Laurance Johnston, Ph.D.

Sponsor: Institute of Spinal Cord Injury, Iceland

Prevalence of SCI Pain

SCI Pain Classification

Pharmaceutical Approaches:

Anticonvulsants (Gabapentin, Pregabalin, Lamotrigine)

Antidepressants (Amtriptyline)

Analgesics (Lidocaine. Ketamine, Alfentanil, Tramadol, Morphine, Clonidine, Capsaicin)

Antispasticity (Baclofen, botulinum toxin, i.e., Botox, Cannabis or THC)

SCI PAIN MANAGEMENT

People with SCI often have some form of pain that compromises quality of life and the ability to carry out many activities. Pain can result from both damage to the spinal cord itself and the lifestyle imposed by the neurological damage (e.g., wheelchair transfers, etc). Unfortunately, efforts to manage such pain have been challenging.

PREVALENCE OF SCI PAIN

Numerous studies document the high prevalence of pain in individuals with SCI, including the following:

1) A survey of 380 individuals with SCI by Dr. P. Fenollosa et al indicated that 66% had experienced chronic pain lasting longer than six months. The most common type of pain was deafferentation or phantom pain due to the loss of sensory input into the central nervous system.

2) Dr. S. Stormer and colleagues (Germany) reported that 66% of 901 surveyed patients with SCI had either pain or pain-related sensations called dysesthesia (uncomfortable, abnormal sensations such as burning, wetness, itching, electric shock, and pins and needles). Sixty-one percent of them rated their pain intensity 7+ on a scale ranging from 0 (no pain) to 10 (as bad as it can get). Seventy-five percent described the pain “as rather or very distressing.” In these patients, 86% reported that the pain was located below the spinal-cord-injury lesion or in the transition zone surrounding it.

3) Dr. A. Ravenscroft and associates (United Kingdom) sent a questionnaire to 216 individuals with SCI listed on a regional SCI database. Of the 67% who responded, 79% indicated that they currently suffered from pain, with 39% describing it as severe. The survey results suggested that complete injury was more likely than incomplete injury to result in chronic pain.

4) Dr. Nanna Finnerup and colleagues (Denmark) mailed a questionnaire to 436 outpatients of a SCI rehabilitation center, of whom 76% responded. The time since injury in these individuals ranged from 0.5 to 39 (average 9.3) years. Overall, 77% of the respondents reported having pain or unpleasant sensations (e.g., dysesthesia), including 67% reporting pain or unpleasant sensations below the area of injury. Nearly half reported that pain-related sensations could be triggered by stimulation of the skin by non-noxious processes that do not normally provoke pain (a condition called allodynia).

5) Dr. P. Siddall et al. (Australia) followed the evolution of pain in 73 patients for five years after injury. Eighty-one percent reported the presence of pain, the most common form being musculoskeletal pain (59%), followed by at-level neuropathic pain (41%), below-level neuropathic pain (34%), and visceral pain (5%), respectively. [These different forms of SCI-related pain are discussed below.]

6) Dr. D. Cardenas et al (USA) reviewed the health records of 7,379 individuals with SCI, who had been entered in a national SCI database. Data analyses indicated that the prevalence of pain remained fairly constant over time, for example, 81% reporting pain one year after injury and 83% 25 years after injury. Although no gender difference was noted, pain prevalence was lower in nonwhites. 

7) Dr. C. Donnelly and associates (Canada) examined the records of 66 individuals with SCI who had been consecutively admitted to a tertiary rehabilitation center. Six months after discharge, 86% reported pain, with 27% reporting pain severe enough to affect many or most activities.

SCI PAIN CLASSIFICATION

There are many different forms of SCI-associated pain. For example, the pain can be located above the level of neurological injury, at or near the injury level, or below the injury level. In addition, the pain can be either nociceptive or neuropathic in origin. Nociceptive pain occurs from damage to non-neural tissues, such as bones, connective tissue, muscle, skin, or other organs, that are still partially or fully innervated. It can be mechanical or musculoskeletal in nature, or arise from damage to or irritation of internal visceral organs affected by SCI.

As the name implies, neuropathic pain results from damage to neural tissue either within the peripheral (nerves outside of the brain and spinal cord) or central nervous system. Two common forms of SCI-neuropathic pain are central and radicular pain. The former is caused by damage to the spinal cord itself. The latter is caused by damage to nerve roots where they connect to the spinal column due to damage from the initial injury or impingement by bone fragments or disk or scar material.

Studies suggest that there are changes in the properties of nerve cells close to the injury site, including 1) increased responsiveness to peripheral stimulation, 2) more background activity, and 3) extended neuron firing following stimulation. Overall, injury results in altered neurotransmission and, as such, the firing properties of spinal neurons.

As indicated in the table, Drs. Thomas Bryce and Kristjan Ragnarsson (USA) have developed a SCI pain classification system that integrates these concepts into 15 different types of pain. 

For illustration sake, a number of these categories are amplified below:

Type 1: An example of above-level, nociceptive pain of mechanical or musculoskeletal origin is shoulder pain resulting from transfers, rotator cuff injuries, etc.

Type 2: An example of this sort of pain is a headache from autonomic dysreflexia (see glossary).

