Treatment of Pain and Autonomic Dysreflexia in Spinal Cord Injury With Deep Brain Stimulation

The current study attempts to utilize deep brain stimulation of the periaqueductal grey
(PAG) for diminution of both neuropathic and nociceptive pain in spinal cord injury
patients. Likewise, the study will look at the effects on autonomic function as well. Deep
brain stimulation, as a treatment, has gained widespread use for the treatment of various
movement disorders. It is currently approved for use by the FDA for treatment of Parkinsons
Disease, Essential Tremor, and Dystonia. Over 100,000 implants have been performed worldwide
for these indications. The safety profile is well defined.

Pain is a tremendous burden for those who suffer with SCI. Persistent pain below or at the
injury level is experienced in 2/3rd of chronic SCI patients. As a result of this pain at
least 1/3rd of this sub-population faces a severely reduced quality of life; some
authorities consider this rate to be much higher, based on surveyed pain ratings. It was
reported that 23% of a sample patients with cervical or high thoracic SCI and 37% with low
thoracic or lumbosacral SCI would sacrifice sexual, bowel and bladder function for good pain
relief.

SCI pain is typically a mixture of nociceptive pain, which is caused by activation of
primary afferents' receptors, and neuropathic pain, which is caused by damage to the nervous
system. Neuropathic pain of SCI is most frequently treated by anticonvulsant agents. There
is good evidence from randomized control trials for some degree of effectiveness of
gabapentin and pregabalin, with weaker evidence for valproic acid. Tricyclic antidepressants
are also used to control SCI pain, but the supporting evidence is not as strong. Thus
amitriptyline has proved somewhat effective when the patient is depressed, but trazodone was
reported not to reduce post-SCI neuropathic pain more than placebo. Traditional analgesics
are also useful. Morphine can provide effective relief of neuropathic pain due to SCI, and
can be combined with the alpha-2 agonist clonidine for this purpose. Subarachnoid or
epidural lidocaine has been used to obtain short-term relief. For the musculoskeletal pain
in SCI, which nociceptive, antispasticity agents are frequently used; intrathecal baclofen,
for example, can be fairly effective. Despite this considerable range of choices,
pharmacological treatment for the pain of SCI remains inadequate. Low effectiveness,
tolerance, side effects or difficulties with prolonged local administration (e.g., subdural)
are among problems encountered.

Due to the combination of severity of chronic pain SCI patients are faced with and the
inadequate medical treatments available that this study is pertinent. Although, prior
attempts at clinical studies to show efficacy of DBS for pain have essentially failed, the
Investigators believe this current protocol offers some unique aspects. Likewise, as
mentioned earlier, both neuropathic and nociceptive pain related to SCI is devastating for
those afflicted. The Investigators have performed a detailed literature search and reviewed
all papers related to DBS and pain. To date there has been very few studies looking at DBS
for pain. Of those papers, the etiology of pain was very variable with only a small subset
related to spinal cord injury. Of the papers, including spinal cord injury none were well
controlled and even fewer reported detailed outcomes, other than to say there was no pain
control. Also of importance was that none of those studies truly looked at the effects of
chronic stimulation on pain control. This is to say, that each paper had as a criteria, that
the patient felt immediate relief of pain at the time of surgery or else the leads were
removed and no further stimulation was given. Most papers to date do not detail the outcome
measures used to determine pain relief. There are various pain scales that can be used to
determine level of pain control, some more accurate than others. Our study will also look at
the effects of alternating stimulation parameters on a monthly basis from therapeutic
stimulation parameters to sub-therapeutic parameters in a double blinded fashion (patient
and examiner). This method of evaluation will give us a unique way to evaluate pain control
yet to be performed in any of these prior studies. Likewise, the Investigators will also
evaluate the subject's ability to decrease both antiepileptic drugs as well as narcotics as
DBS progresses.

