Transcript Buprenorphine Treatment Literature - Slaying the Hydra

Buprenorphine Literature Review:
Slaying the Hydra
Quintin T. Chipley, M.A., M.D., Ph.D.
Prepared for
CAPTASA 2017, January 27-28, 2017
Embassy Suites Hotel, Lexington, Kentucky
DISCLOSURES
Quintin Chipley has no financial interest in any mode of treatment as discussed
in this presentation. He is employed at the University of Louisville as a counselor
to students at the Health Science Center. The U of L is gracious to allow Chipley
latitude to pursue professionally-relevant endeavors outside of his work duties,
but the university should not be considered responsible for the opinions and
conclusions offered in this presentation.
Slaying the Hydra Requires both Blade and a
Blaze, and the Beast Has One Immortal Head.
The Myth
This metaphor comes from Greek mythology. Hercules faced the task of
slaying the Hydra, a labor made difficult by the fact that two heads
would grow immediately from the neck where any head was severed.
This multiplication of the danger could only be stopped if the neck stump were immediately cauterized by fire. As the pottery painting
illustrates the myth, Hercules succeeded by cutting heads while his
nephew, Iolaus, cauterized the necks. The immortal head was then
removed and hidden under a rock for Hercules to use as a venom
source to coat his arrow heads.
https://en.wikipedia.org/wiki/Lernaean_Hydra#Second_Labor_of_Heracles
The Metaphor: Nine Heads of the Hydra which
is the Scientific Literature on Buprenorphine
• 1) The continued false reporting that there is a significant ceiling effect on
euphoria that limits abuse-potential.
• 2) The inappropriate generalization of strictly-controlled, in-patient experimental
outcomes to out-patient clinical situations where the behavior-choices of the
patients are under nothing but personal control.
• 3) The inappropriate generalization of single-opiate/ opioid addicted and/ or
abusing subject studies to poly-substance addicted/ abusing populations.
• 4) The fact that the early (and naïve) claim that buprenorphine would not lend
itself to abuse and diversion has not only been quietly dropped in the wake of
solid evidence of both abuse and diversion, but that the new evidence of abuse
and diversion is now claimed as a reason that buprenorphine should be more
readily available to out patients via physician-office prescribing.
Nine Heads of the Hydra (Continued)
• 5) The entirely unsubstantiated claim that studies show buprenorphine
users, even when only using it as prescribed and without any other drugs
or alcohol, are not at all impaired for driving automobiles.
• 6) The poorly studied and reported comparison of buprenorphine MAT to
Vivitrol (the one-month duration intramuscular injection of Naltrexone)
MAT in real clinical situations.
• 7) The shift from marketing (both to the public and within the academic
literature) 1) low-dose buprenorphine as an analgesic, to 2) high-dosestart, tapered-dose-end of buprenorphine for detoxification, to 3) highdose buprenorphine for lifetime opioid replacement, to 4) a very recent
(and totally untested) desperation option of starting all opioid/ opiate
abusing/ addicted patients on buprenorphine with the defense, that in
theory, such a patient is less likely to be able to overdose on illicit opiates/
opioids in the several days following induction.
Nine Heads of the Hydra (Continued)
• 8) The claim that buprenorphine MAT has been scientifically compared and
found favorable to psycho-social treatments, and that – in particular – it is
superior in outcome when compared to 12 Step Recovery.
• 9) The many possible definitions of “a successful outcome”: 1) abstinence
from all drugs-of-reward, including buprenorphine, with exceptions made
for nicotine and caffeine.) 2) abstinence from all drugs-of-reward, excluding
buprenorphine, with exceptions made for nicotine and caffeine 3)
abstinence from opiates/ opioids, including buprenorphine, but allowance
for use of other illicit and licit drugs-of-reward. 4) abstinence from opiates/
opioids, excluding buprenorphine, but allowing for use of other illicit and
licit drugs of reward. 5) Some reduction of illicit opioid/ opiate drug use
while using buprenorphine. 6) Some reduction in social and medical ills
(crime, HepC, HIV, overdose events)
Goals for this presentation
• It is possible for us to walk through the overview of the Hydra Heads and
my summary points on how each head can be cut and cauterized.
• It is impossible, however, to read every slide and walk through every step
that teaches the process in these 50 minutes.
• It is possible, however, for you to take this presentation home and to then
set aside the time to walk yourself through every slide to experience the
level of detail of evidence and argument that is required to become
competent to resist being bitten by the beast. This material needs to
become a book (I am working on it, so please respect my originality with
the material) and it is easily enough for a 3 hour credit, semester length
course in a Ph.D. program. I aim to place this tool-kit at your feet and I
hope you will pick it up and learn to use it.
Method for this Presentation
• Present and evaluate very recent materials designed to educate the
treatment professionals.
• Start with the materials that come to us from two high-prestige
institutions: Harvard and the Substance Abuse and Mental Health Services
Administration (SAMHSA).
• Examine carefully the statements that are made and/ or the
bibliographies provided, by meticulously tracing claims back into the
source-studies that purport to undergird the claims.
• Focus on buprenorphine application in populations that use heroin
because the recent increase in heroin use has caught the public’s
attention.
Springboard Sources Selected for this Presentation
1)
2014 Buprenorphine Summit. September 22–23, 2014. Report of Proceedings 2014.
U.S. Department of Health and Human Services. Substance Abuse and Mental Health
Services Administration (SAMHSA). Center for Substance Abuse. Treatment Division of
Pharmacologic Therapies.
https://www.samhsa.gov/sites/default/files/proceedings_of_2014_buprenorphine_su
mmit_030915_508.pdf
[NOTE: There are over 400 peer-reviewed articles, all published between 2007 and 2014,
listed in this source. Should any one person take on the task of obtaining, reading, and
digesting each article and the cited sources that support it, it is hard to imagine the entire
task to be completed in less than two years of full time, 40-hours-per-week, work.]
2) Other materials to which that the SAMHSA website directs readers.
3) Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder: Review
of the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2. 2015. 63-75.
The Buprenorphine literature reports that the
drug causes euphoria.
1) Buprenorphine causes euphoria in opiate-naïve patients. This was
published in 1978. The euphoria in this condition is as strong as with
morphine.
2) Buprenorphine increases euphoria when mixed with other opiates.
This was known from studies published in 1994 and 1995.
3) Our recent research which will be presented has addicts reporting
that they increase the buprenorphine high by also taking drugs from
classes other than opiates (e.g benzodiazepines, stimulants)
4) The “Ceiling Effect” on Buprenorphine euphoria does not occur until
32 mg doses. These doses that are well above the standard-of-practice
induction doses. The euphoria achieved below that “ceiling” is
sufficient to drive the drug into recreational abuse and street-market
diversion.
The Buprenorphine Literature confuses studies of
two major designs: Inpatient and Outpatient.
1) The literature recognized as early as 2002 that the strict controls of
an inpatient design would give outcomes that are not easily
comparable to outpatient designs.
2) The literature, however, shows a consistent habit of citing studies
with inpatient designs that are used to support the hypothesis that
buprenorphine is applicable in building outpatient-design studies.
3) This gradual creep in citation-habit leads to claims that
buprenorphine is effective in outpatient clinical applications.
The buprenorphine Literature mixes studies of
subjects with a) prescription-opiate-only abuse, b)
heroin-only opiate abuse, and c) polysubstance
abuse that includes opiates.
1`) There is questionable validity in applying results from one “monosubstance abusing” population to a different “mono-substance
abusing” population, even if the two different substances are within
the same general category of “opiate-opioids.”
2) There is no validity in applying results from “mono-substance”
abusing populations to “polysubstance” abusing populations. This fact
is even more evident when the range of abused substances crosses
categories of opiates/ opioids, sedatives (including alcohol) and
stimulants.
The strongly cited buprenorphine studies tend to
lose 50% of recruited abusing-subjects from the
time of study-start to the time of measured
outcomes.
This fact places the “evidenced-based, controlled science” in the same
quandary with anecdotally-based, clinical observations made about
patients who enter but “wash out” of non-medication assisted
treatment. In different ways, we all end up losing our losers and
measuring our winners.
From the scientific analysis perspective that depends upon statistics as derived by the mathematician Bayes, this
phenomenon of “filtering” changes what are called “prior probabilities,” which will, in turn, change the “post-probabilities”
that are reflected in the outcomes.
A Tangled Thread: Buprenorphine Literature
on the Drug’s Abuse Potential
In 1978, despite the evidence of the “morphine like effects” of initial
buprenorphine exposure, researchers came to the unusual conclusion that
the drug would have low abuse potential as a medication assisted treatment
for opioid/ opiate addicts.
By the 2006, evidence from France clearly demonstrated that 25% of all
buprenorphine was diverted to the black market and that 70% of all users
admitted that they had used the drug to get high. This was happening in
Europe where the dissolvable “film” form of the drug was not sold.
Buprenorphine is now the preferred illegal “currency” in prisons.
Now no one denies these facts. BUT THE PROPONENTS CLAIM THAT MAKING
THE DRUG MORE EASILY AVAILABLE FROM OFFICE PRATICES “MAY” REDUCE
ABUSE AND DIVERSION. THEY HAVE NO STUDIES THAT SUPPORT SUCH A
SUPPOSITION.
DUI?
Legal experts have stretched and distorted old retrospective studies of
accident reports that concluded methadone maintenance patients
show no more impairment in driving than other drivers to make the
same claim for buprenorphine. SAMHSA refers readers to this
document.
First, the conclusion for methadone from such a study-design is
questionable.
Second, there are no similar studies on buprenorphine.
Third, experts in traffic-safety, after reviewing published literature on
driving and all MAT, conclude “There is a complete lack of
experimental studies on methadone and/or buprenorphine and their
effects on actual on-the-road driving,”
Buprenorphine vs. Extended Release Naltrexone
(Vivitrol)
The 2015 Harvard Review of Psychiatry article reports that addicts in
Vivitrol MAT may use a large quantity of recreational opioid in an
attempt to over-ride the “blockade” on euphoria, resulting in overdose
respiratory depression. This is true. The same problem, however, was
identified for buprenorphine in 1999. The 2015 Harvard Review of
Psychiatry article that noted the problem for Vivitrol did not, however,
did not mention the same problem with buprenorphine.
A 2016 study of thousands of addicts in a naturalistic (real-world) outpatient found that Vivitrol MAT patients did better than buprenorphine
MAT patients. [No slight is intended toward the HRP 2015 article in this
regard. This information was not available at that time.]
The History of Buprenorphine: A Drug Looking
for a Patient
1) Buprenorphine was made in 1968 to be a injectable acute pain-reliever. It never
found success as such. In the early 1980’s, the sublingual version was marketed as a
pain reliever. It never found success.
2) Addiction treatment researchers in the 1970’s and 1980’s became convinced that
buprenorphine could be a safer alternative to methadone for MAT.
3) The drug began being tested also as a “step down” substitution for detoxification
form opiates/ opioids. FOR A VERY SELECT POPULATION OF PATIENTS,
BUPRENORPHINE WORKS AS A DETOXIFICATION AGENT.
4) Physicians and agencies in France during the late- 1980’s, early 1990’s HIV/ AIDS
crisis used the drug “off label” as an oral, addicting opioid for “harms reduction”
from infectious diseases transmitted by shared needles among injection opioid
addicts. PUBLISHED STUDIES DO SUPPORT HARMS REDUCTION OF THIS SORT.
The History of Buprenorphine: A Drug Looking
for a Patient (cont.)
5) Starting in 2009, disappointment with patients (88%) who had relapsed on illicit opiates/ opioids
within 3 months of detoxification from buprenorphine led to the conclusion that patients should
stay on buprenorphine for lifetime, just as hypertensives and diabetics stay on medications for a
lifetime. THERE ARE NO PUBLISHED STUDIES THAT SHOW WHAT EFFICACY BUPRENORPHINE WILL
HAVE OVER DECADES OF USE.
6) Starting in 2013, some treatment-center researchers felt that a middle-approach of using
buprenorphine along with drug-testing and 12 Step recovery, with the goal of detoxification from
buprenorphine within 18 months, could be an appropriate use. THERE ARE NO PUBLISHED STUDIES
AS TO THE RESULTS.
7) In 2016, some clinicians in treatment centers began giving buprenorphine to all opioid/ opiate
abusing/ addicted patients within a day of admission, offering the defense, that in theory, such a
patient is less likely to be able to overdose on illicit opiates/ opioids in the several days following
induction. This is particularly troublesome point when the street drugs are now mixed with fentanyl
and carfentanyl. THERE ARE NO STUDIES THAT DEMONSTRATE THE VALIDITY OF BLOCKADE
PROTECTION UNDER THESE CIRCUMSTANCES.
Buprenorphine: Better Than What?
1) Practice guidelines for buprenorphine prescribers ask them to encourage
patients to drug addiction counseling and to recovery options such as 12
Step programs. RECENT DATA (to be presented later this morning) SHOWS
THAT 60% OF PATIENTS, AT MOST, REPORT HAVING BEEN GIVEN THESE
INSTRUCTIONS.
2) There are no head-to-head studies of buprenorphine MAT vs. 12 Step
participation.
3) For opiate/ opioid addicts in the general population, there are no good
studies of what 12 Step, abstinence-only, participation can achieve.
4) A 2008 study reporting on Physician Health Programs does, however,
demonstrate 80% abstinence for physicians who are in non-MAT, random
urine-monitored programs which require either 12 Step participation or an
alternative such as SMART Recovery.
Buprenorphine: Comparing the Apples and
Oranges of Outcomes
The many possible definitions of “a successful outcome”:
1) abstinence from all drugs-of-reward, including buprenorphine, with exceptions
made for nicotine and caffeine.)
2) abstinence from all drugs-of-reward, excluding buprenorphine, with exceptions
made for nicotine and caffeine
3) abstinence from opiates/ opioids, including buprenorphine, but allowing for use
of other illicit and licit drugs-of-reward.
4) abstinence from opiates/ opioids, excluding buprenorphine, but allowing for use
of other illicit and licit drugs of reward.
5) merely some reduction of illicit opioid/ opiate drug use while using
buprenorphine.
6) some reduction in social and medical ills (e.g. - crime, HepC, HIV, overdose
events)
Summary of Conclusions
1) The literature on buprenorphine MAT in the scientific press is enormously
large, but the quality of the studies on buprenorphine MAT ranges widely
from poor to good. I do not find any to be excellent. There are some strong
problems with citing sources that do not actually support claims, especially
when the move is made from primary-research to clinical applications, when
the primary research is invoked in public-policy arenas, and when the
popular-press presents opinions to the layperson.
