Improving Postamputation Functioning by Decreasing Phantom Pain With Perioperative Continuous Peripheral Nerve Blocks: A Department of Defense Funded Multicenter Study

Subjects will receive 2 perineural catheters: a femoral and sciatic. With a high-frequency
linear array ultrasound transducer, the target nerves will be identified in a transverse
cross-sectional view: the sciatic nerve proximal to the anticipated level of amputation and
the femoral nerve at the inguinal crease. For each insertion, normal saline will be injected
via the needle to open the perineural space allowing subsequent insertion of a perineural
catheter 3-5 cm beyond the needle tip. The needle will be removed over the catheter, and the
catheter affixed to the skin and covered with occlusive dressings. Local anesthetic (20 mL,
lidocaine 2% with epinephrine 2.5 µg/ml) will be injected via each catheter.

The nerve blocks will be evaluated 20 minutes following local anesthetic injection and the
catheter insertions considered successful when subjects have a decreased sensation to cold
temperature (alcohol swabs) in the appropriate cutaneous distribution for each target nerve.
Catheters may be re-bolused with lidocaine 2% with epinephrine 2.5 µg/ml, at the discretion
of the Site Director.

Treatment group assignment (randomization). Subjects will be allocated to a treatment only
after confirmation of successfully-inserted perineural catheters, and will be randomized to
one of two groups:

1. Experimental: bupivacaine 0.3% for a total of 7 days

2. Control: bupivacaine 0.1% for 1 day followed by normal saline for 6 additional days

Randomization will be stratified by institution in randomly chosen block sizes of 2 or 4.
Investigational pharmacists at each institution will prepare all study solutions as
determined by the randomization lists. Unmasking will not occur until statistical analysis is
complete (termed "triple masking").

In addition to the perineural infusions, subjects will receive standard-of-care oral and
intravenous postoperative analgesics. The perineural infusions will be initiated within the
operating or recovery room. The continuous basal infusion rate for lower extremity catheters
will be determined by amputation location: below-knee [femoral 3 mL/h; sciatic 5 mL/h] and
above-knee [femoral 5 mL/h; sciatic 3 mL/h]. No patient-controlled bolus dose will be
included.

The morning of postoperative day 1, the local anesthetic reservoirs will be replaced with new
reservoirs containing study infusate: additional bupivacaine 0.3% for the Experimental group;
normal saline for the Control Group. Subjects will be discharged home with portable infusion
pumps when medically ready, without restriction due to study participation and telephoned
daily. If premature dislodgement occurs prior to 72 hours, the subject may opt to have the
catheter replaced as soon as can be arranged with the investigators (a minimum of 72 hours
will be considered a successful treatment application).

Seven days following catheter insertion, subjects or their caretakers will remove the
perineural catheters with instructions given by an investigator via telephone.

Outcome measurements (end points). The primary end point will be mobility at 9 months
following surgery (measured with the Locomotor Capabilities Index). The primary analyses will
compare the two treatment groups. End points will be evaluated at baseline (postoperative day
0), during the initial infusion of either bupivacaine 0.3% or 0.1% (morning of postoperative
day 1); during the second infusion of either bupivacaine 0.3% or placebo (postoperative day
2), following the completion of the infusion (postoperative day 8), and the follow-up period
(postoperative months 1, 3, 6, 9, and 12).

The questionnaires will differentiate among multiple dimensions of limb pain:

Residual limb ("stump") pain: painful sensations localized to the portion of limb still
physically present Phantom limb sensations: non-painful sensations referred to the lost body
part Phantom limb pain: painful sensations referred to the lost body part

Medical history will include the indication for amputation, history of the surgical limb
(e.g. previous surgeries), preoperative limb pain levels (e.g., least, average, worst and
current), comorbidities, medications, and amputation level. In addition, we will apply the
PTSD Checklist (PCL-C) at baseline.

Hypothesis 1: Mobility will be significantly increased within the 12 months following a
surgical amputation with a 7-day high-concentration perioperative CPNB compared with usual
and customary analgesia (as measured with the Locomotor Capabilities Index-5). The primary
outcome measure of the proposed trial will occur at the 9 month time point.

Hypothesis 2: General physical and emotional disability will be significantly lower within
the 12 months following a surgical amputation with a 7-day high-concentration perioperative
CPNB compared with usual and customary analgesia (as measured with the World Health
Organization Disability Assessment Schedule 2.0).

Hypothesis 3: Depression will be significantly decreased within the 12 months following a
surgical amputation with a 7-day high-concentration perioperative CPNB compared with usual
and customary analgesia (as measured with the Beck Depression Inventory).

Hypotheses 4 & 5: Phantom and residual limb pain will be significantly decreased within the
12 months following a surgical amputation with a 7-day high-concentration perioperative CPNB
compared with usual and customary analgesia (as measured with Brief Pain Inventory questions
1-4). Current/present, worst, least, and average phantom pain will be assessed using a
Numeric Rating Scale (NRS) included in the Brief Pain Inventory (short form). These same
measures will be included for residual limb pain as well. Additional pain-related data.
Frequency and average duration of non-painful phantom sensations, phantom limb pain, and
residual limb pain will also be assessed. In addition, other pain locations/severity will be
evaluated using the NRS. Lastly, to investigate masking adequacy, subjects will be queried
the day following catheter removal on the infusion type they believe they received (active
drug vs. placebo).

Hypothesis 6: Opioid consumption will be significantly decreased within the 12 months
following a surgical amputation with a 7-day high-concentration perioperative CPNB compared
with usual and customary analgesia (measured in oral morphine equivalents).

Supplemental analgesic use will be recorded at all time points.

