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To conduct a systematic review of published research on the pharmacological treatment of pain after spinal cord injury (SCI).
Medline, CINAHL, EMBASE and PsycINFO databases were searched for articles published 1980 to June 2009 addressing the treatment of pain post SCI. Randomized controlled trials (RCTs) were assessed for methodological quality using the PEDro assessment scale, while non-RCTs were assessed using the Downs and Black evaluation tool. A level of evidence was assigned to each intervention using a modified Sackett scale.
The review included randomized controlled trials and non-randomized controlled trials which included prospective controlled trials, cohort, case series, case-control, pre-post and post studies. Case studies were included only when there were no other studies found.
Data extracted included the PEDro or Downs and Black score, the type of study, a brief summary of intervention outcomes, type of pain, type of pain scale and the study findings..
Articles selected for this particular review evaluated different interventions in the pharmacological management of pain post SCI. 28 studies met inclusion criteria: there were 21 randomized controlled trials of these 19 had Level 1 evidence. Treatments were divided into five categories: anticonvulsants, antidepressants, analgesics, cannabinoids and antispasticity medications.
Most studies did not specify participants’ types of pain; hence making it difficult to identify the type of pain being targeted by the treatment. Anticonvulsant and analgesic drugs had the highest levels of evidence and were the drugs most often studied. Gabapentin and pregabalin had strong evidence (five Level 1 RCTs) for effectiveness in treating post-SCI neuropathic pain, as did intravenous analgesics (lidocaine, ketamine and morphine) but the latter only had short term benefits. Tricyclic antidepressants only showed benefit for neuropathic pain in depressed individuals. Intrathecal baclofen reduced musculoskeletal pain associated with spasticity; however there was conflicting evidence for the reduction in neuropathic pain. Studies assessing the effectiveness of opioids were limited and revealed only small benefits. Cannabinoids showed conflicting evidence in improving spasticity related pain. Clonidine and morphine, when given together, had a significant synergistic neuropathic pain-relieving effect.
Pain is a frequent complication of spinal cord injury (SCI). Studies examining pain prevalence have noted on average, two-thirds of people with SCI report some form of pain and nearly one-third rate their pain as severe. These estimates have been confirmed in at least two studies1,2, with several recent studies reporting estimates of prevalence as high as 77%–86%.3–7 However, it is notable that individual reports of incidence and prevalence vary widely, due to differences in methodology and/or the populations being studied.8,9
Pain has often been reported as an important factor in decreased quality of life, and has been shown to adversely impact function and participation in a variety of activities (e.g., sleep, activities of daily living (ADLs), community re-integration) in persons with SCI.3,10– 13 Nepomuceno et al.10 noted that 23% of individuals with cervical or high thoracic SCI and 37% of those with low thoracic or lumbosacral SCI reported being willing to sacrifice sexual and/or bowel and bladder function, as well as the hypothetical possibility of a cure of their SCI in exchange for pain relief.
The Task Force on Pain Following SCI, sponsored by the International Association for the Study of Pain (IASP), introduced a taxonomy based upon expert consensus of presumed etiology (Sidall et al. 2000); this classification scheme has been widely accepted (Bryce et al. 2006). In this schema, SCI-related pain is classified as either pain caused by the activation of nociceptors which are primary sensory neurons for pain (nociceptive) or pain caused by damage to the sensory system itself (neuropathic). Nociceptive pain can originate from the skin or musculoskeletal system or visceral organs; while neuropathic pain can involve the peripheral nervous system or in the case of spinal cord injury, the central nervous system. The majority of persons complaining of chronic pain report pain onset within the first 6 months of their injury, irrespective of the type of pain.5,10,14–16 Some studies have reported more delayed pain onset with visceral pain.5,16 Preliminary longitudinal studies have shown relatively stable pain patterns over time in persons with chronic SCI, with few individuals reporting dramatic changes in pain location, type or intensity.17
Despite impressive gains in limiting bladder, skin, cardiovascular and respiratory complications after SCI, chronic pain post SCI has proven to be largely refractory to medical management.18–20 This lack of treatment efficacy has been complicated by an incomplete understanding of pain in individuals with SCIs and, until recently, the lack of a standardized framework upon which to classify SCI-related pain.21 Currently the International Association for the Study of Pain taxonomy sub-committee is in the process of reviewing the pain classification post SCI.
