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THERAPY IN PRACTICE

Pharmacologically Assisted Treatment of Opioid-DependentYouth

Anna Pecoraro • Marc Fishman • Michelle Ma •

Gvantsa Piralishvili • George E. Woody

! Springer International Publishing Switzerland 2013

Abstract Opioid misuse, abuse, and dependence areglobal problems whose patterns vary across cultures. In the

USA, the non-medical use of prescription opioids has

become particularly serious because of its association withaddiction and overdose death. Agonist and antagonist

medications have been shown to be effective for opioid-

dependent adults, and there is a growing body of data thatthey are also effective for youth. Here, we summarize

evidence that detoxification alone results in high rates of

treatment dropout and relapse but that the limited butgrowing data on the extended use of medication-assisted

treatment for opioid-dependent youth have been positive.

The implementation of medication-assisted treatment as astandard practice is feasible, easily integrated with coun-

seling or psychotherapy, and has potential to greatly

improve outcomes. Although concerns about safety andefficacy with youth require more research, and we do not

advocate indefinite maintenance, we suggest that opioid-

dependent youth should be considered as candidates formedication-assisted treatment delivered in a comprehen-

sive, developmentally appropriate context, beginning at the

first episode of care, with the strength of the recommen-dation to use medication increasing with each care episode.

1 Prevalence and Impact of Opioid Use in Youth

The use of opioids for non-medical purposes is an interna-

tional problem. For example, in 2009, the United NationsOffice on Drugs and Crime estimated that 12–21 million

people aged 15–64 years used opioids for non-medical rea-sons, and approximately three quarters were heroin users [1].

In Asia, between 6.4 and 12 million people used opioids, in

Europe between 3.1 and 3.5 million, and in North and SouthAmerica between 1.2 and 1.9 million [1]. Non-medical use of

prescription opioids (i.e., buprenorphine, fentanyl, hydroco-

done, morphine, oxycodone, hydrocodone, and others) hasbecome a serious problem in the USA but is less common than

heroin use in Europe [1]. In some parts of Asia, opium is

common in addition to heroin [1], and in former Soviet states,desomorphine (‘crocodile’) has become increasingly popular

as an inexpensive heroin replacement [2].

Among American adolescents, non-heroin opioid usemore than doubled between 1975 and 2008 from 3.5 % to

A. Pecoraro ! G. E. Woody (&)Department of Psychiatry, Perelman School of Medicine,University of Pennsylvania, 600 Public Ledger Building,150 South Independence Mall West, Philadelphia,PA 19106-3413, USAe-mail: woody@tresearch.org

A. Pecoraro ! G. E. WoodyDelaware Valley Node, Clinical Trials Network,Philadelphia, PA, USA

M. FishmanDepartment of Psychiatry and Behavioral Sciences,Johns Hopkins University School of Medicine,Baltimore, MD, USA

M. FishmanMountain Manor Treatment Center, Baltimore, MD, USA

M. FishmanMid-Atlantic Node, Clinical Trials Network,Baltimore, MD, USA

M. MaUniversity of Michigan Medical School, Ann Arbor, MI, USA

G. PiralishviliInternational Relations and Projects Management Unit,Center for Mental Health and the Prevention of Addiction,Tbilisi, Georgia

Pediatr Drugs

DOI 10.1007/s40272-013-0041-5

Author's personal copy

over 9 % [3] and in 2009, 2.2 million Americans aged

12 years or older used prescription opioids includinghydrocodone, oxycodone, and morphine as their first illicit

drug, a figure second only to the number of new marijuana

users [3]. After marijuana, prescription opioids were thesecond most frequently used illicit drug among Americans

aged 12–17 years in 2005 [4–6] and while not as prevalent,

approximately 250,000 US high school students reportedhaving used heroin at least once, and 77,000 Americans

aged 18–20 years reported using it in the past year, up from56,000 in 2008 [3].

