[ R E V I E W ]
`
`by CHRISTOPHER WELSH, MD; and ADELA VALADEZ-MELTZER, MD, PhD
`
`Dr. Welsh is Assistant Professor and Dr. Valadez-Meltzer is Addiction Psychiatry Fellow—
`Both from Department of Psychiatry, Division of Alcohol and Drug Abuse, University of
`Maryland School of Medicine, Baltimore, Maryland.
`
`Buprenorphine:
`A (Relatively) New Treatment For
`Opioid Dependence
`
`ABSTRACT
`Opioid dependence is a
`significant and growing problem in
`the United States. For nearly a
`century, federal regulations have
`made it illegal for psychiatrists and
`other physicians to
`pharmacologically manage this
`condition in an office-based setting
`using opioids. The passage of the
`Drug Addiction Treatment Act of
`2000 has made it possible for all
`physicians to prescribe
`buprenorphine to patients in such
`a setting. Buprenorphine, a partial
`mu-opoid receptor agonist, has
`unique pharmacologic properties
`that distinguish it from methadone
`and other medications used in the
`treatment of opioid dependence. It
`has been shown to be as effective
`as methadone and is generally safe
`and well-tolerated. It is available in
`two sublingual formulations:
`Subutex, which contains only
`buprenorphine, and Suboxone,
`which also contains naloxone.
`Physicians who wish to prescribe
`either must obtain a special waiver
`from the federal government and
`are currently limited to prescribing
`it for 30 patients at a time.
`
`ADDRESS CORRESPONDENCE TO:
`Christopher Welsh, MD, Assistant Professor, Department of Psychiatry, Division of Alcohol and Drug Abuse,
`University of Maryland School of Medicine, 22 S. Greene Street, Box 349, Baltimore, MD 21201
`Phone: (410)328-3716; Fax: (410)328-7919; E-mail: cwelsh@psych.umaryland.edu
`
`[ D E C E M B E R ] Psychiatry 2005
`
`29
`
`Page 1
`
`RB Ex. 2017
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`

`

`INTRODUCTION
`Opioid dependence
`(addiction) is a serious problem
`in the United States. It is
`characterized by physiologic
`dependence (the development of
`tolerance and withdrawal) as
`well as a maladaptive pattern of
`opioid use with impaired control
`over use, compulsive use,
`continued use despite harm, and
`craving (Table 1). According to
`the National Survey on Drug Use
`and Health, the incidence of
`abuse of prescription opioid pain
`medications (products
`containing codeine, dilaudid,
`fentanyl, hydrocodone,
`hydromorphone, meperidine
`morphine, oxycodone,
`oxymorphone, propoxyphene)
`has risen markedly in recent
`years with 4.4 million people
`reporting non-medical use in
`2004 (up from 2.8 million in
`2000).1 The same survey found
`that in 2004, 118,000 individuals
`in the US used heroin for the
`first time. In 2003, the Drug
`Abuse Warning Network
`reported an estimated 17
`percent of drug-related
`emergency department visits
`were related to opioid analgesic
`abuse (36% of the cases
`specifically seeking
`detoxification) with eight
`percent related to heroin use.2
`According to the Office of
`National Drug Control Policy
`(ONDCP), there were an
`estimated 810,000 to 1,000,000
`individuals addicted to heroin in
`the United States in the year
`2000.3 It is believed that a rise in
`the purity of heroin (from less
`than 10 percent in the 1970s to