Type 4: Above-level, compressive neuropathic pain is generated from impingement of a specific peripheral nerve, an example being carpel tunnel syndrome resulting from the repetitive actions of wheelchair pushing.

Type 6: At-level nociceptive pain of mechanical or musculoskeletal origin is similar to Type 1 pain except located nearer the level of injury, e.g., shoulder pain in the case of a cervical injury.

Type 7: At-level nociceptive pain of visceral origin results from damage, irritation, or distension of internal organs. An example is pain resulting from fecal impaction or bowel obstruction.

Type 8: At-level neuropathic, central pain is caused by damage to the spinal cord. In thoracic injuries, central pain is often characterized by tightness, pressure, or burning; and in cervical injuries by numbness, tingling, heat, or cold. The formation of a fluid-filled syringomyelia cavity within the spinal cord often causes central pain.

Type 9: At-level neuropathic, radicular pain is caused by damage to nerve roots at their connection to the spinal column. Such damage is often due to the initial injury or impingement by bone fragments, disk material, or scar tissue. Pain is often described as radiating, stabbing, shooting, or electric-shock like. 

Type 10: At-level compressive, neuropathic pain is similar to Type 4 pain, except located nearer to the injury site. An example would be repetitive-motion-created carpal tunnel syndrome in an individual with a cervical injury. 

Type 11: With complex regional pain syndrome, pain is 1) not limited to the region of a single peripheral nerve or nerve root, 2) out of proportion to what is expected, and 3) associated with edema, skin blood-flow abnormality, or irregular activity of the nerves that stimulate sweat glands (called sudomotor activity). It is associated with diffuse hand pain, swelling and stiffness.

Type 12: Nociceptive mechanical or musculoskeletal pain below the level of injury occurs in individuals with incomplete injuries or complete injuries with a zone of partial preservation extending to the level of the pain. It is often associated with spasticity.

Type 13: Below-level, nociceptive visceral pain is primarily due to damage, irritation, or distension of internal organs. It occurs in individuals with injuries above the mid-thoracic region and is often vague and poorly localized in nature.

Type 14: Below-level, neuropathic central pain is caused by damage to the spinal cord. It is often regional in nature affecting large areas such as the anal region, the bladder, the genitals, the legs or even the entire body below the injury level. The pain has been described as burning or aching and often continuous in presence.

TREATMENTS FOR SCI-RELATED PAIN

Many approaches have been developed for treating SCI-related pain, ranging from the pharmaceutical to the surgical to the alternative. In general, these approaches have had modest success at best, often depend upon the specific pain that is manifesting, and are frequently accompanied by significant side effects. Overall, pain management is a challenging problem, which will require the continued effort of clinicians and researchers to develop effective solutions.

PHARMACEUTICAL APPROACHES

For better or worse, pharmaceutical approaches remain the cornerstone of most SCI-pain-controlling strategies.  Many different drugs developed for a variety of purposes have been used in an effort to ameliorate SCI pain, including anticonvulsants, analgesics, antispastics, antidepressants, nonsteroidal anti-inflammatory drugs, etc.

Anticonvulsant Drugs

Anticonvulsants are a diverse group of drugs developed for the treatment of epileptic seizures. They have been adopted for use in treating SCI pain because scientists have noted a similarity between the underlying physiology or biochemistry observed in seizure disorders and neuropathic pain, both of which involve abnormal firing of neurons. Several studies summarizing the use of a number of anticonvulsant drugs to treat SCI pain are provided below:

1) Initially developed to treat epileptic seizures, gabapentin has been used to manage neuropathic pain after SCI. Structurally related to a key neurotransmitter called GABA (gamma-amino butyric acid), evidence suggests that gabapentin interferes with the transport of calcium ions into neurons, a process involved in the excitation of neurons.

A) Dr. Funda Levendoglu and associates (Turkey) examined the effectiveness of gabapentin in ameliorating neuropathic pain in 20 subjects (13 males, 7 females) with complete paraplegia. The subjects ranged in age from 23 to 62 (mean 36) years, and the time since injury varied from seven to 48 months.

The study was designed as a prospective, randomized, double-blind, placebo-controlled, crossover clinical trial. Basically, under this study design, an equal number of subjects were randomized to receive either gabapentin or placebo in identical capsules. In the first four weeks, the subjects received increasing doses of the drug/placebo until the maximum dosing level was achieved, which was maintained for four more weeks. After a two-week washout period in which no drug or placebo was administered, treatments were reversed for another four weeks; i.e., gabapentin-treated subjects now received placebo and vice versa.

Pain was measured by several different scales, including the Visual Analog Scale (VAS). With this scale, subjects rated their pain levels on a scale ranging from 0 (no pain) to 100 (worst pain imaginable). As can be seen from the table, the pain levels of gabapentin-treated subjects declined significantly over the treatment period relative to placebo.

With the Neuropathic Pain Scale, subjects rated their pain levels on a scale from 1 to 10 for different aspects of neuropathic pain, including that described as sharp, hot, dull, cold, sensitive, itchy, unpleasant, deep or surface pain. Any score above 4 was considered moderate to severe pain. Over time, gabapentin treatment provided a statistically significant reduction in pain for all aspects except for the itchy, dull, sensitive, and cold categories. For example, before gabapentin treatment, the score for deep neuropathic pain averaged 7.0, but after eight weeks of treatment, it averaged only 3.5.