Pharmacological interventions remain the mainstay of treatment for SCI-related pain. Not unexpectedly, Widerstrom-Noga and Turk22 found that SCI patients with more severe pain were more likely to use pain treatments. The use of simple non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen and non-opioid ‘muscle relaxants’ is common clinical practice in treating SCI pain. Unfortunately, these medications often are ineffective in providing consistent significant pain relief for neuropathic pain and have potential risks, such as gastrointestinal, renal and hepatic toxicity, with prolonged heavy use. For neuropathic or ‘central’ pain seen following SCI, anticonvulsants and psychotropic drugs, i.e. antidepressants, are reportedly the most commonly used.23 However, despite increasing popularity, few of these drugs have regulatory approval for use in neuropathic pain, and their use in individual patients is largely based on anecdotal evidence of off-label use. This systematic review was conducted in order to assess the research evidence of treatment approaches currently used in the pharmacological management of pain in persons with SCI. This study is part of the Spinal Cord Injury Rehabilitation Evidence (SCIRE) project (http://www.scireproject.com)24, an evidence-based review of the literature assessing rehabilitation interventions in SCI patients. SCIRE was first available in 2006 and is currently in its second edition.
A systematic review of all relevant literature, published from 1980 to June 2009, was conducted using multiple databases (MEDLINE, CINAHL, EMBASE, PsycINFO). Key words included: pain, pain treatment, pharmacology, pain management, secondary complications, anticonvulsants, cannabinoids, antidepressants, medications, anaesthetic, analgesic, and antispastic. Retrieved references were scanned for relevant citations that might have been missed by the searches of the various databases.
Studies were included for analysis if they met the following criteria based on the previously established SCIRE methodology.25 Studies were only included for analysis if at least 50% of subjects had a SCI, there were at least three subjects with a SCI, and there was a definable intervention being studied. Only studies published in English language were included. For the following review of pharmacological interventions for pain post SCI, 28 of 814 studies met inclusion criteria. Studies examining all types of pain post SCI (nocioceptive, neuropathic and mixed) were examined.
A methodological quality assessment was conducted for each article by two reviewers, using either the Physiotherapy Evidence Database (PEDro) scoring26 system for randomized controlled trials (RCTs), or the Downs and Black (D&B) tool27 for non-randomized studies. Scoring discrepancies were resolved by a third blind reviewer.
The PEDro was originally developed for assessing RCTs and systematic reviews in physiotherapy. Individual item level and total PEDro scores have been shown to have good agreement between raters.28 The PEDro assessment consists of 11 questions with a maximum score of 10. External validity is measured by the first item, while the other 10 items relate to the study’s internal validity. Foley et al.28 have arbitrarily defined the following criteria for rating the methodological quality of a study: 9–10 excellent; 6–8 good; 4–5 fair; <4 poor.
In an evaluation of 194 different tools, the Downs and Black tool was one of only 6 tools identified as suitable for use in systematic reviews29 for assessing methodological quality in non-randomized studies. In an analysis of 18 tools, Downs and Black (D&B) tool was found to be the best to assess the quality of nonrandomized trials due to its reliability and validity.30 The D&B tool contains 27 items assessing reporting, external validity, internal validity (bias), internal validity (confounding) with a maximum score of 28.
Higher methodological quality for each study was determined by a higher score on either tool. In the present methodology, a PEDro score of 5 or lower was used to designate “poor” quality RCTS, which corresponds to a marginally lower score than the approximate mean value over all RCTs in the PEDro database conducted over the latest reported time periods (i.e., 1995–2002).28
Investigations involving similar interventions were grouped and tabulated. Tables containing summaries of each study included the PEDro or Downs and Black score, the type of study, a brief summary of intervention outcomes, type of pain, type of pain scale and the study findings. A modified Sackett scale, with 5 levels of evidence, was used to determine the strength of evidence for each intervention31 (see Table 1). The modified scale was created in order to simplify the 10 subcategories present in the Sackett scale into a system with 5 Levels. Level 1 included RCTs with a PEDro score of greater than or equal to 6, while RCTs with scores lower than 6 were given a Level 2 evidence. Prospective controlled trials and cohort studies were also included in Level 2 evidence. Level 3 evidence consisted only of case control trials. Prepost studies, post test and case series were considered Level 4 evidence. Lastly, Level 5 evidence consisted of observational studies, clinical consensus, and case reports.
Most pharmacological interventional studies which met our inclusion criteria were supported by strong levels of evidence. 21 of 28 studies were RCTs of which 19 provided Level 1 evidence. When indicated, most studies specifically examined individuals with neuropathic pain post SCI; however, many studies did not distinguish between neuropathic and musculoskeletal pain. Though studies utilized a varying array of pain assessment tools, the two most commonly used scales were the Visual Analogue Scale (VAS; n=17) and the McGill Pain Questionnaire (MPQ; n=8).
Anticonvulsant medications often are utilized in the treatment of neuropathic pain following SCI, as well as a number of other medical conditions.