`between 50 and 90 percent in
`the 1990s), increased cultivation
`of poppies in Mexico, and a
`resultant reduction in price have
`given rise to new populations of
`heroin users (including many
`from the middle and upper
`classes) as heroin is now easier
`to use by noninjection routes,
`such as snorting and smoking.
`
`While opioid use itself can lead
`to serious medical problems,
`such as overdose, many of the
`consequences of opioid use are
`due to the intravenous route of
`administration. Common
`consequences include infection
`with human immunodeficiency
`virus (HIV), hepatitis B and
`hepatitis C, bacterial
`endocarditis, abscesses, emboli,
`and septicemia. Additionally,
`individuals with opioid addiction
`tend to suffer a progressive
`deterioration of quality of life.
`Loss of savings, loss of
`employment, estrangement from
`family and friends, and
`incarceration are frequent social
`consequences.
`Individuals addicted to
`opioids face many challenges as
`they battle this disease. Sudden
`discontinuation of opioids in a
`dependent patient typically
`
`results in an extremely
`uncomfortable withdrawal
`syndrome (Table 2). Some of
`these symptoms, in addition to
`craving for opioids, may persist
`for weeks and months after the
`last use of an opioid. It has been
`demonstrated that treating all
`addictions as chronic disorders
`leads to improved outcomes for
`patients.4 Opioid maintenance
`therapy has been demonstrated
`to be an effective means to
`decrease illicit opioid use in
`addicted patients.5 In the US, the
`primary pharmacologic
`treatment has been methadone.
`However, access to methadone
`treatment has been restricted by
`federal law (The Narcotic Addict
`Treatment Act of 1974) to highly
`regulated treatment programs
`variously referred to as
`Methadone Programs,
`Methadone Maintenance
`
`TABLE 1: DSM-IV-TR diagnostic criteria for substance dependence
`
`A maladaptive pattern of substance use, leading to clinically significant
`impairment or distress, as manifested by three (or more) of the following,
`occurring at any time in the same 12 month period:
`
`1. Tolerance, as defined by either of the following:
`a) a need for markedly increased amounts of the substance to achieve
`intoxication or desired effect
`b) markedly diminished effect with continued use of the same amount of the
`substance
`
`2. Withdrawal, as manifested by either of the following:
`a) the characteristic withdrawal syndrome for the substance
`b) the same (or closely related) substance is taken to relieve or avoid
`withdrawal symptoms
`
`3. The substance is often taken in larger amounts or over a longer period than
`was intended
`
`4. There is a persistent desire or unsuccessful efforts to cut down or control
`substance use
`
`5. A great deal of time is spent in activities necessary to obtain the substance,
`use the substance, or recover from its effects
`
`6.
`
`important social, occupational, or recreational activities are given up or
`reduced because of substance use
`
`7. The substance use is continued despite knowledge of having a persistent or
`recurrent physical or psychological problem that is likely to have been
`caused or exacerbated by the substance.
`
`30
`
`Psychiatry 2005 [ D E C E M B E R ]
`
`Page 2
`
`