Sixty-five percent and 25% of the gabapentin and placebo-treated patients, respectively, reported various side effects, such as nausea, vomiting, weakness, edema, vertigo, sedation, headache, diarrhea, blurred vision, muscle twitching, and itching.

B) Dr. T.P. To et al (Australia) retrospectively reviewed the health records of 38 individuals with SCI to assess gabapentin’s potential to alleviate neuropathic pain. Age averaged 47 (range 15 -75) years. There were 28 males; 19 and 16 with paraplegia and 16 tetraplegia, respectively; and three times more chronic than acute (< six months) injuries. The review indicated periodic assessments of pain using the Visual Analog Scale, which, in this case, ranged from 0 (no pain) to 10 (worse pain imaginable).

Using this scale, 29 of the 38 patients had some degree of pain relief due to gabapentin. There were eight reports of adverse effects, most notably drowsiness. Eleven patients had pain levels assessed at one, three, and six months after starting gabapentin treatment. As indicated in the table, average pain levels in these 11 patients decreased form 8.9 to 4.0 after six months.

C) Dr. Sang-Ho Ahn and associates (Korea) evaluated gabapentin’s effectiveness in treating neuropathic pain in 31 subjects with SCI. These individuals were divided into two groups: 1) 13 whose duration of pain was less than six months and 2) 18 whose duration of pain had lasted more than six months. Subject age averaging 45-46 years old; Group 1 was composed of seven and six individuals with tetraplegia and paraplegia, respectively; and Group 2 included six and 12 individuals with tetraplegia and paraplegia, respectively.

Before gabapentin treatment, all patients had been treated with a variety of other pain medications without improvement. While continuing these preexisting medication regimens, increasing gabapentin doses were administered to the patients until a maintenance dose was reached after 18 days. This maintenance dose was continued for eight weeks. Pain was periodically measured using the aforementioned VAS scale. In addition, interference of sleep by pain was assessed on a scale ranging from 0 (no interference) to 10 (unable to sleep because of pain).

Of the 31 subjects initially recruited, 25 completed the study. For both groups, the amount of pain and sleep interference was significantly reduced after eight weeks of gabapentin treatment. The reduction was greater in Group 1 (pain duration < 6 months) than Group 2 (pain duration > 6 months). Specifically, the average pain score for Group 1 decreased from 7.3 to 3.0 by eight weeks, whereas the Group 2 score decreased from 7.6 to 5.1. In the case of sleep interference, the Group-1 average score decreased from 5.7 to 1.8, while the Group-2 score declined from 5.9 to 4.2.

D) In an effort to determine gabapentin’s long-term effectiveness, Dr. John Putzke and colleagues (USA) identified 31 patients who had been treated with the drug for up to three years. Of these 31 patients, 76% were men, 67% had paraplegia, 76% had incomplete injuries, and 86% reported pain at or below the level of their injury.

Twenty seven of the initial 31 identified patients were contacted six months after initiating gabapentin treatment. Of these 27, six had discontinued treatment due to intolerable side effects. The remaining 21 rated their pain on a scale raging from 0 (no pain) to 10 (most excruciating pain imaginable). Fourteen (67%) of these 21 patients reported a favorable reduction in pain over this six-month time period defined as a 2+ point reduction on this 0-10 scale. Of these 14 subjects, 11 were contacted three years after initiating gabapentin treatment. Ten of these 11 continued to report pain-relieving benefits that they attributed to gabapentin. Side effects included fatigue, forgetfulness, edema, gastrointestinal upsets, sedation, blurred vision, dry mouth, constipation, and dizziness.

2) Pregabalin is also an anticonvulsant drug specifically developed to treat neuropathic pain as well as epileptic seizures. Like gabapentin, pregabalin is structural analog of the GABA neurotransmitter. It also apparently works by affecting calcium ion influx into neurons, which, in turn, modulates the firing of neurons involved in triggering pain sensations.

A) Dr. Philip Siddall and colleagues (Australia) evaluated pregablin’s effectiveness in treating central neuropathic pain in subjects recruited from eight Australian centers. In this study, 137 patients were randomized to receive either pregablin (70 patients) or placebo (67 patients) for 12 weeks. This was a double-blind study, meaning neither patient nor physician knew who was receiving the drug as opposed to the placebo. In the pregabalin-treated group, age averaged 50 years; 60% were men; and 59% and 41% had paraplegic and tetraplegic injuries, respectively. All subjects had been injured for at least a year and had central neuropathic pain lasting three months continuously or alternatively six months intermittently. Subjects were allowed to continue preexisting pain-medication regimens (~70% of subjects), except for gabapentin, which, due to its similarity to pregablin, had to be discontinued a least week before starting the study.

Starting the week before treatment (i.e., baseline assessment) and throughout the 12 week treatment period, all subjects rated their pain upon awakening in the morning for the preceding 24 hours on a scale from 0 (no pain) to 10 (worst possible pain). Using a similar scale, they also rated the degree to which the pain interfered with sleep.