2) The ability to generalize across studies of buprenorphine MAT is made
impossible because of the different outcome measures used. Clinicians must
review the studies themselves to determine if studies have been used
appropriately to direct clinical use.
3) There is a complete absence of studies on abstinence-only 12 Step
recovery in the general opiate/ opioid addicted population. There is one
good study on long-term abstinence-only, non-MAT, urine-monitored,
monitored 12 Step commitment, intervention for opiate/ opioid addicted
physicians, and it works quite well.
Summary of Conclusions (continued)
5) The buprenorphine MAT literature definitively shows that detoxifying addicts
from all agonist opiates/ opioids followed by replacing the active addiction with
nothing a) has not worked, b) does not work, and c) will not work. The question at
hand is NOT whether to replace the substance? The question is with what do we
replace the substance? With another agonist such as buprenorphine? With an
antagonist such as extended-release Naltrexone? With monitored abstinence-only
programs that include fully-engaged 12 Step commitment? This question can only
be answered if there is agreement on what constitutes a successful outcome.
6) The literature does show that polysubstance abusers do not overcome the abuse
of substances other than opiate/ opioids with any MAT if they are only using MAT.
7) There is not yet any published, peer-reviewed study on the Comprehensive
Opioid Response with 12 Steps program outcomes.
8) The 12 Step Program of Narcotics Anonymous has a group-consciousness
statement that forbids NA members on agonist-maintenance therapies from
sharing in meetings, from chairing meetings, and from serving as trusted servants.
NA distinguishes MAT which is specifically directed to the addiction from use of
prescribed medications for problems other than addiction. Alcoholics Anonymous
has not addressed the issue of MAT for alcoholism or for other addictions.
Hydra Head #1
1) The continued false reporting that there is a significant ceiling effect
on euphoria that limits abuse-potential.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder:
Review of the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2.
2015. 63-75.
“Dose-dependent respiratory depression is an adverse effect mainly of methadone, a full mu-opioid
agonist, whereas the partial-agonist properties of buprenorphine prevent dose-dependent respiratory
depression greater than 50% reduction of baseline even at IV doses of 2 mcg/kg in opioid-naive healthy
volunteers.47 This ‘ceiling effect’ on respiratory depression has obvious benefits for tolerability as well as
for accidental or intentional overdose. Similarly, buprenorphine’s partial-agonist properties have a
protective ‘ceiling effect’ that does not induce euphoria in opioid-tolerant individuals, whereas
methadone-induced euphoria may be present in the early treatment of OUD but decreases with steadystate dosing stabilization.48” p. 66. [Highlights added]
47. Dahan A. Opioid-induced respiratory effects: new data on buprenorphine. Palliat Med 2006;20 suppl 1:s3–8.
48. Zweben JE, Payte JT. Methadone maintenance in the treatment of opioid dependence. A current perspective. West J Med
1990;152:588–99.
NOTE: 1) The Dahan 2006 article says absolutely nothing about euphoria. 2) The ZwebenPayte 1990 article says absolutely nothing about buprenorphine. The author has, therefore,
WITHOUT ANY VALID CITATION equated what should properly be called a “floor effect”
(not a “ceiling effect”) for respiration with a “ceiling effect” for euphoria. 3) The author does
not address the fact that buprenorphine certainly causes euphoria in opioid-naïve subjects.
Comer S, Collins E, Fischman MW. “Buprenorphine sublingual tablets: Effects on IV
heroin self-administration by humans.” Psychopharmacology 2001; 154:28–37.
“Buprenorphine produces some agonist effects, thus promoting patient
compliance. However, it also blocks the intense euphoric effects of full agonists
(Bickel et al. 1988b; Jasinski et al. 1978; Rosen et al. 1994; Schuh et al. 1999; Walsh
et al. 1995b).” p.28 [Emphasis added. Red font added.]
NOTE: 1) The words “some agonist effects” means some euphoria. The authors
interpret this promotion of euphoria as a desired effect for the drug. 2) This
summary claims that buprenorphine will “harsh the high”that drugs like heroin and
prescription opioids create. As will be seen in a careful reading of Schuh et al. 1999,
this action by buprenorphine can occur under some conditions, but under some
conditions buprenorphine can ENHANCE the “high” when used with other opioids.
Schuh KJ, Walsh SL, Stitzer ML (1999) “Onset, magnitude and duration of opioid blockade
produced by buprenorphine and naltrexone in humans.” Psychopharmacology 145:162–174
[This is the full citation of the study cited by Comer, Collins Fischman 2001 (see slide
above) as “Schuh et al. 1999.”]
“The present study compared buprenorphine to naltrexone for its ability to attenuate the
effects of an opioid challenge during induction onto daily treatment and after
discontinuation. Buprenorphine produced dose-related opioid agonist effects during
induction. With repeated dosing, tolerance developed to the behavioral, but not the
physiological, effects of buprenorphine. Naltrexone produced no direct effects.” p. 170
[Emphasis added. Red font added.]
NOTE: 1) Concerning changes in reported “euphoria,” Schuh et al. 1999 use the term
“tolerance” rather than “ceiling effect.” Their use is the more accurate term. Tolerance to
“getting high” is observed in all opiate/ opioid agonists.
Schuh KJ, Walsh SL, Stitzer ML (1999) “Onset, magnitude and duration of opioid blockade
produced by buprenorphine and naltrexone in humans.” Psychopharmacology 145:162–
174- CONT.
“Eight male subjects ages 35–49 years (mean age = 39) participated in the study. Years of
opioid abuse ranged from 3 to 26 (mean = 17). Subjects were recruited by word of mouth,
newspaper advertisements, and circulation of flyers. Criteria for acceptance included a
history of recent opioid abuse without physical dependence. Opioid use was confirmed by
opioid-positive urine samples obtained during pre-study screening. Lack of physical
dependence was determined by self-report, observation, and by provision of an opioid-free
urine in the absence of withdrawal symptoms at study intake. Subjects underwent routine
medical screening which included physical examination, electrocardiogram, hematology
and urinalysis testing, and were free of significant medical problems and of any major axis 1
disorders other than their substance abuse. They resided on a closed 14-bed residential
unit to ensure a constant, stable living environment during the study and to preclude nonprotocol drug use.” [Emphasis added. Red font added.]
NOTE: 1) These subjects are opiate/ opioid abusers and not addicts. 2) The in-patient
design of the experiment keeps the abusers from abusing other drugs (whether
opiate/opioid or other classes) and from self-manipulating the doses and frequency of
dosing of the drugs under investigation. Outpatient applications of the drug do not have
such strict controls.
Schuh KJ, Walsh SL, Stitzer ML (1999) “Onset, magnitude and duration of opioid blockade
produced by buprenorphine and naltrexone in humans.” Psychopharmacology 145:162–174
NOTE: The
graphs of
interest for
“euphoria-withinitiation-ofbuprenorphine”
are the two to
the left on the
the top row.
Schuh KJ, Walsh SL, Stitzer ML (1999) “Onset, magnitude and duration of opioid blockade
produced by buprenorphine and naltrexone in humans.” Psychopharmacology 145:162–174
NOTE: As will discussed in detail in
the next slide, the upper-left graph
at the 8 mg dose of buprenorphine
when challenged by Dilaudid
shows an very strong euphoria.
Schuh KJ, Walsh SL, Stitzer ML (1999) “Onset, magnitude and duration of opioid blockade
produced by buprenorphine and naltrexone in humans.” Psychopharmacology 145:162–174
“Magnitude of combined drug effects
When the hydromorphone challenge was given on days 1 and 3 of treatment with buprenorphine
8 mg, subjective ratings of “high” were actually greater in magnitude than those produced by
cumulative hydromorphone dosing during placebo treatment (Fig. 3). Although this difference
reached significance only for the intermediate dose of hydromorphone (2 mg) on days 1 and 3 of
dosing for this particular measure, several other subjective measures, including visual analog
scores for “drug effect,” “good effects” and “liking,” were significantly higher after 4 mg
hydromorphone given in combination with buprenorphine 8 mg compared to scores obtained for
the 4 mg hydromorphone alone (i.e., in the presence of placebo maintenance; Tukey’s test; P <
0.05) on least 2 of 3 treatment days. Respiration rate was also depressed to a somewhat greater
extent (approximately one breath per min) by the combination of buprenorphine and
hydromorphone than with hydromorphone alone; however, this difference was not statistically
significant.” p. 168 [Emphasis added. Red font added.]
NOTE: 1)This finding states that the USUAL OUTPATIENT DOSE of buprenorphine 8 mg.
sublingual, when combined with Dilaudid 6 mg. intramuscular, INCREASES euphoria in opiate/
opioid naïve or detoxified humans compared either to buprenorphine alone or to Dilaudid alone.
2) This finding would be neglected if we were to only read the Comer, Collins and
Fischman 2001 paper which cites this study. Refer to Schuh et al 1999 fig. 3 in the slide
above to see the profound increase in euphoric effect.
Schuh KJ, Walsh SL, Stitzer ML (1999) “Onset, magnitude and duration of opioid blockade
produced by buprenorphine and naltrexone in humans.” Psychopharmacology 145:162–174
– CONT.
NOTE: COMPARE the two slides with the graphs at your leisure. When
buprenorphine at 8 mg sublingual is given to person who is not
currently-tolerant to opiates/ opioids, that person reports getting AS
HIGH as when he (also when equally not currently-tolerant to
opiates/ opioids) receives a total of 6 mg intramuscular
hydromorphone (Dilaudid) (give 0mg – wait 45 minutes – give 2 mg –
wait 45 minutes – give 4 mg). This total dose of hydromorphone that
is 6 times the strength recommended for normal pain control.
Buprenorphine (sublingually: not intramuscularly nor intravenously
administered) clearly creates strong and immediate euphoria in opiate
naïve or opiate-detoxified people even when it is the only opioid
present.
Schuh KJ, Walsh SL, Stitzer ML (1999) “Onset, magnitude and duration of opioid blockade
produced by buprenorphine and naltrexone in humans.” Psychopharmacology 145:162–174
– CONT.
“The present findings suggest that the subjective response to buprenorphine may wane
within 5 days of induction onto maintenance therapy with an 8 mg sublingual dose and,
perhaps, sooner for lower doses. These data are consistent with other studies reporting the
development of tolerance to the subjective euphoric effects of methadone during chronic
treatment (e.g., Dole et al. 1966; Martin et al. 1973a). Finally, it is interesting to note that
there was no evidence of tolerance development during this short maintenance period on
buprenorphine to its miotic or respiratory depressant effects. These findings are consistent
with preclinical studies reporting limited development of tolerance to the respiratory
depressant effects of mu opioid agonists (e.g., Paronis and Woods, 1997) and to previous
clinical studies demonstrating limited development of tolerance to the physiological effects
of methadone during long-term treatment (Martin et al. 1973a; Gritz et al. 1975; McCaul et
al. 1982).” pp. 170-171
NOTE: The neurochemical actions and brain locations that produce
euphoria (a.k.a. - “subjective effects” or “how high you feel”) are NOT the
same as those that produce pain-reduction and are NOT the same as those
that produce slow-breathing or constricted pupils in the eyes.
Schuh KJ, Walsh SL, Stitzer ML (1999) “Onset, magnitude and duration of opioid blockade produced
by buprenorphine and naltrexone in humans.” Psychopharmacology 145:162–174 – CONT.
“It is important to note that under two treatment conditions in the present
study, respiratory rate was significantly depressed by hydromorphone in the
absence of subjective effects; this occurred during maintenance with
buprenorphine 2 mg and following discontinuation of treatment with 100 mg
naltrexone. This dissociation between subjective and physiological responses
could pose a serious clinical danger, as it could lead to overdose in opioid
abusers using high doses of illicit opioids in the absence of subjective
feedback.” p. 173 [Emphasis added. Red font added.]
NOTE: This study’s observation has HUGE implications for using either MAT
agent in an outpatient setting where there is no way to ensure that the
patient is sufficiently dosed. Patients who return to abusing opioids can
find themselves required to use increased quantities to obtain euphoria,
but the breathing center of their brains may become shut down. This
problem has long been noted for methadone which, in itself, induces
tolerance against “highs” long before it induces tolerance for respiratory
depression. This is one reason why strong controls were placed on
methadone clinics.
Bickel WK, Stitzer ML, Bigelow GE, Liebson IA, Jasinski DR, Johnson RE (1988)
“Buprenorphine: dose-related blockade of opioid challenge effects in opioid
dependent humans.” J Pharmacol Exp Ther 247:47–53
Subjects: Over a 9 month period 5 white male opioid users, with an average age of 32.5 years and
an average of 7.25 years of opioid use, were enrolled in a 90 day detoxification protocol. All
participants met routine clinical qualification criteria (for methadone treatment), which included a
history of opioid dependence, physical evidence of recent i.v. drug use (i.e., tracks) and current
opioid use as indicated by urinalysis (i.e., three consecutive opiate-positive urines). All subjects
received a standard medical evaluation before enrollment. Individuals with active psychiatric
disorders or liver or cardiovascular disease were excluded from the study. In order to obtain a
homogenous sample of opioid abusers, individuals were excluded from study participation if their
urinalysis indicated methadone use.” p. 48
“Opiate positive urine tests tended to decline as a function of buprenorphine dose from
approximately 30% positive during the 2-mg buprenorphine dose to approximately 10% positive
during the 16-mg maintenance condition. However this trend was not statistically significant.” p. 53
NOTE: 1) It is impossible to determine from the study text if subjects abused other classes of drugs.
2) This is an outpatient design which means no control over the intrusion of other drugs. 3) The
study does not indicate if the search for a dose-and-schedule that leads to abstinence from otheropioids is the goal, or if simple reduction in other-opioid use is the goal.
Bickel WK, Stitzer ML, Bigelow GE, Liebson IA, Jasinski DR, Johnson RE (1988)
“Buprenorphine: dose-related blockade of opioid challenge effects in opioid
dependent humans.” J Pharmacol Exp Ther 247:47–53
“Furthermore, an interesting dissociation between physiological and self-reported
opioid effects, with self-reports, particularly at the lower challenge doses, being
more sensitive to blockade than was the physiological index of pupillary
constriction. The blocking effects demonstrated provide further support for the
prospective utility of buprenorphine as a pharmacotherapy in the treatment of
opioid dependence.” p. 53 [Emphasis added. Red font added.]
