 16 and 30 years. An estimated 183,000 to 230,000 people currently living with spinal cord injury.1 Individuals who experience spinal cord injury can suffer from many problems that affect their daily lives, including impaired mobility and sexual dysfunction. Despite the multitude of consequences of spinal cord injury, pain is rated as the most difficult symptom to manage. Different types of pain may develop following spinal cord injury including musculoskeletal, visceral, and neuropathic pain. For reasons that are not fully understood, two-thirds of patients experience persistent neuropathic pain after spinal cord injury. Neuropathic pain can be further divided into pain at the level or below the level of the injury. One-third of all patients develop below-level neuropathic pain following spinal cord injury, and this type appears to be the most severe pain and the most difficult to treat.2
Many types of pharmacologic agents have been used to treat neuropathic pain including: antidepressants, antiepileptics, lidocaine analogs, and cannabinoids, but unfortunately the success rate is low, typically around 30%. These oral agents work to decrease neuropathic pain by depressing neuronal activity via many different mechanisms, such as blocking sodium and calcium channels, potentiating inhibitory amino acids, and inhibiting excitatory receptors.3
This article reviews the types of spinal cord injury neuropathic pain, the treatment options available, and the evidence to date regarding oral pharmacologic agents in adults. The studies discussed in this article have been conducted in adults, thus proper treatment and dosing in the pediatric population may differ and will not be discussed in this article.
Types of Neuropathic Pain
Neuropathic pain, commonly described as burning, stabbing, or sharp, is characterized as persistent and spontaneous pain, and as irregular responses of the nerves to stimuli. Allodynia (pain is felt from normally non-painful stimuli) and hyperalgesia (or extreme pain is felt from normally painful stimuli) are common hyperactivities of the nervous system following spinal cord injury. Neuropathic pain that presents soon after spinal cord injury, such as in the first 3 to 6 months, is a poor prognostic indicator of pain, as these patients typically experience worse pain and in longer durations.4
Neuropathic pain following spinal cord injury can be described as 2 separate types: pain that occurs at the level of injury and pain that occurs below the level of injury. Patients can have both types of pain, with both being chronic and difficult to treat. At-level pain, or radicular pain, which occurs in the same area as the injury, typically presents earlier than below-level pain. This type of pain is thought to be due to injury to the nerve roots and dorsal gray matter. Below-level pain likely develops from pathophysiologic changes that occur to the nerves in response to the spinal lesions from injury. This type tends to have a delayed onset after the spinal cord injury, thus the mechanism is thought to be different than at-level pain. Below-level pain occurs due to injury of spinothalamic tracts or deafferentation.5
Basics of Treatment
Once the pain has been determined to be neuropathic in origin, pharmacologic agents are the mainstay of therapy.3 Neuropathic pain is a chronic problem, thus oral medications need to be used, since the usefulness of chronic intravenous pain relievers is minimal. Oral pharmacologic agents are designed to target the mechanisms that cause neuropathic pain, this mainly being hyper-excitability of the neurons. Medications are commonly used that depress neuronal activity in various ways, including inhibiting sodium and calcium channels, inhibiting serotonin and norepinephrine reuptake, inhibiting glutamate receptors, and potentiating the inhibitory gamma amino-butyric acid receptors. Due to their mechanisms, antidepressants and antiepileptics are most commonly used, and have been studied the most in postspinal cord injury neuropathic pain in adults. Medications that have been used for treatment of neuropathic pain, and their mechanisms of action, can be found in Table 1, while their dosing and common side effects can be found in Table 2.
As discussed above, patients can present with many different symptoms of pain, presumably caused by different mechanisms. Unfortunately, clinical trials have yet to prove which medications work best for specific symptoms. Currently, recommendations for first line agents in adults, specifically in spinal cord injury, come from review articles3,7and European guidelines.8
Types of Therapy
Tricyclic antidepressants are one of the oldest medications used for neuropathic pain. In 2002, a randomized-controlled trial of amitriptyline versus placebo, studied patients with spinal cord injury occurring more than 6 months prior to trial. An active placebo of benztropine mesylate was chosen, as it produces similar side effects to amitriptyline. The median dose of amitriptyline used was 50 mg/day, and it showed no beneficial effect in pain control or quality of life. Another study in a similar population used higher doses of amitriptyline, a mean of 150 mg/day, versus an active placebo of diphenhydramine, and saw positive results in pain reduction.9 These studies also pointed out the common adverse effects of tricyclic antidepressants including drowsiness (17%), dry mouth (17%), constipation (14%), and increased spasticity (11%).10 These typical adverse effects of tricyclic antidepressants are often problematic in the spinal cord injury population and probably limit their use as a first-line agent in this setting.
