Effectiveness of Controlled-Release Morphine for Chronic Neuropathic Pain After Spinal Cord Injury

Neuropathic pain occurs as a result of damage to neural tissue either in the peripheral or
in the central nervous system. Three types of neuropathic pain after SCI are especially
difficult to treat: at level central pain (ALCP), at level radicular pain (ALRP), and below
level central pain (BLCP). Various analgesic medications with distinct mechanisms and sites
of action are currently used in clinical practice for treatment of neuropathic pain after
SCI, including antidepressants, anticonvulsants, nonsteroidal anti-inflammatory drugs
(NSAIDs), and opioids. These analgesic medications, when evaluated in animal models of SCI
pain and in the treatment of other neuropathic pain states, have been shown to have only
modest pain reducing effect. This modest effect is seen clinically as the majority of
persons with SCI receiving these drugs continue to experience pain, which is severe and
disabling in one third of cases.

This study proposes to examine the efficacy of oral modified release morphine in reducing
pain in persons with neuropathic pain after SCI who have not adequately responded to other
oral pharmacologic, psychologic, or physical interventions. Only subjects who have failed
prior pain treatment regimes will be enrolled. Failure of pain regimen is defined as the
presence of pain in spite of medication(s) or other pain treatment, such as biofeedback or
other psychological or physical therapy interventions prescribed by a physician.

The following hypothesis will be tested: morphine, when added to non-opioid medications, is
more effective than placebo in reducing pain and increasing activity and subjective
well-being, in persons with ALCP, ALRP and BLCP. In order to test this hypothesis, a
randomized, double blind, placebo-controlled, two period cross-over trial is proposed,
during which subjects with ALCP, ALRP, and BLCP will receive daily placebo or modified
release morphine while being closely monitored and assessed for: (1) adverse effects, (2)
quality and intensity of pain, (3) intensity of allodynia and hyperalgesia, and (4) activity
levels and well-being.

All subjects whether assigned to the placebo or active drug will be able to continue any
previously prescribed or non-prescribed (over-the-counter) non-opioid medication that has
been taken on a regular basis, without dose change, for at least three weeks prior to study
entry. These medications may include but are not limited to the analgesics: acetaminophen
and any non-steroidal anti-inflammatory drugs; local anesthetics- topical patches such as
the lidocaine patch or otherwise; and adjuvant pain medications of the anti-depressant or
anticonvulsant classes. Subjects will not be allowed to take any opioid medication,
including non-opioid-opioid combination analgesics, other than the study drug for the
duration of the study.

Inclusion Criteria:

- Age 18 - 65

- Diagnosis of traumatic spinal cord injury

- Neuropathic pain (pain related to the nervous system) rated at least 4 on a 11-point
numeric rating scale at the time of screening

- Pain classified as at level radicular pain (ALRP), at level central pain (ALCP) or
below level central pain (BLCP).

- Pain that is present regularly for at least 3 months prior to enrollment, in spite of
medication or other pain treatment. This pain can be paroxysmal in nature (attacks of
pain).

- Ability to understand instructions and reliably provide pain assessments

- Willingness to stop current opioid medications, if any

- If a female with childbearing potential, using an approved method of birth control
(intrauterine device (IUD), barrier protection, a contraceptive implantation system
or injection (Norplant® or Depo-Provera®), oral contraceptive pills, or celibacy)

Exclusion Criteria:

- A known sensitivity to opioids

- A history of substance or alcohol abuse within the past 2 years

- A need for elective surgery involving preoperative or postoperative analgesics or
anesthetics during the study period

- Other chronic pain that cannot be differentiated from ALCP, ALRP, or BLCP

- A history of active cancer, excluding basal carcinoma of the skin, in the past 3
years

- Serum creatinine levels >= 2.5 mg/dl or hepatic (liver) dysfunction with serum ALT,
AST, GGT, or total bilirubin >= 3 times the upper limit of normal

- Participation in any drug study in the last three months

- Currently pregnant or breastfeeding