Pain in SCI: Elusive Causes and Management Challenges

Every inch of progress toward curing paralysisseems to make national headlines, but effortsto manage chronic pain in patients with spinalcord injury (SCI) may go further towardimproving quality of life. Fortunately, moreresearch is being focused on the complexitiesof SCI-related pain.

"Research has been done mostly on 'the cure,' but patient needs involve more immediate things," said Eva Widerstrom-Noga, PhD, research associate professor of neurological surgery at the University of Miami and health scientist for the Miami Veterans Administration. "Pain is a major problem. It drains patients' energy and just takes over to the point where patients have been willing to trade function for pain relief."

The need for effective management of SCI-related pain may be apparent, but it's far less clear which of a multitude of therapeutic options--if any--will ultimately provide pain relief in a patient with SCI.

"Because only very few trials have been performed and those performed generally have been small, we actually know very little about the effectiveness of various drugs on SCI pain. But our clinical experience clearly suggests that this type of pain is very difficult to treat and tends to persist despite various treatment attempts," Nanna B. Finnerup, MD, a research fellow at the Danish Pain Research Center in Aarhus, Denmark, told Applied Neurology.

HETEROGENEITY OF SCI PAIN

A challenge of treating chronic pain in patients with SCI is that the pain may be any of several types that also may differ by location. Nociceptive pain may be musculoskeletal, visceral, or neuropathic.

In a study by Philip J. Siddall, MBBS, PhD, clinical senior lecturer at the Pain Management Research Institute in Sydney, Australia, and colleagues from the University of Sydney, musculoskeletal pain was reported by 43 of 73 patients 5 years after their SCI, but chronic musculoskeletal pain--that is, pain stemming from overuse (particularly in the upper extremities), muscle spasms, or vertebral column defects--did not correlate strongly with the presence of similar pain in the first 6 months postinjury.¹

Visceral nociceptive pain generally presents as abdominal discomfort that may not necessarily be related to bowel, bladder, or kidney dysfunction. A team from the University of Alabama in Birmingham reported that rates of visceral pain in patients with SCI increased from 10% at 5 years postinjury to 22% at 10 years and 32% at 15 years.² They also found that those persons who had experienced visceral pain at any time within 10 years of injury had a statistically significant lower quality of life than those who had never had visceral pain. Also, Siddall and colleagues found that those persons with visceral pain at 5 years were most likely to rate their pain as severe or excruciating.

Neuropathic pain attributed to SCI is characterized according to the location of the pain source relative to the vertebral level of injury.³ Below-level neuropathic pain is generally a central pain related to the spinal cord trauma, which Siddall and colleagues found in 34% of patients at 5 years post-SCI.¹ At-level (including 2 vertebral segments above and below) neuropathic pain may have both peripheral (of nerve root origin) and central (of spinal cord or supraspinal origin) components.⁴ Siddall and associates reported at-level neuropathic pain in 42% of patients at 5 years post-SCI.¹ Above-level neuropathic pain includes compressive mononeuropathies, often associated with repetitive motion in use of wheelchairs or other assistive devices, and complex regional pain syndrome.³

"It's difficult to prescribe a therapy based on the mechanism because a patient may have 3 or 4 types of pain at the same time," Widerstrom-Noga said. "It's common that patients have more of a musculoskeletal type of pain above the level of injury, neuropathic at level, and another kind of neuropathic pain below the level of injury."

INTERFERENCE POTENTIAL

As in other chronic pain populations, pain in patients with SCI often interferes with sleep and other daily activities. Widerstrom-Noga and colleagues found that 77.3% of 217 patients with SCI and chronic pain reported frequent interference in at least 1 of 5 activity categories: sleep, work, exercise, household chores, and other daily activities.⁵ Of 300 chronic pain components reported by 265 veterans with SCI in a telephone survey conducted by a team from the Michael E. DeBakey Veterans Affairs Medical Center in Houston, 67% were said to interfere with daily activities: 38% interfered "a lot" while 29% interfered "somewhat."⁶

In another study of 66 patients with SCI discharged from a tertiary rehabilitation center, it was found that interference with many or most activities of daily living were reported by 53% of patients at admission, 25% at discharge, and 27% after 6 months of community living.⁷ The study authors also found that pain intensity accounted for 25% of the variance in scores on the Reintegration to Normal Living Index.