Gabapentinoids (gabapentin and pregabalin), are now considered to be first-line treatment for post-SCI neuropathic pain.32 Gabapentinoids mimic the neurotransmitter GABA; however, unlike baclofen they don’t act directly with the GABA receptor. Instead, therapeutic effectiveness for neuropathic pain is believed to be through interaction with voltage gated N-type calcium ion channels at the α2δ subunit and also indirectly with the NMDA receptor. Both of these drugs have been shown to increase the activity of inhibitory neurons resulting in a decrease in transmission of nociceptive signals. 33,34
Rintala et al.35 conducted a RCT comparing the effects of gabapentin, amitriptyline, and an active control (diphenhydramine) on pain intensity post SCI in individuals with neuropathic pain. At 8 weeks gabapentin, when compared to amitriptyline or diphenhydramine, was not more effective in reducing pain intensity in participants scoring high (≥10) or low (<10) baseline scores on the Center for Epidemiologic Studies Depression Scale-Short Form (CESD-SF).
In a RCT conducted by Siddall et al.,36 those in the treatment group (n=70) receiving 150 to 600 mg/daily (BID) of pregabalin experienced a significantly greater improvement in pain and sleep than those in the control group (n=67). In a RCT conducted by Vranken et al.,37 patients in the treatment group received escalating doses of pregabalin (150–600 mg daily), while those in the control group received a placebo. Subjects in the treatment group reported a significant decrease in pain (p<0.01), along with improvements in the EQ-5D VAS and utility scores (p<0.01), as well as the Bodily Pain subscale of the SF-36 (p<0.05), relative to the control group.
Levendoglu et al.,38 in a cross-over study involving 20 paraplegics with neuropathic pain more than 6 months, found gabapentin was more effective (p<0.05) than placebo at reducing neuropathic pain. Tai et al.39 studied the impact of gabapentin on pain in a small RCT involving only 7 patients. There was a significant reduction in ‘unpleasant feelings’ with gabapentin vs. placebo (p=0.028), while reduction in ‘pain intensity’ and ‘burning pain’ only trended towards significance (p=0.094 and 0.065, respectively). No differences were detected for other pain descriptors, such as ‘sharp’, ‘dull’, ‘cold’, ‘sensitive’, ‘itchy’, ‘deep’, or ‘surface’.
To et al.40 studied the impact of gabapentin in a case series of 44 SCI patients with neuropathic pain, and reported a significant decrease in pain (p<0.001) as measured by the visual analog scale (VAS) in 76% of subjects. Ahn et al.,32 in a before and after trial of SCI patients with pain, found gabapentin was effective (p<0.05) in decreasing neuropathic pain refractory to conventional analgesics. The impact was greater among those patients whose pain had been present for less than 6 months. Putzke et al.41 found that, among the 21 patients who answered their questionnaire, 67% (n=14) reported a reduction in pain while on gabapentin.
Lamotrigine, a voltage-gated Na+ channel acting anticonvulsant, was utilized by Finnerup et al.42 in a 9 week RCT to treat neuropathic pain post SCI in 22 patients. This study found no significant improvement in overall pain post SCI; however, a subgroup of patients with incomplete SCI reported a significant reduction in their at- or below-level neuropathic pain.42
Valproic acid is a broad spectrum anticonvulsant sometimes used in the treatment of pain. Studies indicate it works directly on voltage-gated Na+ channels, resulting in the suppression of high frequency firing neurons. It also indirectly increases GABA concentrations in the brain.43 In a double-blind cross-over study (n=20), Drewes et al.44 examined the effects of a 3 week treatment course of valoproic acid on chronic central pain in individuals who had sustained a SCI. Overall, they found no significant differences between the control and treatment groups; however, there was a trend towards improvement in the treatment group.
Levetiracetam is an oral anticonvulsant, with structure and mechanism unrelated to other anticonvulsants. It has multiple analgesic mechanisms of action such as inhibition of N-type voltage gated calcium channels and acts as a GABAA agonist.45 Finnerup et al.45 conducted a randomized, double blind, crossover trial of levetiracetam in SCI individuals with pain. Participants were either placed in the levetiracetam or placebo group for 5 weeks and then crossed over after a 1 week washout period. The study found no significant difference between the levetiracetam and the placebo treatment group in improving pain intensity (p=0.46).
There is Level 1 evidence that gabapentin and pregabalin improve neuropathic pain post SCI. There is Level 4 evidence that gabapentin is more effective when SCI pain has been present for < 6 months versus > 6 months. There is Level 2 evidence that lamotrigine is effective in reducing neuropathic pain in individuals with incomplete SCI. There is Level 1 evidence that valproic acid does not significantly relieve neuropathic pain post SCI; however a non-significant trend toward improvement in pain was seen; this warrants further study. One Level 1 study showed levetiracetam is not more effective in reducing neuropathic pain post SCI than placebo.
