According to a survey produced by the National Institute on Drug Abuse in 2003, 3.

7
million Americans have used heroin at some point in their lives, with approximately 314,000
Americans using within the previous year. In 2003, 57.4 percent of the past years heroin users
were classified with dependence on or abuse of heroin, and approximately 281,000 people
sought treatment for heroin abuse.1 Even more disturbing is the dramatic increase in
prescription opioid abuse in recent years. Americans constitute only 4.6 percent of the worlds
population, but consume 80 percent of the worlds opioid supply, including 99 percent of the
worlds hydrocodone supply.2
Data from the 2006 National Survey on Drug Use and Health (NSDUH), sponsored by
the Substance Abuse and Mental Health Services Administration (SAMHSA), indicate that the
number of persons aged 12 and older using prescription pain relievers doubled from 2.6 to 5.2
million, equating to 17 times the number of persons who had used heroin. In 2006, 2.2 million
people aged 12 and older used prescription pain relievers illicitly for the first time; this is more
than any other illicit drug, surpassing marijuana at 2.1 million new users, and heroin at 91,000
new users. The progression from illicit use of opioids to dependence has severe consequences
for this population, including significant medical and psychiatric morbidities, and a yearly
mortality rate of approximately 2 percent. Sustained remission from opioid use is also very
difficult to achieve.2
This increase in illicit use of prescription pain relievers certainly calls for attention. With
more people abusing opioids, more treatment options must be made available and feasible for
opioid-dependent patients. Current pharmacologic therapies for management of opioid abuse
include methadone, a long-acting synthetic opioid agonist at mu-receptors, and buprenorphine, a
mu-opioid partial agonist. The replacement of heroin with legally obtained opioid agonists

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reduces withdrawal symptoms and cravings. By doing so, many risk factors associated with a
drug-abusing lifestyle, including needle-sharing and risk of blood-borne illnesses like HIV and
hepatitis, can be mitigated.2,3 This paper will compare methadone maintenance treatment (MMT)
with buprenorphine maintenance therapy (BMT), proving that the stigmatization and negative
characteristics associated with methadone makes BMT a more appropriate choice for some of
these patients. However, the reality of addiction is that without significant psychological care,
the efficacy of either drug is weakened.
Methadone maintenance therapy has been the standard of care for opioid-addicted
patients for more than 30 years.2 Because of methadones long elimination half-life (8-59 hours),
it can be dosed once daily and replaces the craving for multiple daily heroin doses, ideally
stabilizing these patients lifestyles. Despite the fact that methadone is an effective and widely
accepted intervention for opioid dependence, it also has a number of negative characteristics
which have warranted research in other pharmacologic therapies. Because methadone is a full
opioid agonist at the mu-receptor, there is no ceiling effect to the level of respiratory depression
or sedation that it can induce, leading to potentially fatal adverse reactions or overdose.
Methadones abuse potential, as well as its unique use for the management of opiate
addicts, has limited its availability for these patients to methadone maintenance clinics.2 Many of
these patients also struggle with the stigmatization that comes with receiving MMT, since the
general public and even medical professionals often consider opioid dependence as a flaw rather
than a disease. For all patients, regardless of stigma, there are barriers to enter MMT. Patients
must meet specific requirements, including documented opioid dependence for one year, being at
least 18 years of age, and meeting DSM-IV criteria for opioid dependence upon evaluation.4,5 In
addition to the requirements, there is limited availability of MMT to many patients who would