The pain level in the pregablin-treated subjects decreased from 6.5 before treatment to 4.2 at the end of the study. In contrast, the pain levels for placebo-treated individuals only decreased from 6.7 to 6.3. Forty-two percent of the pregablin-treated subjects had at least a 30% reduction in pain compared to only 16% for the placebo-treated individuals. In addition, 22% of the pregablin-treated subjects had at least a 50% reduction in pain compared to only 8% for those who were treated with placebo.

Furthermore, pregablin-treated patients had a similar reduction in sleep problems. For example, in contrast to the placebo-treated subjects who had only a minimal reduction in sleep interference over the treatment period (4.9 to 4.7), the sleep interference score decreased from 4.2 to 2.8 in pregablin-treated subjects.

The most frequently reported adverse effects were drowsiness (41%), dizziness (24%), edema (20%), weakness (16 %), dry mouth (16%), and constipation (13%).

B) Dr. Jan Vranken and associates (The Netherlands) examined pregabalin’s effectiveness in a randomized, double-blind, placebo-controlled clinical trial. The investigators recruited 40 subjects with a variety of neurological disorders predisposing them central neuropathic pain, including 21 with complete and incomplete spinal cord injuries. These individuals were randomized to receive either pregabalin or placebo daily for four weeks. In addition, they were allowed to continue any preexisting pain-medication regimens if it had been stable in nature. The exception was gabapentin, which had to be discontinued at least three days before study initiation. To be enrolled, all subjects had to have a pain level of at least 6 using the previously described 0-10 pain-intensity scale.

As shown in the graph, pain intensity was significantly less in those treated with pregablin. Specifically, although pain levels in placebo-treated individuals essentially remained unchanged over the four-week trial period, pain in the pregabalin-treated subjects decreased from 7.6 to 5.1, a decrease the investigators described as a reduction from severe to modest. Seven pregabalin-treated subjects had a reduction in pain of more than 50% compared with only one placebo-treated subject. Roughly equal adverse effects were observed for both the pregabalin and placebo group, indicating that, at least in the case of this study, pregabalin-related side effects were minimal.

3) Lamotrigine is another anticonvulsant drug used to treat epilepsy, bipolar disorder, and, secondarily, neuropathic pain. Unlike gabapentin and pregabalin, it is not a structural analog of the GABA neurotransmitter.

Dr. Nanna Finnerup and associates (Denmark) evaluated lamotrigine’s pain-treating effectiveness in 30 individuals with SCI-related neuropathic pain below the level of the lesion. To be enrolled, subjects had to have a 3+ pain level on the 0 (no pain) to 10 (worst imaginable pain) scale discussed previously. The study was designed as a randomized, double-blind, placebo-controlled, crossover trial. Specifically, subjects were randomized to receive either lamotrigine or placebo for nine weeks, after which there was a two-week washout period in which no drug/placebo was given. When this washout period was finished, treatments were reversed and the lamotrigine-treated subjects now received placebo for nine weeks, and the placebo-treated individuals were given the active drug.

Of the 30 enrolled patients, 22 completed the study. Of these remaining subjects, age ranged from 27 to 63 (average 49) years; 18 were men; and 9, 11 and 2 had cervical, thoracic, and lumbosacral injuries, respectively (including both complete and incomplete injuries). Study results indicated that lamotrigine only reduced pain levels in those with incomplete injuries. Specifically, for these individuals, the difference in pain reduction between drug- and placebo-treated averaged a modest 25%. The drug had had no statistical significant effects for those with complete injuries. The number of adverse side effects were comparable in both lamotrigine and placebo groups.

Antidepressants Drugs

Several antidepressant drugs have been used to treat SCI pain, including the following:

1) Amitriptyline treats depression symptoms by raising the levels of naturally occurring substances in the central nervous system. For example, like other antidepressants, amitriptyline increases serotonin, a key mood-influencing neurotransmitter. In addition to depression, the drug has been used to treat pain generated from a variety of disorders, including SCI.

In a 2007 article, Dr. Diana Rintala and colleagues (USA) compared the effectiveness of amitriptyline relative to gabapentin in ameliorating chronic, SCI-associated neuropathic pain. Thirty-eight individuals with SCI were randomized to receive either amitriptyline, gabapentin, or an active placebo (Benadryl, an over-the-counter allergy medication). After a baseline interval in which subjects received no pain medications, one of these three agents was administered for nine weeks. This was followed by a one-week washout period in which no drugs were administered. Thereafter, a different drug was administered for another nine-week period, e.g., the amitriptyline-treated individuals were now given gabapentin or placebo, etc. After another washout period designed to remove residues from the body of the previously administered drug, the third agent would be given, e.g., the subjects who had been initially given amitriptyline followed by gabapentin were now treated with placebo, etc.

Of the 38 subjects who started the study, 22 completed the study. Average age was 43 (range 22-65) years; time since injury averaged 13 (range 1-33) years; and 90% were men. Subjects included individuals with both tetraplegia and paraplegia, as well as complete and incomplete injuries.

Pain was periodically assessed using the previously discussed VAS measure which subjectively rated pain on scale ranging from 0 (no pain) to 10 (worst possible pain).  In addition, depression levels in subjects were periodically evaluated using another subjective scale.