Like adult opioid users [7, 8], their adolescent coun-

terparts experience a wide range of substance-relatedproblems. For example, adolescent heroin addicts recruited

on the streets in Spain showed high levels of psychopa-

thology, especially mood and personality disorders [9].Treatment-seeking American adolescent opioid users,

compared with those who used alcohol and/or marijuana,

were more likely to drop out of school, abuse multiplesubstances, and have severe depression [10]. Among

injection drug users aged 16–25 years in Los Angeles and

New York, over 90 % of those who began using pre-scription opioids later used heroin, and many of them

started by injecting prescription opioids before transition-

ing to intravenous heroin [11] with the associated risks ofcontracting hepatitis B and C, and human immunodefi-

ciency virus (HIV). In a randomized clinical trial com-

paring extended with short-term buprenorphine-naloxonefor opioid-dependent youth, almost half of the patients

reported injection drug use, and one fifth had hepatitis C

[12].A US study comparing treatment-seeking adolescents

using prescription opioids with heroin-using adolescents

[10] found that the prescription opioid users were morelikely to use other substances (e.g., marijuana, alcohol,

sedatives, and other stimulants), have more than one sub-

stance use disorder meeting Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition (DSM-IV)

criteria, underutilize substance abuse treatment services

[13], and be court mandated to treatment. Both groups hadhigh rates of psychiatric disorders but the prescription

opioid users were more likely to have attention-deficit

hyperactivity disorder and to have had psychiatric treat-ment, while the heroin users were more likely to drop out

of school, meet DSM-IV criteria for opioid dependence,

and report injection drug use and needle sharing.

2 Pharmacologically Assisted Treatments

Pharmacologically assisted treatments for opioid depen-

dence have been well studied in adults. Full (methadone)and partial agonist (buprenorphine) medications are used

for detoxification and maintenance, and an antagonist

(naltrexone) can be used for long-term relapse preventionin patients who have been detoxified, particularly in set-

tings where agonists are either legally unavailable (e.g.,

Russian Federation [14, 15]), less likely to be used (e.g.,criminal justice system [16]), or functionally inaccessible

because of insurance or travel restrictions. Psychosocially

assisted pharmacological treatments for opioid dependenceare recommended as efficacious by the World Health

Organization [17], with agonist maintenance viewed as themost effective.

Unlike treatment for opioid-dependent adults, most

adolescent treatment is predominantly psychosocial, con-sisting of short-term detoxification and subsequent indi-

vidual or group therapy in residential or outpatient settings

[12]. According to the Treatment Episode Data Set(TEDS), which records admissions to publically funded

inpatient and outpatient drug and alcohol treatment in the

USA, of the 251,930 admissions of patients aged 12–20years for treatment of opioid use disorders in 2010, only

4,575 (2 %) were associated with a treatment plan using

buprenorphine or methadone [18]. Few studies of phar-macologically assisted treatments for opioid dependence

have been done with adolescents, [19, 20] as seen in a

systematic review [21] that identified only two clinicaltrials [12, 22], both of which were positive. While this

article is not a systematic review, we searched Scopus and

PubMed for relevant studies on medication-assisted treat-ments used with adolescents, with no date or language

restrictions.

2.1 Detoxification

Detoxification, or brief managed withdrawal, is typicallythe first step in treatment, but relapse without on-going

treatment after completing detoxification is high [7, 23],

and few studies have been done with adolescents. Gandhiet al. [24] examined outcomes of 123 heroin-dependent

patients aged between 18 and 25 years who received a

3-day outpatient detoxification with buprenorphine; noattempts were made to engage them in subsequent treat-

ment. Relative to baseline, they found a reduced frequency

and intensity of opioid use over the 3-month follow-upperiod, but this was without evidence of remission, and

there were low rates of engagement in subsequent treat-

ment. Although 96 % of the patients were retained over the3-day detoxification, only 6.7, 10.1, and 11.8 % had opi-

oid-negative urines at 1, 3, and 6 months, respectively.

A systematic review of outcomes following detoxifica-tion [25] found just two randomized trials among adoles-

cents. One [26] compared buprenorphine with clonidine for

a 28-day outpatient detoxification and found no significantdifferences in dropout rates or withdrawal symptoms

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between the groups, but the small number of participants

(N = 36) had limited statistical power for group compari-sons [25]. The other study [12] (discussed below) com-

pared short-term (14-day) detoxification with

buprenorphine with extended treatment with buprenorphineand found that patients who received extended treatment

had much better outcomes.

2.2 Agonist Treatments

Methadone, a long-acting l opioid agonist pioneered as a

maintenance treatment by Dole and Nyswander [26], is the

most well-known medication used for this purpose. Thoughoften used for detoxification [27], it is most effective when

used as part of a long-term maintenance program as seen in

many studies that have shown that it reduces illicit opioiduse, retains patients in treatment where they can receive

services for other problems [28], and reduces mortality and

morbidity [29], illegal activities [30], and the chances ofbecoming infected with HIV [31].

