Scientific/Medical Rationale:
Improved function is a high yield goal in back pain in specific, and pain in general. There
are a number of self-report scales measuring 'physical functioning', 'quality of life' or
ability to complete activities of daily living available. Unfortunately these tests, though
sometimes mentioned as 'tests of physical function', retain the significant limitation of
being fully subjective as they rely entirely on subject perception and report. These
subjective metrics are considered useful in that they show good preliminary correlation with
measured functional abilities and true functional performance. There have been many attempts
to bring more objective and quantitative functional scales to bear, and these efforts have
achieved variable success. Scales that are recorded by a professional observer, such as a
physical therapist, lend more 'objectivity' to the assessment, as with the Barthel index. The
Functional Capacities Evaluation (FCE) type metrics are highly validated, although geared
more toward patients with back pain in the forensic arena. As such they are not as yet
practical in the context of CLBP research, multi-center trials, or even the clinic.
Subjective, yet quantified pain ratings are commonly used to follow a patient's response to
analgesic treatment,and although having good clinical value for within-subject comparison,
between-subject contrasts are less reliable. Multiple factors including culture, memory, the
meaning and context of pain, personality types, affective state and a variety of operant
variables can influence reported pain,making these outcomes less scientifically adequate than
more objective outcomes.
Objective and Quasi-objective instruments have been developed to assess some relevant aspects
of the pain experience. For instance, gross functional assessments, such as return to work
and health care utilization, have been adapted and validated for pain research. While fully
objective testing such as fMRI holds the promise of being able to quantify human pain, this
will not be practical in the near future. As there will always be a need for simple "bedside"
measures and practical pain laboratory testing, as well as a great need to add objectivity to
this otherwise subjective diagnostic set. Logically, function should be a high priority
outcome in pain research.
Many measures have been validated over the years that can concurrently assess psychological
spheres of the pain experience. While it is clear that the impact of pain and mood are
critical components for characterizing the overall clinical pain experience, unfortunately
the pain literature is based entirely on self-report psychometric scales, and the subjective
nature of these measures make them less than fully satisfactory for research. Thus, there is
a critical need to shift the paradigm away from subjective measures (where possible) to more
objective methodologies. It is likely that objectification will lower cost in clinical trials
through the mechanism of improved power (thus lower numbers of subjects required to
demonstrate statistical response).
Finally, traditional statistical schemes require large, expensive trials to show
significance; the use of more powerful techniques such as hierarchical statistical models
with time series analysis and Bayesian analysis will allow for smaller, less expensive trials
to be conducted.
Drugs, Dosages, and Regimens:
First a 2-week washout of any opioid medication (if necessary; if not necessary subject can
proceed directly to); baseline week (Single Blind Placebo Lead In (SBPLI), using the placebo
film resembling the 75 mcg dose; then randomization to a ~ 2 week up titration either to
effective Buprenorphine Buccal Film (BBF) dose 2 day average pain better than or equal to
3/10 NRS), highest tolerated dose BBF and/or maximum dose BBF of 900 mcg BID, or identical
placebo material up to these parameters. This up titration is at the discretion and timing of
the blinded and experienced PI. Subject will be allowed two doses of
hydrocodone/acetaminophen 5/325 daily during the washout period.
A single experienced practitioner will manage the titration as to safety, detail and timing;
and determine when the subject enters the 8 week stable dose trial; this practitioner will
remain blinded throughout unless there is an urgent, safety reason for unblinding.
Patient population:
A total of 36-40 outpatients of age 18-65, any gender or race with Chronic Non-Radicular low
Back Pain (≥ 3 months; CNRBP) diagnosed by history and physical examination will be
identified for the trial. Subjects will be recruited from outpatient pain management offices.
Materials and instruments:
Personal Health History Subjects will be asked to complete a Personal Health History
Form at their first visit. This general questionnaire will assess demographic
information (sex, age, marital status, race/ethnicity, and education), pain history
(injury, onset/duration, description, self-reported diagnostic testing history, and
treatment history), and general health history (other medical/surgical history,
concurrent medications, health behaviors, a general symptom checklist, and health-care
utilization).
Numeric Rating Scale (NRS): the NRS is a convenient, understandable, and accessible
quantification of pain that is often used in pain research. It will be used on the
e-diary, at phone contacts, at defined moments in functional testing (before and after a
function) and in the clinical visits. The use of the metric in any context will always
be referenced as "Pain on a zero to ten scale, with zero being no pain and 10 being the
worst pain imaginable".