`

`TABLE 2: Signs and symptoms of
`opioid withdrawal
`
`Abdominal Cramping
`Anorexia
`Anxiety
`Diarrhea
`Dysphoria
`Elevated Blood Pressure
`Fatigue
`Fever
`Headache
`Insomnia
`Lacrimation
`Muscle Spasms
`Mydriasis
`Myalgia
`Nausea
`Piloerection
`Restlessness
`Rhinorrhea
`Tachypnea
`Tachycardia
`Vomitting
`Yawning
`
`Programs, Narcotic Replacement
`Programs, and Opioid Treatment
`Programs (OTP). These
`programs typically have
`stringent entrance criteria and
`long waiting lists. They are often
`located in urban areas, and
`public opposition often makes it
`difficult for new programs to
`open. Several states do not have
`maintenance programs. The
`combination of the under-
`availability (approximately 1100
`programs nationally), the stigma
`(with the general public,
`patients, and healthcare
`practitioners), and the
`inconvenience (patients are
`required to attend a clinic on a
`daily basis) associated with
`receiving methadone in the OTP
`has contributed to the low rate
`of treatment among patients
`with opioid addiction. The
`National Survey on Drug Use
`and Health found that 283,000
`people in the US had received
`any treatment for heroin
`dependence in 2004.1
`Since the Harrison Narcotics
`Act of 1914, office based-
`treatment of opioid addiction
`
`has not been available in the
`United States (Table 3). Most
`physicians have become
`accustomed to treating the
`disorders related to opioid
`addiction (infectious diseases,
`abscesses, psychiatric sequelae,
`etc.) but not the addiction itself.
`The Drug Addiction Treatment
`Act of 2000 (DATA)6 has made it
`possible for physicians to
`manage opioid-dependent
`patients with opioid
`maintenance in an outpatient
`setting. This act states that a
`physician can prescribe and a
`pharmacist can dispense
`Schedule III, IV, or V “narcotic”
`medications approved by the
`Food and Drug Administration
`(FDA) for the treatment of
`narcotic-use disorders. In
`October, 2002, the FDA
`approved buprenorphine
`(Subutex®) and a combined
`formulation of buprenorphine
`plus naloxone (Suboxone®) for
`use in the treatment of opioid
`dependence.
`As of the first quarter of 2005,
`more than 4,500 physicians had
`obtained the waiver required to
`prescribe buprenorphine.
`Approximately two-thirds of
`these physicians reported that
`they had actually prescribed the
`medication.7
`
`BUPRENORPHINE
`Buprenorphine is a semi-
`synthetic opioid derived from
`thebaine, a naturally occuring
`alkaloid of the opium poppy,
`Papaver somniferum.
`Buprenorphine is a partial mu
`receptor agonist originally
`developed as analgesic but its
`potential utility for the
`management of opioid
`dependence has been discussed
`since early research in the
`1970s.8 Due to its partial agonist
`properties, buprenorphine offers
`some potential pharmacologic
`advantages over methadone in
`the management of opioid
`addiction, such as decreased
`
`respiratory depression, less
`sedation, less withdrawal
`symptoms, lower risk of toxicity
`at higher doses, and decreased
`risk of diversion. There is also
`the potential for better
`acceptance by the general
`public, patients, and healthcare
`professionals, as well as the
`ability for physicians to provide
`more integrated treatment for all
`medical/psychiatric conditions.
`Buprenorphine has three FDA
`indications: opioid
`detoxification, opioid
`maintenance, and pain
`management. Opioid
`detoxification describes the
`process in which a physically
`dependent individual is
`gradually tapered off all opioids.
`Opioid maintenance, on the
`other hand, is the long-term
`substitution with a regulated
`opioid with the goal of
`decreasing illicit drug use.
`Buprenorphine is a DEA
`Schedule III medication. Under
`federal law, buprenorphine
`(Suboxone and Subutex) can
`only be prescribed for opioid
`addiction by “qualified
`physicians” (Table 4). The
`physician is required to have an
`active DEA registration and a
`waiver to prescribe
`buprenorphine. Buprenex (the
`parenteral formulation) is not
`FDA-approved for the treatment
`of opioid dependence, and its
`use for that purpose is illegal
`and may be punishable by law.
`Additionally a “qualified
`physician” must have the
`capacity to refer patients for
`appropriate addiction counseling
`and ancillary services and must
`certify that he or she will treat
`no more than 30 patients at one
`time with buprenorphine. For
`further information on locations
`of the required eight-hour
`course or its online equivalent,
`see Table 5.
`Pharmacology.
`Buprenorphine exerts the
`majority of its effects at the mu
`
`[ D E C E M B E R ] Psychiatry 2005
`
`31
`
`Page 3
`
`