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benefit from it; it is estimated that established methadone clinics can only accommodate 15-20%
of US heroin addicts.2,4
In comparison, buprenorphine offers several benefits to opioid-addicted patients that
methadone does not. Buprenorphine is a semisynthetic mu-opioid partial agonist that also
suppresses opioid withdrawal and cravings, but the property of partial agonism produces a
ceiling effect in which higher doses cause no additional effects (i.e. respiratory depression).
This ceiling effect provides a wider safety margin than methadone, allowing buprenorphine to be
administered outside of clinics and therefore making office-based treatment of opioid addiction
possible. Additionally, because of buprenorphines tight binding to the mu-receptor and long
duration of action, the action of subsequently administered opioid agonists will be blocked. By
preventing the euphoric effect of opioids, buprenorphine can reduce withdrawal as well as help
decrease the use of heroin. Physical dependence to buprenorphine is also considered milder than
with methadone, making discontinuation less difficult for the patient.4,6 In the United States,
buprenorphine is combined with naloxone, an opioid antagonist that is poorly absorbed
sublingually and orally, but is well-absorbed intravenously. Therefore, if an opioid-dependent
patient attempts to inject the medication, naloxone will occupy the mu-opioid receptors
preventing the buprenorphine from activating the receptors and thus inducing withdrawal.4
These unique characteristics of buprenorphine make it a viable option for opioid-dependent
patients who do not want or qualify for methadone maintenance.
In a landmark trial investigating the comparative efficacy of methadone to newer
pharmacologic agents for narcotic dependence, Rolley Johnson et al. randomized 162 treatmentseeking opioid addicts in a double-blind manner to receive buprenorphine or low-/high-dose
methadone treatment over a 17-week maintenance phase followed by an 8-week detoxification

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phase. The purpose of the study was to assess the efficacy of buprenorphine as a short-term
maintenance therapy when compared to two dosage levels of methadone. The three primary
outcome measures were patient retention time in treatment and two measures assessing illicit
opioid use from urine toxicology screens (three weekly urine samples negative for opioids, and
failure to maintain drug abstinence defined by two consecutive Monday urine samples positive
for opioids following four weeks of treatment).7
A total of 113 men and 49 women met the inclusion criteria for the study. The criteria
required for study participation included being within the ages of 21 and 50 years, having a selfreported duration of present addiction of at least four months, an average of two or more
episodes of heroin use per day, a self-reported daily value of heroin use of greater than or equal
to fifty dollars, a rating of four or greater on a self-reported level-of-withdrawal scale twelve
hours after the last heroin dose (0 indicating no withdrawal; 9 worst withdrawal ever
experienced), and presentation of three consecutively collected daily urine samples, at least two
of which were positive for opioids but negative for methadone by radioimmunoassay. Reasons
for exclusion from participation in the study included any acute or chronic medical (including
pregnancy) or psychiatric condition (score of 7 or higher on the Addiction Severity Index range
0-9) which may have compromised their ability to complete the study. Patients were unpaid
volunteers seeking treatment for opioid addiction, and enrollment began in September of 1988
and continued through November of 1989. The study was conducted using the outpatient
facilities at the Addiction Research Center, National Institute on Drug Abuse in Baltimore,
Maryland.7
To maintain the integrity of the study, patients received treatment with both oral and
sublingual doses daily where one dose contained the assigned treatment while the other was

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placebo. Fifty-three patients received buprenorphine hydrochloride 8 mg/day sublingually, 55

patients received methadone hydrochloride 20 mg/day orally, and 54 patients received
methadone 60 mg/day orally (patients were titrated up from 20 mg/day by daily increases of 10
mg until the 60 mg/day dosage was reached). The authors chose 20 mg/day as a treatment arm in
reaction to a published national survey of narcotic treatment programs that stated that one-tenth
of patients in methadone clinics were treated with this dose. At the time the study was produced,
it had also been recently reported that 31% of patients entering methadone treatment can be
successfully maintained on this dose for four weeks. The 60 mg/day dose of methadone was
chosen because it is approximately the median dosage used for patients in MMT. The 8 mg/day
dose of buprenorphine was selected based on previous reports that suggested efficacy
comparable to those seen with 60 mg/day doses of methadone. The authors hypothesized both
the high-dose of methadone and the buprenorphine dose to be more effective than the low-dose
of methadone.7
Patients were stratified into treatment groups by age (21 to 35 years, and 36 to 50 years),
gender, and Clinical Institute Narcotic Assessment (CINA) scores. CINA scores reflect the
results of a naloxone challenge test given to all patients prior to entering the study to further
ensure that one group was not overly represented by individuals having levels of physical
dependence on opioids greater or less than another group. Patient age was used as a stratification
variable since differences in relapse and retention rates have been shown in different age groups.
Gender differences have also been reported to affect retention in MMT, as well as potential
differences in pharmacokinetics.7
Study participants were required to come to the clinic daily to receive their medication.
Participants who missed three consecutive days of medication were dropped from the study.