NOTE: 1) Early studies were already detecting a difference in euphoria and somatic
physiology. 2) The reasoning implied in the last sentence presupposes that the
person with addiction who is able in an outpatient life to manipulate prescribed
and non-prescribed drugs against medical advice will choose not to act against
medical advice. This hypothesis about outpatient addict behavior does not hold
up under naturalistic conditions.
Jasinski DR, Pevnick JS, Griffith JD (1978) “Human pharmacology and abuse
potential of the analgesic buprenorphine.” Arch Gen Psychiatry 35:501–516
“In single doses, buprenorphine produced typical morphine-like effects. Subjects
and observers identified it predominately as an opiate (Tables 2 and 3) and
reported morphine-like symptoms and signs (Tables 3 and 4). The drug constricted
pupils and produced significant scores on the opiate symptom and opiate sign
scales (Fig 2). Buprenorphine was a "euphoriant" as indicated by the significant
scores on scales that measure euphoria—"liking" and morphine-"Benzedrine"
group (MBG) scale scores. Scores on the LSD (a measure of dysphoria) and the
pentobarbital- chlorpromazine-alcohol group (PCAG, a measure of apathetic
sedation) scales were similar for buprenorphine and morphine (Fig 2).” p. 507
NOTES: 1) The Tables and Figures mentioned are in the published study and are not
reproduced in this presentation. 2) The scales (e.g. – LSD and PCAG) are standard
ways used for subjects to classify their subjective feelings after being exposed to a
drug. 3) This study shows that people who have a history of opiate/opioid abuse
and/ or addiction are readily able to classify accurately buprenorphine as an
opiate/opioid, and that buprenorphine IS, IN FACT, A EUPHORIANT.
Jasinski DR, Pevnick JS, Griffith JD (1978) “Human pharmacology and abuse
potential of the analgesic buprenorphine.” Arch Gen Psychiatry 35:501–516
“Our studies indicate that in man, buprenorphine produces morphine-like subjective, behavioral, and
physiologic effects and is capable of producing physical dependence.” p. 510
“Since buprenorphine is an analgesic with morphine-like mode of action in man, its role in therapeutics
will depend to a large extent on its liability to be abused. In this regard, the relative ability to produce
typical morphine-like (1) subjective effects including euphoria and (2) physical dependence is a valid
indicator of the relative abuse potential of morphine-like drugs. Both with acute and chronic
administration, buprenorphine produced morphine-like euphoria.” pp.511-512
“In conclusion, buprenorphine has a unique pharmacology with immediately obvious therapeutic
applications as an analgesic of low abuse potential and as a maintenance drug in narcotic addiction.” p.
516 [Emphasis added. Red font added.]
NOTE: 1) Buprenorphine was administered subcutaneously in this study. 2) The study began with five
male subjects (prisoners) who were detoxified opiate addicts. Two subjects dropped out of the study. 3)
There is no simple way to explain the authors’ final conclusion given on p. 516 after having read the
authors’ findings summarized on p. 510 and the intermediate conclusions on pp. 511-512. It would seem
more rational to conclude that buprenorphine has high abuse potential. 4) This study did not track the
drug-using behavior of the prison inmate subjects beyond 60 days and did not expose the subjects to the
real-world experience of having the freedom of choices that out-patient, non-incarcerated patients
would have. It would seem premature to conclude that it is effective as a maintenance drug.
Walsh SL, Preston KL, Bigelow GE, Stitzer ML (1995) “Acute administration of
buprenorphine in humans: partial agonist and blockade effects.” J Pharmacol Exp
Ther 274:361–372
“Participants were 17 healthy adult male volunteers who were opioid-experienced but not physically
dependent on opioids at the time of the study. Volunteers were recruited through local newspaper
advertisements and were paid for their participation. Before study entry, subjects received complete
physical examinations including ECG and blood and urine chemistries. All Subjects reported regular abuse
of illicit drugs other than heroin, with i.v. cocaine being the most frequently reported secondary drug of
abuse. Study enrollment was continuous, and a maximum of three subjects could participate
simultaneously. Eight subjects failed to complete the protocol; two subjects requested discharge because
they did not like the effects of the study drugs and six subjects were discharged for reasons unrelated to
the study. Data are presented from the nine subjects who completed the study….” Subjects resided on a
closed 14-bed residential research facility throughout the study.” p. 362 [Emphasis added. Red font
added.]
NOTE: 1) These are polysubstance users, which characteristic could be very helpful in generalizing results
to the real world of out patient clinical applications. 2) The study design, however, is inpatient with strict
control of the subjects access to any drugs other than the study drugs. This fact limits the ability to
generalize results to outpatient clinical populations. 3) Nearly half of subjects recruited failed to be
retained. That is to say, only about 50% of the initially “interested” drug users proved to be a good
match for the requirements of this protocol. Consider carefully the analogous problem of initiallyinterested drug users who present for drug treatment, drug-recovery communities or 12 Step programs
but who either self-select to leave or who fail to meet requirements for being continued. Outcome
results in all instances are affected by some prior selection effect. This phenomenon alters priorprobabilities of post-treatment outcomes.
Walsh SL, Preston KL, Bigelow GE, Stitzer ML (1995) “Acute administration of
buprenorphine in humans: partial agonist and blockade effects.” J Pharmacol Exp
Ther 274:361–372
“We reported recently findings from a dose-ranging safety study in human volunteers with opioid
abuse histories at does up to 70 times greater than the recommended therapeutic dose for
analgesia (Walsh et al. 1994). No serious adverse effects were noted in that study, but high doses of
buprenorphine (32 mg sublingual) produced subjective reports of euphoria and pupillary
constriction that persisted for up to 3 days after a single acute dose. The preliminary findings
suggested that there was a ceiling on the subjective and physiological effects of buprenorphine;
however, because the doses were administered in an ascending order for safety purposes, it was
impossible to assess the potential confound of order effects.” p. 362 [Emphasis added. Red font
added.]
[Walsh S.L., Preston, K.L., Stitzer, M.L., Cone E.J. and Bigelow, G.E.: Clinical pharmacology of buprenorphine:
Ceiling effects at high doses. Clin. Pharmacol. Ther. 55: 569-580, 1994.]
NOTE: The paragraph seems internally inconsistent: On the one hand, it reports high-dose (32 mg
sublingual) euphoria that persists for 3 days. On the other hand, it reports that the 1994 study
established the ceiling effect for subjective effects (i.e. – euphoria). Recourse to the cited 1994
article will be required and follows in the next slides.
Walsh S.L., Preston, K.L., Stitzer, M.L., Cone E.J. and Bigelow, G.E. 1994. “Clinical
pharmacology of buprenorphine: Ceiling effects at high doses.” Clin. Pharmacol.
Ther. 55: 569-580.
NOTE: 1) The “ceiling effect” for buprenorphine
euphoria is not observed until the single-bolus
sublingual dose is at 32 mg. 2) Keep in mind that
this dose is extremely high; much higher that the
dose that is recommended for buprenorphine
induction into MAT treatment (see
http://www.buppractice.com/node/12106 ) for
the partially-withdrawing addict. (Buprenorphine
induction is not to be started until withdrawal
signs are noted.) 3) A ceiling effect created by
ordered increase of dosing cannot be ruled out in
this study. A return to Walsh et al. 1995 is
required to consider what happens when dosesize is randomized rather than sequentially
increased.
Walsh SL, Preston KL, Bigelow GE, Stitzer ML (1995) “Acute administration of
buprenorphine in humans: partial agonist and blockade effects.” J Pharmacol Exp
Ther 274:361–372
NOTE: 1) These results, where drug doses are given
randomly, are fairly close to Walsh et al 1994 in
which drug doses were advanced in order; but
notice: the “euphoria” measurement does NOT
decline at 32 mg buprenorphine sublingual. 2) The
curves for buprenorphine certainly flatten at higher
doses when compared to the curves for methadone,
and it does appear that order of dose administration
is not strongly implicated in this ceiling effect. BUT
THE EXPERIMENTALLY DEMONSTRATED CEILING
EFFECT ON EUPHORIA AT HIGH DOSES OF
BUPRENORPHINE MAY HAVE NO CLINICAL EFFECT
IN DETERRING ABUSE AS WALSH ET AL. 1995 WILL
CONCLUDE (NEXT SLIDE):
Walsh SL, Preston KL, Bigelow GE, Stitzer ML (1995) “Acute administration of
buprenorphine in humans: partial agonist and blockade effects.” J Pharmacol Exp
Ther 274:361–372
“The limit on the euphoric effects of buprenorphine also could be beneficial
if this ceiling effect decreased the abuse liability and illicit diversion of
buprenorphine. However, higher doses of buprenorphine produced euphoric
and sedative effects that were equivalent in magnitude to those produced by
60 mg of methadone. This p.o. methadone dose is approximately equivalent
to 30 mg of parenteral morphine (Martin et al., 1973), which has often been
used as the prototypic high dose for comparison in abuse liability studies of
opioids (Jasinski, 1977; Bigelow, 1991). Moreover, illicit buprenorphine abuse
has been reported frequently in countries where, historically, access to the
drug has been less restricted than in the United States (Quigley et al., 1984;
Rainey, 1986; Robertson and Bucknall, 1986; O’Connor et al., 1988).
Therefore, although the euphoric effects of buprenorphine do not increase
dose-dependently, the ceiling on its euphoric effects may not decrease the
abuse liability or diversion potential of the drug.” p. 370 [Emphasis added.
Red font added.]
Rosen MI, Wallace EA, McMahon TJ, Pearsall HR, Woods SW, Price LH, Kosten
TR (1994) “Buprenorphine: duration of blockade of effects of intramuscular
hydromorphone.” Drug Alcohol Depend 35:141–149
“Six opioid dependent subjects gave written, informed consent and were paid to complete this
study. Mean age was 31.3 (range 20 – 40 years old). Five were male, five abused cocaine, two
abused benzodiazepines, and one abused alcohol prior to hospitalization. Subjects were
hospitalized on either of two restricted wards of the Connecticut Mental Health Center; the
Treatment Research Unit (TRU) or the Clinical Neuroscience Research Unit (CNRU). Subjects on the
TRU had urine toxicologies checked three times a week to monitor for illicit drug use, subjects on
the CNRU did not have any visitors for the duration of their hospitalization. .... Subjects were
assigned sequentially to each of three daily sublingual buprenorphine doses --- 2, 6, and 12 mg – for
at least five days until there were no clinically apparent signs of opiate withdrawal or intoxication
and until hydromorphone challenges could be scheduled. ” p. 142
NOTE: 1) This study does not intend to measure subjective (i.e. – euphoria) or physiological effects
upon induction of buprenorphine substitution. It intends to measure the effects of hydromorphone
(i.e. - Dilaudid) doses of 6 mg, 12 mg and 18 mg when given at 24, 48, and 72 hours after
buprenorphine cessation. That is to say, the study wants to determine the time-course of
buprenorphine blockade loss (i.e. – loss of protection when challenged by another opioid).
[continued on next slide]
Rosen MI, Wallace EA, McMahon TJ, Pearsall HR, Woods SW, Price LH, Kosten
TR (1994) “Buprenorphine: duration of blockade of effects of intramuscular
hydromorphone.” Drug Alcohol Depend 35:141–149
NOTE (Continued): 2) The subjects are polysubstance addicts/ abusers, which fact should increase the
generalizability of the findings to clinical populations. 3) The study strictly controlled, however, the
subjects’ access to any substances other than those specified in the study protocol, which limits the
generalizability to clinical outpatient applications where such control is absent.
“…the main effect of duration and the interactions involving duration had only two isolated significant
effects on dependent variables. The first was a significant duration effect on ‘good’ hydromorphone
effects, but the direction of the effect was opposite than predicted. Across buprenorphine x
hydromorphone combinations, the mean rating of ‘good’ at 24 h was 11.61, at 48 h it was 9.48 and at 72
h it was 9.39.” p. 144 [Emphasis added. Red font added.]
NOTE: This contrary finding shows that -- for some reason yet to be explained -- a higher retained plasma
level of buprenorphine amplified -- rather than reduced -- the subjective (i.e. – good feeling or euphoria)
effect created by adding Dilaudid (hydromorphone) into the plasma. This finding of an “amplified high”
is consonant, however, with the finding in Schuh et al. 1999 as discussed in a note in a previous slide. It
is also consistent with clinical reports from patients who admit they know how to manipulate dose levels
and dose sequencing of buprenorphine in combination both with other opioids or opiates and with other
classes of drugs to increase the experience of a “high.”
Hydra Head #2
• 2) The generalization of strictly-controlled, in-patient experimental studies to outpatient clinical situations where the behavior-choices of the patients are under
no control.
NOTE: Please review the analysis of the studies that deal with buprenorphine as a
euphoriant. The “NOTES” clarify whether the studies are in-patient or out-patient.
As an example of the recognition of the problem, see
Mark K. Greenwald , Kory J. Schuh, John A. Hopper , Charles R. Schuster, Chris-Ellyn
Johanson. “Effects of buprenorphine sublingual tablet maintenance on opioid drugseeking behavior by humans.” Psychopharmacology (2002) 160:344–352 DOI
10.1007/s00213-001-0975-0 :
“Third, the present study and our prior research (Greenwald et al. 1999a) were
conducted with outpatient volunteers, whereas others studied inpatient volunteers
(Mello and Mendelson 1980; Mello et al 1982; Comer et al. 2001). Utilizing
outpatient volunteers is a potential limitation because certain factors (e.g. heroin
use) are not controlled compared to studies with inpatient participants.” p. 350
Hydra Head #3
• 3) The inappropriate generalization of single-opiate/ opioid addicted
and/ or abusing subject studies to poly-substance addicted/ abusing
populations.
White J, Bell J, Saunders J, Williamson P, Makowska M, Farquharson
A, Beebe K, “Open-label dose-finding trial of buprenorphine implants
(Probuphine) for treatment of heroin dependence.” Drug Alcohol Depend
2009; 103:37–43.
“Eligible subjects were male or non-pregnant females; age 18–55 inclusive, who had received a clinical DSM-IV
diagnosis of opioid dependence and were on maintenance treatment with sublingual buprenorphine. To
qualify, subjects needed to have been receiving sublingual buprenorphine for at least 3 months, and have been
on a stable dosage for at least 1 month. Subjects were excluded if they met criteria for dependence on any
substance other than nicotine at the time of study entry. A past history of use or dependence with regard to
other addictive substances was allowable. Subjects were also excluded if they had any severe or uncontrolled
medical or psychiatric illnesses, showed abnormal renal, hepatic, biliary or coagulation function, or were
currently prescribed use of anticonvulsants, disulfiram, benzodiazepines, anticoagulant therapy, or
immunosuppressive medications (including systemic steroids).”p. 38
NOTES: 1) This only purpose of this study is to compare two different modalities of
buprenorphine administration. 2) With exception of allowing nicotine, the study
tries to test on heroin-only users.
Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN, Jones K, Collins J, Raisch D, Casadonte P,
Goldsmith RJ, Ling W, Malkerneker U, McNicholas L, Renner J, Stine S, Tusel D. “Office-based
treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone.”
N. Engl. J. Med. 2003; 349(10):949–958.
“Men and women who met the diagnostic criteria for opiate dependence according to the Diagnostic and
Statistical Manual of Mental Disorders, fourth edition (DSM-IV), who were seeking opiate-substitution
pharmacotherapy, who were between the ages of 18 and 59 years, and who were able to give informed
consent and comply with study procedures were eligible to participate. Participants were enrolled
between October 21, 1996, and September 30, 1997. Women who were pregnant or nursing were
excluded. Other criteria for exclusion included any medical condition that made study participation
medically hazardous; aspartate or alanine aminotransferase levels greater than three times the upper
limit of normal; a current, primary, Axis I psychiatric diagnosis (according to the DSM-IV) other than
opiate, caffeine or nicotine dependence; and use of methadone, levomethadyl acetate, or naltrexone
within the 14 days before enrollment. Subjects were compensated $10 per day to complete the study
assessments during the double-blind trial; they were not paid for taking any of the study treatments.”
pp. 21-22
NOTE: 1) The laboratory tests mentioned are used to detect ethanol abuse. 2) The
study only allowed subjects who are simultaneously addicted to opiates and either
(or both) nicotine and caffeine. 3) the study compares two MAT drugs: naloxone (a
complete opiate receptor antagonist) and buprenorphine (an opiate receptor
agonist that has some antagonistic action)
Greenwald M, Schuh K, Hopper J, Schuster C, Johanson C. “Effects of
buprenorphine sublingual tablet maintenance on opioid drug-seeking
behavior by humans.” Psychopharmacology 2002; 160:344–352.
“Eligible volunteers (males and females 18–50 years old) were heroin dependent based on self-reported daily
use, opioid-positive urine samples, and Structured Clinical Interview for DSM-IV (First et al. 1996). Participants
provided a medical history, blood and urine samples for laboratory and drug testing, and received a tuberculin
skin test, physical examination, and electrocardiogram. Those selected had no current axis I psychiatric
disorders except opioid and nicotine dependence, no chronic health problems, and were not taking prescribed
medications. They were not seeking treatment but were willing to be maintained on buprenorphine and
undergo short-term detoxification. Volunteers provided informed consent before the study. Participants were
paid $15 per session, a $15 per session completion bonus, and could receive up to $16 per session depending
on the number of money choices. Twenty-eight individuals enrolled, but 14 stopped attending or were
terminated for using non-opioid drugs (mostly cocaine)”p. 349
NOTE: 1) Recruited subjects are supposedly only heroin-only or heroin-withnicotine addicts. 2) One-half of them terminated, some (percent
unspecified) due to polysubstance use that would contaminate the study
design. Again, note that pre-test exclusion changes prior-probabilities of
post-treatment outcome.
Comer S, Collins E, Fischman MW. “Buprenorphine sublingual tablets: Effects on IV
heroin self-administration by humans.” Psychopharmacology 2001; 154:28–37.
“Fourteen heroin-dependent individuals (nine non-Hispanic Caucasian males, four Hispanic males, and one African American
female), who currently were not seeking treatment for their drug use, began the 6-week protocol. Eight male (six nonHispanic Caucasian, two Hispanic) healthy volunteers aged 30 to 38 years (mean: 33.6 years) completed the study. Volunteers
who completed the study reported using heroin for an average of 10.9 years (range: 5–19 years). All participants were
currently dependent on heroin, and reported spending an average of $55 per day (range: $25 to $90) on heroin. Seven
participants smoked tobacco cigarettes (10–20 cigarettes per day), six participants used cocaine (two times per week or less),
two participants used alcohol (three times per week or less), and two participants used marijuana (once per month). After an
initial telephone interview, eligible participants received additional screening at the laboratory, which included completing
detailed questionnaires on drug use, general health, and medical history, and a medical and psychological evaluation.
Participants were told that they might be maintained on an opioid for the duration of the study, and that different doses of
the maintenance medication might be tested. An electrocardiogram and Mantoux test or chest X-ray were also performed.
Routine laboratory analyses included a blood chemistry panel, thyroid function test, syphilis screening, and urinalysis. Urine
drug toxicologies (opioids, cocaine, benzodiazepines, cannabinoids, and amphetamines) were also performed using a
radiative energy attenuation and fluorescence polarization immunoassay system (ADx System; Abbott Laboratories, Abbott
Park, Ill., USA). Participants were excluded from the study if they were pregnant or nursing, seeking drug treatment,
dependent on illicit drugs other than opioids, or had a major axis I psychiatric diagnosis other than opioid dependence. Those
who had recent histories of violence or who were on parole/probation were excluded from the study. Participants were
required to be physically healthy, and fully able to perform all study procedures. They were dependent on opioids, as verified
by a naloxone challenge test (Wang 1974), and reported having had experience using heroin by the intravenous route.” p. 29
NOTE: 1) Subjects who use heroin and nicotine are included; other substances can be present but not at level
of addiction. 2) Parole/ probation status excludes from the study. 3) The study lost nearly 50% of subjects. 4)
This is an inpatient study that blocked the subjects from obtaining other preferred illicit drugs during the study.
Greenwald M, Johanson C, Schuster C. “Opioid reinforcement in heroin dependent
volunteers during outpatient buprenorphine maintenance.” Drug Alcohol Depend
1999; 56:191–203.
“All volunteers were interviewed and diagnosed as heroin dependent by an experienced clinician
using the Structured Clinical Interview for DSM-IV (SCID) (Modules A–H and Antisocial Personality
Disorder (ASPD); First et al., 1996) and Addiction Severity Index (ASI) (McLellan et al., 1985).
Volunteers were excluded if they reported a current history of an Axis 1 psychiatric disorder, other
drug-dependence disorders (excluding heroin and nicotine) or ASPD. During screening, volunteers
were required to provide a urine sample that tested positive for opioids but was negative for
methadone, cocaine, benzodiazepines, and barbiturates; a breathalyzer sample had to be negative
for alcohol.” p. 192
NOTE: 1) Subjects are addicted to heroin or heroin-and-nicotine. All other
substance addictions are excluded; and even the use of other substances (including
alcohol) as indicated by testing excludes subjects.
Ling W, Charuvastra C, Collins J, Batki S, Brown LS, Jr, Kintaudi P, Wesson DR, McNicholas L, Tusel DJ,
Malkerneker U, Renner JA, Jr, Santos E, Casadonte P, Fye C, Stine S, Wang RI, Segal D.
“Buprenorphine maintenance treatment of opiate dependence: A multicenter, randomized clinical
trial.” Addiction 1998; 93(4):475–486.
“Patients had to meet DSM-III criteria for opioid dependence and, in some instances, federal or state criteria
for methadone maintenance. Daily use of opioids during the previous 6 months was a requirement but
patients were excluded if in a methadone maintenance program during the previous days. They were also
excluded from the study if they had a diagnosis of alcohol dependence or a medical condition (such as active
tuberculosis, unstable cardiovascular or liver disease, unstable diabetes or AIDS) that would have made
participation in the study medically hazardous. Patients using neuroleptics, anticonvulsants or disulfiram were
also excluded.” ….
When 12 mg/day sublingual buprenorphine and 65 mg/day methadone were compared to 4 mg/day
buprenorphine and 20 mg/da methadone22 in 30 subjects dually addicted to opioids and cocaine, the high
doses of buprenorphine and methadone were found superior to both low doses. Buprenorphine was found to
deter illicit opioid, but not cocaine use.” [Highlights added]
NOTE: 1) Opioid addiction (not specifically heroin addiction) is required. 2) Among possible streetsubstance conditions, it appears that only co-morbid alcohol dependence excludes from the study.
3) Cocaine use is allowed. 4) No tested level of buprenorphine use deterred cocaine use.
Hydra Head #4
4) The fact that the early (and naïve) claim that buprenorphine would
not lend itself to abuse and diversion has not only been quietly
dropped in the wake of solid evidence of both abuse and diversion, but
that the robust evidence of abuse and diversion is now claimed as a
reason that buprenorphine should be more readily available to
outpatients via physician-office prescribing.
Jasinski DR, Pevnick JS, Griffith JD (1978) “Human pharmacology and abuse
potential of the analgesic buprenorphine.” Arch Gen Psychiatry 35:501–516
“In conclusion, buprenorphine has a unique pharmacology with
immediately obvious therapeutic applications as an analgesic of low
abuse potential and as a maintenance drug in narcotic addiction.” p.
516 [Emphasis added. Red font added.]
NOTE: This opinion was early and dominate. If, in fact, the intended
patient population were only patients requiring good analgesia for
acute pain (the original purpose of buprenorphine), this opinion may
have proven true. The leap into the next use, i.e. “maintenance drug in
narcotic addiction,” applies the drug at hugely amplified doses in the
context of a COMPLETELY DIFFERENT PATIENT POPULATION WITH A
VERY DIFFERENT BEHAVIORAL PROFILE.
Soyka M (2014) “Buprenorphine Use and Risk of Abuse and Diversion.” Adv
Pharmacoepidemiol Drug Saf 3:145. doi:10.4172/2167-1052.1000145
https://www.omicsgroup.org/journals/buprenorphine-use-and-risk-of-abuse-anddiversion-2167-1052.1000145.php?aid=22419
“An interesting study was performed recently in the US by Lofwall and Havens [81]. The study examined the
frequency and source of and risk factors for diverted buprenorphine use over a 6-month period in an
Appalachian community sample of prescription opioid abusers. Of the 503 participants at baseline, 471
completed the study. Psychiatric disorders and demographics, drugs use, and social network characteristics
were ascertained at baseline and follow-up. Multivariable logistic regression was performed over the 6-month
period. Results indicate that lifetime buprenorphine use “to get high” was 70.1%; 46.5% used diverted
buprenorphine over the 6-month period; and 9.6% were daily users and 50%-60% sporadic users (1-2 uses over
the 6 months). The most common sources were dealers (58.7%) and friends (31.6%). Predictors of increased
risk of use of diverted buprenorphine included inability to access buprenorphine treatment (AOR: 7.31),
meeting criteria for generalized anxiety disorder, and use in the past 30 days of oxycodone, methamphetamine,
and/or alcohol. The authors concluded that these results ‘suggest that improving, rather than limiting, access
to good quality affordable buprenorphine treatment may be an effective public strategy to mitigate
buprenorphine abuse. Future work should be an effective public health strategy to mitigate buprenorphine
abuse’ [81].” [Emphasis and red font added. No pagination in the HTML open-access article. Foot-noted
reference given below.]
81 Lofwall MR, Havens JR (2012) “Inability to access buprenorphine treatment as a risk factor for using diverted buprenorphine.” Drug Alcohol Depend
126: 379-383.
NOTE: Here is where the logic leading to the conclusion seems contorted. Definitive abuse, with
euphoria as the goal, somehow indicates an inadequate access? One of the strongest predictors of
abuse is poly substance abuse, and the conclusion is that the poly substance abusers do not have
adequate legal access?
Soyka M (2014) “Buprenorphine Use and Risk of Abuse and Diversion.” Adv
Pharmacoepidemiol Drug Saf 3:145. doi:10.4172/2167-1052.1000145
https://www.omicsgroup.org/journals/buprenorphine-use-and-risk-of-abuseand-diversion-2167-1052.1000145.php?aid=22419
“France has quite “liberal” prescribing regulations for buprenorphine, the
predominant maintenance medication, which may account for buprenorphine’s
diversion into the black market . Prescriptionmonitoring programs may reduce the
risk for doctor shopping. The risk of buprenorphine misuse (and benzodiazepine
misuse and rates of depression) is underestimated by physicians, as shown in a
cross-sectional study by Lavie et al. Data from France from 2006 show that up to
25% of French buprenorphine doses were diverted into the black market (Narcotics
Control Board 2006).” [Emphasis added. Red font added.No pagination provided in
the HTML open-access online article.]
“Buprenorphine and buprenorphine/naloxone are administered sublingually. A
novel buprenorphine film has been developed, but so far it is available only in the
US and Australia.” [No pagination provided in the HTML open-access article.]
Soyka M (2014) “Buprenorphine Use and Risk of Abuse and Diversion.” Adv
Pharmacoepidemiol Drug Saf 3:145. doi:10.4172/2167-1052.1000145
https://www.omicsgroup.org/journals/buprenorphine-use-and-risk-of-abuse-anddiversion-2167-1052.1000145.php?aid=22419
“Take-home doses of buprenorphine can be prescribed in most countries. In
some cases, patients are given take-home doses after they are stabilized, and
in others a less than daily dosage of buprenorphine is possible for patient
convenience. Advantages of at-home use include saving time for travel,
facilitating social integration, emphasizing and promoting patient
responsibility for treatment, reinforcing compliance, improving a trusting
relationship between staff and patients, engaging in normal day activities,
and reducing workload for the dispenser. Some of the apparent risks are the
risk of diversion to another person and injection of the oral medication.
Patients who should not be candidates for take-home doses include those
with repeated intoxication on presentation for dosing at the clinic, concerns
about child welfare and safety, current chaotic and unpredictable behavior,
risk of self-harm, and hazardous use of opioids.”[Emphasis and red font
added. No pagination in the HTML open-access article.]
Soyka M (2014) “Buprenorphine Use and Risk of Abuse and Diversion.” Adv
Pharmacoepidemiol Drug Saf 3:145. doi:10.4172/2167-1052.1000145
https://www.omicsgroup.org/journals/buprenorphine-use-and-risk-of-abuse-anddiversion-2167-1052.1000145.php?aid=22419
“In some cases, crushing the tablets before giving them to patients may be a
simple approach to reduce risk of misuse, as shown in Scandinavian studies.
In general, one must consider that a reduced risk of buprenorphine/naloxone
misuse can be balanced and outweighed by the risk of abusing other drugs,
e.g. other opioids, alcohol, or benzodiazepines, which may have an even
higher risk for fatal intoxications. A very “conservative” attitude of the
treating physician and too low dosages of buprenorphine may encourage
doctor shopping and related behaviors, as shown in French studies. On the
other hand, too “liberal” regulations may also enhance risk of diversion.