`

`TABLE 3: Select history of pharmacologic treatments for opioid dependence
`
`1860s
`
`Various “cures” for morphine and opium addiction began to appear
`
`1870s
`
`Use of cocaine to treat morphine addiction began
`
`1874
`
`Diacetyl-morphine (Heroin) was synthesized
`
`1898
`
`Heroin was marketed by Bayer for cough; also used to treat morphine
`addiction
`
`1912
`
`Morphine maintenance clinics began in Jacksonville, Florida
`
`1914
`
`Harrison Narcotics Act: used federal taxation to limit sale/transfer of
`“narcotics”
`
`1923
`
`Opioid maintenance was outlawed by the US government.
`
`1965
`
`Article published in JAMA describing success of methadone
`maintenance.
`
`1971
`
`First FDA regulations for Methadone Maintenance
`
`1972
`
`Revision of FDA regulations
`
`1973
`
`Methadone Diversion Control Act
`
`1974
`
`Narcotic Addict Treatment Act (Gave DEA power over storage, licensing,
`etc.)
`
`1970s
`
`Research with LAAM was conducted; heroin clinics started in UK; first
`use of clonidine for detoxification
`
`1985
`
`Naltrexone approved in US to treat opioid dependence
`
`1990s
`
`Buprenorphine used for detoxification from opioids; further trials with
`morphine and heroin maintenance
`
`1993
`
`LAAM approved in the US to treat opioid dependence
`
`1995
`
`2000
`
`IOM report recommending reduced regulations for methadone
`maintenance
`
`Drug Abuse Treatment Act (Section 3502 of The Children’s Health Act of
`2000)
`
`2002
`
`FDA approved Subutex and Suboxone
`
`2003
`
`Subutex and Suboxone available in pharmacies
`
`2005
`
`DATA amended: 30 patient per group practice limit lifted
`
`opioid receptor where it acts as
`a partial agonist. Because of the
`relatively decreased activation
`(compared to a full agonist),
`there is a plateau of receptor
`activation with no further effect
`from further increase in dose.
`This is in contrast with full
`opioid agonists, such as
`
`methadone and heroin, which
`exert greater opioid receptor
`activity as the dose is increased
`(Figure 1). Buprenorphine also
`has a high affinity for and slow
`dissociation from mu opioid
`receptors. This allows
`buprenorphine to block the
`effects of other opioids taken
`
`after buprenorphine. It also
`allows the clinical effects of
`buprenorphine to last
`significantly longer than would
`be expected based solely on its
`elimination half-life.
`Buprenorphine is readily
`absorbed through the
`gastrointestinal and mucosal
`membranes. However, due to
`extensive first-pass metabolism,
`buprenorphine has very poor oral
`bioavailability (10% of the
`intravenous route) if swallowed.
`Its availability is significantly
`increased with sublingual
`administration (30–50% of the
`intravenous route),9,10 making this
`a feasible route of administration
`for the treatment of opioid
`dependence. The mean time to
`maximum plasma concentration
`following sublingual
`administration is one hour,
`ranging from 30 minutes to 3.5
`hours. Buprenorphine has a large
`volume of distribution and is
`highly protein bound (96%). It is
`metabolized primarily in the liver
`via the cytochrome P-450 3A4.
`The primary products of this
`metabolism are norbuprenorphine
`and its conjugate.
`Norbuprenorphine has little
`ability to cross the blood brain
`barrier and so its effects are
`negligible. The terminal half-life
`ranges from three hours after
`intravenous administration to 28
`to 37 hours after sublingual
`administration.10 It is unclear why
`there is such a difference in half
`life depending on the route of
`administration but this may be
`related to sequestring of
`buprenorphine in the oral
`mucosa. Most of the
`buprenorphine is eliminated in
`the feces, with approximately 10
`to 30 percent excreted in urine.11
`In addition to the primary
`effects on the mu opioid receptor,
`buprenorphine also appears to act
`as an antagonist at the kappa
`opioid receptor (possibly involved
`with spinal analgesia and
`antidysphoric effects), as an
`
`32
`
`Psychiatry 2005 [ D E C E M B E R ]
`
`Page 4
`
`

