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When Opioids Fail in Chronic Pain Management:
The Role for Buprenorphine and Hospitalization
Article in American journal of therapeutics · April 2013
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2. When Opioids Fail in Chronic Pain Management: The Role
for Buprenorphine and Hospitalization
Daniel W. Berland, MD, ABAM,1Ã
Herbert L. Malinoff, MD, FACP, FASAM,2
Mark A. Weiner, MD, ABAM,3
and Robert Przybylski, BS1
Clinicians are increasingly being challenged by patients who are treated for chronic pain with high-
dose opioids that can cause medical, social, and societal harm. These patients may best be improved
by psychological approaches, adjuvant medications, and opioid reduction or removal, rather than
ever-escalating dosing that has become common. Opioid reduction or removal can be a difficult
process that, when done incorrectly, may cause patient dissatisfaction or severe discomfort. Bupre-
norphine, a partial opioid agonist, is slowly becoming recognized as an effective pain treatment,
possessing a wide safety margin while offering the opportunity for stabilization of opioid dosing or
even removal. We have developed a protocol for hospitalization of the most fragile or toxic patients
detailed herein that can permit a comfortable conversion to buprenorphine from prior high-dose full
agonist opioid therapy. Seventy-six consecutive patients with serious medical, psychological, or
addiction comorbidities, treated with morphine equivalent doses exceeding hundreds of milligrams
per day, were followed after conversion for up to 25 months. Two-thirds reported moderate to
dramatic improvements of pain and functional status with an increase seen in employment. Median
length of hospital stay was 2 days, and the median daily buprenorphine discharge dose was 8 mg.
No adverse reactions or outcomes were observed. A brief hospitalization for conversion from high-
dose opioid therapy to a safer, more effective buprenorphine regimen can produce life-altering
improvement.
Keywords: chronic pain, management, opioids, toxicity, buprenorphine, hospitalization, outcomes
INTRODUCTION
Chronic nonterminal pain (CNTP) is a major cause of
loss of physical, psychological, and social function and
is now thought to affect approximately one-third of the
US population.1
Pain advocacy and policy initiatives,
such as the Joint Commission requirement for adequate
pain assessment and treatment, along with increasing
pressure on clinicians to have high patient satisfaction
scores, have resulted in a vast increase in the use of
opioids for CNTP.2
This has not been accompanied by
strong supporting evidence of improved functional
capacity or a dramatic reduction in disability in most
patients receiving opioids,3,4
while increasing costs.5
Opioid users may, in fact, have a lower quality of
life, with higher rates of depression and health care
utilization.6
Clinicians are now faced with CNTP patients who
are treated with large doses of opioids (greater than
the equivalent of morphine 100 mg/d) who suffer
unacceptable toxicity, worsening pain, and worsening
functional capacity, perhaps with the demonstration of
aberrant behaviors, with increased risk for overdose
and death.7,8
The dilemma of providing ever-increasing
opioid dosages versus “weaning” and discontinuing
opioids is problematic. Opioid “weaning” is often
poorly tolerated by patients who may experience opioid
Departments of 1
Medicine and; 2
Anesthesiology, University of
Michigan, Ann Arbor, MI; and 3
St. Joseph Mercy Hospital, Ann
Arbor, MI.
The authors have no conflicts of interest to declare.
Ã
Address for correspondence: 3119 Taubman Center, #0376,
1500 E. Medical Center Drive, Ann Arbor, MI 48109. E-mail:
danielbe@umich.edu
American Journal of Therapeutics 20, 316–321 (2013)
1075–2765 Ó 2013 Lippincott Williams & Wilkins www.americantherapeutics.com

3. withdrawal symptoms in addition to worsening per-
ceived pain.
Buprenorphine treatment is slowly gaining recogni-
tion in the United States as an effective opioid pain
treatment alternative or a route to opioid removal.