Data collection. Subject demographic, surgical and CPNB administration data will be uploaded
from each enrolling center via the Internet to a secure, password-protected, encrypted
central server (RedCap, Department of Outcomes Research, Cleveland Clinic, Cleveland, Ohio).
The questionnaires for all subjects-regardless of enrolling center-will be administered by
telephone from the University of California San Diego. Staff masked to treatment group
assignment will perform all assessments.

Statistical Plan and Data Analysis Primary analyses will be modified intent-to-treat, such
that all randomized patients who receive at least some of the study intervention will be
included in the analyses. All patients will be analyzed in the group to which they were
randomized.

Aim 1 - Mobility (H1). We will assess the treatment effect of continuous peripheral nerve
blocks (CPNB) versus standard therapy on the primary outcome of the Locomotor Capabilities
Index (LCI) at 9 months using a proportional odds logistic regression model, as long as the
proportional odds assumption holds (i.e., P-value > 0.05 assessing proportional odds). In the
event that the proportional odds assumption does not hold, we will compare groups using an
extension of the Wilcoxon rank-sum test to allow covariate adjustment. The primary analysis
will use the total LCI score (range 0-56), while the basic and advanced LCI
subscales-comprised of 7 questions each-will be considered as secondary. Additional secondary
analyses will compare groups at each of 6 and 12 months on the same outcome. We do not use
repeated measures or longitudinal data models because we do not expect the treatment effect
to be consistent across 6, 9 and 12 months.

Aim 1 - General physical and emotional disability (H2). We will assess the effect of CPBN on
general physical and emotional disability as measured by the World Health Organization
Disability Assessment Schedule 2 (WHODAS2) questionnaire across time points 1, 3, 6, 9 and 12
months post-randomization using a linear mixed effects model to account for the
within-subject correlation over time (assuming an auto-regressive correlation structure).
Baseline WHODAS2 scores will be adjusted for in order to gain precision in the treatment
effect estimates. The WHODAS2 overall score across the 36 items and the 6 subscale scores
will be calculated for each exam using the complex scoring algorithm (called
"item-response-theory" (IRT) based scoring) which takes into account multiple levels of
difficulty for each WHODAS 2.0 item. Scores will then be converted to a 0 (no disability) to
100 (full disability) scale for ease of interpretation.

Aim 1 - Depression (H3). We will assess the effect of CPBN on depression at 12 months post
randomization as measured by the Beck Depression Inventory (BDI-II) using a multiple linear
regression model to adjust for baseline BDI scores and clinical site, as well as to assess
the treatment group-by-site interaction.

Aim 2 - Phantom limb pain (H4), Residual limb pain (H5), opioid consumption (H6). We will
assess the effect of CPBN on each of phantom limb pain, residual limb pain and opioid
consumption over time using linear mixed effects models as specified above for analysis of
the WHODAS2 score. In these models we will assess the treatment-group by time interaction
over all times (postoperative days 1, 2, 8, months 1, 3, 6, 9, 12) and also the interaction
between treatment group and early times (postoperative days 1, 2, 8) versus late times
(postoperative months 1, 3, 6, 9, 12).

Opioid consumption will be log-transformed (or other appropriate transformation) to achieve
normality in the observed data before modeling and will be analyzed as the amount of opioids
being consumed at each time point. Throughout these models we will adjust for baseline pain
score or opioid consumption as a covariate to improve precision of the treatment effect
estimates.

Interim analyses. We will conduct interim analyses for efficacy and futility at each 25% of
planned enrollment using a group sequential design and gamma spending function for alpha
(efficacy, parameter -4) and beta (futility, gamma parameter -2).

Sample size considerations. We powered this trial to be able to detect a clinically important
difference between groups on the primary outcome of the LCI-5 at 9 months post-randomization
with 90% power at the 0.05 significance level. While the minimal clinically important
difference (MCID) for the LCI remains undetermined, current literature suggests that the MCID
for similar instruments is about 10% of the possible range of the scores, or else, similarly,
about half of a standard deviation of the score (please see following paragraph for details
on the MCID). For our study we therefore power the study to detect a difference of 5.6 on the
56-point LCI total score, and we assume a SD of 11 for the total score (Larsson, 2009
observed SD of 9 and 11 for two different time points). With the given assumptions we would
require 89 subjects per group, or a total of 178 for a 2-sample t-test. While the analysis
will utilize a proportional odds logistic regression, with a range of 56 points the outcome
variable might be close to normally distributed and the power for the planned test is
expected be close to that of a 2-sample t-test on the same data. Incorporating the planned
interim analyses at each 25% of total enrollment, the study requires a maximum total of 203
subjects. Expecting a maximum of 7-8% of patients lost-to-follow-up or withdrawn by 9 months,
we will enroll a maximum total of 218 patients to achieve the goal of N=203 for analysis.

Inclusion Criteria:

- scheduled for a unilateral lower limb amputation distal to the femoral head and
including at least one metatarsal bone

- continuous peripheral nerve blocks are planned for perioperative analgesia

- willing to have their perineural infusion extended for a total of 7 days

- willing to undergo ambulatory perineural infusion following hospital discharge

Exclusion Criteria:

- Known hepatic or renal insufficiency

- allergy to any study medication

- pregnancy

- incarceration

- inability to communicate with the investigators

- comorbidity precluding either perineural catheter insertion or subsequent ambulatory
perineural infusion (e.g., current infection at the catheter insertion site,
immune-compromised status of any etiology)

- weight < 45 kg

- inability to contact the investigators during the perineural infusion, and vice versa
(e.g., lack of telephone access)

- investigator opinion that the potential subject is not a good candidate for this
particular study