The overall results indicated that amitriptyline was more effective than gabapentin in relieving pain. Specifically, after eight weeks of treatment, pain levels on the 0-10 VAS scale averaged 3.5 for amitriptyline-treated subjects, 4.8 for gabapentin-treated subjects, and 5.1 for placebo-treated subjects. Underscoring the relationship of pain to depression, amitriptyline’s pain-relieving benefits were greater in those individuals who started the study with the most depression. Documented side effects for amitriptyline included mouth dryness, constipation, increased spasticity, and painful urination.

Different results were observed in an earlier study (2002) carried out by Dr. Diana Cardenas and colleagues (USA). In this study, 44 and 40 subjects were randomized to receive either escalating doses of amitriptyline or placebo, respectively, for six weeks. Because a common side effect of amitriptyline is dry mouth, an active placebo (i.e., not inert) was chosen that also produced dry mouth (specifically, benztropine, a drug used for Parkinson’s disease). This was done to preserve the study’s blinded nature so that subjects could not readily distinguish amitriptyline from the placebo. 

In the amitriptyline-treated subjects, age ranged from 21 to 63 (average 41) years; 59%, 39%, and 2% had cervical, thoracic, and lumbar/sacral injuries, respectively; approximately half had complete injuries; and 73% were men. The average time since injury was about 13 years.

As in the previously discussed studies, pain was periodically evaluated on a scale ranging from 0 (no pain) to 10 (as bad as could be). In this study, no statistically significant difference in pain levels was observed between the amitriptyline and placebo-treated groups. One possible reason for the different outcomes compared to the previous discussed study is that the Rintala study was limited to individuals with neuropathic pain while the Cardenas study included a variety of types of SCI-related pain, each of which may respond differently to various medications.

Analgesics

A number of traditional painkilling drugs have demonstrated some effectiveness in treating SCI-related pain, including the following:

1) Lidocaine has a variety of medical applications, pain killing and otherwise. Most commonly it has been used as a topical agent to relieve itching, burning, and pain from skin inflammation; or through injection as a dental numbing agent or as a local anesthetic for minor surgery. In addition, it has been intravenously administered to treat abnormal heart rhythms, i.e., arrhythmias. Physiologically, lidocaine affects the flux of sodium ions into neurons needed to propagate nerve signals. By so doing, scientists theorize that the neuronal hyperexcitability that characterizes SCI neuropathic pain may be dampened.

A) In 2005, Dr. Nanna Finnerup et al (Denmark) reported the results of a study treating 24 subjects with neuropathic pain at or below the level of the injury with lidocaine. Subjects were randomized to receive either an intravenous infusion of lidocaine or saline solution. Subject age ranged from 28 to 66 years; 17 were men; 9, 12, and 3 had cervical, thoracic, and lumbosacral injuries/dysfunction, respectively; and the sample included a range of both complete and incomplete injuries. Among other measures, pain was assessed on a subjective 0-100 scale before infusion, and 25 and 35 minutes after infusion was started. After at least six days, treatments were reversed; i.e., lidocaine-treated subjects now received the placebo infusion and vice versa. 

The average difference in pain reduction between lidocaine- and placebo-treated subjects was 36%. Eleven lidocaine-treated subjects had at least a 33% reduction in pain compared to only two placebo-treated subjects. Nineteen lidocaine-treated subjects experienced various adverse side effects, including drowsiness, dizziness, impaired speech, lightheadedness, blurred vision, etc.

B) In 2000, Dr. N. Attal and associates (France) evaluated the effectiveness of intravenously administered lidocaine in alleviating pain in 16 individuals with stroke (6) or spinal cord injury/dysfunction (10).  The study focused on central pain, including  spontaneous ongoing pain and evoked pain such as allodynia produced by stimuli that does not normally provoke pain (such as skin brushing; see introductory discussion. Of the 16 patients enrolled, 10 were women and six men; mean age was 55; and duration of pain averaged 47 months. Subjects were randomized to receive either a 30-minute, intravenous infusion of lidocaine or saline solution. Among other measures, pain levels were assessed before treatment and periodically thereafter using a subjective pain scale ranging from 0 (no pain) to 100 (worst possible pain).

When compared to controls, the lidocaine-treated subjects had statistically significant less spontaneous pain at the end of the treatment and for up to 45 minutes afterwards. Specifically, the pain levels in lidocaine-treated subjects decreased from 61 to 31 while the pain levels in placebo-treated subjects decreased only to 46. However, after 45 minutes, the difference in pain levels between the two groups diminished. Similarly, lidocaine-treatment reduced the intensity of allodynia for 30 minutes after treatment was completed. Few, if any, long-term benefits were observed. The investigators concluded that “in least in patients with central pain, long-term analgesic effects of lidocaine are uncommon.” Adverse side effects included lightheadedness/dizziness, drowsiness, nausea/vomiting, impaired speech, malaise, etc. 