As a partial opioid agonist, it offers significant advan-
tages with a wide safety margin in the treatment of
chronic pain, although at this point, there has been
only limited literature.9–11
Malinoff et al10
have previ-
ously shown that CNTP patients can be successfully
treated in an outpatient setting with sublingual (SL)
buprenorphine or buprenorphine/naloxone. Since that
report, we began treating CNTP patients with profound
medical, psychological, and addictive comorbidities
treated with high-dose opioids with buprenorphine.
Although many patients may be initiated on buprenor-
phine in the office setting, some patients require a brief
hospitalization for monitoring and nursing care to ini-
tiate buprenorphine therapy due to the very high doses
of opioids they have been prescribed, the need for par-
enteral short-acting opioid “bridging” before buprenor-
phine induction, so as to minimize the duration of the
required opioid withdrawal symptoms, and because of
the more fragile psychological state of these patients.
We now report our results in treating 76 consecutive
CNTP patients with very high doses of full mu-1 agonist
therapy (median, 400 mg/d morphine equivalents),
often on polypharmacy regimens including high-dose
sedative therapy. We describe the protocol for inpatient
buprenorphine induction and ancillary care and report
on up to 25 months of follow-up. In patients with CNTP
receiving high doses of opioids, buprenorphine induc-
tion during a brief hospitalization is safe, effective,
can ultimately lead to opioid removal, and results in
superior functional outcomes in the majority of patients
treated.
METHODS
Patient selection
This was a two-center, institutional review board–
approved, retrospective study of a consecutive series
of chronic pain patients admitted during the years
2009–2010. These patients were evaluated by 1 of 3
Internal Medicine/Addiction Medicine physicians
during inpatient consultations at a university pain cen-
ter or in a private pain practice. Ambulatory patients
were electively admitted to either a university hospital
or a large affiliated community hospital. All patients
had experienced worsening pain and function despite
escalating doses of short- and long-acting opioids.
Table 1 shows patient demographics and pretreatment
characteristics. Patients usually did not or were not
able to participate in normal life activities such as
employment, caring for children, having hobbies, or
engaging in outside social activities. Virtually all of
the patients had been treated for many years, even
more than 20 years, with more than minimal doses
of opioids. Patients were excluded if payment for
buprenorphine could not be obtained.
Patient evaluation
All patents underwent a comprehensive medical and
psychological evaluation before treatment that included
a history and physical examination, with particular
attention to co-occurring psychiatric and addictive dis-
orders. Psychiatric and addictive disorders were diag-
nosed by Diagnostic and Statistical Manual of Mental
Disorders (Fourth Edition) criteria. Before treatment,
patients underwent blood testing for renal and liver
function and urine drug testing utilizing both an
enzyme-linked screening immunoassay and gas
chromatography/mass spectroscopy and a check of
the state prescription management program was per-
formed. Selection for hospitalization versus outpatient
management was made on the basis of level of medica-
tion, toxicity, and severity of any medical or psychiatric
comorbidities. In general, patients on a total morphine
equivalent opioid dose of greater than 200 mg/d
required admission, independent of other factors.
Before hospitalization, all patients and their signifi-
cant others were educated as to the rationale, risks,
and benefits of the transition to partial agonist therapy.
Table 1. Baseline patient characteristics.
Gender (n 5 76) 44 F, 32 M
Age range (yrs) 19–82, median 48
Employed, n (%) 13 (17)
Frequent pain types, n (%)
Back 25 (33)
General, multiple, “fibromyalgia” 23 (30)
Abdomen 9 (12)
Other 19 (25)
Highest prior opioid treatments
Morphine, oral (mg/d) 900
Morphine IV (mg/h) 35
Oxycodone (mg/d) 720
Fentanyl patch (mg/h) 200
Methadone (mg/d) 200
Psychiatric comorbidity, n (%) 70 (92)
Benzodiazepine treated, n (%)Ã
30 (39)
Evidence for addiction, n (%) 18 (24)
F, female; M, male.
Ã
Not including benzodiazepine-like hypnotics.