For the reasons above, the Investigators feel our study is different from those of the past.
The Investigators believe that due to the severity of the problem and lack of effective
therapeutic options combined with the less than stringent studies to date that our study
should be done. The Investigators realize that prior attempts at pain control with DBS have
been lackluster. However, our study is not only based on prior clinical attempts but also on
basic science research from the Miami Project to Cure Paralysis. These studies performed by
Dr. Ian Hentall (co-investigator) suggest strongly that stimulation of the periaqueductal
grey on a chronic basis is effective for pain control. Likewise, they suggest a beneficial
effect on autonomic dysreflexia, a potentially life threatening complication of SCI, as
well. As a result, our study will also focus on evaluating the effects of DBS on autonomic
dysreflexia with very stringent outcome measures, another unique aspect of this study. There
is also data in humans to suggest that the PAG is a central control center for autonomic
function.

Key Points:

Primary Rationale

1. Need. Many patients with chronic neuropathic pain due to spinal cord injury (SCI)
experience long-term suffering and have no recourse to adequate alternative therapy.
Analgesic drugs are at best of weak or inconsistent efficacy for a given patient and
can produce serious side effects at typical doses. This clinical trial is therefore
qualitatively different from trials comparing some improved drug (etc.) with a
currently used one.

2. Prospects. Pain of many types is responsive acutely to stimulation in the
periaqueductal/periventricular gray region (PAG/PVG; our anatomical target). There is a
large confirmatory literature on this in both animals and man, going back 3-4 decades.
A review analyzing PAG/PVG stimulation in prior clinical studies for all types of
drug-refractory pain uncovered 148 cases with a 79.1% success rate after lead
internalization.

3. Clinical evidence. With regard to acute relief of chronic SCI pain by DBS in PAG/PVG,
the Investigators believe that useful evidence is non-existent at present, but that the
benefits of PAG/PVG stimulation for other kinds of pain strongly justify a targeted
evaluation. In the above-cited 2005 meta-analysis, pain originating from spinal cord
injury was identified in 10 cases and leads were internalized in 7 of these cases, of
which 5 showed good long-term pain relief. Unfortunately, it is impossible to tell from
the cases described in the original articles, many from the 1970s, whether the sensory
thalamus (a different brain region, probably less appropriate) or the PAG/PVG or both
were stimulated. Moreover, the clinical literature on DBS for SCI pain rarely describes
the type of injury (segmental level, completeness, age or onset, etc.) and often
includes non-typical SCI in its summary categories (e.g., root avulsion, myelopathy).
Because of the conflation of stimulation sites and the poor characterizations of the
injuries, these factors need to be revisited in a more thorough analysis.

4. Preclinical evidence. Prolonged DBS improves other symptoms of SCI as well as pain. The
Investigators have found that various types of sensory and motor performance and
anatomical damage are restored. Recovery of autonomic dysreflexia, and improvements in
gastric emptying, insulin level and glucose control have been measured more recently.
These improvements remain when the stimulation ceases. Separately from pain, it is
important to find out in man whether the Investigators can safely replicate these
findings, with possible great benefit to patients. Thus there is a potential for (a)
immediate pain relief, (b) long-term changes in pain status (such that the stimulation
can be reduced or stopped), (c) general improvement in different visceral or motor
symptoms of the SCI syndrome.

5. Surgical issues. In the past, typically, at some point during the surgery, tests were
done on whether the patient's pain is reduced immediately upon stimulation. If not,
then leads were never internalized. The Investigators believe that this protocol may
have reduced success rates needlessly. Acute effects of electrode insertion may have
been present that prevented immediate benefits of the stimulation. Also, the most
benefits the Investigators postulate are due to long-term effects of the stimulation.
So the efficacy of DBS for pain, including SCI pain, may have been greatly
underestimated. The present study will include patients that do not show an acute
benefit immediately after surgical electrode implantation.

6. Safety. DBS has a very low rate of complications, which are mostly correctable.

Other Authorities

1. The Granting Agency (DOD), Regulatory Agency (FDA) and Device Manufacturer (waiver from
Medtronic Corp) have all supported the validity of this study.