C) In 1991, Dr. P. G. Loubser and associates (USA) evaluated lidocaine’s pain-killing effectiveness in 21 individuals with chronic SCI. In this study, subjects were randomized to receive either lidocaine or saline placebo by injection into the lumbar subarachnoid space (i.e., the area filled with cerebrospinal fluid). After a sufficient washout period, treatments were reversed. Subject age ranged from 18 to 58 (average 42) years; 14 subjects were men; and 5, 14, and 2 had cervical, thoracic, and lumbar injuries, respectively. All subjects had had chronic pain of at least six months duration.

Pain was assessed before and periodically after treatment using a variety of assessments. Thirteen lidocaine-treated subjects showed an average 38% reduction in pain lasting on average about two hours. Eight lidocaine-treated subjects showed no changes. In a many subjects, lidocaine affected the distribution of pain throughout the body and nature of the pain sensations. In a number of cases, there were spinal canal blockages, which prevented the lumbar-region-administered lidocaine from reaching and exerting painkilling effects in areas above the blockage.

2) Ketamine has been primarily used to generate brief periods of anesthesia, during which the patient feels dissociated or separated from the body. Due to these altered-consciousness effects, the drug has a history of substance abuse. Ketamine has also been medically used to treat pain, depression, and asthmatics or individuals with chronic obstructive airway disease. Ketamine interferes with a key neurotransmission process involved in generating pain.

In 2004, Dr. Ann Kvarnstrom et al (Sweden) evaluated the effectiveness of intravenous ketamine and lidocaine in treating below-level, neuropathic pain. Ten individuals with SCI were randomized to receive 40-minute intravenous infusions of either ketamine, lidocaine, or saline solution. After at least four days, one of the other agents was similarly administered, and after another four days, the final agent was given. Of the 10 subjects, nine were men; age ranged from 30-60 (average 45) years; 1 and 9 had complete and incomplete injuries, respectively; and 5, 4, and 1 had cervical, thoracic, and lumbar injuries, respectively.  The average pain duration in subjects had been nine years.

Pain was evaluated before the start of the infusion and 15, 45, 60, 120 and 150 minutes afterwards using the subjective 0 (no pain) to 10 (worst pain imaginable) scale. Using this scale, the average pain reduction was 38% for the ketamine-treated subjects, 10% for the lidocaine-treated subjects, and 3% for the placebo-treated subjects. Five of the ketamine-treated subjects had at least a 50% reduction pain compared to only one lidocaine-treated subject, and none for placebo-treated subjects. Of the responders, all claimed that ketamine was better than any other painkilling medications they had tried.

Adverse side effects were common in both the ketamine- and lidocaine-treated subjects, including drowsiness, dizziness, out-of-body sensations, changes in hearing and vision, nausea, etc. 

3) Alfentanil is a potent, short-acting opioid-like agent used for surgical anesthesia.

Opioids are psychoactive, naturally occurring and synthetic molecules that bind to various receptors on the surface of neurons, including those in the spinal cord. This binding alters communication between neurons, which can mute pain perception. The most well-known example of a naturally occurring opioid-containing material is opium isolated from the poppy. Opium is the source of many painkilling and substance-abuse drugs, such as morphine, its derivative heroin, codeine. In addition, a number of opioid-like molecules are actually produced by the body, such as the endorphins – a word actually created by combining morphine and endogenous. Endorphins are neurotransmitters associated with the feel-good endorphin rush or runner’s high generated by exercise and other stimulus. 

In 1995, Dr. Per Kristian Eide and associates (Norway) compared the potential of both alfentanil and ketamine to reduce pain after SCI. Nine patients were randomized to receive an intravenous infusion of either alfentanil, ketamine, or a saline placebo solution. Each drug infusion was separated by two hours. Age ranged from 25-72 (average 41) years, and all but one of the subjects were men. The sample included four cervical, four thoracic, and one lumbar injuries, and five complete and four incomplete injuries. The duration of pain in these subjects ranged from 14 to 94 months, starting in all cases less than a half year after injury.

Continuous pain and pain evoked by various stimuli was assessed using a VAS scale ranging from 0 (no pain) to 100 (unbearable pain). As shown in the graphs below, both alfentanil and ketamine reduced both types of pain. Although no severe side effects were observed, a variety of weak or modest side effects were noted for both drugs, including nausea, fatigue, dizziness, mood changes, changes in vision and hearing, feelings of unreality.

4) Another opioid drug, tramadol has been extensively used to treat moderate to severe pain. In addition to binding to neuronal opioid receptors, tramadol also increases levels of serotonin, a key mood-influencing neurotransmitter.

In a 2009 study, Dr. Cecilia Norrbrink and colleagues (Sweden) examined tramadol’s ability to relieve SCI-related neuropathic pain. Of the 35 recruited subjects, 23 were randomized to receive tramadol and 12 randomized to receive an identical appearing placebo agent for an average of 21 days. Twenty-eight of the 35 recruited subjects were men; 16 and 19 had tetraplegia and paraplegia, respectively; and the time since injury averaged 15 years. To avoid biasing results, subjects maintained their existing pain-relieving medications throughout the study.

Pain was evaluated using a variety of assessments, including a 0-10 pain scale which combined numerical and verbal ratings. Using this scale, subjects would periodically record various aspects of the pain they had experienced, including intensity of present pain, general pain, and worst pain. Compared to placebo, tramadol-treated subjects had statistically significant less pain in all three of these categories. In addition, tramadol-treated subjects had less anxiety and greater life satisfaction and sleep quality. 