Chronic Pain, Buprenorphine and Hospitalization 317
www.americantherapeutics.com American Journal of Therapeutics (2013) 20(4)

4. Patients gave informed consent (opioid treatment
agreement) for therapy with buprenorphine and had
instruction on the proper use of SL medication. All
prior treating physicians were contacted before hospi-
talization to assure medical stability, agreement, and
cooperation with the planned treatment.
Hospital induction protocol
Patients were instructed to continue their prior opioid
treatment until admission for conversion to avoid
inadvertent withdrawal. Alternatively, if patients were
treated with fentanyl patches or methadone, then those
agents were discontinued 5 days before admission
and replaced with up to 200 mg/d immediate-release
oral morphine or 40 mg/d oral hydromorphone (HM)
divided into every 4-hour dosing to maintain adequate
pain treatment while avoiding opioid withdrawal, thus
permitting the long-acting agents to clear so as to min-
imize length of hospital stay. Upon admission, mor-
phine or HM patient-controlled analgesia (PCA) was
initiated, and all other opioids were discontinued. The
average total hourly consumption of morphine by
PCA fell in the range of 3–8 mg/h (HM 0.6–1.6 mg/h).
Benzodiazepines or other sedatives were also with-
drawn or converted to phenobarbital before initiating
buprenorphine.12
After appropriate clearing of oral or transdermal
opioids, the PCA was discontinued for 6 or more hours
before beginning buprenorphine. The Clinical Opioid
Withdrawal Scale (COWS), often cited as a way to
determine that adequate opioid withdrawal has been
achieved to permit buprenorphine initiation without
provoked withdrawal, was not utilized as it is with
heroin-addicted patients as our patients failed to man-
ifest significant COWS scores. Readiness for buprenor-
phine induction was determined by time, presence of
objective withdrawal signs, or the appearance of pain
in a new location and occurred approximately 6 or
more hours after discontinuation of PCA. Either intra-
muscular (IM) or SL buprenorphine was then admin-
istered. When given IM, buprenorphine 0.3 mg was
given every 6 hours until regression of withdrawal
symptoms and pain occurred. After 1–4 doses of IM
buprenorphine, patients were transitioned to SL
buprenorphine at target doses derived from their pre-
hospitalization opioids, but generally in the range of
6–12 mg/d divided into 3–4 doses, much lower than
typical addiction treatment doses. Alternatively, bupre-
norphine was initiated as 1-mg SL doses every 30
minutes for 4 doses, observing for regression of
any withdrawal symptoms and pain over the next 1–
2 hours. Depending on symptoms, 3–4 subsequent
2-mg SL doses were given at 4-hour intervals before
beginning the target dose the next day. Depending on
their symptoms, patients were monitored for 3–12
hours after conversion before discharge from the hos-
pital, often the same day as when initiated. They were
discharged on an initial dose of SL buprenorphine
approximately as shown in Table 2 and instructed
against further use of any sedatives or other opioids.
The time to first follow-up appointment in the clinic
was 1–3 weeks.
Subsequent management
Patients were initially seen at least monthly after hos-
pital conversion. The dosing of buprenorphine was
adjusted based on patient reports of opioid abstinence
symptoms and pain complaints. Functional improve-
ment was monitored by having patients describe their
achievement of activity goals identified before bupre-
norphine conversion. Periodic checks of the state pre-
scription monitoring program and urine drug testing
were performed to assure compliance and safety.
Patients’ medication was later tapered, if tolerated.
Data abstraction
All data were abstracted from patients’ medical records
by the authors into a spreadsheet tool with entries for
age; gender; medical, psychiatric, and addiction comor-
bid diagnoses; preconversion opioid total doses in
morphine equivalents; other sedative drugs; hospital
length of stay; final therapies; duration of outpatient
Table 2. Suggested starting buprenorphine dose.Ã
Preconversion total oral opioid dose
(in morphine equivalent), mg/d Starting buprenorphine dose (SL)
,50 2–4 mg/d (given as a half film or tablet divided into twice a day to
4 times a day dosing)
50–100 4–6 mg/d (given as half to 1 film or tablet in 3 times a day or 4 times
a day dosing)
.100 8 mg/d (1 film or tablet 4 times a day)
Ã
These are not validated but are based on outcomes from hundreds of patients. Required doses may be higher when psychiatric
symptoms or addiction is a more prominent patient issue.