SLEEP PROBLEMS

A number of factors, including voiding and GI impairments, can contribute to disordered sleep in patients with SCI. A questionnaire-based comparison of 408 patients with SCI and 339 able-bodied persons found that the patients with SCI as a group were significantly more likely than the control group to have difficulty in falling asleep, to sleep less well, to snore more frequently, and to have had sleep medications prescribed for them.⁸ However, of the sleep-related problems reported by the SCI group, pain and paresthesia were the most frequently cited primary problems (cited by 31.7% of the respondents).

The findings were confirmed by another questionnaire-based study⁹ that found that the patients with SCI with continuous pain had significantly poorer sleep quality (difficulty in falling asleep, awakening during the night, poorer overall sleep quality, and sleepiness in the morning and daytime) than patients with SCI with no pain. However, no differences were seen between those with no pain and patients with intermittent pain, suggesting that the presence of pain in and of itself is not related to disordered sleep in this patient population. Furthermore, Widerstrom-Noga and colleagues found that pain-related sleep interference in 123 patients with SCI increased in frequency during the 18-month period between an initial survey and a second survey, a finding that conflicts with the commonly held belief that patients with SCI experience less interference over time as they adapt to the limitations of their injuries.¹⁰

PSYCHOSOCIAL CONTRIBUTORS

Multiple studies from the University of Washington,^11-13 presented at recent meetings of the American Pain Society (APS), suggest that psychosocial factors can significantly affect the experience of pain in patients with SCI--but that the importance of specific psychosocial variables may vary from one patient to another. In a study of 41 patients with SCI who reported chronic pain in 2 surveys conducted 6 months apart, research associate Marisol Hanley, PhD, and colleagues¹¹ found that psychosocial factors contributed significantly to changes in pain interference (accounting for 24% of the variance) and psychological function scores (accounting for 48% of the variance) from the first survey to the second. In particular, they found that increased levels of catastrophizing were associated with increased pain interference and decreased mental health and that perceived control over pain was associated with decreased pain interference and improved mental health.

This last finding contrasts with a 157-patient, single-survey study by the same group that found that perceived control over pain was not related to either pain-related interference or psychological functioning.¹² Wellness-focused coping, such as task persistence, positively influenced both types of function, while illness-focused coping, such as asking for assistance, was linked to greater levels of pain interference.

However, the study also found that social support was associated with improved psychological function, which contrasts with an earlier study from the same institution in which social support did not significantly influence either psychological or physiologic function.¹³ In that study, which was subsequently published in the February 2006 issue of The Journal of Pain, questionnaires were completed by 70 patients with SCI and their spouses. Spouse responses-- primarily negative responses--accounted for 13% of the variance in pain interference and 23% of the variance in depression.

Catastrophizing is a psychosocial variable that tends to be consistently associated with physical and psychological functioning in patients with SCI and chronic pain, both in studies and anecdotally, said Mark P. Jensen, PhD, professor of rehabilitation medicine at the University of Washington and a coauthor of all 3 studies. Other variables, such as perceived control over pain or social support, may be significant only in select patients.

"When studying factors as they relate to pain, if you find a factor that pops up in all 20 studies, you say, 'This is a factor.' Catastrophizing is one," Jensen said. "Some never pop up. Then you have this larger group of variables that pop up in some cases and not in others."

In addition to psychosocial considerations, clinicians treating chronic pain in patients with SCI must take into account other complicating factors that are unique to that patient population. Patients with SCI often have limited mobility, which can make them reluctant to seek treatment. Paralysis can also affect the way patients with SCI perceive pain, which can make it difficult for a clinician to identify the source of the pain based on the patient's description.

"If a patient is paralyzed from the waist down and they have sciatica, the way they feel sciatica is going to be very different from the way an otherwise able-bodied person feels sciatica," said Anthony Chiodo, MD, director of Spinal Cord Injury Medicine at the University of Michigan.

Bladder and bowel control issues in patients with SCI can also influence a pain management strategy, particularly with regard to medications with adverse effects that affect those biologic functions. Tricyclic antidepressants, for example, are commonly used to treat neuropathic pain, but adverse effects include constipation and urinary retention.

"A medication may work for a patient who has chronic pain but normal bowel function, for whom a little constipation is not a big problem. But for a person with bowel impairment, that can be a big problem," Widerstrom-Noga said.