Unfortunately, there was a high incidence of adverse effects. Specifically, 21 of the tramadol-treated subjects (91%) experienced at least one adverse effect, including 11 subjects that withdrew from the study as a result. The most commonly reported adverse effects were tiredness, dry mouth, and dizziness.

5) The most abundant opioid in opium, morphine is used to treat severe pain. Due to its euphoria-producing, anti-anxiety properties, the drug has considerable addictive and substance-abuse potential. Morphine is closely related to heroin; in fact, the body converts heroin to morphine before it binds to CNS neurons. This binding produces the drug’s painkilling and psychoactive effects.

In a 2002 study, Dr. N. Attal and colleagues (France) examined the potential of intravenously administered morphine to relieve central neuropathic pain in six patients with stroke and nine with SCI. The study included nine women and six men with an average age of 54 years. All subjects had had continuous pain of duration ranging from 1.5 to 20 years. In this double-blind, placebo-controlled, crossover study, subjects were randomized to receive either an intravenous infusion of morphine or saline solution. Two weeks later, the treatments were reversed, i.e., the morphine-treated subjects now received the placebo infusion and vice versa.

Using a scale rating pain from 0 (no pain) to 100 (worst possible pain), pain intensity was assessed before treatment and 15, 30, 45, 60, 90, and 120 minutes afterwards. A variety of central-pain components were assessed, including ongoing pain and pain produced by stroking the skin with a brush (i.e., allodynia). With respect to ongoing pain, seven subjects responded to morphine. However, statistically there were no significant differences in pain levels between the morphine- and placebo-treated subjects at any point in time. In contrast, morphine produced a statistically significant reduction in the brush-induced pain lasting up to 90 minutes after treatment. In nine subjects, this evoked pain was reduced by at least 50% by the end of the injection. The investigators concluded that morphine’s painkilling benefits were probably limited to certain components of central pain. The most frequent morphine-induced side effects were drowsiness, nausea, and headaches.

Within one week of completing the study’s intravenous phase, subjects began taking sustained-release, oral morphine and started recording their pain levels daily using the aforementioned 1-100 scale. Many of the subjects eventually dropped out of the study due to unacceptable side effects of the oral morphine or the absence of pain-relieving benefits. As a result, only three subjects were still taking the oral morphine a year later. The investigators noted that morphine-responsive subjects in the study’s intravenous phase study were more likely to accrue benefits from oral morphine.

6) Clonidine has been used to treat high blood pressure, various pain conditions, attention-deficit hyperactivity disorder (ADHD), and anxiety/panic disorders.

In a 2000 study, Dr. Philip Siddall et al (Australia) examined the potential of clonidine, morphine, and a combination of the two to alleviate SCI-related neuropathic pain in 15 subjects with SCI. Ranging from 26 to 78 (average 50) years old, subjects had below-level and/or at-level neuropathic pain (see introductory discussion). In this study, the drugs were administered into the lumbar-region, intrathecal space surrounding the spinal cord.  Subjects were randomized to receive clonidine, morphine, or saline via this route of administration. When either a pain-relief or side-effect response was observed, testing of the next drug was initiated the following day. After all three agents had been tested, subjects received the clonidine-morphine combination. Pain was assessed using a 0-100 rating scale and verbal pain rating (none, mild, moderate, severe, or very severe).

Neither intrathecal administration of clonidine or morphine resulted in a statistically significant reduction in pain. However, intrathecal administration of the clonidine-morphine mixture did result in statistically significant reduction. Specifically, the drug combination resulted in an average reduction of pain to 63% of the baseline score. A greater percentage of subjects with at-level, neuropathic pain obtained substantial pain relief than those with below-level neuropathic pain. The investigators suggested that this difference may be due to the different physiological origins that underlie at-level versus below-level neuropathic pain. The investigators also noted that scarring around the injury site may inhibit the migration of the drugs, which were intrathecally administered below the injury site, to cervical regions above the injury site. Given the relatively small sample size, this issue may have lessened observed pain-reduction effects.

The most common side effects were itching (morphine associated), low blood pressure (mostly clonidine associated), nausea, sedation, and hypoxia (decreased oxygen levels).

7) Capsaicin is the active component of hot peppers; it produces the hot sensation when the peppers are eaten. Medicinally, it is used in topical ointments to relieve various types of pain, e.g., backache, muscle sprains, etc. Physiologically, capsaicin-exposed neurons are depleted of a key neurotransmitter (called substance P) involved in transmitting pain signals.  Basically, a sustained capsaicin burning sensation overwhelms the neuron’s capability to report pain, leading to a reduction in pain sensitivity.

In 2000, Drs. Paul Sanford and Paula Benes (USA) reported the results of treating eight individuals with localized pain at or just below the level of injury with capsaicin cream topically applied four times daily (9).  Age ranging from 18 to 66, six subjects were men. All but one subject had paraplegia, and subjects were equally divided between those complete and incomplete injuries. Patients who had not responded to capsaicin (~ half of treated patients) were not among the subjects included in this discussion – i.e., the article only reported the positive results.