318 Berland et al
American Journal of Therapeutics (2013) 20(4) www.americantherapeutics.com

5. follow-up; level of function; pain control; evidence of
rehospitalization; and other complications. Health Insur-
ance Portability and Accountability Act compliance was
assured.
Statistical analysis
This is mainly a descriptive outcome study with pre–
post data regarding the treatments, symptoms, and
functional status of the patients studied. The data var-
iables are summarized as medians and ranges where
appropriate.
RESULTS
A total of 76 patients were electively admitted for con-
version to buprenorphine and were followed for up to
25 months. As shown in Table 1, these patients were
often quite psychologically fragile usually with gener-
alized anxiety, depression, borderline personality
disorder, or posttraumatic stress disorder. Medical
comorbidities were common and included patients
with severe coronary artery disease, uncontrolled dia-
betes, acquired immunodeficiency syndrome, cancer,
bone marrow transplantation, sickle cell disease, seiz-
ures, strokes, chronic obstructive pulmonary disease,
morbid obesity, and sleep apnea. Patients had up to
10 hospital admissions in the preceding year, and
1 patient was continuously hospitalized during the
2 months before initial consultation.
The duration of PCA treatment depended on the
predicted time for clearance of previously used long-
acting opioid and whether bridging was used before
admission and ranged from several hours to 5 days.
Total PCA doses fell into the range of 3–8 mg/h for
morphine or 0.6–1.6 mg/h HM. During the required
opioid-free interval after stopping PCA and before ini-
tiation of buprenorphine, patients typically had mini-
mal symptoms consisting of mild worsening of their
pain complaints, anxiety, diaphoresis, or mild abdom-
inal symptoms. Had the COWS been utilized, scores
would have been 0–1.
Outcomes are summarized in Tables 3 and 4. The
conversion protocol was well tolerated with no epi-
sodes of provoked opioid withdrawal, severe symp-
toms, or death. During the period of follow-up, more
than half of the patients remained on buprenorphine,
whereas 15% ultimately became opioid free or were
satisfactorily treated with tramadol. Approximately
20% returned to full agonist opioids, either by return-
ing to their prior treating physician or moving on to
another prescriber. Of this very difficult cohort of
patients, two-thirds reported pain control to be bet-
ter, whereas one-third reported being much better or
pain free at the end of the follow-up period.
More significantly, nearly two-thirds were function-
ally improved with 25% employed and new employ-
ment in 5 patients.
DISCUSSION
Patients with chronic pain syndromes are often best
improved not by attempting to locate and intervene
with a specific pain generator, or by ever-increasing
doses of opioid medicines, but by psychosocial inter-
ventions, adjuvant pain medications such as antide-
pressants or anticonvulsants, physical measures, and
a reduction or removal from opioid therapy, often
quite different from current practice.13
These patients
frequently have a history of childhood abuse, Cluster B
traits (borderline, dependent, or narcissistic personal-
ity disorders), lower income, low functional state,
Table 3. Treatment outcomes.
Hospital length of stay (median), d 1–6 (2)
Duration of follow-up (median), mo 0–25 (9)
Daily SL buprenorphine dose at
discharge (mg)
2–20 (median 8)
Final opioid treatment at
follow-up, n (%)
Buprenorphine 41 (54)
Returned to full agonist opioid 16 (21)
Tramadol 4 (5)
No further opioid 8 (10)
Lost to follow-up 7 (9)
Reported pain
“Much better, good, pain free” 26 (34)
“Fair, better, tolerable” 25 (33)
“No improvement, not great, worse” 25 (33)
Functional state
“Much better” 38 (50)
“Somewhat better” 8 (10)
“No change, worse or no report” 25 (33)
Newly employed 5 (7)
Table 4. Adverse outcomes.