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Patients completed self-report questionnaires assessing opioid withdrawal symptoms daily

throughout the study. Bi-weekly, participants completed an adverse effect questionnaire, the
Beck Depression Inventory, and visual analog scales assessing urge and need for other
drugs. To evaluate and ensure the medical safety of buprenorphine, blood samples for
hematology and chemistry panels and urine samples for analysis were collected on study days
30, 60, 90, 120, and 180. Observed urine samples were collected three times weekly on
Mondays, Wednesdays, and Fridays. A sample was considered to be positive for opioids or
cocaine if the amount of opioid or cocaine metabolite in the sample was at least 300 ng/mL.
Missing samples were counted as positives. Vital signs and patient-reported adverse effects were
monitored every two weeks or as clinically appropriate. Urine pregnancy tests were obtained
every two months. Patients were offered but not required to attend 30-60 minutes of individual
counseling weekly.7
Patient retention rates were analyzed using Coxs proportional hazards model for failuretime data for both the first 17 weeks and the total 25 weeks of the study. Patients were
considered active study participants until their third consecutive missed medication visit.
Survival analysis was used to analyze the two consecutive Monday urine samples assayed for the
presence of opioids. Monday, Wednesday, Friday urine samples were analyzed for cocaine and
opioids separately for the maintenance (17 week period) and detoxification (8 weeks following)
phases using summary Mantel-Haenszel chi-squared statistics. A chi-squared analysis was also
used to compare the data from the adverse effects questionnaire for each effect by week during
the maintenance phase. Significance was defined at a p-value of 0.05 or less.7
After the first 17 weeks of the study, patients receiving buprenorphine or methadone 60
mg/day had approximately equal retention rates (42% vs. 32%), while the retention rate of

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patients receiving methadone 20 mg/day was just 20%. When survival curves were compared
through week 17, low-dose methadone was associated with significantly poorer retention in
treatment than buprenorphine (p<0.04), but not than the high-dose methadone. No significant
difference was observed between the high-dose methadone and the buprenorphine. Low-dose
methadone was also associated with a significantly poorer retention in treatment (p<0.05), with
only 6% of patients in this group completing the entire 25 weeks of the study, vs. 30% of patients
in the buprenorphine group and 20% of patients in the high-dose methadone group. Over the 17
week maintenance phase of the study, 53% of urine samples were negative for opioids in the
buprenorphine treatment group, vs. 44% in the high-dose methadone group and 29% in the lowdose methadone group. Both the buprenorphine and high-dose methadone treatments were
significantly better than the low-dose methadone group (p<0.001, p<0.04). When only the
patients who completed the maintenance phase were considered, buprenorphine proved to be
statistically better than methadone, either low- or high-dose (p<0.02), however there was no
statistically significant difference between the groups in association to percent of urine samples
negative for cocaine. Low-dose methadone was also associated with a significantly greater fail
rate than buprenorphine (p<0.03), but not high-dose methadone, when survival curves were
compared through week 17 for two consecutive Monday urine samples positive for opioids.7
During the detoxification phase of the study, the buprenorphine and high-dose methadone
groups were associated with an average of 33% and 34% of urine samples negative for opioids,
compared to low-dose methadone, with an average of 23%; there was no significant difference
between any of the treatment groups. Significant differences between groups for the total
number of patient-reported adverse effects were observed on five measures: decreased appetite,
difficulty urinating, anxiety, sedation/drowsiness, and constipation; however, these differences