Both trazodone and amitriptyline are commonly used antidepressants, which act on adrenergic and 5HT2A receptors respectively, resulting in increased serotonin and/or norepinephrine concentrations in the central nervous system.46 Sandford et al.47 have speculated that tricyclic antidepressants exert an analgesic effect by increasing serotonin in the CNS, thereby potentiating the inhibition of afferent pain signals. These properties have resulted in significant pain reduction in a number of clinical conditions.
Amitriptyline is a tricyclic antidepressant which is thought to modulate pain by inhibiting the synaptic reuptake of norepinephrine and serotonin in the central nervous system (CNS). Therefore, amitriptyline has effects on both the adrenergic and 5HT receptor signal transduction pathway. Rintala et al.35 conducted a RCT comparing the effects of amitriptyline, gabapentin, or an active control (diphenhydramine) in the treatment of neuropathic pain post SCI. At 8 weeks, pain intensity in the amitriptyline group was significantly lower than in the gabapentin (p=0.03) or the diphenhydramine groups (p=0.012). The study found amitriptyline was significantly more effective in treating neuropathic pain in individuals with high (≥10) baseline score of CESD-SF when compared to the active placebo (p=0.035); however, no such difference was seen when compared to gabapentin (p=0.61). Furthermore, no significant improvement in pain intensity was seen in participants with low (<10) baseline CESD-SF scores. In an earlier RCT, Cardenas et al.,48 compared amitriptyline’s efficacy against an inactive control in a mixed group of SCI patients with either neuropathic or nociceptic pain. The study found no significant difference in SCI patients randomized to receive either amitriptyline or placebo given 1–2 hours before bedtime for a period of 6 weeks.
Trazodone is reported to selectively inhibit serotonin and norepinephrine reuptake in a ratio of 25:1, and is thought to produce greater analgesia and less anti-cholinergic side-effects than more non-selective agents like amitriptyline. Davidoff et al.49 found, in a 6 week double-blind placebo-controlled trial, that trazodone was ineffective at relieving pain in 18 SCI patients with chronic neuropathic pain (see Table 3). Heilporn,50 using combinations of melitracin (a previously available antidepressant) and TENS, reported relief of pain in 8 of 11 SCI patients with neuropathic pain.
There is Level 1 evidence that the tricyclic antidepressant trazodone does not reduce post-SCI neuropathic pain more than placebo. There is Level 1 evidence that amitriptyline is effective in the treatment of post-SCI pain, but only in depressed individuals.
Given the severity and intractability of post-SCI pain, treatments such as lumbar epidural and subarachnoid infusions of analgesics have been studied. Loubser and Donovan 51 conducted a within subject RCT involving 21 patients, administering a placebo and 5% lidocaine injection in a randomized sequence. Following the lidocaine injections, 13 patients reported a significant mean reduction in pain from baseline averaging 2 hours when compared to placebo (p<0.01). Attal et al.,52 reported on 15 patients who received lidocaine intravenously and experienced a greater reduction in pain than those who received placebo, with an effect lasting up to 45 minutes post injection, and a reduction in the intensity of brush-induced allodynia and mechanical hyperalgesia. In a RCT study by Finnerup et al.,53 those patients who received lidocaine intravenously (n=24) in two treatment sessions 6 days apart reported significantly less pain than those who did not receive lidocaine.
Chiou-Tan et al.54 provided 15 SCI individuals with either oral mexiletine (an orally administered derivative of lidocaine) or placebo (150mg 3 × daily) in a double-blind cross-over RCT. There was no appreciable improvement in pain severity, as measured either on a VAS or using the McGill Pain Questionnaire, within either group.
Ketamine is a NMDA receptor antagonist sometimes used to treat neuropathic pain. Two studies have looked at the effect of ketamine on post-SCI pain. In one RCT of 10 subjects, Kvarnstrom et al.55 found ketamine was successful in reducing spontaneous neuropathic pain post SCI. Eide et al.56 in another small RCT (n=9), compared intravenous ketamine hydrochloride (an NMDA receptor antagonist), alfentanil (a μ-opioid receptor agonist) and placebo as either a combination bolus or continuous intravenous infusion. The bolus dose was administered for 60 seconds and the continuous intravenous infusion was started simultaneously for 17–21 minutes during testing. A significant reduction in allodynia was noted for the ketamine and alfentanil treatments relative to placebo. Alfentanil and ketamine reportedly reduced wind-up pain when compared to placebo, but not when compared to each other. Wind-up pain is produced by repeated stimulation of c-nociceptive afferents resulting in temporal summation of pain perception.56 There was a high correlation between the serum concentration of ketamine and the degree of reduction in continuous and wind-up pain.