Provoked opioid withdrawal at initiation 0
Significant toxicity other than mild opioid
withdrawal symptoms
0
Deaths from conversion 0
Readmissions related to pain treatment 0
Unrelated deaths at end of follow-up
period, n (%)
2 (3)
Chronic Pain, Buprenorphine and Hospitalization 319
www.americantherapeutics.com American Journal of Therapeutics (2013) 20(4)

6. excessive use of multiple medications, and frequently
utilize medical services.14–18
Evidence supports the
existence of multiple central nervous system mecha-
nisms that produce amplification of pain signals.19
Opioid treatment can exacerbate this process,20–22
while increasing cost and patient risk.
Reduction or removal from opioid therapy alone
can produce improvements in pain.23,24
It can be a dif-
ficult and intensive process that requires considerable
patient–clinician trust and, if done incorrectly, may
cause the patient severe discomfort. In the past,
a gradual taper of medication was the only option,
often resulting in prolonged discomfort or abandon-
ment of the attempted plan by the patient. With the
introduction of buprenorphine, a mu-1 partial opioid
agonist, it has become possible to offer a replacement
pain treatment with an agent that is potent, may be
antihyperalgesic,25
permits improved mu-1 opioid
receptor function, a marked improvement in physical
and cognitive function, and from which comfortable
removal is possible. Malinoff et al10
reported that 86%
of 95 patients they studied had substantial improve-
ments in pain control, functional capacity, and mood,
often within days of conversion to SL buprenorphine
from pure mu-1 opioid agonist therapy.
Buprenorphine is prescribed as a pain medication
at considerably lower doses (1–12 mg/d, typically
4–8 mg) than doses that are used for the treatment of
opioid addiction (8–16 mg/d) and, for pain, is divided
into 2–4 doses per day rather than given as a single
daily dose. During up to 25 months of follow-up,
acquired tolerance did not seem to occur, likely a fea-
ture of its partial agonist activity. Monitoring its pres-
ence in the urine merely requires a qualitative dipstick
test, and buprenorphine does not interfere with testing
for other opioids that may be abused, meaning the
commonly ordered opioid enzyme-linked immunoas-
say urine screening test remains negative.
Because of its high mu-1 opioid receptor affinity
and as a partial agonist, buprenorphine requires that
patients be removed from other opioids before initia-
tion to avoid provoking acute opioid withdrawal
symptoms. Although most patients may be initiated
on buprenorphine in the office setting, because of
medical or psychiatric frailty or the extreme doses
with which they have previously been treated, some
require hospital admission for bridging therapy,
monitoring, and encouragement so that the duration
of the uncomfortable opioid withdrawal phase may
be minimized and comfort may be maximized.
Patients treated with high-dose opioids, especially
long-acting agents such as extended-release morphine,
oxymorphone, methadone, and transdermal fentanyl,
can require 2–7 days off of their prior treatment before
buprenorphine may be begun. It is usually intolerable
for patients suffering from pain, physical opioid depen-
dence, and psychiatric distress to suffer additional
symptoms of opioid withdrawal, often with severe agi-
tation, nausea, vomiting, diarrhea, and sleeplessness for
many days. Hospitalization for conversion using bridg-
ing therapy with PCA makes this process quite tolerable
and often avoids most symptoms that would otherwise
prevent making this conversion possible.
SUMMARY
We have demonstrated that improvement of intractable
pain and opioid toxicity can be facilitated by removal
from high-dose full agonist opioid therapies and conver-
sion to buprenorphine. The detailed protocol described
herein is safe, can produce dramatic improvements in
subjective symptoms and demonstrable functional out-
comes, and can permit a return to a more normal life for
persons who have often been nonfunctional for more
than a decade. For the most dramatically physically or
psychologically disturbed individuals, a brief hospitali-
zation for conversion from high-dose full opioid agonist
therapy is well tolerated and can be the best opportunity
for clinicians to offer markedly brighter futures for their
patients.
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