Determining the Prognostic Value of Continuous Intrathecal Infusion

Recruitment: Subjects will be recruited from patients seen at the University Hospitals Pain
Medicine clinics by attending physicians. Screening will be done before obtaining consent by
an investigator. If patients are deemed appropriate for an intrathecal device they will
undergo normal procedures and guidelines in place prior to being considered candidates for an
implantable device. No subject will be compensated for participation.

Consent Process: Subjects will be consented by one of the investigators. An explanation in
lay terms for the reasons of the study and the proposed prognostic benefits will be used to
promote patient understanding. If interested, eligible individuals will be given the
opportunity to ask and have all questions addressed before signing the informed consent
document. The procedure will occur at their next visit, and continued consent of study
participation will be confirmed.

Study Design: This is a randomized, double-blind, placebo controlled cross over study
comparing prognostic intrathecal testing with an admixture of bupivacaine and fentanyl versus
saline. None of the procedures in this study deviate from usual clinical care that patients
receive at UHCMC or nationally. Baseline scores using the numerical rating scale (NRS) for
pain (a scale form 0-10, where 0 signifies no pain at all, and 10 the worst possible pain)
will be recorded, both in the sitting or supine position (least pain) and with ambulation or
standing (worst pain). Patients will be given weight based cefazolin (or vancomycin if
indicated) prior to placing the externalized intrathecal catheter. Placement of the
percutaneous intrathecal catheter will be done in the operating room with minimal or no
sedation in the prone or lateral decubitus position under fluoroscopic guidance. Needle entry
will occur in the mid-upper lumbar spine and through the needle an intrathecal catheter will
be advanced until its tip is positioned in the posterior intrathecal space in the lower
thoracic spine. The needle is then removed and the catheter is secured in place with
steri-strips and a clear sterile bio-occlusive dressing will be placed. Patients will then be
transferred to the PACU where they will be initiated on one of two solutions that will be
prepared for each patient by the investigational pharmacy staff at UHCMC. The solutions will
be labeled as "Intrathecal solution 1" and "Intrathecal solution 2" and will be contained in
a sterile 50 ml bag. Solution 1 and 2 may contain either:

1. Preservative-free normal saline

2. Fentanyl 1 mcg/ml and bupivacaine 0.625 mg/ml

The content of Intrathecal solution 1 and 2 will be unknown to all investigators and
participants in the study with the exception of the investigational pharmacy. The order of
the Intrathecal solution (1 or 2) will be determined by pharmacy using a computer generated
random sequence allocation. The intrathecal catheter will be attached to a pump delivering
solution 1 or 2 at around noon time, in the recovery area on the day the catheter is placed.
A bolus of 1cc will be given through the infusion pump at initiation of therapy and the
patient will then be started on an infusion rate of 0.5 ml/hr. After 3-4 hours (around 3-4
pm) and similarly around 6-7 pm the rate will be titrated depending on patient's response up
to a maximum of 0.8-1.0 ml/hr. If the patient has achieved > 50% pain relief compared to
baseline, no up-titration will occur; i.e. the rate will be increased only if the patient has
not had 50% or more reduction in baseline pain on the NRS. The intrathecal rate will be kept
the same provided the patient had 50% or greater decrease in pain scores or has reached the
1.0 ml/hr rate (whichever comes first). The rate will be unchanged from 6-7 pm until around
6-7 am the next morning when the infusion will be stopped and the patient will be assessed
for pain relief. In the morning, the patient will be asked to rate the pain score at rest (in
bed or chair) and with ambulation/standing. The pain scores will be recorded and the catheter
will be aspirated at the hub to ensure continued cerebrospinal fluid flow and the patient
will be started on a solution of preservative-free normal saline at 0.2 ml/hr to keep the
catheter patent. After 6 hours, around noon time, the patient will be crossed over to
Intrathecal solution 1 or 2, depending on what she/he had the day before, given 1.0 ml of
that solution as a bolus and then infusion will be started at 0.5 ml/hr and the same protocol
as the day before will be repeated with the patient discharged the next morning. Patients who
experience greater than 50% pain relief (relative to baseline) with either intrathecal
solution will be offered the implant of a permanent IDDS that will deliver a combination of
bupivacaine and low-dose fentanyl. Patients not responding to both solutions with greater
than 50% pain relief will be considered to have failed the intrathecal test and would not
proceed to implant. The patients will be asked to pick which solution provided better pain
relief: solution 1 or solution 2 and responses will be recorded. Additionally, pain scores
obtained periodically as part of patients' usual clinical care vital signs and recorded by
the nursing staff on the hospital ward will be collected throughout the study. Un-blinding
for patients who had a successful intrathecal prognostic infusion test with greater than 50%
pain relief will not occur until 12 months have elapsed since the pump implant.

Outcome measures will include:

1. Baseline prior to commencement of the prognostic infusion test: Pain intensity using the
Numerical Rating Scale [NRS], patient global impression of change [PGIC], Oswestry
disability index [ODI] and painDETECT.

2. At 14-18 hours: Pain intensity in Numerical Rating Scale [NRS], patient global
impression of change [PGIC], complications and side effects.

3. Prior to second infusion: Pain intensity in Numerical Rating Scale [NRS], patient global
impression of change [PGIC], complications and side effects.

4. At prognostic infusion test completion: Pain intensity in Numerical Rating Scale [NRS],
patient global impression of change [PGIC], complications and side effects, Oswestry
disability index [ODI] and painDETECT.

