Subcutaneous Methylnaltrexone Versus Placebo for Postoperative Ileus Prevention

Postoperative Ileus refers to the transient interruption of propulsive motor activity of the
gastrointestinal (GI) tract that prevents effective movement of its contents and tolerance of
oral intake. Although POI is generally considered to significantly increase hospital stays
and inpatient costs after spinal surgery, the incidence, associated risk factors, and
effective preventative strategies remain poorly characterized. The proposed etiologies
underlying POI are broad and remain incompletely characterized. They include post surgical
sympathetic nervous system activation, inflammatory factors, and the effects of analgesics on
GI tract motility. Treatment often consists of aggressive bowel regimens, nasogastric tube
insertion for decompression, and the application of various laxatives, suppositories, and
enemas. The widespread use of these measures is unfortunately not supported by high level
evidence. The incidence of POI after spinal fusion is reported to range between 0.6 to 16.7%.
This estimated range likely represents a gross underestimate of POI given the retrospective
nature of studies undertaken to date. Fineberg and colleagues reported that the risk
increases nearly 3-fold following anterior lumbar spinal fusions as compared to posterior
surgeries. Furthermore, the only risk factors they identified to be correlated with POI is
male gender, = 3 fusion levels, alcohol abuse, anemia, electrolyte abnormalities, and weight
loss. Kiely and colleagues found that ileus was associated with the administration of certain
intravenous solutions such as lactated ringers and sodium chloride. Interestingly, they found
that albumin administration was associated with a reduced incidence of ileus postoperatively.
Lee and colleagues evaluated POI following orthopedic surgery and reported an incidence of
2.1%. They found that patients who developed POI were more likely to be older, had higher
blood loss during surgery, and also had higher rates of preoperative constipation. This
study, however, included all types of orthopedic surgeries (not limited to spinal fusion).
Early clinical studies evaluated the effectiveness of MNTX in treating opioid-induced
constipation (OIC). Several clinical trials confirmed that MNTX was well tolerated and
counteracted the GI effects of opioids, thereby enhancing gut motility without inhibiting
their analgesic properties. Only two studies to date have evaluated the potential
effectiveness of MNTX in reducing the incidence of POI following GI surgery. Both studies
were unfortunately hampered by serious design flaws. Most importantly, neither study included
pre-operative administration of MNTX. As such, MNTX remains at this time approved only for
chronic OIC based on two double-blind, randomized, placebo-controlled trials conducted in
patients with advanced illness wherein MNTX rapidly induced laxation as compared to placebo.

Inclusion Criteria:

- Subject is scheduled to undergo a 1 - 3 level lumbar spinal fusion for degenerative
spinal conditions including neurogenic claudication and/or lumbar radiculopathy with
stenosis and/or spondylolisthesis.

- Subject must be over the age of 18 years old.

- Subject has been unresponsive to conservative care for a minimum of 6 months.

- The subject must in the investigator's opinion, be psychosocially, mentally, and
physically able to fully comply with this protocol and have the ability to understand
and give written informed consent.

Exclusion Criteria:

- Previous Treatment with MNTX

- History of mechanical gastrointestinal obstruction

- History of OIC refractory to outpatient medical management

- Presence of a peritoneal catheter for intraperitoneal chemotherapy or dialysis

- Clinically relevant active diverticular disease

- Recent history of bowel surgery within previous 12 months

- Use of vinca alkaloids within previous four months

- Renal failure defined as EGFR <30 ml/min per 1.73 m^2 or requires dialysis

- Known or suspected allergy to MNTX or similar compounds (e.g. naltrexone or naloxone)

- Participation in a study with investigational products within 30 days before first
dose of MNTX

- Pregnant or nursing

- Clinically important abnormalities that may interfere with participation or compliance
to the study, as determined by investigator.