Subjects subjectively assessed their pain levels using a 0 (no pain) to 10 (unbearable pain) scale. As shown in the table, capsaicin-treated patients often had substantial reductions in pain levels (again, only patients who benefitted are reported). In most cases, pain levels increased again after capsaicin treatment was discontinued. Other than initial burning sensations when the cream was applied, few side effects were observed.

Anti-Spasticity Drugs

1) Baclofen is primarily used to treat spasticity associated with various neurological disorders, including SCI, multiple sclerosis, and cerebral palsy. Like several of the anti-convulsant drugs previously discussed, baclofen is structurally related to GABA, a key neurotransmitter involved in pain perception. Baclofen is given either orally or infused into the intrathecal space surrounding the spinal cord.

A) Because chronic pain and spasticity often co-exist, in 1992, Dr. Richard Herman and colleagues (USA) evaluated baclofen’s ability to ameliorate pain in nine individuals with spinal lesions due to SCI, MS, and transverse myelitis (disorder involving inflammation of the spinal cord) (1).  Three of the subjects were men, and age ranged from 33 to 63. In a double-blind trial, seven of the nine were randomized to receive on successive days either an intrathecal infusion of baclofen or placebo. Baclofen treatment significantly reduced dysesthetic pain (see earlier discussion) in six of the seven randomized patients within 5-20 minutes of treatment. It also eliminated all spasm-related pain. After this double-blind trial had been discontinued, two additional individuals with SCI were treated with baclofen. In one, dysesthetic pain was eliminated completely, and in the other, spasm-related pain was markedly reduced. As the baclofen cleared from the body, the pain returned 8-12 hours later.

B) In 1996, Drs. Paul Loubser and Nafiz Akman (USA) reported the pain-reducing influence of baclofen treatment intrathecally administered through an implanted pump (2). Twelve treated patients had chronic pain before the intervention, including six with neurogenic pain, three with musculoskeletal pain, and three with both types of pain. All were men except one, age ranged from 21-63, and injury level was equally divided between cervical and thoracic injuries. Pain status was evaluated before pump implantation and 6 and 12 months afterwards using a variety of assessments, including the previously discussed visual analog scale rating pain from 0 to 10.  

Although no statistically significant reduction in neurogenic pain was observed at either 6 or 12 months, five of the six patients with musculoskeletal pain had a significant pain reduction. The investigators concluded that “intrathecal baclofen reduces chronic pain associated with spasticity but does not decrease neurogenic pain symptoms when used at dosages aimed at controlling spasticity.”

2) The most powerful neurotoxin known, botulinum toxin is produced by the bacteria Clostridium botulinum.  At one time, the fatality rate for botulinum poisoning was 60% due to respiratory muscle paralysis. In spite of its lethality, botulinum toxin has a variety of low-dose medical uses related to its ability to decrease muscle activity. By far, its most well know application is cosmetic (i.e., Botox injections) to prevent the development of wrinkles through paralyzing facial muscles.

Due to its muscle-weakening ability, botulinum toxin is also used to treat spasticity-associated hyperactive muscles and dystonia-related involuntary muscle contractions. Botulinum toxin prevents the release of the acetylcholine neurotransmitter from a neuron into the gap between the neuron and muscle. Under normal circumstances, the released acetylcholine would interact with muscle-cell receptors on the other side of the gap, activating the muscle. In addition, evidence indicates botulinum toxin has the ability to lessen pain distinct from its spasticity-lowering effects. Specifically, botulinum toxin also appears to inhibit the release of substance P, a neurotransmitter, which, as discussed previously for capsaicin, is involved in transmitting pain signals.

A) In 2008, Dr. C. Marciniak and associates (USA) evaluated the use of botulinum toxin to treat spasticity and, as one of several secondary assessments, reduce pain (3). In this retrospective study, the charts of 28 individuals with SCI who had been treated with botulinum toxin for spasticity were reviewed.  Patient age averaged 48 (range 20-76) years, and in 20, the cause of SCI was traumatic injury.  Of the six individuals who had identified pain as an issue before treatment, five (83%) reported less pain afterwards. The investigators did not know whether this pain reduction was the result of less spasticity or due to botulinum toxin’s influence on pain transmitters, such as substance P.

3) Tetrahydrocannabinol (THC) is the active agent in cannabis, i.e., marijuana. Cannabis preparations have a long history of use for treating various neurological disorders and pain, including being used thousands of years ago as traditional Chinese and Indian (i.e., Ayurvedic) herbal remedies. THC binds to receptors on the surface of central-nervous-system cells. Research suggests that this binding affects the activity of GABA, which, as discussed before, is a key neurotransmitter involved in pain perception.

A) In a 2007 study, Dr. U. Hagenbach and colleagues (Switzerland) examined THC’s influence on primarily SCI spasticity (4). In addition, a number of secondary effects were also evaluated, including pain through self assessments. Twenty-five subjects with SCI were initially recruited for the various study arms. Of these, 11 and 14 had paraplegia and tetraplegia, respectively; all but two were men; and age ranged from 19 to 73. Of the 22 subjects treated with an oral THC preparation, 15 consumed the drug for six weeks. Although the results indicated an initial statistically significant reduction in pain, the effect did not persist over time.