Morphine is an opium-derived analgesic which acts directly on the central nervous system (CNS) to relieve pain by binding and activating the mu opioid receptor (MOR).57 There are many endogenous opioids including endorphins, endomorphins and nociceptin produced naturally within the human central nervous system and even more opioids manufactured as analgesics. The mu opioid receptor (MOR) is often targeted pharmacologically for its analgesic effects as the MOR reduces the presynaptic release of GABA.58 The anti-nociceptive effects of clonidine are thought to be mediated via inhibitory interaction with pre- and post-synaptic primary afferent nociceptive projections in the dorsal horn,59 and possibly by inhibition of substance P release.60, 61 Clonidine is a central acting alpha-2 agonist; Ackerman et al.59 have demonstrated that selective alpha-2 adrenergic antagonists (e.g. Yohimbine) can reverse clonidine-induced analgesia.
Siddall et al.62 conducted an RCT/cross-over trial of intrathecal morphine, clonidine or placebo given at the lumbar level in 20 subjects with post-SCI neuropathic pain. Once a subject achieved satisfactory pain relief or suffered drug side effects with one of the three treatments, that subject was treated with a mixture of clonidine and morphine. Both morphine and clonidine given alone demonstrated a trend towards pain reduction; however, when the combination of morphine and clonidine was administered, there was a significant reduction in pain. Siddall et al.62 postulated that administering half the effective minimum dose of clonidine and morphine together resulted in a synergistic benefit and reduction in pain.
Uhle et al.63 reported on 10 SCI patients who were given 0.01mg morphine (1ml) followed by clonidine (30μg) intravenously. If there was no significant reduction in pain, an additional 50μg of clonidine was given. When given clonidine, patients reported good to excellent reductions in pain. Eight of the 10 patients had pumps implanted to ensure continuous intrathecal administration of clonidine. The average daily dose of clonidine stabilized at 44μg. The authors concluded that combining intrathecal clonidine and opioids reduced pain.63
Attal et al.64 in a RCT administered either saline or morphine bolus injections in 15 SCI individuals. The study found morphine significantly reduced dynamic mechanical allodynia pain for up to 90 minutes (p<0.01); however, it had no effect on other types of pain. Patients receiving morphine also experienced significantly greater side effects than those receiving the placebo (p=0.005); however these adverse effects were mild and reversible.
Tramadol is a low affinity μ opioid agonist which also acts as a weak monoamine reuptake inhibitor. Norrbrink and Lundeberg65 conducted a double-blind RCT to assess the efficacy of tramadol in 35 SCI individuals diagnosed with at- or below-level neuropathic pain. The authors reported significant differences between the two group pain ratings (p<0.05). Tramadol was also found to be effective in improving anxiety, global life satisfaction and sleep quality in post-SCI individuals (p<0.05). However, no significant improvement was seen in pain unpleasantness and depression levels.
Capsaicin is a vanilloid receptor 1 (VR1) agonist which has been used for decades to relieve pain. Vanilloid receptors, specifically the VR1, are neuronal membrane recognition sites that are stimulated by capsaicin, noxious heat (>43°C) and low pH; as such they have been identified as an integrator of chemical and physical stimuli that elicit pain.66 Capsaicin works by activating distinct sensory neurons (noiciceptors) which then transmit nociceptive information back to the CNS and release substance P.67 The excitation of these neurons is followed by long lasting desensitization periods due to the depletion of substance P. In a survey of 8 patients with pain at or just below the level of injury, Sandford and Benes67, reported that capsaicin topical cream reduced post-SCI radicular pain symptoms in most patients after 6 months.
There is Level 1 evidence that lidocaine, delivered through a subarachnoid lumbar catheter, provides more short-term neuropathic pain relief than placebo. There is Level 1 evidence that either intravenous ketamine or alfentanil significantly reduces neuropathic pain relative to placebo. There is Level 1 evidence from 1 RCT and Level 2 evidence from a prospective controlled trial (PCT) that a combination of intrathecal morphine and clonidine results in a significant reduction in neuropathic pain. There is Level 1 evidence that intravenous morphine alone significantly improves dynamic mechanical allodynia pain post SCI. There is Level 1 evidence that tramadol is effective in reducing neuropathic pain post SCI. There is Level 1 evidence that mexilitene does not improve SCI neuropathic pain when compared to placebo. There is Level 5 evidence that capsaicin topical cream may reduce post-SCI pain.