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occurred on separate weeks of the maintenance phase, and there was no pattern of results that
suggested any consistent effects either between treatments or across time.7
Based on the results of this study, retention in treatment and decreased opioid use among
patients receiving buprenorphine maintenance therapy was shown to generally be equivalent to
that seen with 60 mg/day of oral methadone and was significantly better than with 20 mg/day of
methadone. As a short-term maintenance therapy, buprenorphine appears to be as efficacious as
higher doses of methadone; however, the study does exhibit some flaws. Replacement therapies
should generally be given for at least one year, and some patients may be maintained on
replacement indefinitely. The doses of methadone used in the study were also inadequate;
methadone should be used in doses of at least 60 mg/day as lower doses are generally less
effective.4,8 The authors of the study did not assess the patients readiness to stop using, which
also plays a large part in the success of treatment.
Effectiveness of opioid dependency is largely influenced by the state of the patient prior
to seeking treatment. Individuals go through several stages, including pre-contemplation,
contemplation, action, maintenance, and relapse. When patients reach the action stage, they have
the necessary enthusiasm towards change, and willing enrollment in treatment occurs. During
maintenance, the patient learns important skills and techniques to accept change and prevent
relapse. To be successful, the patient must learn new ways to adapt to life problems. While
relapse is unfortunately common, it may predispose success in the next treatment attempt.4
In patients seeking treatment for opioid dependency, psychosocial treatment plays just as
important of a role as medication replacement therapy and outcomes are improved when used in
combination. Psychosocial treatment includes development of coping skills, involvement of
group or individual therapy, support groups, and change in the patients environment. It is also

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important to address and treat comorbid psychiatric conditions, such as depression, anxiety, and
personality disorders that often accompany these patients drug dependence.4
In conclusion, it is clear that other therapies are necessary for the successful treatment of
opioid dependence. While the rise of narcotic dependence is on the rise in the United States,
there are steps that can be taken to help patients who fall into addiction. MMT may be an
appropriate option for some patients and has been the mainstay of treatment for over 30 years,
but there are other therapies now available for patients in whom this may not be an option.
Buprenorphine has been shown as effective as methadone for the treatment of opioid dependence
and with less adverse events. Among the benefits of buprenorphine are its ceiling effect, its
ability to be managed outside of a clinic, and its combination with naloxone that discourages
diversion. A critical point for treatment in regards to these patients, however, is that medication
therapy should not be their only therapy. Psychosocial treatment is just as important in the
effectiveness of maintenance therapy and should not be overlooked. With the help of new
medications such as buprenorphine and the appropriate counseling, the epidemic of opioid abuse
can hopefully be reduced.

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Works Cited
1. Heroin Abuse and Addiction. National Institute on Drug Abuse Research Report Series.
NIH Publication Number 05-4165. Printed October 1997; Revised May 2005. Available
at: http://www.drugabuse.gov/sites/default/files/rrheroin.pdf. [Accessed June 20, 2012].
2. Preda A. Opioid Abuse. Medscape Reference. Updated February 29, 2012. Available at:
http://emedicine.medscape.com/article/287790-overview#a0199.[ Accessed June 20,
2012].
3. Methadone Monograph. Clinical Pharmacology. Revised February 16, 2010. Available at:
http://0-www.clinicalpharmacologyip.com.helin.uri.edu/Forms/Monograph/monograph.aspx?cpnum=380&sec=monphar.
[Accessed June 20, 2012].
4. Raisch DW, Fye CL, Boardman KD, Sather MR. Opioid dependence treatment, including
buprenorphine/naloxone. Annals of Pharmacotherapy 2002; 36:312-321.
5. Krambeer LL, Mcknelly WV, Gabrielli WF, Penick EC. Methadone therapy for opioid
dependence. Am Fam Physician 2001; 63:2404-2411.
6. Ling W, Wesson DR, Charuvastra C, Klett J. A controlled trial comparing buprenorphine
and methadone maintenance in opioid dependence. Arch Gen Psychiatry 1996; 53:401407.
7. Johnson RE, Jaffe JH, Fudala PJ. A controlled trial of buprenorphine treatment for opioid
dependence. JAMA 1992; 267:2750-2755.
8. Mattick RP, Kimber J, Breen C, Davoli M. Buprenorphine maintenance versus placebo or

methadone maintenance for opioid dependence (Review). The Cochrane Library 2008;
3:1-43.

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