Millman et al. [32] described the outcomes of 153 her-

oin-dependent adolescents treated with methadone between1968 and 1977 in New York. The mean daily dose was

40 mg (range 10–70 mg), and the program included

counseling, medical care, and educational, vocational,legal, and recreational services. Patients were slowly

withdrawn from methadone when they met specific criteria

demonstrating that returning to heroin use was unlikely andwere offered continued counseling and access to other

program services. A total of 59 patients (39 % of those

admitted) completed a dose taper, and 41 (70 %) of themremained drug free. As of 1977, of the 153 patients who

entered the program, 49 (32 %) had continued on metha-

done; 45 (29 %) had completed a dose taper and remainedin the program, and 51 (33 %) had been discharged. Of

those who were discharged, 10 % dropped out voluntarily,

12 % were transferred, 11 % were asked to leave theprogram for disciplinary reasons, 4 (2.6 %) were incar-

cerated, and 4 (2.6 %) died.

Another agonist medication is buprenorphine, a partial lopioid agonist with a higher safety margin and less severe

withdrawal than methadone [33–35]. The US Food and Drug

Administration (FDA) approved it for patients aged 16 yearsandolderin2002,anditcanbeprescribedingeneralhealthcare

settings in the USA by qualified practitioners without daily

frequently observed dosing, as required for methadone. It hasbeen formulated as a sublingual tablet that must be dissolved

under the tongue to be effective and is available as a ‘mono’

product (Subutex", Reckitt Benckiser), and as a tablet con-taining four parts of buprenorphine to one part naloxone (Su-

boxone", Reckitt Benckiser) to discourage patients from

crushingandinjectingit.Morerecently,aSuboxone"filmwasdeveloped, that like the tablets, isdissolvedunder the tongue.

Both Suboxone" and Subutex" are available outside the

USA; however, regulations for how they are administeredvary by country. For example, in France, any physician can

prescribe buprenorphine, while in the USA it can be pre-

scribed for opioid-dependence treatment only by physi-cians who have completed an 8-h training course and are

approved by the Drug Enforcement Administration. In

September 2010, Reckitt Benckiser took Subutex" tabletsoff the market in the USA in response to reports of

diversion and abuse. In late September 2012, ReckittBenckiser announced that it will stop distributing Subox-

one" tablets in the USA and only provide the Suboxone"

film because of five overdose deaths in children whoinadvertently took tablets belonging to adults [36].

Smyth et al. [37] conducted a retrospective study of 100

heroin-dependent adolescents who were maintained on anagonist medication at a specialized youth clinic in Ireland

over an 8-year period. Methadone was the only available

medication there until buprenorphine became available in2005. Methadone or buprenorphine (Subutex", Subox-

one") were the main treatments, but individual and group

counseling and family therapy were available; 81 patientsreceived methadone, and 19 received buprenorphine.

Methadone was initiated at 20 mg and titrated to

40–70 mg; buprenorphine was initiated at 2 mg in themorning of the first day, with 2–6 mg in the afternoon, and

titrated to 6–12 mg/day. Half of the patients were retained

in treatment for 12 months or more, and of those patients,39 % were abstinent from heroin at that time point.

Overall, 22 % left the program through planned detoxifi-

cation, 32 % dropped out, 8 % were incarcerated, and39 % were referred to an adult program after turning

20 years of age. There were no deaths during treatment.

Bell and Mutch [38] conducted a retrospective medicalrecords review of 61 heroin-dependent adolescents treated

with methadone or buprenorphine in Australia. They found

that time in treatment was significantly longer for patientswho received methadone, and patients who received bu-

prenorphine re-entered treatment significantly sooner. They

concluded that methadone is more effective than bupr-enorphine in this population, but these findings need to be

tested in a randomized controlled study.

Woody et al. [12] conducted a randomized trial ofextended versus short-term buprenorphine-naloxone with

152 opioid-dependent adolescents aged 15–21 years in the

USA. Patients in the extended-treatment group were pre-scribed up to 24 mg/day for 9 weeks and then tapered to

0 mg by week 12; those in the short-term group were

prescribed up to 14 mg/day and tapered to 0 mg by day 14;both groups were offered individual and group counseling

for 12 weeks. Patients who received extended treatment

reported less opioid use and injecting, stayed in treatmentlonger, and at weeks 4 and 8 had significantly fewer opioid-

Treatment of Opioid-Dependent Youth

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positive urine drug screens. Both groups had high levels of

opioid use at follow-up, after treatment ended. The authorsconcluded that buprenorphine-naloxone is effective for

opioid-dependent youth and patients may benefit from a

longer course of treatment with the medicine.