`

`agonist at the delta receptor
`(clinical significance uncertain),
`and as a partial agonist at the
`opioid-receptor-like 1 (ORL-1).12
`Clinical trials. Several
`meta-analyses of studies
`comparing buprenorphine to
`placebo and methadone for the
`maintenance treatment of opioid
`addiction indicate
`buprenorphine is more effective
`than placebo and as effective as
`methadone with both drugs
`being more effective at higher
`doses.13–16 Some studies appear
`to show that buprenorphine may
`not be as effective as methadone
`for patients requiring higher
`doses of methadone (See Table
`5 for a summary of some of the
`key controlled trials). When
`reviewing the literature of
`clinical trials with
`buprenorphine, it is important to
`remember that the majority of
`earlier studies were conducted
`with a sublingual liquid solution.
`Because the absorption of this
`solution is different than
`absorption of the FDA-approved
`tablet, exact dosing comparisons
`cannot be made.
`Fewer studies have been
`conducted on short-term
`detoxification with
`buprenorphine. One large,
`multicenter study with both
`inpatients and outpatients
`demonstrated that
`buprenorphine was clearly
`superior to clonidine in
`measures of completion of
`detoxification and negative
`urine samples at the end of the
`detoxification (77% vs 22% in
`the inpatient condition; 29% vs
`5% in the outpatient
`condition).25 However, a large
`proportion of both groups did
`not complete the out-patient
`detoxification. Further research
`is needed to determine the
`longer-term outcomes of
`patients detoxified from opioids
`versus those who remain on
`buprenorphine maintenance.
`Safety. It is estimated that
`
`buprenorphine has been
`prescribed to over 100,000
`people in the United States7 and
`close to 200,000 worldwide.26 It
`is very well tolerated with side
`effects similar to other opioids
`though tending to be less severe
`and seen less often. The most
`common side effects include
`constipation, headache, nausea,
`urinary retention, and sedation.27
`Although a decrease in
`respiratory rate may be
`observed, this is generally not
`clinically significant.28 There are
`reports of fatal overdose
`involving buprenorphine and
`benzodiazepines.29,30,31 These
`reports have all come from
`Europe (where the
`buprenorphine/naloxone
`combination is not used) and
`generally involved individuals
`who appear to have injected
`benzodiazepines with dissolved
`buprenorphine tablets. Although
`there are no reports of
`significant buprenorphine
`overdoses when taken orally or
`sublingually, buprenorphine
`should be used with caution in
`individuals who have a history of
`benzodiazepine misuse.
`Mild elevation in liver
`enzymes (AST and ALT) has
`been reported in patients
`receiving buprenorphine,27,32
`
`though the clinical significance
`of this is uncertain. There is also
`a report of hepatitis following
`intravenous misuse of
`buprenorphine.33 Because of this
`potential effect on liver
`enzymes, it is recommended
`that liver function tests be
`monitored periodically during
`the course of treatment with
`buprenorphine.
`Since buprenorphine is
`metabolized primarily via the
`cytochrome p450 3A4 system,
`there is potential for interaction
`with medications that induce or
`inhibit this pathway. Common
`inducers of this enzyme include
`phenytoin, phenobarbital,
`carbamazepine, rifampin,
`afavirenz, and nevirapine.
`Common inhibitors include
`fluconazole, erythromycin,
`indinavir, ketoconazole,
`metronidazole, ritonavir, and
`saquinavir. With the exception of
`a few studies with protease
`inhibitors (see “Patients with
`HIV infection” in the “SPECIAL
`POPULATIONS” section below),
`very little research has been
`done to formally assess the
`extent of drug-drug interactions
`with buprenorphine. Clinicians
`should be aware of the potential
`for interactions with other
`medications metabolized by the
`
`TABLE 4: Requirements to become qualified to prescribe buprenorphine
`
`The physician has the capacity to refer patients for counseling and ancillary
`services. The physician is licensed under state law and meets at least one of the
`following requirements:
`
`1. Board certification in addiction psychiatry
`2. Certification in addiction medicine from the American Society of Addiction
`Medicine (ASAM)
`3. Board certification in addiction medicine from the American Osteopathic
`Association (AOA)
`4. Completion of at least eight hours in the treatment and management that is
`provided by the ASAM, AOA, the American Medical Association, the American
`Academy of Addiction Psychiatry, or the American Psychiatric Association.
`5. Participation in the clinical trials leading to the approval of buprenorphine
`6. Training or experience deemed sufficient by the physician’s state licensing
`board
`7. Training or experience deemed sufficient by the Secretary of Health and
`Human Services.
`
`[ D E C E M B E R ] Psychiatry 2005
`
`33
`
`Page 5
`
`