From a scientific point of view, in particular more European studies on the
risk of diversion and toxicological studies on safety issues are warranted.”
[Emphasis and red font added. No pagination is provided in the HTML openaccess article.]
Soyka M (2014) “Buprenorphine Use and Risk of Abuse and Diversion.” Adv Pharmacoepidemiol
Drug Saf 3:145. doi:10.4172/2167-1052.1000145
https://www.omicsgroup.org/journals/buprenorphine-use-and-risk-of-abuse-and-diversion2167-1052.1000145.php?aid=22419
NOTE: Sokya 2014 reaches a conclusion that would seem to contradict
the notion offered by Lofwall MR, Havens JR (2012) “Inability to access
buprenorphine treatment as a risk factor for using diverted
buprenorphine.” Drug Alcohol Depend 126: 379-383. (cited above) who
blame buprenorphine diversion on restricted access. The Lofwall and
Havens (2012) suggestion that increased legal dispensing of
buprenorphine will eclipse diverted use of buprenorphine is only
theoretical. The assertion depends on market assumption that demand
can be saturated by supply. THIS IS A VERY DANGEROUS ASSUMPTION
TO MAKE ABOUT PEOPLE WITH ADDICTION whose very behavior
already indicates that they do NOT RESPOND TO COMMON
PSYCHOLOGICAL AND ECONOMIC PARAMETERS.
Genis, Daniel. “Prison Poison: This Anti-Heroin Drug Is Now King of the Jailhouse Drug Trade.” The
Daily Beast. July 17, 2014. http://www.thedailybeast.com/articles/2014/07/17/suboxone-is-now-kingin-the-jailhouse-drug-trade.html
“Economically, there’s just no point in dealing heroin in jail anymore. After
all, a dose of Suboxone that can be shared by eight convicts only costs five
dollars on my corner in Brooklyn.
On the street, Suboxone is plentiful because it is prescribed, so junkies get
their monthly allotment of several dozen doses, pay with a Medicaid card,
and sell it off at five dollars a pill or strip to buy a real bag of dope. Seems to
me like they are missing the point, but the addiction makes the decision for
them.”
NOTE: Though the report is anecdotal, the report is real. The tax payers who
support Medicaid may find themselves uninterested in subsidizing this
system and might be convinced to oppose it should they become better
informed.
Hydra Head #5
• 5) The entirely unsubstantiated claim that studies show
buprenorphine users, even when only using it as prescribed and
without any other drugs or alcohol, are not at all impaired for driving
automobiles.
Know Your Rights: Rights for Individuals on Medication-Assisted Treatment. U.S. Department of Health
and Human Services Substance Abuse and Mental Health Services Administration Center for
Substance Abuse Treatment.”
“Acknowledgments: This publication was prepared for the Substance Abuse and Mental Health Services Administration (SAMHSA) by the Legal Action Center (LAC) for
the Partners for Recovery Initiative under Abt Associates, Inc., under contract number 270-03-9000, with SAMHSA, U.S. Department of Health and Human Services
(HHS). Shannon Taitt, M.P.A. served as the Government Project Officer. Disclaimer: The views, opinions, and content of this publication are those of the author and do
not necessarily reflect the views, opinions, or policies of SAMHSA or HHS.” http://atforum.com/documents/Know_Your_Rights_Brochure_0110.pdf [Empaasis added.
Red font added.]
“Do Methadone and Buprenorphine Impair Physical or Mental Functioning?
When provided at the appropriate do se to a person stabilized on methadone or buprenorphine,
these medications have no adverse effects on intelligence, mental capability, physical functioning
or employability. Research studies demonstrate that MAT patients are comparable to non-patients
in reaction time and their ability to learn, focus, and make complex judgments. MAT patients do
well in a wide array of work settings, including professional positions, service occupations, and
skilled, technical, and support jobs. MAT patients are lawyers, engineers, secretaries, truck and taxi
drivers, teachers, computer programmers, and others.
For more information about MAT and driving, read New York State’s Office of Alcoholism and
Substance Abuse’s 1997 publication, ‘Driving Performance of Methadone Maintenance Patients,’
and Legal Action Center’s 2000 publication, ‘Methadone Maintenance Treatment: Memorandum
on Driving & Psychomotor Studies and Background Information about Methadone Treatment.’“ p. 5
NOTE: 1) If this article does not represent the “views, opinions, or policies” of SAMHSA or HHS, why
publish it? 2) Please see the next slide for a critique of the Legal Action Center’s errors.
Know Your Rights: Rights for Individuals on Medication-Assisted Treatment. U.S. Department of Health and
Human Services Substance Abuse and Mental Health Services Administration Center for Substance Abuse
Treatment.”
“Acknowledgments: This publication was prepared for the Substance Abuse and Mental Health Services Administration (SAMHSA) by the Legal
Action Center (LAC) for the Partners for Recovery Initiative under Abt Associates, Inc., under contract number 270-03-9000, with SAMHSA, U.S.
Department of Health and Human Services (HHS). Shannon Taitt, M.P.A. served as the Government Project Officer. Disclaimer: The views,
opinions, and content of this publication are those of the author and do not necessarily reflect the views, opinions, or policies of SAMHSA or
HHS.” http://atforum.com/documents/Know_Your_Rights_Brochure_0110.pdf
NOTE: 1) The quotation given in the previous slide represents an
egregious overreach of evidence interpretation in general. 2) There is
no citation for studies involving buprenorphine and driving even after a
patient is “stabilized” in maintenance, and there is no citation given as
to how the period of induction into maintenance should be handled as
regards to operating vehicles or other machinery. 3) A review of the
articles covered regarding buprenorphine and euphoria, as given above
in this presentation, demonstrates that there is a split between
physiological effects, including sedation, and subjective effects.
Maren Cecilie Strand , Bente Fjeld , Marianne Arnestad & Jørg Mørland
(2013) Can Patients Receiving Opioid Maintenance Therapy Safely Drive? A Systematic Review of
Epidemiological and Experimental Studies on Driving Ability With a Focus on Concomitant Methadone
or Buprenorphine Administration, Traffic Injury Prevention, 14:1, 26-38, DOI:
10.1080/15389588.2012.689451
“Can Recommendations be Made for Maintenance Patients Based on the Present
Literature?
The up-to-date literature published within the corresponding field appears to be too
limited to draw any clear and precise conclusions regarding opioid maintenance therapy
and driving ability. However, studies seem to have demonstrated that low doses of both
methadone and buprenorphine may cause impairment in performance tasks of relevance
to driving among opioid-naive subjects. Consequently, it may be stated that both drugs are
known to have impairing potentials, but the scientific literature so far does not allow any
clear-cut conclusions to be drawn as to whether opioid maintenance therapy patients, or
certain subgroups of patients, should or should not be allowed to drive. Some studies
indicate large individual differences. Other authors imply that patients passing several tests
without any signs of impairment may be able to drive. Epidemiological studies show large
variations in the risk of traffic accident involvement. To the best of our present knowledge,
an individual evaluation of the driving performance in the opioid maintained patient seems
to be the only and most informative procedure in approaching the question of ability to
drive.” [Emphasis added. Red font added.]
NOTE: Who is qualified to make such an “individual evaluation’? The prescriber? The DMV?
Maren Cecilie Strand , Bente Fjeld , Marianne Arnestad & Jørg Mørland
(2013) Can Patients Receiving Opioid Maintenance Therapy Safely Drive? A Systematic
Review of Epidemiological and Experimental Studies on Driving Ability With a Focus on
Concomitant Methadone or Buprenorphine Administration, Traffic Injury Prevention, 14:1,
26-38, DOI: 10.1080/15389588.2012.689451
“There is a complete lack of experimental studies on methadone
and/or buprenorphine and their effects on actual on-the-road driving.
In addition, there is a lack of experimental studies using comparator
drugs and studies measuring blood drug concentrations at the time of
experimentation. Such studies should therefore be performed in the
future.” p. 35 [Emphasis added. Red font added.]
NOTE: It would seem prudent to expect anyone taking an opioid
agonist (partial or not) to follow the rules for all patients taking opioid/
opiate medications. The pharmacist places a fluorescent sticker on
those bottles that warn against driving.
Hydra Head #6
• 6) The poorly studied and reported comparison of buprenorphine
MAT to Vivitrol (the one-month duration injection of Naltrexone) MAT
in real clinical situations.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder:
Review of the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2.
2015. 63-75.
“Naltrexone has no risk for reduced respiratory drive, but attempts to
‘override’ blockade with high-dose opioid use poses a risk for
accidental-overdose death (see Vivitrol® package insert).” p. 67
NOTE: This statement is true. A similar risk exists for any attempt to overcome buprenorphine MAT
also exists, which is why all informed consents for use of buprenorphine always emphasizes the
caveat that the medication can be considered unlikely to cause respiratory depression only when
used alone. Remember Schuh KJ, Walsh SL, Stitzer ML (1999) “Onset, magnitude and duration of
opioid blockade produced by buprenorphine and naltrexone in humans.” Psychopharmacology
145:162–174 as reviewed above: “This dissociation between subjective and physiological responses
could pose a serious clinical danger, as it could lead to overdose in opioid abusers using high doses
of illicit opioids in the absence of subjective feedback.” p. 173 [Emphasis added. Red font added.]
NOTE: It is somewhat disconcerting that Vivitrol was singled out for this danger when the
problem is also evident for buprenorphine as demonstrated above in the presentation.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder:
Review of the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2.
2015. 63-75.
“The addition of agonist maintenance to relapse-prevention treatment at
least doubles the probability, compared to relapse-prevention treatment
alone, that an individual will achieve opioid abstinence during active
treatment,24–27 and the addition of antagonist maintenance nearly doubles
opioid abstinence.23 Oral naltrexone, although FDA approved to treat OUD,
is excluded from consideration here due to poor adherence rates and
significant opioid-overdose mortality following medication discontinuation in
clinical studies of OUD treatment outcomes.28–31
NOTE: 1) Remember that oral naltrexone, and not the extended-acting
Vivitrol preparation is discussed in this quotation. 2) The poor-adherence
rate can be addressed with Direct Observed Treatment protocols (i.e. – some
responsible person watches the patient swallow daily medications). This
method has been used with success with some impaired physicians who are
in recovery.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder:
Review of the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2.
2015. 63-75.
“A phase 4, multisite RCT comparing naltrexone ER to
buprenorphine/naloxone maintenance is currently under way,
with the expectation that results will resolve safety and efficacy
questions regarding naltrexone ER as a treatment for OUD (NIDA
Clinical Trials Network protocol 0051 [Principal Investigator: John
Rotrosen/NewYork University School of Medicine];
ClinicalTrials.gov identifier NCT02032433).
NOTE: Consider the recent study presented in the next slide.
Paul Crits-Christoph, Ph.D., Hannah M. Markell, B.A., Mary Beth Connolly Gibbons,
Ph.D., Robert Gallop, Ph.D., Christie Lundy, Ph.D., Mark Stringer, M.A., David R.
Gastfriend, M.D. “A Naturalistic Evaluation of Extended-Release Naltrexone in Clinical
Practice in Missouri.” Journal of Substance Abuse Treatment.2016. 20: 50-57
“The treatment group sizes for individuals with an opioid use problem were as follows: XR-NTX (N =
154), oral naltrexone (N = 86), buprenorphine/naloxone (N = 394), and psychosocial treatment only
(N = 8362).” p. 53
“Within the opioid sample, XR-NTX-treated patients again showed significantly better retention, but
not superior composite outcomes, compared to psychosocial treatment only. Comparisons with
other MATs, however, revealed statistically significant superiority of XR-NTX vs. both oral naltrexone
and buprenorphine/naloxone on the composite outcome. The effect for the comparison with
buprenorphine/naloxone was small (d = .17), but moderate in size for the comparison with oral
naltrexone (d=.45). Secondary analyses of individual components of the composite outcome
suggested that the superiority of XR-NTX to oral naltrexone was driven by clinically meaningful
changes on rates of self-help participation (changes of 32.4 vs. 1.8 percentage points for XR-NTX
and oral naltrexone, respectively) and no arrests (changes of 10.5 vs. −13.4 percentage points).
These findings on the secondary measures, as mentioned above, await replication in prospective
trials.” p. 56
NOTE: 1) Connery did not have the advantage of this article when she prepared the Harvard Review
of Psychiatry, 2015 article. 2) It is not clear if these “opioid use problem” subjects ONLY had
problems with opioids or if they were polysubstance-affected, but the study infers that these
subjects were NOT purely opioid abusers.
Paul Crits-Christoph, Ph.D., Hannah M.Markell, B.A., Mary Beth Connolly Gibbons, Ph.D.,
Robert Gallop, Ph.D., Christie Lundy, Ph.D., Mark Stringer, M.A., David R. Gastfriend, M.D. “A
Naturalistic Evaluation of Extended-Release Naltrexone in Clinical
Practice in Missouri.” Journal of Substance Abuse Treatment.2016. 20: 50-57
NOTE: The Composite Outcome Score includes
measures beyond a simple “retention in
treatment.” Other variables that contribute to
the score are employment status, arrests for
criminal activities, and abstinence.
Hydra Head #7
• 7) The shift from marketing (both to the public and within the
academic literature) 1) low-dose buprenorphine as an analgesic, to 2)
high-dose-start, tapered-dose-end of buprenorphine for
detoxification, to 3) high-dose buprenorphine for lifetime opioid
replacement, to 4) a very recent (and totally untested) desperation
option of starting all opioid/ opiate abusing/ addicted patients on
buprenorphine with the defense, that in theory, such a patient is less
likely to be able to overdose on illicit opiates/ opioids in the several
days following induction.
Nancy D. Campbell and Anne M. Lovell. “The History of the Development of Buprenorphine As an Addiction
Therapeutic.” Annals of the New York Academy of Sciences. Issue: Addiction Reviews. 1248. 2012. 124-139.
The history of buprenorphine up until the most recent shifts toward lifetime MST (Medication Substitution Therapy) and the
applications for overdose prophylaxis, is presented the excellent, well-balanced, and carefully researched article cited above.
This history was presented in some detail at CAPTASA 2016. Restated in summary:
Five Periods of Development, Pitch, and Legislation
1) 1966- 1978: Marketplace: Reckitts (a British household-chemicals manufacturer) search for a non-addictive opiate
analgesic which they hope can be nonprescription. They discover buprenorphine in 1966 and start human trials.
