Buprenorphine vs. Opioid Dose Escalation Among Patients With Chronic Pain

Increasingly, Veterans are prescribed potent opioid analgesics for the treatment of chronic
pain despite limited evidence for efficacy and increasing evidence of serious harms
including addiction and non-fatal and fatal overdose. While guidelines recommend
consideration of dose increase for patients not benefitting from opioid therapy, the rates
of major harms are directly related to dose. Higher doses may also be more likely to
precipitate opioid-induced hyperalgesia, a paradoxical increased pain response, in
susceptible individuals. In summary, opioid dose increase, a currently accepted clinical
response to poorly controlled pain, may offer little benefit and certainly increases risk,
especially in patients already on moderate-high doses (30-100 mg daily morphine
equivalents). Alternative treatment strategies to opioid dose escalation that lessen risk
and possibly increase benefit are much needed.

Switching to buprenorphine/naloxone (BUP/NX), a partial opioid agonist approved for use in
the treatment of opioid abuse/dependence, may be a safe and effective alternative strategy
to opioid dose escalation in the treatment of chronic pain. As a partial agonist, there is a
ceiling to BUP/NX's respiratory depressant and other opioid-like effects, meaning it is less
likely to cause addiction and overdose. Additionally, there are pre-clinical data to suggest
BUP/NX is less likely to produce opioid-induced hyperalgesia and may even reverse it in
patients switched from full agonist opioids. Case series have demonstrated improvements in
pain, functional status and quality of life among patients switched from full agonist
opioids to BUP/NX for chronic pain. Controlled trials are needed to establish BUP/NX's
efficacy compared to opioid dose escalation in the treatment of poorly-controlled pain.

The investigators propose a pilot 12-week, open label randomized trial of BUP/NX compared to
opioid dose escalation among patients with poorly-controlled pain on the primary outcome of
pain intensity. As patient acceptance of either opioid dose escalation or BUP/NX is unknown,
the investigators' first objective is to assess willingness to enroll in a randomized trial
and reasons for and against enrollment among eligible patients. The study will compare
treatments on the primary outcome of pain intensity, measured using the 11-point pain
numerical rating scale, and secondary outcomes of pain interference, using the Brief Pain
Inventory functional interference subscale, medication adherence and patient global
assessment of change. Mixed models will be employed in the analysis to accommodate potential
unbalanced repeated measures with missing data. Effect size estimates will be used to
generate sample size projections for a definitive trial. This line of research is a direct
extension of the PI's HSR&D-funded CDA-2 project developing a screening tool to identify low
efficacy opioid use in primary care and also well-aligned with the Strategic Plan and
Focused Area of Research of the Pain Research, Informatics, Medical comorbidities, and
Education (PRIME) Center's proposal for a Center of Innovation (COIN) and its strategic
objective to "Promote access, continuity, and sustainability of safe and effective
interventions for pain and pain-related disability."

Inclusion Criteria:

- Aged 18 and older

- 3 months of continuous opioid therapy for chronic pain;

- 30-100 mg morphine equivalent daily opioid dose based on pharmacy records of standing
and as needed opioids prescribed.

- 28 (out of 70) on the 7-item Brief Pain Inventory (BPI) functional interference
subscale at screening

- Numerical pain rating of 4 or greater (i.e., moderate pain or greater) at screening
on the 11-point pain numerical rating scale (NRS)

- Females must (a) be using birth control pills or depo provera injections, or have an
intrauterine device; or (b) be post-menopausal, or (c) have undergone surgically
sterilization.

- Primary care provider's (PCP) assent for patient participation, ascertained via
encrypted email or in-person query.

Exclusion Criteria:

- DSM-IV defined substance use disorder, except nicotine dependence. Participants known
to using marijuana, including those who are apparently legally authorized to use
marijuana by non-VHA providers, will be excluded since opioid dose escalation in
regular marijuana users is contraindicated.

- Opioid therapy for palliative care

- Participation in another investigational pharmaceutical trial within 30 days of
screening

- Pregnancy or lactation

- Recently decompensated medical illness necessitating inpatient hospitalization (past
30 days)

- Transaminases (aspartate aminotransferase/alanine aminotransferase) greater than five
times the upper limit of normal within 90 days of assessment phase

- Not well-controlled psychiatric symptoms at the time of physician assessment,
including suicidal ideation or untreated psychosis; or recently decompensated
psychiatric illness necessitating inpatient hospitalization (past 30 days).

- Use of a moderate to strong CYP3A4 inhibitor