`

`TABLE 5: Randomized controlled trials of buprenorphine as a maintenance treatment
`
`TYPE OF STUDY
`
`#
`PTS
`
`RANDOMIZATION GROUPS
`
`OUTCOMES
`
`Double-blind double-
`dummy randomized
`trial17
`
`162
`
`Bup 8mg/day
`sublingual liquid
`
`Methadone
`20mg/day
`(low dose)
`
`Methadone
`60mg/day (high dose)
`
`Double blind
`randomized trial18
`
`140
`
`Bup 2mg/day
`Sublingual liquid
`
`Bup 6mg/day
`Sublingual liquid
`
`Methadone 35mg/day
`Methadone 65mg/day
`
`Double blind double-
`dummy randomized
`trial19
`
`162
`
`Bup 8-16mg/day
`flexible;
`sublingual liquid
`
`Methadone
`50–90mg/
`day flexible
`
`Double blind
`randomized trial20
`
`225
`
`Bup 8mg/day
`sublingual liquid
`
`Methadone
`30mg/day
`
`Methadone 80mg/day
`
`Retention in the program and percent
`negative urines. At the end of 17 weeks, 42%
`of the buprenorphine patients remained in the
`program vs 20% and 32% of low and high
`methadone patients. Urine screening showed
`similar results with the buprenorphine group
`having more negative urines than those in the
`methadone group.
`
`The 6mg buprenorphine dose reduced illicit
`opioid use better than the 2mg dose but was
`not associated with better retention. Both
`methadone doses were associated with better
`retention than either buprenorphine dose.
`
`Buprenorphine and methadone were equal in
`measures of treatment retention (56%) and
`counseling attendance. They had similar
`effects on opiate positive urines.
`
`The 8mg/day buprenorphine dose was less
`effective than the 80mg methadone dose for
`treatment retention and negative opioid
`urines. It was comparable to the 30mg
`methadone dose.
`
`Double blind
`randomized trial21
`
`116
`
`Bup 4mg/day
`sublingual liquid
`
`Bup 12mg/day
`sublingual liquid
`
`Methadone
`20mg/
`day
`
`Methadone
`65mg/
`day
`
`Both higher methadone and buprenorphine
`groups had better negative urine opioid
`positive results (45%, 58% vs 72%,77%).
`Treatment retention was similar in all groups.
`
`Multi-site double-blind
`random trial22
`
`736
`
`Bup 1mg/day
`sublingual liquid
`
`Bup 4mg/day
`sublingual
`liquid
`
`Bup 8mg/day
`sublingual
`liquid
`
`Bup
`16mg/day
`sublingual
`liquid
`
`The 8 and 16mg groups had significantly
`better rates of treatment completion. There
`was more sustained abstinence in the 16mg
`group.
`
`Double blind
`randomized trial23
`
`106
`
`Bup 16mg/day
`tablet
`
`Placebo
`
`Randomized control
`trial24
`
`220
`
`Bup 16–32mg
`3 times/week
`
`LAAM 75–100mg
`3 times/week
`
`High dose
`Meth
`60–100mg/day
`
`Low dose
`Meth
`20mg/day
`
`Retention in treatment was significantly
`better for the buprenorphine group (30%)
`than the placebo group (2%).Reported opioid
`use was significantly lower in the
`buprenorphine group.
`
`Retention in treatment and negative urine
`toxicologies at the end of 17 weeks. The
`mean retention time was 96.4±4 days for bup
`group, 89±6 days for the LAAM group , 105±4
`days for the high dose methadone group and
`70±4 days for the low dose methadone group.
`The percent of patients with twelve or more
`consecutive opioid negative urines was 26,
`36, 28 and 8 for bup, LAAM, high and low
`methadone dose, respectively. The authors
`concluded that buprenorphine, LAAM and high
`dose methadone substantially reduced illicit
`opioid use compared to low dose methadone.
`
`cytochrome p450 3A4 system
`and talk with patients about the
`possible effects on
`buprenorphine levels.
`Formulations and costs.
`Buprenorphine is currently
`available in the US in three
`formulations (Table 6). A
`transdermal product has been
`
`approved and marketed in
`Europe.34 A long-acting, depot
`formulation is also under
`development.35,36 Buprenex is a
`liquid form administrated
`intramuscularly or intravenously
`for pain management. Subutex is
`a sublingual tablet used for
`opioid addiction. Suboxone is a
`
`formulation that contains
`buprenorphine and naloxone in
`4:1 ratio. Naloxone, an opioid
`antagonist, was added to deter
`injection of dissolved pills, thus
`reducing abuse liability and the
`potential for diversion. Because
`naloxone is poorly absorbed
`sublingually, its effect when
`
`34
`
`Psychiatry 2005 [ D E C E M B E R ]
`
`Page 6
`
`