Laboratory: In 1975, buprenorphine garners interest among U.S. researchers as a possible addiction treatment
before approved as analgesic use in U.K. in 1978.
2) 1978- 1982: Market: Poor sales as an injectable analgesic for acute pain.
Lab: U.S. researchers classify it as partial agonist/ antagonist within the larger groups of antagonist opioids. These
researchers want to find a “magic bullet” antagonist.
3) 1982 –1993: Market: sublingual for acute pain introduced, but Reckitts has been losing interest due to weak sales;
sells most marketing rights to other companies.
Lab: U.S. researchers want to make it an addiction treatment. French clinicians are already using it off-label as a
“harms reduction” addiction treatment.
4) 1993 - 2002: Market, Lab, and Law mingle: search for new indications (e.g. - refractory depression (not labelled for
this use yet, but pay attention to the implications); treating opiate addiction; France officially allows use for addiction
treatment. Drug Abuse Treatment Act (DATA) of 2000 in U.S. allows outpatient office treatment of addiction unlike
specially licensed clinics required for methadone.
5) 2002 to the present: Market, Lab and Law merge: labelled use for treating “opiate addiction” gains FDA approval
in 2002, to fill the demand created by DATA 2000.
Buppractice: DATA 2000 Qualifying Buprenorphine Training
http://www.buppractice.com/node/12086
“Phases of Buprenorphine Treatment
Buprenorphine maintenance can be divided into three phrases: induction, stabilization, and
maintenance.
Induction
The goal of the induction is to find the patient's ideal daily dose of buprenorphine. The ideal daily
dose minimizes both side effects and drug craving. For most opioid-dependent patients, the daily
dose is 12 to 16 mg/day of the buprenorphine+ naloxone combination film or tablet. Induction
usually takes 2 to 4 days to complete.
Stabilization
Stabilization occurs in the 6 to 8 weeks following induction. This period begins when the patient is
no longer experiencing withdrawal symptoms or intense cravings. The main goal of stabilization is to
eliminate opioid use, as noted by patient reports and confirmed by urine drug testing.
Maintenance
The maintenance phase lasts indefinitely (SAMHSA 2004). Long-term maintenance is recommended
due to high relapse rates. For example, in one study of 255 individuals, approximately 87% relapsed
at 3 months (Ling 2009). During this phase, the patient is maintained at a comfortable dose and
reports minimal craving or side effects.”
NOTE: MST, Medication Substitution Treatment, is now being touted as best-practice and standard
of care. A close look at the Ling 2009 article is required.
Walter Ling, Maureen Hillhouse, Catherine Domier, Geetha Doraimani, Jeremy Hunter,
Christie Thomas, Jessica Jenkins, Albert Hasson, Jeffrey Annon, Andrew Saxon,
Jeffrey Selzer, Joshua Boverman, and Richard Bilangi. “Buprenorphine tapering schedule and illicit
opioid use.” Addiction. 2009 February; 104(2): 256–265. doi:10.1111/j.1360-0443.2008.02455.x.
“Recruitment began in June 2003 and data collection was completed in November 2005. Eligible
participants were at least 15 years of age, and seeking treatment for opioid dependence at one of
the 11 participating treatment programs in 10 US cities in Colorado, Washington, Oregon,
Connecticut, New York, Virginia and North Carolina. Methods of recruitment included word of
mouth, radio announcements, newspaper advertisements and referrals from local opioid treatment
and outreach programs, alcohol and drug abuse clinics, primary care providers, local mental health
centers, crisis clinics and hospital emergency rooms.
Participants were excluded if they provided a urine sample testing positive for methadone or
benzodiazepine, were in poor general health, had a self-reported allergy to buprenorphine or
naloxone, were pregnant or nursing, or had a medical or psychiatric condition that could make
participation unsafe. Participants were also excluded if they were dependent on alcohol or any drug
other than opioids (per DSM-IV criteria), or had participated in an investigational drug study, or
methadone or levo-alpha acetyl methadol (LAAM) maintenance or detoxification in the previous 30
days. Pending legal action and inability to remain in the area also precluded participation. Females
of childbearing potential could participate if they agreed to use an acceptable form of birth control.”
NOTE: This study attempted to start with Opiate-only addicts.
Walter Ling, Maureen Hillhouse, Catherine Domier, Geetha Doraimani, Jeremy Hunter,
Christie Thomas, Jessica Jenkins, Albert Hasson, Jeffrey Annon, Andrew Saxon,
Jeffrey Selzer, Joshua Boverman, and Richard Bilangi. “Buprenorphine tapering schedule and illicit
opioid use.” Addiction. 2009 February; 104(2): 256–265. doi:10.1111/j.1360-0443.2008.02455.x.
“Upon completion of the induction/stabilization phase, participants were assigned randomly to
either the 7-day or 28-day taper schedule.”
NOTE: This study hoped to show that a longer taper gave better outcomes (decreased “dirty urine”
measures) at 1 month and 3 month follow-ups after tapered detoxification.
“Opioid-free at end of taper
Comparison of the 7-day (n = 255) and 28-day (n = 261) taper groups showed that the primary
outcome (opioid-free urine test result at end of taper period) differed significantly by taper group
(χ2 1,516 = 11.52; P = 0.0007 ϕ = 0.150), with a larger percentage of the 7-day group (44.3%) having
an opioid-negative test result compared to the 28-day group (29.9%).“
NOTE: 1) Neither taper showed abstinence at the end of tapered detox. 2) The 7-day taper showed
cleaner urines at the end of detox that the 28 day taper.
Walter Ling, Maureen Hillhouse, Catherine Domier, Geetha Doraimani, Jeremy Hunter,
Christie Thomas, Jessica Jenkins, Albert Hasson, Jeffrey Annon, Andrew Saxon,
Jeffrey Selzer, Joshua Boverman, and Richard Bilangi. “Buprenorphine tapering schedule and illicit
opioid use.” Addiction. 2009 February; 104(2): 256–265. doi:10.1111/j.1360-0443.2008.02455.x.
“Opioid abstinence at follow-ups
To assess whether outcome changed over time as a function of taper group, the percentages of
participants in each taper group providing opioid-free urine samples were compared at the 1-month
and 3-month follow-up assessments. As shown in Table 2, no statistically significant differences
were found between the groups at either follow-up point.”
NOTE: After only 1 month of being fully detoxed from buprenorphine, it does not matter if the detox
takes 7 days or 28 days. The results are the same. This is also true for 3 months after the end of
each detox condition. The next slide shows how bad the results are.
Walter Ling, Maureen Hillhouse, Catherine Domier, Geetha Doraimani, Jeremy Hunter,
Christie Thomas, Jessica Jenkins, Albert Hasson, Jeffrey Annon, Andrew Saxon,
Jeffrey Selzer, Joshua Boverman, and Richard Bilangi. “Buprenorphine tapering schedule and illicit
opioid use.” Addiction. 2009 February; 104(2): 256–265. doi:10.1111/j.1360-0443.2008.02455.x.
NOTE: AT three months out, 88% of
urine drops were dirty for illicit opiates.
At three months out, some 90 % of urine
drops are dirty for illicit drugs OTHER
than opiates.
This record would not seem to speak
well for buprenorphine, would it?
AND YET, this very study leads to the
next phase of buprenorphine use: The
conclusion that the problem is NOT
buprenorphine, but that the problem is
with the foolish notion that opioid/
opiate addicts should ever be detoxified
from opiates/ opioids.
Robert G. Newman. “Comparing Buprenorphine ‘Tapers’ – To What End?” Addiction. 104. 1428-1429
vs.
Walter Ling, Maureen Hillhouse, Catherine Domier, Geetha Doraimani, Jeremy Hunter,
Christie Thomas, Jessica Jenkins, Albert Hasson, Jeffrey Annon, Andrew Saxon,
Jeffrey Selzer, Joshua Boverman, and Richard Bilangi. “ Long-suffering of Prolonged Suffering? Time
Matters.” Addiction. 104. 1429-1430
NOTE: A debate by letters-to-the-editor of Addiction followed the Ling et al 2009 taper study.
Newman writes: “The key conclusion to be drawn from the data would seem to be that withdrawal
has been demonstrated once again to be unsuccessful for most opioid-dependent patients if the
therapeutic goal is to achieve even relatively brief periods of abstinence. Such a summation might
have caused rethinking among clinical colleagues for whom, it is claimed, ‘the eventual
discontinuation of buprenorphine is a common treatment goal’. Instead, the authors conclude, ‘The
current study provided empirical evidence supporting consideration of a short taper schedule’. As
stated at the outset, this might be true—but only if one accepts the view that detoxification ‘. . . is a
worthwhile aim in itself ’.” p. 1429
Ling et al respond: “It is a delight to have Dr Robert Newman [1] weighing-in on the paper
describing our study [2].We have no quarrel whatsoever with his point that the most likely outcome
of detoxification, by whatever means, is relapse. In fact one of us (Ling) has been credited with—
more probably accused of—the following quote: ‘Detoxification may be good for a lot of things;
staying off drugs is not one of them’. p. 1429
Robert G. Newman. “Comparing Buprenorphine ‘Tapers’ – To What End?” Addiction. 104. 1428-1429
vs.
Walter Ling, Maureen Hillhouse, Catherine Domier, Geetha Doraimani, Jeremy Hunter,
Christie Thomas, Jessica Jenkins, Albert Hasson, Jeffrey Annon, Andrew Saxon,
Jeffrey Selzer, Joshua Boverman, and Richard Bilangi. “ Long-suffering of Prolonged Suffering? Time Matters.”
Addiction. 104. 1429-1430
NOTE: What can we make of this debate? I conclude the obvious: Both
parties are both correct. Detox -- as an end in itself -- is an open door
and if the patient has nothing with which to replace the substance, the
road leads to relapse. Two questions, remain, however. 1) Is there
some non-substance replacement that can fill the void left by
detoxification from all opioids, including from buprenorphine? 2) Is
there any evidence that buprenorphine, when taken for years on end,
will continue to supply the addict with sufficient relief so that the
addict will not still relapse on the preferred opiates/ opioids? The Ling
et al 2009 tapering study did NOT look at those questions. The
Newman letter-to-the-editor does not answer these questions.
Robert G. Newman. “Comparing Buprenorphine ‘Tapers’ – To What End?” Addiction. 104. 1428-1429
vs.
Walter Ling, Maureen Hillhouse, Catherine Domier, Geetha Doraimani, Jeremy Hunter,
Christie Thomas, Jessica Jenkins, Albert Hasson, Jeffrey Annon, Andrew Saxon,
Jeffrey Selzer, Joshua Boverman, and Richard Bilangi. “ Long-suffering of Prolonged Suffering? Time Matters.”
Addiction. 104. 1429-1430 (Continued)
The leap, however, to suggest that Ling et al 2009 article on tapering somehow allows the
conclusion, “The maintenance phase lasts indefinitely (SAMHSA 2004). Long-term maintenance is
recommended due to high relapse rates,” is more than troublesome, as is taught in
Buppractice: DATA 2000 Qualifying Buprenorphine Training http://www.buppractice.com/node/12086 .
Similarly, as will be explored below, a popular-press journalist has taken cited a study (“A recent
study that included the entire population of people being treated for opioid addiction in the U.K. —
over 150,000 participants studied over four years ….”) to immediately conclude (“… the treatment
I’m talking about involves long-term, possibly lifelong use.”)
Maia Szalavitz. “Treating Opioid Addiction: A Radical Way; The War On Drugs Reexamined.” The American Spectator. January 11, 2017. Web.
https://spectator.org/treating-opioid-addiction-a-radical-way/ Accessed January 14, 2017, citing: Pierce, M., Bird, S. M., Hickman, M., Marsden,
J., Dunn, G., Jones, A., and Millar, T. (2016). “Impact of treatment for opioid dependence on fatal drug-related poisoning: a national cohort study
in England.” Addiction, 111: 298–308. doi: 10.1111/add.13193.
NOTE: This is not “evidenced-based medicine.” It is either
delusional inference, or savvy marketing. Or both.
Buppractice: DATA 2000 Qualifying Buprenorphine Training
http://www.buppractice.com/node/12121
“There is a high risk for relapse, even if maintenance has been stable for a
while, when medication assisted treatment is discontinued (SAMHSA, 2004;
Stephenson, 2008). To explain that continuing the medication reduces risk of
relapse to patients, it can be helpful to draw a parallel to medication for a
chronic condition, such as hypertension being continued indefinitely.”
NOTE: The analogy to continuous medical treatment of chronic conditions such as diabetes
and hypertension is equally troublesome. I HAVE BOTH OF THOSE CONDICTIONS. 1) My
amlodipine and metformin and Levamir (an insulin variant) are not bought and sold on the
street with taxpayer funds to facilitate “highs,” and they are not becoming prison currency.
2) If I had a simple program of consistent steps with no-cost meetings that self-support at a
dollar a visit, I would toss the meds (which have side effects and risks) and get to my
meetings. In fact, I would consider shouldering the cost of random lab testing if that
addition amplified my accountability to the basic program.
Anecdoctal: Some Centers and Agencies are, as policy, not simply offering buprenorphine
MAT but are encouraging it within the first day of detox (some evidence of withdrawal is
required prior to an induction dose) as a proposed prophylaxis for overdose in case the
addict leaves the center abruptly against medical advice. If there were articles, I would
supply them.
There are no studies that show efficacy in prevention of overdose in this manner.
As was noted above, there is, in fact, the same risk as noted with naltrexone that
unsupervised addicts (such as those who leave treatment abruptly against medical
advice) will be lead to overdose as they seek to override the lingering blockade of
euphoria even while the blockade of physiological functions (e.g. – respiratory rate)
has waned.
This theoretical problem becomes more apparent in the context of street heroin
cut with fentanyl and carfentanyl, and in the context of counterfeit prescription
opiate pills that are fentanyl. I can find no study any where that demonstrates
buprenorphine in the 8 mg to 32 mg sub-lingual range is effective in blocking
street-fentanyls in the high doses which are trafficked.
[For fentanyl-mixed heroin, see: Drug Enforcement Agency (DEA). “DEA Issues Nationwide Alert on Fentanyl as
Threat to Health and Public Safety.” March 18, 2015. Web.
https://www.dea.gov/divisions/hq/2015/hq031815.shtml . Accessed January 10, 2017.