Selective serotonin and serotonin/norepinephrine reuptake inhibitors have also been studied in various types of neuropathic pain. These agents are more selective for these receptors than tricyclic antidepressants, so they do not exhibit the anticholinergic side effects (such as dry mouth) that tricyclic antidepressants do.
The side effects that patients should be aware of for selective serotonin and serotonin/norepinephrine reuptake inhibitors (duloxetine and venlafaxine in Table 2) include gastrointestinal effects, sexual dysfunction, and variable somnolence/hyperactivity.
No spinal cord injury/neuropathic pain studies have been conducted with selective serotonin reuptake inhibitors; but trazodone, which works on serotonin receptors, was not shown to make a statistically significant improvement in pain control.11 Serotonin/norepinephrine reuptake inhibitors, venlafaxine, and duloxetine, have proven efficacy in diabetic neuropathy,12,13 but have yet to be studied in spinal cord injury. Based on their effectiveness in diabetic neuropathy, they have been recommended by some as a second-line agent for spinal cord injury.3 Duloxetine is typically started at 30 mg/day and increased to 60 mg/day if needed. Doses above 60 mg have not been shown to be any more beneficial, although 120 mg doses have been administered. Venlafaxine should be started at 37.5 mg/day, increased to 75 mg/day, and titrated up to 225 mg/day if needed and if tolerated.3 Adverse effects such as nausea, dizziness, and somnolence (Table 2) typically improve as the patient acclimates to the medication, so patients should be encouraged to continue, especially if it is producing positive results.
Antiepileptics that work via numerous mechanisms to depress neuronal activity are the second class of medications that have been studied in various types of neuropathic pain. Lamotrigine is an antiepileptic that has been proven successful in the treatment of both central and peripheral neuropathic pain.14 In 2002, a randomized-controlled trial of 22 patients receiving lamotrigine or identical placebo tablets for neuropathic pain postspinal cord injury was conducted. A median dose of 400 mg/day of lamotrigine was achieved following gradual titration from 25 mg/day. Lamotrigine appeared to be successful with at-level or below-level pain in those with incomplete spinal cord injury lesions, but overall showed no reduction in pain scores.14 As done in this study, patients should be gradually titrated to their target dose to limit the risk of developing a rash that could progress to Steven Johnsons Syndrome (Table 2).
Gabapentin and pregabalin are 2 antiepileptics that provided pain relief in randomized-controlled trials. In a 2004 study, paraplegic patients postspinal cord injury were given 8 weeks of therapy with gabapentin at doses <3600 mg/day versus placebo. Statistically significant results were seen in reducing the frequency and severity of pain, along with improving the quality of life for the patients. Although side effects, with the most common being weakness (25%), peripheral edema (15%), and dizziness (15%), were reported in many patients, they were not severe enough to cause patients to discontinue the medication.15
Two other studies have been reported that showed beneficial effects of gabapentin; both showed patients achieving a statistically significant reduction in pain scores.16,17 With gabapentin being one of the only medications to show positive results in randomized controlled trials, it has become one of the first line agents for neuropathic pain following spinal cord injury.
Pregabalin, a similar agent to gabapentin, is also considered a first line option for this indication after demonstrating some success in spinal cord injury-neuropathic pain. In 2004, a 12-week randomized-controlled trial using doses of 150 to 600 mg/day of pregabalin versus placebo resulted in a significant reduction in pain and secondary endpoints of disturbed sleep and anxiety. The results showed a number needed to treat of 3.9 for a 30% pain reduction or a number needed to treat of 7.1 for a 50% pain reduction. The mean dose that was achieved was 460 mg/day, divided twice daily. The most common side effects reported were somnolence (41.4%), dizziness (24.3%), and peripheral edema (20%), causing 21% of people to discontinue the medication versus 13% in the placebo group.18 The results of this study should be interpreted cautiously as patients who were on gabapentin at baseline were forced to stop taking it 1 week prior to the study, likely inducing withdrawal. The study does not show how these patients were randomized, and what percentage of these patients were in each group. An important point for extrapolation is patients were excluded if they had creatinine clearance <60, as pregabalin is mainly renally eliminated. This, in combination with the relatively prevalent adverse effect profile, could be a treatment barrier to patients.