2. The procedure (DBS in PAG/PVG for pain) is currently being used in the United Kingdom,
Germany, Australia and other countries.

Inclusion Criteria:

1. Age 22-60 years of age

2. Level of injury at or above T12

3. Neuropathic pain at or below the level of injury, as determined based on pain in an
area with neurological deficit and described as burning, shooting, electric, stinging
etc.

4. The injury must have occurred at least 1 year prior to entering the study and
participants must have experienced chronic pain for a minimum of six months.

5. The injury level must be at or above T12, and the disability must have a grade on the
American Spinal Injury Association Impairment Scale (AIS) of ASIA-A, ASIA-B, ASIA-C
or ASIA-D as determined by a qualified examiners.

6. Autonomic dysreflexia can be present, but is not a requirement. This is defined as a
rise of systolic pressure by more than 30 mmHg during noxious skin stimulation or
when the bladder or bowel is full, or apparently spontaneously over a period of
minutes.

7. Pain (neuropathic) of moderate severity or greater is present, when the patient is
taking medication, with a score of at least 4 on a numerical rating scale (range of 0
to 10).

8. Treatment with at least two of the following drug classes must have failed to give
satisfactory pain relief within the last two years: anticonvulsants e.g., pregabalin,
gabapentin); antidepressants (e.g., trazodone, amitriptyline); NSAIDS (e.g.,
ibuprofen). In addition, at least one of the following must have proved ineffective:
exercise-based rehabilitation, massage therapy using a variety of methods,
acupuncture using pressure, needles, heat, or electrical stimulation on specific
points on the body and psychological interventions such as cognitive therapy.

9. The subject must be taking pain medication to maintain a stable level of medication
from 4 weeks before surgery to 12 weeks after (the primary endpoint), except on the
day of surgery.

10. Participants on medications for other conditions, such as diabetes, will be
considered as candidates for this study. The dose will be monitored throughout the
trial. (They will be excluded if the drug is being used to treat epilepsy,
Parkinson's diseases, or other brain degenerative diseases.)

11. The subject must be willing to comply with the protocol including all scheduled
visits.

12. Literate at 8th grade level or above.

13. Subject must provide a letter of clearance for the DBS surgery from primary care
physician

Exclusion Criteria for Admission to study:

1. Unable to give informed consent

2. Prisoner or ward of the state

3. Pregnancy

4. Prior history of abusing nonprescribed drugs

5. Recent (one-year) history of alcohol abuse

6. ASIA motor exam unobtainable

7. History of cardiac arrhythmia

8. Renal disease, heart disease or uncontrolled hypertension (except due to autonomic
dysreflexia), liver disease or hepatic cirrhosis

9. Active major medical or psychiatric illness

10. Significant post-traumatic encephalopathy from head trauma sustained at SCI

11. Languages without local expertise

12. Pain is only nociceptive, or due to muscle spasms

Exclusion Criteria for Treatment/Intervention procedure:

1. Coagulopathy requiring anticoagulation therapy

2. Thrombocytopenia or platelet dysfunction

3. Peripheral vascular disease

4. Comorbid neurological diseases or disorders, including a history of seizures

5. Active systemic infection or concurrent immunosuppressive therapy

6. Existing implantable cardiac pacemaker, defibrillator,or neurostimulator

7. Requiring short-wave or microwave diathermy treatment

8. Inability to cooperate

9. Any contraindication to MRI studies (All future MRIs, with the exception of brain
MRIs, are excluded.)

10. Adverse reaction to stimulation (such as inability to stimulate at analgesic levels
without causing clinical hypertension or hypotension) or allergy or hypersensitivity
to any materials of the neurostimulation system

11. Depression, as defined by a Beck Depression Inventory (BDI-1a) score above 30.

12. Subjects with any clinically significant abnormality, not expected on the basis of
age (age-related), that is seen in magnetic resonance imaging (MRI).