TRACKING TREATMENT UTILIZATION

Even before a clinician begins examining clinical trial data, he or she can get a sense of the relative effectiveness of various pharmaceutic options for treating chronic pain in patients with SCI by noting which therapies are actually being used by patients. In a survey of 117 patients with SCI and chronic pain, University of Washington researchers found stark contrasts in some cases between treatment options that a patient might have tried in the past and those that the patient was still using.¹⁴

The most frequently tried pharmaceutic therapies--NSAIDs and acetaminophen--were still being used by more than half of those surveyed; by comparison, 38% had tried the anticonvulsant gabapentin (Neurontin) but only 17% were still using it. In a 2003 study by Widerstrom-Noga and Turk,¹⁵ opioids were the pharmaceutic treatment most frequently cited by patients with SCI as a method to manage pain in the previous 18 months, but even opioids were used by only 22.5% of the 120 patients studied. Following opioids were NSAIDs (20%), acetaminophen (18.3%), and anticonvulsants (17.5%); antidepressants accounted for 12.5%. Thirty-nine percent of patients had used nonpharmaceutic therapies, the most common being massage (26.7%).

Notably, even the most popular pharmaceutic treatments were reported to have had little or no effect on pain severity by more than two thirds of those who had tried them; by comparison, 47.5% of those who had received physical therapy reported that the pain had become "considerably better" as a result.

The findings from this study are generally consistent with those of a study by Finnerup and colleagues¹⁶ in which 43% of 330 patients with SCI were taking analgesics for pain or dysesthesia at the time they were surveyed (median time from injury, 9.3 years). In this study, simple analgesics were cited most frequently (21%), followed by opioids (14%) and spasmolytics (14%); only 4% of respondents reported taking antidepressants and 3%, anticonvulsants. Nearly half of respondents (47%) were receiving nonpharmaceutic treatment, most often physical therapy. Similarly, a team from the Karolinska Institute in Stockholm found that 41% of 130 patients with SCI and pain used analgesic drugs during a 12-month period, with opiates most frequently cited (28%), followed by NSAIDs (19%), antidepressants (8%), and anticonvulsants (5%).¹⁷

The wide range of therapeutic use--and the surprising number of patients who have given up on treatment--reflects the complexities of the chronic pain experience in the SCI population.

"The effectiveness of medications tends to vary from person to person," Jensen said. "There's a subset taking gabapentin and pregabalin [Lyrica], and there's a subset of those for whom the anticonvulsants really provide benefit. There's a smaller subset that respond to the tricyclic antidepressants. Very few take opioids. Many say they really decrease the pain, but when we ask, 'Are you still using them?' they say no, because of the adverse effects."

Thus far, clinical trials of most medications have not been able to identify the subsets of patients with SCI who might benefit most from a specific drug, primarily because of small sample sizes, which, in turn, are the result of recruit- ing challenges. In a study by researchers at the University of Washington in which 84 patients with SCI and chronic pain were randomly selected to receive either amitriptyline or an active placebo (benztropine [Cogentin]), no significant differences in pain intensity or pain-related disability were found--but the authors noted that they could not rule out the possibility that subgroups might benefit from the drug.¹⁸

"If you look at the averages, a study may conclude that there's not a significant difference between a drug and placebo, but looking at the averages disregards the patients in whom there was an effect," Widerstrom-Noga said. "So we need to look at those patients and ask whether there's something we can predict about the way they will respond."

RCT RESURGENCE

Despite the disappointing results that historically have come from most randomized controlled trials (RCTs) of potential therapies for chronic pain in the SCI population,¹⁹ drugs studied in more recent trials have increasingly been shown to be effective--at least to some degree. This is largely because of strong showings on the part of sodium channel blockers, but amitriptyline and anticonvulsants also have fared well of late.

A randomized triple-crossover study that compared amitriptyline, gabapentin, and an active control medication in 22 patients with SCI and central neuropathic pain found that mean pain intensity was significantly lower after 8 weeks of amitriptyline than after therapy with the comparison medications, which were not significantly different from each other.²⁰ However, the authors noted that some individual patients experienced the greatest reductions in pain intensity after 8 weeks of gabapentin therapy. Gabapentin also was associated with significant reductions in pain intensity in an RCT of 20 patients with complete SCI and neuropathic pain of more than 6 months' duration.²¹

At last year's annual meeting of the APS, held in Boston in early spring, Siddall and colleagues²² reported that pregabalin significantly reduced pain and sleep interference in an RCT of 137 patients with SCI-related central neuropathic pain. After 12 weeks of treatment, mean pain scores and sleep interference scores were significantly lower in the intervention group, and 42% of pregabalin-treated patients had at least a 30% decrease in pain, compared with 16.4% of placebo-treated patients.