For counterfeit prescription opiates with fentanyl, see: Drug Enforcement Agency (DEA). “DEA Report:
Counterfeit Pills Fueling U.S. Fentanyl and Opioid Crisis: Problems resulting from abuse of opioid drugs
continue to grow.” July 22, 2016. Web. https://www.dea.gov/divisions/hq/2016/hq072216.shtml . Accessed
January 10, 2017.]
Hydra Head #8
• 8) The claim that buprenorphine MAT has been scientifically
compared and found favorable to psycho-social treatments, and that
– in particular – it is superior in outcome when compared to 12 Step
Recovery.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder: Review of
the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2. 2015. 63-75.
“A 2005 Cochrane review noted that the available evidence was insufficient to
support psychosocial treatment alone as effective for OUD. (101) The evidence
remains insufficient, even to predict which individuals, if any, are likely to do well
without MAT.”
101. Mayet S, Farrell M, Ferri M, Amato L, Davoli M. Psychosocial treatment for opiate abuse and dependence.
Cochrane Database Syst Rev 2005;(1):CD004330.
NOTE: 1) The Mayet et al. 2005 article was withdrawn from the Cochrane Library in
2014 with the note: “The editorial group responsible for this previously published
document have withdrawn it from publication.”
http://onlinelibrary.wiley.com.echo.louisville.edu/doi/10.1002/14651858.CD00433
0.pub3/full
After 2014, no researcher should be citing the Mayet et al. 2005 article either to
support or to reject the notion of psychosocial treatments for opiate use disorders.
A look at that article, however, does reveal that none of the psychosocial
treatments reviewed in it were 12 Step programs of recovery.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder: Review of
the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2. 2015. 63-75.
NOTE: Contrary to Connery’s conclusion (quoted above), there is evidence of at least one
population of OUD individuals – impaired physicians -- can and do recover without MAT. The first
wave of report on this study on PHP (Physician Health Program) efficacy is found in
McLellan, A. T., Skipper, G. E., Campbell, M. G. & DuPont, R. L. (2008). Five year outcomes in a
cohort study of physicians treated for substance use disorders in the United States. British Medical
Journal, 337:a2038.
Article co-author DuPont reported to Congress in 2015:
“We recently extended our analysis of our PHP data to compare the outcomes for physicians who
were dependent on opioids to those who were dependent on alcohol alone, and to the physicians
who were dependent on other drugs with or without alcohol. The physicians in all three groups
were randomly monitored for any use of alcohol, opioids or any other drugs for five years. The
opioid dependent physicians did not receive buprenorphine or methadone but a few used
naltrexone (in many cases because of problems with alcohol rather than opioids). The opioid
dependent physicians did as well as the physicians in the other two groups with 75% to 80% of all
three groups never testing positive for alcohol or other drugs including opioids. Of course, the
physician addicts are different demographically from typical MAT patients. Nevertheless, these data
demonstrate that the biological disease of opioid dependence can – in this situation at least – be
successfully treated without substitution therapy.” p. 5
Robert L. DuPont. “Statement of Robert L. DuPont, M.D., President, Institute for Behavior and Health, Inc., before the House Subcommittee On Oversight
and Investigations Regarding Combatting the Opioid Abuse Epidemic: Professional and Academic Perspectives.” April 23, 2015.
http://docs.house.gov/meetings/IF/IF02/20150423/103367/HHRG-114-IF02-Wstate-DuPontR-20150423.pdf
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder: Review of
the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2. 2015. 63-75.
“Longer-term, abstinence-based residential treatment without MAT
shows limited effectiveness, especially among recently detoxified
heroin users,97,98 and loss of tolerance during this period of
abstention poses an increased risk of fatal overdose if one relapses to
opioid use upon discharge to home. Youth is a predictor of early
dropout from psychosocial treatment of OUD,99 whereas medication
adherence and early opioid abstinence predict greater retention and
treatment success among youth treated with buprenorphine/
naloxone.100”
Note: The footnote references are explored in detail starting in the next
slide.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder: Review of
the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2. 2015. 63-75.
97. Keen J, Oliver P, Rowse G, Mathers N. Residential rehabilitation for drug users: a
review of 13 months’ intake to a therapeutic community. Fam Pract 2001;18:545–8.
The generally agreed aim of residential rehabilitation, such as that studied in this
investigation, is to achieve long-term abstinence. Nonetheless, the conclusions of
Mattick and Hall make it clear that a fairly low rate of ‘success’ can be expected if
abstinence is the desired goal. Studies looking at other outcomes of residential
rehabilitation, however, such as reductions in illicit drug use, improved family
outcomes, 2 reductions in criminal activity and overall harm minimization, have
demonstrated more positive results. 3–5 p. 546
“An analysis of data of this sort faces two major problems: the identification of what
constitutes success or failure and the difficulty in assessing the impact of one
treatment episode on the future course of a patient’s addiction.” p. 547
NOTE: 1) There is no description of what the components of the residential
treatment are. 2) The other positive results (reduction in illicit use, etc.) are similar
in magnitude to those reported for buprenorphine MAT and no studies to date
demonstrate that buprenorphine MAT outpatient exceeds efficacy of “therapeutic
community” on those non-abstinence measures.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder: Review of
the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2. 2015. 63-75.
98. Kosten TR, Gorelick DA. The Lexington narcotic farm. Am J Psychiatry 2002;159:22.
NOTE: This article is a one page summary of the history of the Lexington facility. The authors do not
address in any form or fashion any of the topics mentioned by Connery to which readers are
directed in this footnote. There is no conceivable reason that this citation was added to support the
article texrt.
99. McHugh RK, Murray HW, Hearon BA, et al. Predictors of dropout from psychosocial treatment in
opioid-dependent outpatients. Am J Addict 2013;22:18–22.
“Eligible study participants were randomized to receive one of two psychosocial treatments. Both
treatment conditions entailed 12 individual weekly 1‐hour sessions plus three booster sessions and
focused on enhancing utilization of adaptive coping strategies.”
NOTE: 1) Young-age is the best predictor of early drop out. 2) The study does a good job of
identifying a characteristic called “Distress Intolerance,” which is positively correlated to early drop
out. Basically, it is the subjective notion of “I cannot withstand these anxious, negative feelings in
this situation and I must escape these feelings.” 3) The two different treatment conditions share a
common problem: they are woefully under-dosed (only offering an hour session once a week) and
they lack any “group-of-peer” meeting components.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder: Review of
the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2. 2015. 63-75.
24. Fudala PJ, Bridge TP, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet
formulation of buprenorphine and naloxone. N Engl J Med 2003;349:949–58.
“Individualized counseling was available at the clinics, but the subjects were also encouraged to obtain
behavioral-treatment services outside the study.”
NOTE: This is the ONLY mention in the study of anything that might be construed as a psychosocial treatment.
There is no content described. The design for the study is clearly three arms: placebo medication
buprenorphine, and buprenorphine/naloxone combination. There is no way that this study supports Connery.
25. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended buprenorphinenaloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch Gen
Psychiatry 2011;68:1238–46.
NOTE: To critique this, we must see:
21. Weiss RD, Potter JS, Provost SE, Huang Z, Jacobs P, Hasson A, Lindblad R, Connery HS, Prather K, Ling W. A
multi-site, two-phase, Prescription Opioid Addiction Treatment Study (POATS): rationale, design, and
methodology. Contemp Clin Trials. 2010;31(2):189-199.
26. Woody GE, Poole SA, Subramaniam G, et al. Extended vs short term buprenorphine-naloxone for
treatment of opioid addicted youth: a randomized trial. JAMA 2008;300:2003–11.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder: Review of
the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2. 2015. 63-75.
“The addition of agonist maintenance to relapse-prevention treatment at least
doubles the probability, compared to relapse-prevention treatment alone, that an
individual will achieve opioid abstinence during active treatment,24–27 and the
addition of antagonist maintenance nearly doubles opioid abstinence.23
24. Fudala PJ, Bridge TP, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of
buprenorphine and naloxone. N Engl J Med 2003;349:949–58.
“All the subjects received counseling regarding human immunodeficiency virus infection and up to one hour of individualized
counseling per week. Emergency counseling (e.g., after a relapse) and referrals (e.g., to community legal aid programs) could be
provided, but no other counseling or services (e.g., regarding family or employment issues)were offered. [….] Individualized
counseling was available at the clinics, but the subjects were also encouraged to obtain behavioral-treatment services outside the
study.” p. 951
NOTE: These three sentences contain the ONLY mention in the study of anything that might be construed as a psychosocial treatment. The
content and theoretical mode of the counseling is not described. Counseling was only offered for one-hour a week. There is no mention of
participation in 12 Step recovery nor any mention of monitoring the degree of participation in 12 Step recovery. The design for the study is
clearly three arms: placebo medication buprenorphine, and buprenorphine/naloxone combination.
“The percentages of opiate-negative urine samples in both active-treatment groups were significantly greater than those in the
placebo group during the double-blind trial. Although the percentages, averaged over four weeks, may appear low, this finding was
neither unexpected nor indicative of a poor treatment response. The trial was designed to show efficacy by the four-week point, not
the achievement of a full clinical effect.” p. 956
Note: Here the authors are defending against the fact that 65% of the buprenorphine-plus-naltrexone
(Suboxone) in conjunction with the counseling (i.e. –the active-treatment group of interest) were still using
illicit opiates after four weeks of treatment.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder: Review of
the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2. 2015. 63-75.
25. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2phase randomized controlled trial. Arch Gen Psychiatry 2011;68:1238–46.
“Manual-based SMM, which has previously demonstrated efficacy,30 was provided to all the participants by physicians certified to prescribe buprenorphine. During
the initial session in each phase (45-60 minutes in phase 1 and 30-60 minutes in phase 2), the physician reviewed the patient’s medical, psychiatric, and substance use
problems; recommended abstinence; and referred the patient to self-help groups. In subsequent 15- to 20-minute visits, the physician assessed substance use, craving,
and buprenorphine-naloxone response; recommended abstinence and self-help participation; and prescribed buprenorphine- naloxone [,,,] In addition to SMM, half
the patients were randomly assigned to receive manual-based ODC,23 delivered in 45- to 60-minute sessions by trained substance abuse or mental health
professionals (Figure 1). The ODC was based on drug counseling manuals31,32 with demonstrated efficacy,33,34 modified for this study of prescription opioid
dependence treatment with buprenorphine. Counselors educated patients about addiction and recovery, recommended self-help groups, and emphasized lifestyle
change. Using a skills-based format with interactive exercises and take-home assignments, ODC covered a wider range of relapse prevention issues in greater depth
than did SMM, including coping with high-risk situations, managing emotions, and dealing with relationships.” p. 1240
30 O’Connor PG, Oliveto AH, Shi JM, Triffleman EG, Carroll KM, Kosten TR, Rounsaville BJ, Pakes JA, Schottenfeld RS. A randomized trial of buprenorphine maintenance
for heroin dependence in a primary care clinic for substance users versus a methadone clinic. Am J Med. 1998;105(2):100-105.
23 Pantalon MV, Fiellin DA, Schottenfeld RS, Gordon L, O’Connor PG. Manual for Enhanced Medical Management of Opioid Dependence With Buprenorphine. New
Haven, CT: Yale University; 1999.
31 Mercer DE, Woody GE. Individual Drug Counseling. Rockville, MD: National Institute on Drug Abuse; September 1999. NIH publication No. 99-4380.
32 Woody G, Stockdale D, Hargrove E. A Manual of Drug Counseling With Opiate Addicts. Philadelphia: University of Pennsylvania; 1977.
33 Crits-Christoph P, Siqueland L, Blaine J, Frank A, Luborsky L, Onken LS, Muenz LR, Thase ME, Weiss RD, Gastfriend DR, Woody GE, Barber JP, Butler SF, Dale D,
Salloum I, Bishop S, Najavits LM, Lis J, Mercer D, Griffin ML, Moras K, Beck AT. Psychosocial treatments for cocaine dependence: National Institute on Drug Abuse
Collaborative Cocaine Treatment Study. Arch Gen Psychiatry. 1999; 56(6):493-502.
34 Woody GE, Luborsky L, McLellan AT, O’Brien CP, Beck AT, Blaine J, Herman I, Hole A. Psychotherapy for opiate addicts: does it help? Arch Gen Psychiatry. 1983;
40(6):639-645
NOTE: 1) This is a study on Prescription Opiate Abusers. Heroin users were excluded. 1) The manual-based psycho-social treatments used (whether SMM or ODC) are
individual-therapy and educational in content. The ODC “encourages” 12 Step participation, but there is no expressed component that quantifies or qualifies that
“Encouragement.” That is, there is no statement of monitoring number of meetings per week, no documenting that the addict is working closely with a 12 Step
sponsor, no attempt to monitor progress through the 12 steps themselves.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder: Review of
the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2. 2015. 63-75.
26 Woody GE, Poole SA, Subramaniam G, et al. Extended vs short-term buprenorphine-naloxone for
treatment of opioid addicted youth: a randomized trial. JAMA 2008; 300:2003–11.
“Patients were scheduled for 1 individual and 1 group session per week with more frequent
sessions if needed. Most counselors were licensed clinical addictions specialists or had master’s
degrees in counseling or social work. Counseling used methods in NIDA manuals 20,21 and was
standardized by a 3-hour training. One to counselors treated study patients at each site and were
supervised using local procedures. Counseling encouraged making positive relationships and
stopping drug use, taking medication as prescribed, tolerating stressful events without using drugs,
keeping appointments, teaching ways to avoid drug-using situations, educating about addiction,
giving positive feedback for achieving goals, referring for treatment of associated problems, and
participating in age-appropriate self-help groups.”
20 Mercer DE,Woody GE. An individual drug counseling approach to treat cocaine addiction: the collaborative cocaine treatment study model
[Therapy Manuals for Drug Abuse: 3; NIH Publication No. 99-4380]. http://www.nida.nih.gov/TXManuals/IDCA /IDCA1.html. Accessed
September 29, 2008.
21. Daley DC, Mercer DE. Counseling for cocaine addiction: the collaborative cocaine treatment study model [Therapy Manuals for Drug Abuse:
3; NIH Publication No. 99-4380]. http://www.nida.nih.gov/TXManuals/IDCA/IDCA1.html. Accessed September 29, 2008
NOTE: The psychosocial component does include group, but dosing is still only 2 times a week as
standard, and there is no mandated peer-mentor element. Perhaps “self-help groups” means 12
Step groups, but there is no stated minimum number of meetings per week, no monitoring of
attendance, no monitoring of connection with a sponsor, and no monitoring of progress through the
12 Steps.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder: Review of
the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2. 2015. 63-75.