Other broad-spectrum antiepileptics, such as topiramate, valproate, and levetiracetam, have also been researched in spinal cord injury in hopes that they can provide pain relief for these patients. Topiramate was examined in a randomized-controlled trial of mixed neuropathic pain that has yet to be published, although the results of the 14 spinal cord injury patients were published. The results showed doses of <800 mg/day of topiramate was not beneficial for neuropathic pain in spinal cord injury patients. These results, in combination with the poor results in diabetic peripheral neuropathy, make topiramate less attractive for future use in spinal cord injury neuropathic pain.3
Valproate, which has several mechanisms of action including potentiating gamma amino-butyric acid function, was involved in a 3-week study against placebo that showed a trend toward improvement in pain control, but the results were not statistically significant.19
In 2009, levetiracetam and placebo were studied in a randomized controlled trial of spinal cord injury patients, in which levetiracetam was found to have no effect on pain reduction, spasticity, or any of the secondary endpoints of the study.20
Other agents have been investigated such as mexiletine, which is an oral lidocaine analog. A study in 1996 found no benefit in patients with spinal cord injury dysesthetic pain.21 Cannabinoids have shown some beneficial roles in pain management in other disease states, but their use in spinal cord injury has not been studied.3
Tramadol was studied in a 4-week randomized, controlled trial for postspinal cord injury patients. The results found decreases in pain scores, but the withdrawal rate due to side effects occurred in >40% of patients. This led the authors to conclude that tramadol may provide benefits after first and second line agents have been tried.22
The literature and evidence basis for treatment recommendations for spinal cord injury-associated neuropathic pain are slim. When choosing among oral agents, practitioners should consider many factors, including concomitant disease states, renal function, and side effects of the drug. For example, patients with poor renal function have decreased elimination of pregabalin and gabapentin (Table 2), thus, they are at increased risk for side effects. These patients would likely benefit from a tricyclic antidepressant or serotonin/norepinephrine reuptake inhibitors as first-line to avoid these problems. Patients postspinal cord injury may suffer depression for numerous reasons, so having a tricyclic antidepressant or serotonin/norepinephrine reuptake inhibitor as first-line or part of combination therapy would be recommended.
Combination therapies should be beneficial for postspinal cord injury patients as there are multiple mechanisms of pain thought to be at play. When choosing combination therapies, use agents with different mechanisms of action. For example, using gabapentin with tricyclic antidepressants or serotonin/norepinephrine reuptake inhibitors would provide multiple targets at the nerves, while using combinations such as gabapentin with pregabalin will only augment side effects. More statistically, robust studies are needed to determine efficacy of these agents, head-to-head and in combination, and studies of longer duration are needed to assess the medications ability to continue being effective and how the side effect profile differs with long-term treatment. Neuropathic pain following spinal cord injury is difficult to treat and evidence regarding pharmacologic agents needs to be improved.
| The Bottom Line |
- Neuropathic pain is a common and debilitating condition found in spinal cord injury patients.
- Neuropathic pain following spinal cord injury is difficult to treat and current evidence with positive results are lacking.
- First line agents include gabapentin and pregabalin while second line agents include serotonin/norepinephrine reuptake inhibitors and tricyclic antidepressants.
- There are likely multiple mechanisms of pain present, so combinations of these agents will potentially be needed.
- More statistically robust studies are needed to better determine effective agents, and combinations of agents, as well as the long-term efficacy and side effects of the medications.
- Backonja MM, Serra JM. Pharmacologic management part 2: lesser-studied neuropathic pain diseases. Pain Med. 2004; 5(Suppl 1):S48-S59.