Until recently, few sodium channel blockers other than lidocaine had been studied in the SCI population, with lidocaine demonstrating inconsistent effectiveness.¹⁹ But an RCT presented at the 2006 APS meeting by researchers from Brigham and Women's Hospital in Boston found that intravenous fosphenytoin, a prodrug of the sodium channel blocker phenytoin, significantly reduced mean pain intensity in 17 patients with central neuropathic pain following SCI when given at a dose of 12 mg of phenytoin equivalents per kilogram.²³

After 240 minutes, the 12 mg/kg dose resulted in a mean change in pain intensity of 31% from baseline; lower doses were associated with positive trends in pain reduction that were not statistically significant. Patients with incomplete SCI experienced more pain relief than those with complete injuries (40% vs 18%).

Four years earlier, in an open-label trial of the sodium channel blocker oxcarbazepine for spontaneous SCI pain, the research team found almost complete relief (mean, 84%) in 6 patients with touch-evoked allodynia but only minimal relief in 4 patients without allodynia.²⁴

Intravenous lidocaine fared well in a double-blind crossover trial conducted by Finnerup and colleagues,²⁵ wherein the drug regimen significantly reduced at- and below-level pain more effectively than placebo in all 24 patients studied. The number of those with more than 33% pain reduction did not differ significantly between the group of patients with evoked pain (6 of 12) and the group without (5 of 12).

The study tested a 5 mg/kg dose of lidocaine, which may be significant, since a small triple-crossover RCT published the previous year by a team from Uppsala University Hospital in Sweden reported that 2.5 mg/kg of IV lidocaine resulted in 50% pain relief in only 1 of 10 patients who had SCI with below-level pain.²⁶ The researchers found that a 0.4 mg/kg dose of IV ketamine reduced pain intensity by at least half in 5 of 10 patients.

OTHER THERAPEUTIC OPTIONS

Chiodo²⁷ has found that intra- articular spinal injections can be as effective for pain relief in patients with SCI as in the general population of patients with back pain. The injection, performed under fluoroscopic guidance, involves a corticosteroid for inflammation or either lidocaine or bupivacaine for a diagnostic block, he said.

"Back problems and back pain are ubiquitous in our society. Seventy-five to 80% of the population will have a back problem at some point. So why not treat patients with SCI [in a similar way]?" said Chiodo. "Pain is as common for me to see as it is for your local family physician. But because there are so few people like me who have dual interests [in pain and SCI], these techniques really haven't been used in patients with SCI very much."

On the nonpharmaceutic end of the therapeutic spectrum, Jensen and colleagues at the University of Washington have had success using hypnotic therapy to not only decrease pain in the short-term but also to give patients with SCI a tool with which to better manage pain on their own. In a series of 22 patients with SCI-related pain, Jensen and colleagues²⁸ found that pain intensity and pain unpleasantness decreased in 86% of patients after 5 hypnosis sessions and that the relief experienced during a session was maintained afterward.

"Hypnosis is simply a state of focused attention," Jensen said. "When a person focuses on something, his awareness of other things in his environment fades into the background, and relaxation goes along with that. Also his critical judgment kind of goes away. So it's possible that another person can make a suggestion [to enable] the brain to remember how to get to this state of comfort."

Another team from the same university is using cognitive restructuring techniques to address--and possibly prevent--psychological symptoms such as catastrophizing that can complicate the pain experience in patients with SCI.

"If you're in pain, you can think helpful thoughts or unhelpful thoughts. Even if the unhelpful thoughts are true, they're still unhelpful," said team leader Dawn Ehde, PhD, associate professor of neuropsychology and rehabilitation. "We try to shift patients from thinking they are hopeless and powerless to thinking that there are things they can do to cope with the pain."

Ehde and colleagues²⁹ conducted a feasibility study of 18 patients with disability-related pain (including 10 patients with SCI) in which cognitive restructuring was associated with reductions in pain. Her team is now in the last year of a 3-year study in which patients with new SCI or limb loss and acute pain are undergoing a protocol by which they will randomly receive cognitive restructuring, hypnosis, or an educational intervention during the first 6 months following injury.

GOING FORWARD

Experts hypothesize that the best approach may ultimately be a multifaceted one--perhaps an individualized combination of drug therapy that combines pharmaceutic and nonpharmaceutic resources. They emphasize the need for multidisciplinary team management of SCI-related chronic pain that includes neurologists, psychologists, and physical and occupational therapists. Researchers continue to work at identifying subsets of patients who respond to particular treatments or who have found ways to effectively cope with their pain.

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