Cannabinoid receptors bind endogenous ligands such as endocannabinoids and exogenous ligands known as cannabinoids. These receptors modulate a variety of physiological processes including pain, mood and memory.68 Tetra hydrocannabinol (THC), a cannabinoid, is the active compound in cannabis and is one of the most common compounds used to target cannabinoid receptors during drug therapy. THC binds and activates the cannabinoid receptor type 1 (CB1).69 It has been anecdotally noted that the use of marijuana provides benefits for central neuropathic pain in some patients.
Hagenbach et al.70 conducted a study primarily examining the effectiveness of THC in improving spasticity and secondarily, in improving pain with SCI individuals. In the first phase of the study, 22 individuals received 10mg of oral THC which was then dose titrated until maximum tolerance or treatment dose was reached for 6 weeks. The study found a significant reduction in SCI individuals’ pain post treatment (p=0.047). The third phase of the study, involved a double blind randomized control trial which included 13 of the previously mentioned individuals receiving either individual maximum treatment dosage previously determined or a placebo dose. In this phase, Hagenbach et al.70, found individuals in the treatment group had no significant pain reduction compared to those in the placebo group.
There is conflicting evidence for the use of THC in reducing spastic pain in SCI individuals.
Baclofen is a GABAB receptor agonist that acts at the level of the spinal cord to suppress spasticity in SCI patients.71 GABA is known to be involved in several analgesic pathways,72 and experimentally-induced allodynia can be suppressed by baclofen73; however, baclofen appears to be most effective in reducing the musculoskeletal pain associated with spasticity. Continuous intrathecal infusion of baclofen has been shown to further reduce post-SCI spasticity and/or pain (whether it be neuropathic, musculoskeletal, or neuropathic)74,75 (see Table 6).
In a RCT, Herman et al.75 found intrathecal baclofen significantly suppressed neuropathic (burning) pain among 6 of 7 subjects (p<0.001), while only 1 of the 2 patients in the non-RCT group receiving placebo reported that their neuropathic pain was abolished. Intrathecal baclofen appeared to have an impact on post-SCI neuropathic pain, in addition to treating spasticity. In contrast, Loubser and Akman76 performed a before-and-after study of implanted baclofen infusion pumps provided for spasticity. Twelve of the 16 patients who had pre-existing chronic pain experienced a reduction on VAS measuring severity of neuropathic pain at 6 and 12 months; however, this difference was not statistically significant (p=0.26). In contrast to neuropathic pain, there was a significant decrease in musculoskeletal pain at both 6 and 12 months (p<0.005) following intrathecal baclofen pump insertion.
Botulinum toxin (BTX) is a naturally occurring neurotoxin. Many clinicians now use botulinum toxin for the treatment of pain associated with focal spasticity. One study77 examined the effects of BTX injection given for spasticity control in SCI individuals and reported dramatic improvements in pain following treatment.
There is conflicting evidence (Level 1 and a Level 4 study) that intrathecal baclofen reduces neuropathic pain post SCI. There is Level 4 evidence that intrathecal baclofen reduces musculoskeletal pain post SCI, in conjunction with spasticity reduction. There is Level 4 evidence that botulinum toxin results in reduction of post-SCI pain associated with spasticity. Oral baclofen has not been studied in the treatment of pain post SCI.
This systematic review assessed the efficacy of pharmacological treatments on post-SCI pain. Despite the fact that the total number of studies exploring pain management after SCI was small, over 70% of the studies reviewed were RCTs. Pharmacological interventions tend to lend themselves well to RCTs. Most studies lacked evidence of numbers to treat and effect size calculations. Most studies assessed pain using primarily two assessment tools, the Visual Analogue Scale and the McGill Pain Questionnaire. Both these tools have been shown to be reliable and valid in the assessment of pain and both are well accepted by pain researchers and clinicians.78,79 However, neither has been specifically validated for assessment of post-SCI pain. In the end, a more specific and standardized post-SCI pain scale may be of greater value.
Table 7 summarizes the effectiveness of the treatments with respect to the types of SCI pain. There was strong evidence supporting the use of anticonvulsants in the treatment of pain post SCI, particularly central or neuropathic pain. Gabapentin32,38–40 and pregabalin36,37 have both been shown to be effective in reducing such pain post SCI. Siddall et al.36, in a high quality Level 1 study, found pregabalin was not only significantly effective in reducing pain post SCI but also in improving sleep and anxiety. These drugs are relatively well tolerated, with few and largely transient side effects.36 They also have the benefit of limited interactions with other medications and lack organ toxicity.38
Several of the studies reviewed were unblinded. One area of concern with unblinded studies is the patients’ awareness they were receiving the active medication likely biased their responses to the drug or their reporting of pain post SCI. Although several studies reported gabapentin as effective in pain management, Rintala et al.35 in a RCT found gabapentin had no significant effect on pain post SCI when compared to an active control. This was a relatively small study and with more positive studies in favor of using gabapentin we did not feel that it negated the usefulness of this agent. However, it does raise the idea that use of the active control medication makes it more difficult for the patient to distinguish between the interventional medication and the control, thereby reducing bias. Larger studies using active controls may be needed.