`

`Suboxone is taken properly is
`minimal. However, if the tablet is
`dissolved and injected, the
`naloxone blocks mu receptors
`and prevents receptor activation
`or precipitates withdrawal in
`opioid dependent patients.
`A 30-day supply of an average
`dose of Suboxone (two 8/2mg
`Suboxone tablets per day) costs
`approximately $287.50 from a
`retail pharmacy.37 Subutex is
`slightly more expensive than
`Suboxone. This is to discourage
`the use of Subutex, which has a
`higher potential for abuse.
`Dosing. Maintenance
`treatment of opioid addiction
`with buprenorphine can be
`divided into the following three
`phases: 1) induction, 2)
`stabilization, and 3)
`maintenance.38
`The induction phase generally
`entails the initial transition from
`illicit opioid use to
`buprenorphine, typically lasting
`from 3 to 7 days. Patient
`education is extremely important
`with emphasis on the risk of
`precipitated withdrawal if
`buprenorphine is initiated too
`soon after last opioid use
`(generally 12–24 hours for short-
`acting opioids and 24–48 hours
`for long-acting). Patients should
`also be advised to not drive or
`operate machinery until the
`effects of buprenorphine have
`been determined and the dose
`stabilized. For initiation, it is
`recommended to use Suboxone
`(combination tablet) for the
`majority of patients. Exceptions
`include pregnant women who are
`deemed appropriate for
`buprenorphine and some
`patients who are using long-
`acting opioids, such as
`methadone, in which case
`Subutex may be used initially. In
`the latter case, the patient
`should be switched to Suboxone
`after the first day.
`After it has been determined
`that the patient is exhibiting
`signs of opioid withdrawal (Table
`2), the initial doses of
`
`FIGURE 1: Mu Opioid Receptor Activation
`
`buprenorphine, usually 4/1mg of
`the buprenorphine/naloxone
`tablet (2mg if patient dependent
`on long-acting opioid) should be
`administered under direct
`observation by the physician.
`Over the next several hours, the
`patient should be monitored for
`both precipitated withdrawal and
`excessive opioid agonist effects,
`such as sedation. If, after two
`hours, the patient continues to
`exhibit signs of opioid
`withdrawal, another dose of
`4/1mg Suboxone can be
`administered. If the patient is
`dependent on long-acting opioid,
`2mg can be administered every 1
`to 2 hours. The total
`recommended dose of
`buprenorphine for the first day is
`8mg. If the patient continues to
`complain of some symptoms of
`withdrawal, other symptomatic
`treatments can be provided.
`On the second day of
`induction, the extent of
`withdrawal should be
`determined. If the patient
`reports no symptoms of
`withdrawal, the total dose from
`the first day should be repeated
`and the patient should remain on
`that daily dose. If the patient
`reports symptoms of opioid
`withdrawal, 4/1mg in addition to
`the total dose from the first day
`should be administered.
`
`Subsequent dose increases of
`2/0.5 or 4/1mg may be
`administered to a total dose of
`16mg of buprenorphine.
`Over the subsequent days of
`the induction phase, the above
`procedure should be repeated to
`a maximum dose of 32/8mg per
`day by the end of the first week.
`If the patient continues to
`complain of opioid withdrawal,
`illicit opioid use should be
`suspected. If the patient
`continues to struggle with opioid
`use, increased psychosocial
`intervention is likely to be
`necessary.
`The stabilization phase
`generally lasts 1 to 2 months and
`is a period of adjusting the
`medication to establish the
`minimum dose required to
`eliminate withdrawal symptoms,
`reduce opioid craving, and
`minimize side effects. For most
`patients, this will be achieved at
`a daily dose of 12/3 to 24/6mg of
`Suboxone per day. Some patients
`may require 32/8mg per day.
`Frequent contact with the
`patient may be necessary during
`this period to facilitate dose
`adjustment and enhance
`adherence. The need for further
`psychosocial addiction treatment
`should continue to be assessed
`during this period. Some
`evidence suggests that, with a
`
`[ D E C E M B E R ] Psychiatry 2005
`
`35
`
`Page 7
`
`