Pain Disability Index30: A seven-item, validated instrument that assesses perceived
disability in seven key life areas. It provides a total disability score, and is an
indirect measure of self-efficacy that will be acquired at all in person visits.
Patient's Global Impression of Function The PGIF is a 10 point scale (0= no functional
limitation, 10= non-functional) and asks the subject to rate his/her Function and
Activities of Daily Living.
PROMIS-29 The P-29 is a distillation of multiple psychometric scores using Item Response
Theory.
Functional Testing Protocol ©: Quasi-objective measures of functional abilities will be
obtained.
Actigraph (whole body 3d accelerometer type system) Participants will wear this device
from the beginning to the end of the trial. The data will provide different indexes of
participants' level of activity and activity organization, and these functional
parameters will also be measured by other psychometric methods. Activity will be
monitored via data portal for compliance by the research staff and PI.
Study Design:
Following wean of opioid medication, if necessary, all subjects will participate in a two
week single blind placebo lead in to wash out any placebo response. Following the single
blind placebo lead in, subjects will be randomized into either a placebo group, or active
drug group. Both groups will be titrated to effect during a two week period. Subsequently,
subjects will then participate in a total of 12 visits, some telephone, some in person.
Throughout the duration of the study, participants will be asked to fulfill daily e-diary
requirements which will include NRS, Patient Global Impression of Function, Patient Global
Impression of Sleep, and some subjective functional testing. Subjects will also wear an
actigraph device which will provide data about sleep and daily movements. Urine drug
screening and pill counts will be completed at all in person visits.
Side effects: Subjects who report intolerable side effects will be released from the study.
Intolerable side effects would be defined as:
• Allergy to the study drug with rash, anaphylaxis, pruritis, respiratory depression, or any
other symptom that is deemed by the subject as "intolerable".
Common side effects associated with Buprenorphine Buccal Film include, but are not limited
to:
Nausea
Vomiting
Feeling sleepy (sedation)
Feeling drunk
Constipation
Dry mouth
Muscle weakness
Headache
Skin Rash
Dizziness
Blurred vision
Feeling hot
Flu-like illness
Bladder spasm
Low blood pressure
Respiratory depression (slowed
breathing)
Pupil narrowing
Sweating
Itching
Hives
Bronchospasm (difficulty
breathing)
Anaphylactic Shock (severe
allergic reaction)
Elevated cerebrospinal fluid
pressure (which could lead to
decreased blood flow to the
brain)
Safety Information/data:
Screen: Subjects will be excluded if hypersensitivity to buprenorphine or Belbuca®, subjects
with severe or untreated psychiatric disturbance (e.g. mania, depression [esp suicidality],
anxiety, substance dependent), subjects with a clinical diagnosis of spinal stenosis,
fibromyalgia or polymyalgia rheumatic, subjects with severe ongoing or unaddressed medical
conditions (e.g. Renal or Hepatic disease [creatinine>1.5 ml/dl; AST or ALT> 3x normal
limit], Severe or uncontrolled hypertension, pulmonary disease, seizure disorder,
gastroparesis or urinary retention.
Each visit: vital signs, medical events, side effects and device and drug compliance will be
reviewed; concerns and problems will be solicited.
Phone contacts: side effects and device and drug compliance will be reviewed; concerns and
problems will be solicited by open ended questions.
Minor, non-significant side effects or adverse events that occur during the study will be
recorded in the subject's chart and on an adverse event reporting form. Any serious adverse
events or side effects that occur will be recorded in the subject's chart and on the adverse
events reporting form and will be reported immediately to the WCG IRB, the Food and Drug
Administration, and BDSI officials. An adverse event will be considered serious if it is
fatal or immediately life threatening or requires or prolongs inpatient hospitalization,
necessitates long-term outpatient treatment, causes permanent disability, is a congenital
anomaly, cancer, or overdose. Questions of 'tolerance' will be considered and decided at the
discretion of the PI in the context of these reports in consultation with the subject, and if
necessary, with BDSI officials. Serious and unexpected adverse events will be reported to the
IRB within 24 hours of discovery.
Data will be continually monitored by the study coordinator and consultant and regularly
reported to the principal investigator who will review the data and all adverse events after
each subject is studied.