Other anticonvulsants which have been studied included: lamotrigine, levetiracetam, and valproate. Lamotrigine was found effective in the sub-group of incomplete SCI. Levitiracetam and Valproate have shown some effect in treating neuropathic pain in other pain populations, but failed to show effect in SCI pain. Both of these agents have more negative side effect profiles than either gabapentin or pregabalin80 and this makes them a less desirable treatment choice overall. Older but still commonly used anticonvulsants, such as phenytoin (Dilantin) and carbamazepine (Tegretol) have long been used to treat neuropathic pain; however, these drugs have not been studied in post-SCI pain. They have significant side effects and even in neuropathic pain they are increasingly being supplanted by gabapentin and pregabalin.80
Antidepressants have been used to treat pain in a number of populations81 and have been shown to have some benefit in conditions such as neuropathic pain and fibromyalgia but not low back pain; however, only a limited number of studies have examined their use in post-SCI pain. Tricyclic antidepressants (TCA) have been shown to be partially effective in some SCI patients with neuropathic pain although it is still uncertain whether this is due to an antinociceptive effect or whether the diminished reports of pain are related to the antidepressant effect. Sandford et al.47 noted that pain and depression may be linked; depression can lower an individual’s pain threshold or pain tolerance, thereby increasing the patient’s experience of pain. Rintala et al.35 found similar results with amitriptyline being effective in reducing pain in depressed individuals; while ineffective in treating pain in the general SCI population. Trazodone proved to be ineffective in treating pain in SCI individuals. Given the often problematic side effect profile of the tricyclic antidepressants, further research into the use of these medications in post-SCI pain is likely not warranted; however, the use of newer, less toxic antidepressants such as the selective serotonin re-uptake inhibitors,(SSRIs) and serotonin norepinephrine re-uptake inhibitors (SNRIs) may be helpful.
Lidocaine, an intravenously administered analgesic drug, was shown to be effective in treating post-SCI pain,51–53 with one exception.55 The one exception may be due to the fact the study’s authors used only half the dosage seen in the other studies with a small sample size. One important disadvantage of intravenous lidocaine is it is not selective for pain specific sodium channel subtypes which may result in a higher risk of adverse effects.55 The other is that as an intravenous therapy it is not a practical long term management solution.
Mexiletine was found to be ineffective as a treatment for post-SCI pain. This could be due to the use of a relatively smaller dose (450 mg/day) than the 750 mg/day shown to be beneficial in patients with chronic non-SCI neuropathic pain.54
There was strong evidence that intravenous ketamine is effective in the treatment of post-SCI central or neuropathic pain.55,56 Ketamine has been shown to be especially effective in treating wind-up pain, which may be due to the fact that temporal summation of pain (wind-up pain) is mediated by NMDA receptors. Eide et al.57 provided strong evidence that central pain after SCI is dependent on the activation of NMDA receptors. However, intravenous treatment for chronic pain is not practical and oral ketamine has not been studied in the SCI population.
Tramadol is a more recent analgesic which has become quite popular. A previous Cochrane review assessed its effectiveness in treating neuropathic pain.82 This review found 3 trials showing significant overall pain relief when compared to placebo or baseline measures; however no differences were seen when comparing it to clomipramine or morphine. One RCT65 examined the effect of tramadol in improving pain post SCI. The study demonstrated that tramadol was not only effective in reducing pain post SCI, but also other secondary outcomes such as anxiety, global life satisfaction and sleep quality.
It is not uncommon when treating any difficult pain state to use more than one type of analgesic medication. Two studies62,63 have demonstrated the synergistic effects of intrathecal morphine and clonidine. Their findings suggest that different subtypes of neuropathic pain may respond differently to pharmacological interventions; pain localized to the level of the SCI may be more susceptible to drugs directed at the spinal level, while pain below the level of the SCI may be associated with changes at the thalamic (central) level.62 Accordingly, deafferent and dysaesthetic neuropathic pain may also respond differently to specific treatments although there are challenges in distinguishing between the two; moreover, most studies did not specify the type of neuropathic pain and hence effectively evaluating treatments was not possible.