27 Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy
versus no opioid replacement therapy for opioid dependence. Cochrane
Database Syst Rev 2009;(3): CD002209.
NOTE: 1) Meta analysis review article that only found 11 studies that met
criteria. Only three of the 11 mentioned counseling treatment. Of those
three, only one specified frequency (weekly) and included both individual
and group. The third of the three was in a prison setting with counseling
offered while in prison but only “passive referral” for the addict to continue
counseling after discharge. Not one of the studies mentioned 12 Step
programs. 2) The MAT was with methadone; not buprenorphine. This is
important because office-based buprenorphine treatment has never offered
the structure that methadone clinics offer.
Connery, Hilary Smith. “Medication-Assisted Treatment of Opioid Use Disorder: Review of
the Evidence and Future Directions. “ Harvard Review of Psychiatry. 23:2. 2015. 63-75.
23 Krupitsky E, Nunes EV, Ling W, Illeperuma A, Gastfriend DR, Silverman BL.
Injectable extended-release naltrexone for opioid dependence: a doubleblind, placebo-controlled, multicenter randomised trial. Lancet
2011;377:1506–13.
NOTE: 1) A study of injected extended release naltrexone (i.e. – Vivitrol) and
not of buprenorphine. 2) There is no psychosocial treatment at all, either
alone or in combination. There is only inert placebo injection. This study
seems entirely irrelevant to Connery’s sentence “The addition of agonist
maintenance to relapse-prevention treatment at least doubles the probability, compared
to relapse-prevention treatment alone, that an individual will achieve opioid abstinence
during active treatment,24–27 and the addition of antagonist maintenance nearly doubles
opioid abstinence23” in which Krupitsky et al. 2011 the citation is placed.
Pierce, M., Bird, S. M., Hickman, M., Marsden, J., Dunn, G., Jones, A., and Millar, T.
(2016). “Impact of treatment for opioid dependence on fatal drug-related poisoning:
a national cohort study in England.” Addiction, 111: 298–308. doi: 10.1111/add.13193.
“NDTMS records four types of treatment: community OAP, community psychological support, in-patient withdrawal management and drug-free
residential rehabilitation. Enrolment in in-patient and residential treatment each provided a small number of person-years (1224 and 2601, respectively).
We noted that this reduced statistical power for an intervention level analysis. As both interventions are abstinence orientated, we judged it appropriate
to create a combined grouping (labelled ‘residential’).” p. 299. NOTE: The assumption that detoxification is abstinence TREATMENT is HUGELY FLAWED.
Detox without some kind of replacement is a ticket to relapse (See Ling et al 2009). A study cannot solve a statistical power problem by combining apples
and oranges in order to compare the vitamin C content of the combined produce against a bottle of Vitamin C in the pharmacy.
“Widely delivered in the United Kingdom, community-setting psychological support comprises a broad set of structured change methods which aim to
reduce the opioid-dependent person's cognitive behavioural symptoms, intra/interpersonal difficulties and social problems and build motivation for
recovery. The patient is assigned a clinical key worker to help develop, implement and review their care plan [11]. Psychological support interventions are
also provided by residential rehabilitation services; these programmes are guided by a characteristic philosophical approach and vary in duration and
intensity.
NICE recommends that people with drug-related problems are provided with information about self-help groups and that those outside
structured treatment are offered brief motivational interventions [12]. NICE endorses contingency management (which uses practical reinforcers to
motivate adherence to treatment and behaviour change) as an adjunctive therapy during OAP but judges that there is insufficient evidence to
recommend routine use of cognitive behavioural therapy or psychodynamic therapy. Standalone psychological support for opioid dependence is also not
recommended….” p. 299
12 National Institute for Health and Clinical Excellence. Drug Misuse: Psychosocial interventions. London: National Institute for Health and Clinical
Excellence; 2007. [NOTE: This document can be found at https://www.nice.org.uk/guidance/cg51/chapter/1-Guidance .
NOTE: The only mention of 12 Steps is as follows: “1.3.2 Self-help 1.3.2.1 Staff should routinely provide people who misuse drugs with information about
self-help groups. These groups should normally be based on 12-step principles; for example, Narcotics Anonymous and Cocaine Anonymous. 1.3.2.2 If a
person who misuses drugs has expressed an interest in attending a 12-step self-help group, staff should consider facilitating the person's initial contact
with the group, for example by making the appointment, arranging transport, accompanying him or her to the first session and dealing with any
concerns. There is no criterion set for numbers of meetings per week, obtaining a sponsor, or working the Steps sequentially.]
“We also acknowledge several limitations. […] Thirdly, NDTMS data did not specify the specific methods of psychological support received by patients;
thus, variability in the receipt of such treatment could not be explored. Similarly, it was not possible to distinguish the relative effects of methadone and
buprenorphine within OAP, and this may have led to a loss of information.” p. 304.
NOTE: This third acknowledgement means that the researchers had no way of measuring the quantity, quality, and frequency of the psychological
support interventions.
I WISH I HAD AN ARTICLE TO CITE HERE
NOTE: There simply are no head-to-head comparisons of any wellestablished psycho-social interventions without buprenorphine MAT
against buprenorphine MAT alone or against buprenorphine MAT-in
conjunction-with-psychosocial components. NONE. NOT ONE. It is
impossible to make statements about superior or inferior efficacy.
With the exception of the Physician Health Programs Blueprint Study,
there are no good studies of Abstinence Only Treatment (AOT) for
people with opioid use disorder.
The burden of this criticism must be shared by both the AOT and the
buprenorphine MAT/ MST proponents and their treatment centers.
Hydra Head #9
• 9) The many possible definitions of “a successful outcome”: 1)
abstinence from all drugs-of-reward, including buprenorphine, with
exceptions made for nicotine and caffeine.) 2) abstinence from all
drugs-of-reward, excluding buprenorphine, with exceptions made for
nicotine and caffeine 3) abstinence from opiates/ opioids, including
buprenorphine, but allowance for use of other illicit and licit drugs-ofreward. 4) abstinence from opiates/ opioids, excluding
buprenorphine, but allowing for use of other illicit and licit drugs of
reward. 5) Some reduction of illicit opioid/ opiate drug use while
using buprenorphine. 6) Some reduction in social and medical ills (i.e
– harms reduction) such as crime, HepC, HIV, and overdose events.
Pierce, M., Bird, S. M., Hickman, M., Marsden, J., Dunn, G., Jones, A., and Millar, T. (2016).
“Impact of treatment for opioid dependence on fatal drug-related poisoning: a national
cohort study in England.” Addiction, 111: 298–308. doi: 10.1111/add.13193.
“Aims
To compare the change in illicit opioid users’ risk of fatal drug-related poisoning (DRP) associated
with opioid agonist pharmacotherapy (OAP) and psychological support, and investigate the
modifying effect of patient characteristics, criminal justice system (CJS) referral and treatment
completion.” p. 298
NOTE: 1) The aim is overtly a Harms-reduction goal, with the harm identified as overdose death
(their term is Drug Related Poisoning). Reducing deaths is, of course, a good goal. 2) It is impossible
to determine from this study, however, if the results are due to methadone or buprenorphine
because both agents are used. 3) This naturalistic study did NOT compare the opioid agonists
against an opioid anatagonist like extended release naltrexone. It is impossible to say which of the
two categories (agonist or antagonist) would work better at reducing overdose death in that
naturalistic environment. 4) The observation period for this study was for four years (2005 – 2009).
The LONGEST PERIOD POSSIBLE TO BE ON BUPRENORPHINE MAT WOULD BE FOUR YEARS. This
length of time cannot be scientifically compared to “lifetime maintenance.” This study does not
extrapolate to “lifetime” use. A popular-press journalist, however, does, as will be examined below.
[see Maia Szalavitz. “Treating Opioid Addiction: A Radical Way; The War On Drugs Reexamined.” The American Spectator. January 11, 2017.
Web. https://spectator.org/treating-opioid-addiction-a-radical-way/ Accessed January 14, 2017. ]
Robert L. Dupont. “Statement of Robert L. Dupont, M.D., President, Institute for Behavior and Health, Inc.,
before the House Subcommittee On Oversight and Investigations Regarding Combatting the Opioid Abuse
Epidemic: Professional and Academic Perspectives.” April 23, 2015.
http://docs.house.gov/meetings/IF/IF02/20150423/103367/HHRG-114-IF02-Wstate-DuPontR-20150423.pdf
“To move forward we must define the goal for substance abuse treatment. What is the
standard against which all substance abuse treatments, both those using medicines and
those not using medicines, can be measured? [….] Recovery includes no use of alcohol and
other drugs.” p. 4
“We recently extended our analysis of our PHP data to compare the outcomes for
physicians who were dependent on opioids to those who were dependent on alcohol
alone, and to the physicians who were dependent on other drugs with or without alcohol.
The physicians in all three groups were randomly monitored for any use of alcohol, opioids
or any other drugs for five years. The opioid dependent physicians did not receive
buprenorphine or methadone but a few used naltrexone (in many cases because of
problems with alcohol rather than opioids). The opioid dependent physicians did as well as
the physicians in the other two groups with 75% to 80% of all three groups never testing
positive for alcohol or other drugs including opioids. Of course, the physician addicts are
different demographically from typical MAT patients. Nevertheless, these data
demonstrate that the biological disease of opioid dependence can – in this situation at
least – be successfully treated without substitution therapy.” p. 5 [Emphasis added. Red
font added.]
Maia Szalavitz. “Treating Opioid Addiction: A Radical Way; The War On Drugs
Reexamined.” The American Spectator. January 11, 2017. Web.
https://spectator.org/treating-opioid-addiction-a-radical-way/ Accessed January 14,
2017.
“A recent study that included the entire population of people being treated for opioid addiction in the U.K. — over 150,000
participants studied over four years — found that people who enrolled in this treatment had a death rate that was 50 percent
lower than those who used other methods, including those that are most popular in the U.S.; other research has found that it
lowers the death rate by even more. Yet more studies find that it cuts crime, infectious disease, death rates for people
already infected with HIV and, of course, relapse.
Unfortunately, the treatment I’m talking about involves long-term, possibly lifelong use of one of two medications:
methadone or buprenorphine (brand name: Suboxone). That violates the politically correct stance historically taken by
America’s treatment system — which is that abstinence from all drugs and participation in 12-step programs like Narcotics
Anonymous is the only acceptable approach.”
Pierce, M., Bird, S. M., Hickman, M., Marsden, J., Dunn, G., Jones, A., and Millar, T. (2016). “Impact of treatment for opioid dependence
on fatal drug-related poisoning: a national cohort study in England.” Addiction, 111: 298–308. doi: 10.1111/add.13193.
NOTE: The study cited is the one examined above. Pierce et al. made NO LEAP to the
possibility of lifelong use. Their scientific study has enough problems in itself, but these
problems become an absolute violation of the mantra “evidence based medicine” when a
popular-press journalism over extends the findings. Furthermore, Pierce et al. recognized
in their own study that concomitant abuse/ addiction with other drugs and alcohol more
than doubles the risk of overdose death. This journalist ignores the “evidence based
medicine” goal of abstinence from drugs of reward in an attempt to sell the public on the
notion that opioid-substitution will keep the addict alive and happily using other drugs and
alcohol.
Robert L. DuPont. “Statement of Robert L. DuPont, M.D., President, Institute for Behavior and Health, Inc., before
the House Subcommittee On Oversight and Investigations Regarding Combatting the Opioid Abuse Epidemic:
Professional and Academic Perspectives.” April 23, 2015.
http://docs.house.gov/meetings/IF/IF02/20150423/103367/HHRG-114-IF02-Wstate-DuPontR-20150423.pdf
“One controversial issue in defining recovery is whether a person can be considered to be in recovery
while using medications including buprenorphine, methadone and naltrexone. I emphatically answer
“yes” to that question – as long as the medication use is consistent with the prescribing physicians’
instructions, and as long as the patient is not also using alcohol other drugs of abuse.
I recognize that the ultimate goal of sustained recovery is difficult to achieve, and even controversial. I
also recognize that there are many interim goals of treatment along this path to sustained recovery that
are worthy of evaluation and support. In addition, I recognize that some opioid dependent people
achieve sustained recovery without treatment. Nevertheless, I am convinced that failure to define this (or
some other ultimate goal of treatment) means that the entire treatment enterprise lacks focus. In
addition, it is difficult to compare the outcomes of alternative treatments in the absence of a shared
definition of the goal of treatment.” p. 6 [Emphasis added. Red font added.]
NOTE: 1) We know definitively that the most at-risk populations DO NOT use medications as
prescribed, and they do not abstain from other drugs and alcohol. It would appear foolhardy to issue
them outpatient access with no meaningful monitoring system in place. 2) We are still waiting for the
evaluation of “interim goal” programs and it would seem foolhardy to expand their implementation
until we have the results from the pilot programs. 3) It is not simply difficult to compare outcomes
without a shared definition; it is IMPOSSIBLE to compare outcomes.
Hazelden Betty Ford: Comprehensive Opioid
Response with 12 Steps (COR-12)
Marv Seppala. “A comprehensive response to the opioid epidemic: Hazelden's approach.”
Minnesota Medicine. 2013. March. 96 (3): 45-47.
NOTE: Describes what they hope to do. This is not a controlled study report.
Joe Sonka. “The Suboxone Solution: Can Medication Assisted Treatment Effectively Curb the Heroin
Epidemic and Save Lives?” Louisville Insider. April 28, 2016. Web.
http://insiderlouisville.com/metro/mediation-assisted-treatment-and-suboxone-another-addictionto-replace-heroin-or-a-life-saving-medication/ Accessed Jan 09 2017.
“The results of the new treatment program — Comprehensive Opioid Response with 12 Steps, aka
COR-12 — for Hazelden’s patients in Center City, Minn. were astounding, as post-treatment
overdose deaths in the first year plunged to zero.”
NOTE: Sonka does not cite his source for the statistics. The hyper-link imbedded in the text takes the
reader to the Hazelden website and a description of the program. The program offers participants
three possible treatment: no MAT, MAT with Vivitrol, and MAT with Suboxone. All choices include
strong 12 Step participation. When an MAT option is chosen, the program goal is to end in
abstinence from the MAT medication; ostensibly at 18 months. There are at this time no peerreviewed articles that report on the outcomes.
What is the Hydra’s Immortal Head?
In my opinion, it is the delusion shared by all people with the disease of
addiction -- and by the naïve normal folks who want to help them -that some day, in some way, those with addiction will somehow be able
to use addicting substances like normal people. This head is still
attached to the neck.