Randomized, Double-Blind Cross-Over Trial Of Buprenorphine and Low-Dose Naloxone Versus Buprenorphine

Treatment of chronic pain typically relies on the effectiveness of opioid analgesics,
however, side effects and the potential for users to develop tolerance and addiction may make
physicians hesitant to prescribe them. The development of opioid analgesics with fewer side
effects and decreased potential tolerance and addiction would increase the ability to safely
and effectively treat pain. This study will determine whether the addition of an ultra-low
dose of naloxone, an opioid antagonist, to buprenorphine, an opioid analgesic pain
medication, increases the analgesic potency and reduces side effects compared to
buprenorphine alone. Low doses of naloxone added to buprenorphine have been shown to increase
the potency and reduce the side effects of buprenorphine in animal studies and in a human
study with healthy volunteers. The current study aims to extend these findings by assessing
the analgesic potency and side effects of a 15:1 ratio of buprenorphine to naloxone in a
sample of 12 outpatient participants with moderate pain (4 or greater pain intensity) who are
experienced with opioid analgesics. Participants will be randomly assigned to begin blinded
treatment starting with one of two medication regimens: IV buprenorphine + ultra-low-dose
naloxone or IV buprenorphine alone. Participants receive 5 daily doses of medication (no more
than 2 days between each dose) followed by crossover to the opposite treatment condition for
5 additional daily doses. Each study day, participants will provide a daily pain assessment,
receive administration of study medication, and will then be monitored and assessed for pain
and side effects over the next six hours. Outcomes for the study include: (1) pain intensity
as measured using the Brief Pain Inventory, pain intensity numerical rating scale, and the
Beck Depression Inventory, and (2) self-reported side effects/adverse events. After
completion of study participation, participants will resume pre-study pain treatments with
their own physician.

Inclusion Criteria:

Participants must meet all of the following:

1. 18 years of age or older

2. Have chronic pain that is not related to cancer, defined as pain expected to last a
month or more,(i.e. musculoskeletal pain or neuropathic pain)

3. Report pain of moderate to moderately-severe intensity during the week prior to the
baseline screening visit (a score greater than or equal to 4 for average pain in the
past week on the 0-10 point Pain Intensity-Numerical Rating Scale)

4. Have used prescription opioid and/or non-opioid analgesics for the pain on at least 15
of the 30 days prior to the initial baseline/screening visit and have clearance from
their prescribing physician to discontinue all non-study-related opiates during study
participation

5. Willing and able to comply with study procedures

6. Willing and able to provide written consent

7. If female, not pregnant or lactating and willing to use an acceptable method of birth
control (e.g., condoms, IUD, birth control pills, or Depo-Provera)

Exclusion Criteria:

Participants must not meet any of the following:

1. Have a history of dependence on opiates, stimulants, alcohol, or benzodiazepines, as
defined by DSM-IV criteria, within the past year (physical dependence on prescribed
opioid analgesics is allowed but opioid dependence according to DSM-IV, i.e. opioid
addiction, is not)

2. Use of any illicit or recreational drugs (heroin, cocaine, methamphetamine, marijuana,
etc.) ; or use of any long-acting opioid (i.e., methadone) in the 30 days prior to the
initial screening visit

3. Concomitant use of medications that are inhibitors of CYP3A4 (e.g., azole antifungals,
macrolide antibiotics, and HIV protease inhibitors), or medications that induce CYP3A4
activity (e.g., anticonvulsants and rifampin) that may alter the metabolism of
buprenorphine

4. Have a medical condition that, in the study physician's judgment, may interfere with
safe study participation for the individual study candidate. Because medical
conditions may differ in terms of safe participation on an individual basis, this
criterion must be based on a physician's determination after a medical history, exam,
and lab tests and may also involve consultation with a study candidate's primacy care
physician. Some examples of medical conditions that may be exclusionary for a
particular individual, however include active tuberculosis, unstable and/or
significant cardiovascular or liver disease, unstable diabetes (i.e., glycosylated
hemoglobin A1C of 12%), uncontrolled HIV infection, altered renal function (serum
creatinine males and females:>3x upper limit of normal) or clinically significant
elevated liver enzymes (ALT or AST greater than 3x the upper limit of normal)

5. Have a current neurological disorder (e.g., organic brain disease, dementia) or
current major psychiatric disorder (e.g., schizophrenia, bipolar illness, or PTSD)
that would make study agent compliance difficult, that would compromise informed
consent, or that would jeopardize safety

6. Have a history of suicide attempts in the past 180 days and/or current serious
suicidal risk

7. Have any history of a seizure disorder

8. Have a known allergy or sensitivity to buprenorphine or naloxone

9. Receiving long-acting opioids, such as methadone, LAAM, or sustained release morphine,
for treatment of pain (due to problems with initiating buprenorphine treatment among
patients receiving long-acting opioids)

10. Have recent surgery or a major medical procedure that could potentially interfere with
study participation

11. Any other circumstances that, in the opinion of the investigators, would interfere
with study participation