`

`TABLE 6: Available formulations of buprenorphine
`
`TRADE NAME
`
`ROUTE OF
`ADMINISTRATION
`
`INDICATION
`
`DESCRIPTION
`
`Subutex
`
`Sublingual
`
`Opioid maintenance
`and detoxification
`
`White oval tablet with
`sword inlay
`
`AVAILABLE
`STRENGTHS
`
`2mg, 8mg
`
`Suboxone
`(combination
`buprenorphine and
`naloxone)
`
`Buprenex
`(also available as a
`generic)
`
`Sublingual
`
`Opioid maintenance
`and detoxification
`
`Orange hexagonal
`tablet with sword
`inlay
`
`2mg (with 0.5mg
`naloxone
`8mg (with 2mg
`naloxone)
`
`Intravenous
`Intramuscular
`
`Pain management
`
`Liquid
`
`0.3mg/mL
`
`16mg sublingual dose, it may be
`possible for patients to take
`buprenorphine every other
`day.39,40
`The maintenance phase is
`indefinite and must be
`determined individually with
`each patient, taking into
`consideration his or her specific
`goals of treatment. During this
`period, it is important that the
`physician continue to monitor
`the patient for illicit drug use,
`cravings, and triggers to relapse.
`It is also important to insure that
`psychosocial issues are being
`addressed, either within the
`physician’s practice or by other
`counseling or self-help
`mechanisms. The decision to
`discontinue buprenorphine must
`be carefully discussed with each
`patient. A plan for dealing with
`relapse should be defined.
`For detoxification, Suboxone
`or Subutex may be used. The
`initial dose is generally 4 to 8mg
`of buprenorphine with 2 to 4mg
`as needed for additional signs
`and symptoms of withdrawal.
`Twice per day dosing may be
`preferable during acute
`detoxification. The dose is then
`tapered over a variable amount
`of time (days to weeks). The
`physician is not limited to the
`72-hour, directly observed
`dispensing that is required with
`the use of other opioids for
`
`detoxification.
`For patients admitted to a
`general hospital for a condition
`other than opioid dependence
`specifically, buprenorphine can
`be used to manage opioid
`withdrawal while the other
`condition is being treated. In
`this specific situation, the
`prescribing physician does not
`need to have their federal
`buprenorphine waiver. Similar
`doses to those used in
`outpatient detoxification may be
`used. Higher and more frequent
`doses may be more effective in
`managing concomitant, mild to
`moderate pain, such as that
`experienced with cellulites or
`an abscess.
`Special populations.
`Pregnant patients.Infants
`exposed to opioids in utero,
`whether illicit or prescribed,
`typically show signs of
`withdrawal after birth. This
`withdrawal is referred to as the
`neonatal abstinence syndrome
`(NAS). Methadone maintenance
`has been shown to improve
`maternal and newborn outcomes
`in pregnant opioid dependent
`patients.41 A review of the
`current literature suggests that
`maintenance with
`buprenorphine may also
`improve maternal and fetal
`outcomes and that the resultant
`NAS may be less intense than
`
`that seen with methadone.42,43
`Buprenorphine is currently a
`Category C drug in pregnancy.
`There is more evidence to
`support the use of methadone,
`which is Category B, in
`pregnant patients. If methadone
`is unavailable and it is deemed
`necessary to treat with
`buprenorphine, the risks and
`benefits should be explained to
`the patient and Subutex, not
`Suboxone, should be used.
`Breast feeding patients.
`Although the data are limited, it
`is clear that buprenorphine does
`pass into the breast milk of
`lactating women.44 Because of
`the poor oral bioavailability, it is
`not clear how much of this
`buprenorphine is absorbed by
`the nursing infant. Limited
`clinical reports appear to show
`that NAS is not suppressed by
`the presence of this
`buprenorphine and that NAS
`does not generally develop when
`breast feeding is stopped.43,45
`Although the Suboxone and
`Subutex package inserts advise
`against breast feeding while
`taking buprenorphine, the
`apparently minimal effect on the
`infant may not necessitate
`discontinuation of the
`medication. Further research
`should help clarify this issue.
`Adolescent patients.
`Although the use of
`
`36
`
`Psychiatry 2005 [ D E C E M B E R ]
`
`Page 8
`
`

`

`buprenorphine has not been
`systematically studied in this
`population, it is reasonable to
`consider it as a first-line
`pharmacologic treatment after
`detoxification and “drug-free”
`treatment has been attempted.
`Rules concerning the need for
`parental consent for an
`adolescent to receive addiction
`treatment vary from state to
`state. It is important for any
`physician considering the use of
`buprenorphine in an adolescent
`to be thoroughly familiar with
`the appropriate laws in his or
`her state. It is also useful to
`have some knowledge of
`treatment resources available
`for adolescents as these are
`often different than those
`available for adults.
`Geriatric patients. There is
`no specific literature addressing
`the use of buprenorphine in
`elderly patients. Because of the
`potential differences in
`absorption, distribution, and
`metabolism, caution should be
`exercised in elderly patients,
`especially during the induction
`phase. Potential medication
`interactions should be
`considered.
`Patients with HIV infection.
`HIV infection is a common
`comorbid condition with opioid
`dependence. Buprenorphine has
`the potential to both help
`prevent HIV transmission and
`improve the adherence with
`treatment in patients already
`infected with HIV.46 The current
`standard of care for HIV
`infection is highly active
`antiretroviral therapy (HAART).
`One study examined the use of
`buprenorphine for opioid-
`dependent patients taking
`HAART. It concluded that
`patients receiving
`buprenorphine were more likely
`to adhere to the HAART
`regimen than untreated opioid
`dependent patients47 and tha