5. At 6 and 12 months post-implant for implanted patients Pain intensity in Numerical
Rating Scale [NRS], patient global impression of change [PGIC], Oswestry disability
index [ODI] and painDETECT.

Study Methodology/Procedures: The study will include 36 patients with intractable chronic low
or mid back pain due to failed back surgery syndrome or vertebral fracture who failed
conservative management including epidural steroid injection and medical therapy and were
referred to our practice for pain management.

Patient will undergo the usual psychological and medical evaluations before the initiation of
the prognostic infusion test. Patients who are considered candidates for intrathecal pump
implant fulfilling the inclusion/exclusion criteria above and who elect to participate in the
study will be randomly assigned to two groups.

Group I tested with continuous infusion of intrathecal bupivacaine 0.625 mg/ml and fentanyl 1
mcg/ml for 14-18 hours followed by a trial with normal saline for another 14-18 hours.

Group II tested with intrathecal normal saline for 14-18 hours followed by intrathecal
Bupivacaine 0.625 mg/ml and fentanyl 1 mcg/ml for another 14-18 hours.

Note that drugs will be delivered by the pharmacy to a blinded physician and labeled as
Intrathecal solution 1 and Intrathecal solution 2 to be administered sequentially, separated
by a 4-6-hr infusion of preservative-free saline.

Outcomes will be assessed and documented on all patients upon admission to the preoperative
area. The patients will be taken then to the procedure room and a standardized intrathecal
catheter will be placed under fluoroscopic guidance where the tip of the catheter will be
placed at the T7-T11 posterior intrathecal interspace. Patients will be discharged to the
PACU where they will be started on a rate of 0.5 ml/hr.

Six to eight hours following initiation of the infusion, all the patients will be titrated to
0.8-1.0 ml/hr, provided less < 50% improvement in pain scores occurs. A physician who is
blinded to the treatment will assess NRS after approximately 12 hrs (around 6-7 am of the
following day). A 4-6 hours washout period will ensue with infusion of preservative-free
normal saline at a rate of 0.2 ml/hr after which the physician will document a return of the
NRS to baseline before switching therapies or record the value at 6 hrs after infusing normal
saline and switch then to solution 2. NRS will be reassessed around 6 am the following
morning. Additionally, pain scores documented with usual clinical care vital signs will be
captured. All reported adverse events will be recorded.

No pain medications will be prescribed during the admission. If such medications are needed,
the patient will be excluded from continuing on with the study and will be recorded as a
prognostic-infusion-test failure.

The intrathecal catheter will be aspirated for confirmation of free cerebrospinal fluid flow
(about 1 ml) between all solution changes and at the end of the prognostic infusion test.

After the completion of the prognostic infusion test, the catheter will be removed and
patients will be discharged home.

Only patients who report >50% reduction from baseline NRS while receiving either intrathecal
solution will be considered for intrathecal drug delivery system implant. It is conceivable
that some patients may get >50% reduction in pain scores with both the active solution and
saline or have better outcome with the saline solution. The patients will be asked to answer
a binary question rating preference to solution 1 vs. solution 2. Patients with pain relief
greater than 50% will be implanted with an IDDS and will receive an intrathecal solution of
fentanyl and bupivacaine. All subjects with >50% pain relief with either or both intrathecal
solutions will be implanted. Even if the patient gets >50% pain relief only from the saline
solution, or the patient chooses the saline solution over the active solution (when asked if
#1 vs. #2 was better relief) each patient will receive active drug after being implanted. All
patients will be compared in long-term outcome (secondary outcome measures) at 6 months and
12 months versus the response to the prognostic test solutions.

Unblinding of solution 1 and 2 will not occur until 12 months have elapsed since pump
implant. The six and twelve month visits will be coordinated with a pump refill visit.

Data Collection: Randomization will be performed, and baseline data will collect on admission
to the preoperative area. A physician or physician assistant will obtain all data.

Baseline data collected will include name, last 4 digits of social security number, age, sex,
race, duration of pain, treatment group, average 0-10 low back numerical rating scale (NRS)
pain scores over the past week and analgesic medication consumption.

The primary outcome variable will be the change in pain intensity score [NRS] 0-10 numerical
rating scale back pain score at the end of the intrathecal prognostic infusion testing period
around 6am between Intrathecal solution 1 and Intrathecal solution 2.

Secondary outcome variables will be Oswestry disability score, changes in painDETECT, Patient
Global Impression of Change (PGIC) and side effects (medications) and complications
(injections). These variables will be recorded at baseline, at the completion of each phase
of the prognostic infusion test, and at 6 and 12 months post-implant.

Inclusion Criteria:

- Previous lumbar or thoracic spine surgery or lower thoracic/lumbar vertebral
compression fracture

- Intractable pain of trunk (more than limbs)

- Patient who passed psychological evaluations as part of the usual clinical care prior
to consideration of IDDS and are stable with current pain condition and medications

- Failed more conservative management.

Exclusion Criteria:

- Untreated coagulopathy or infection.

- Immune compromised state precluding having an implant.

- Allergic reactions to bupivacaine or fentanyl.

- Pregnancy

- Patients using more than 30 mg oral equivalents of morphine daily or who are unable to
wean down below that dosage for more than 4 weeks before the prognostic intrathecal
infusion test.

- Neurological deficits characterized as weakness in lower extremities with evidence of
nerve damage

- Patients with cognitive disorders who would not be able to provide meaningful outcome
responses