One concern with opioids is the potential for addiction or opioid abuse, particularly in younger patients with a history of substance abuse, and clinical trials have not yet been designed to evaluate this.83 Unfortunately oral opiates have not been studied in the SCI pain setting and therefore cannot be commented on despite their frequent use. Oral Clonidine has also not been studied in individuals post SCI, however, Remy-Neris et al.84 found that given clonidine’s lipophilic nature intrathecal clonidine is not likely to be more effective than the oral or transdermal method of delivery.
Use of capsaicin to relieve radicular pain was supported by Level 5 evidence; however, more studies need to be conducted using larger sample sizes in order to fully understand its effectiveness in post-SCI pain.
Cannabinoids have increasingly been used in the management of pain given that they have been shown to be relatively safe.84,86 Hagenbach et al.70, showed that THC may have some analgesic properties to help SCI patients with spasticity related pain. Wade et al.87 conducted an RCT of sublingual 2.5 mg THC and/or cannabidiol and found that it significantly reduced pain, muscle spasm, spasticity and sleep difficulties in a group consisting largely of multiple sclerosis patients with neuropathic pain. Unfortunately, only a small number of the patients in this study had a SCI, so it did not meet our inclusion criteria. There is anecdotal evidence that marijuana smoking is not uncommon among patients post SCI, and that it may be of some benefit in the management of post-SCI pain; however, there remain social and legal concerns with regard to its use, as well as potential medical concerns about smoking as a delivery system. Oral and sublingual cannabinoids are safe and effective in other populations with chronic pain. They should be furthered studied in the SCI setting.
The antispasticity medication, baclofen, appears to improve chronic post-SCI pain, though the actual mechanism behind the pain relief has not been fully established. There is evidence that baclofen infusion pumps may be helpful for both neuropathic and musculoskeletal pain post SCI.76 However, studies have shown that intrathecal baclofen only reduces SCI pain when the pain is related to muscle spasms.88,89 There is need for confirmatory research, due to the small sample size and lack of significant improvement in a later before and after trial. Oral baclofen has not been studied as an antinocioceptive agent in SCI.
Marciniak et al.77 noted a decrease in pain post botulinum injection in SCI individuals. This decrease was likely attributable to a decrease in spasticity due to botulinum injection; however, boulinum has been shown to inhibit the release of substance P and other pain neuromodulators and the analgesic effect of botulinum may be more than just the reduction in muscle tone. More research using botulinum in post-SCI pain needs to be conducted in order to understand its mechanism and effectiveness.
There was strong evidence supporting the use the anticonvulsants such gabapentin or pregabalin for post-SCI neuropathic pain. Other anticonvulsants had limited or lack of evidence for their use with the exception of lamotrigine in the setting of incomplete SCI. Tricyclic antidepressants were supported by limited evidence in those patients with superimposed depression. They have been shown to be effective in other neuropathic pain states; however side effects can be quite significant. There was evidence that some local anaesthetics, such as lidocaine infused into the lumbar subarachnoid space or ketamine given intravenously, provide pain relief; however their effect appeared to be short lived and the impractibility of the delivery system was not conducive to long-term community management. Intrathecal baclofen has been shown to reduce neuropathic pain post SCI, and to reduce musculoskeletal pain associated with post-SCI spasticity. Opioids are commonly used for both musculoskeletal and neuropathic pain; however there was only limited research into their intravenous use in individuals with post-SCI pain and no research on oral use in SCI. Given the frequency of opioid use in SCI pain additional research seems warranted. Tramadol is a newer oral analgesic which shows some promise in SCI pain. Intrathecal clonidine appears to work synergistically with morphine for neuropathic or central pain. Cannabinoids has been shown to have some potential for use post SCI, given evidence supporting their use in other neuropathic pain conditions; however, clinical trials in SCI are lacking.
Pain is an important complication of SCI which leads to decreased function and quality of life. There remain large gaps in the evidence for the treatment of both nociceptive and neuropathic pain following SCI. Future research needs to examine response of specific pain subtypes in spinal cord injured populations, using larger sample sizes and utilizing SCI specific pain assessment tools. Future research should also include a multi-modal approach to treating pain post SCI as it is being increasingly recognized as important due to the multi-factorial nature of pain post SCI. Non-pharmacological treatments in these circumstances can be used as an effective adjunct to pharmacological interventions, enhancing the overall impact of pain-relieving interventions for the SCI patient. Behavioral approaches are also often applied in pain management and can be used alone or in conjunction with pharmacological and physical therapies.
We would like to acknowledge the Ontario Neurotrauma Fund, Rick Hansen Man in Motion Foundation and SCI Solutions Network for their support of the project.
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