- Wrigley PJ, Press SR, Gustin SM, et al. Neuropathic pain and primary somatosensory cortex reorganization following spinal cord injury [published online ahead of print November 21, 2008]. Pain. 2009; 141(1-2):52-59.
- Baastrup C, Finnerup NB. Pharmacological management of neuropathic pain following spinal cord injury. CNS Drugs. 2008; 22(6):455-475.
- Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ. A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. Pain. 2003; 103(3):249-257.
- Wasner G, Lee BB, Engel S, McLachlan E. Residual spinothalamic tract pathways predict development of central pain after spinal cord injury (published online ahead of print July 31, 2008]. Brain. 2008; 131(9):2387-2400.
- Micromedex 1.0 (electronic version). Thomson Reuters (Healthcare) Inc, Greenwood Village, Colorado. http://www.thomsonhc.com. Accessed December 18, 2010.
- Backonja MM, Serra JM. Pharmacologic management part 1: better-studied neuropathic pain diseases. Pain Med. 2004; 5(Suppl 1):S28-S47.
- Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision [published online ahead of print April 9, 2010]. Euro J Neurol. 2010; 17(9):1113-e1188.
- Rintala DH, Holmes SA, Courtade D, Fiess RN, Tastard LV, Loubser PG. Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury. Arch Phys Med Rehabil. 2007; 88(12):1547-1560.
- Cardenas DD, Warms CA, Turner JA, Marshall H, Brooke MM, Loeser JD. Efficacy of amitriptyline for relief of pain in spinal cord injury: results of a randomized control trial. Pain. 2002; 96(3):365-373.
- Davidoff G, Guarracini M, Roth E, Sliwa J, Yarkony G. Trazodone hydrochloride in the treatment of dysesthetic pain in traumatic myelopathy: a randomized, double-blind, placebo-controlled study. Pain. 1987; 29(2):151-161.
- Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy? Pain. 2005; 116(1-2):109-118.
- Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004; 110(3):697-706.
- Finnerup NB, Sindrup SH, Bach FW, Johannesen IL, Jensen TS. Lamotrigine in spinal cord injury pain: a randomized controlled trial. Pain. 2002; 96(3):375-383.
- Levendoglu F, Ogun C, Ozerbil O, Ogun T, Ugurlu H. Gabapentin is a first line drug for the treatment of neuropathic pain in spinal cord injury. Spine (Phila PA 1976). 2004; 29(7):743-751.
- Ahn S, Park H, Lee B, et al. Gabapentin effect on neuropathic pain compared among patients with spinal cord injury and different durations of symptoms. Spine. 2003;28(4):341-347.
- Putzke JD, Richards JS, Kezar L, Hicken BL, Ness TJ. Long-term use of gabapentin for treatment of pain after traumatic spinal cord injury. Clin J Pain. 2002; 18(2):116-121.
- Siddall PJ, Cousins MJ, Otte A, Griesing T, Chambers R, Murphy TK. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology. 2006; 67(10):1792-1800.
- Drewes A, Andreasen A, Poulsen L. Valproate for treatment of chronic central pain after spinal cord injury. A double-blind cross over study. Paraplegia. 1994; 32(8):565-569.
- Finnerup NB, Grydehøj J, Bing J, et al. Levetiracetam in spinal cord injury pain: a randomized controlled trial [published online ahead of print June 9, 2009]. Spinal Cord. 2009; 47(12):861-867.
- Chiou-Tan FY, Tuel SM, Johnson JC, Priebe MM, Hirsh DD, Strayer JR. Effect of mexiletine on spinal cord injury dysesthetic pain. Am J Phys Med Rehabil. 1996; 75(2):84-87.
- Norrbrink C, Lundeberg T. Tramadol in neuropathic pain after spinal cord injury: a randomized, double-blind, placebo-controlled trial. Clin J Pain. 2009; 25(3):177-184.
Drs DeFrates and Cook are from the Department of Pharmacy Services, University of Kentucky HealthCare; Dr. Cook is also from the University of Kentucky College of Pharmacy, Department of Pharmacy Practice and Science, Lexington, Kentucky.
Drs DeFrates and Cook have no relevant financial relationships to disclose.
Correspondence should be addressed to: Sean DeFrates, PharmD, 800 Rose St H110A, Lexington, KY 40536 (email@example.com).