2.3 Antagonist Treatment

Naltrexone is a long-acting l opioid antagonist that com-

petitively blocks receptors so that patients feel no opioideffects unless they use extremely high doses [39, 40]. It

will precipitate withdrawal if given to someone who is

physiologically dependent on opioids and should only beused in patients who have completed opioid detoxification

and have no residual signs or symptoms of physiological

dependence, which can be confirmed by a negative nal-oxone challenge. It was originally developed as a 50-mg

tablet to be taken daily, but low patient interest and poor

adherence limited the usefulness of the tablets, exceptamong highly motivated individuals who would likely have

severe adverse consequences if they used drugs, such as

those on probation or parole or healthcare professionalsbeing monitored by state boards [41, 42]. These problems

led to the development of sustained-release formulations.

One product is injected, provides opioid blockade for1 month (Vivitrol"; XR-NTX), and was approved by the

US FDA for opioid-dependence treatment in 2011 [43]. A

second product is an implant that blocks opioid effects for2–3 months and is approved for use in the Russian Fed-

eration (Prodetoxon") [15]. A third is an implant that

blocks opioid effects for 3–6 months and has been used inover 3,000 patients in Australia but has not been approved

by any regulatory agency [44].

A literature search revealed only two naltrexone studiesdone with adolescents. One was a medical records review

in Australia [45] of eight high-risk adolescent heroin users

who received a single or double naltrexone implant one ormore times and demonstrated a dramatic reduction in

hospitalizations for accidental opioid overdose. Single

implants provided an estimated blockade for 80 days, anddouble implants provided an estimated blockade for

165 days. Of interest was that all patients had multiple

hospitalizations for overdoses before receiving the implant,but only two overdoses were reported afterwards, and both

occurred after the implant had stopped working. One sub-

ject had an overdose 83 days after a single implant, andanother had an overdose 333 days after a double implant.

A case-series study on XR-NTX for opioid-dependent

youth was conducted in Maryland on 16 opioid-dependentindividuals with a mean age of 18.5 years [46] who were

treated in an outpatient program after residential opioid

detoxification using buprenorphine. The program includedmonthly XR-NTX, twice-weekly group and once-weekly

individual cognitive behavioral/motivation enhancement

therapy, and physician visits beginning weekly and taper-ing to monthly. Ten patients were retained in treatment for

4 or more months and had ‘good’ outcomes, as seen by

markedly decreased opioid use, improvement in at leastone psychosocial area, and no new problems related to

substance use.

3 Clinical Decision Making

Although no comprehensive international standards on

opioid maintenance treatment in adolescents exist [37],several countries have guidelines. For example, the UK

recently published best practice guidelines on pharmaco-

logically assisted treatments for young people and recom-mended use of methadone and buprenorphine for short-

term detoxification. Although they stated that agonist

maintenance is not usually a goal for this age group, theyrecommended methadone and buprenorphine for short-

term maintenance followed by a slow reduction within the

context of a comprehensive treatment program for thosewith severe dependence aged 16 years and older, with the

expectation that they had relapsed after a previous attempt

at drug-free treatment [47]. Previous Canadian [48]guidelines stated that adolescents should not receive opioid

maintenance unless they have failed a detoxification

treatment, but the latest guidelines do not require faileddetoxification as a condition for maintenance treatment

[49].

US law (42 CFR 8.12) allows patients aged under18 years who have failed two previous drug-free or

detoxification attempts within a 12-month period to receive

methadone maintenance with parent/guardian permission[50]. In the USA, methadone is administered at licensed,

regularly inspected clinics that are designed for people over

18 years of age. Clinics are required to have daily oralmost daily observed dosing for the first 3 months, after

which take-home doses can be given if there is proof that

the patient is making progress and will use the methadoneresponsibly [50]. In contrast, buprenorphine is approved for

the treatment of opioid-dependent individuals aged

16 years and older and can be prescribed by physicianswho have completed an 8-h course and are approved by the

Drug Enforcement Administration. There is a limit of 30

patients in treatment at any one time during the first year,but physicians can apply to treat up to 100 patients there-

after [51]. Naltrexone is not a controlled substance and has

no prescribing restrictions.An important principle for medication-assisted treat-

ment or any treatment is that it should be developmentally

appropriate in the context of a safe location with rules thatare clearly stated, consistently enforced, and with

A. Pecoraro et al.

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reinforcing enough to facilitate compliance as well as

retention. The physical condition of the patient should bechecked at intake and periodically during treatment, look-

ing for injecting sites, cellulitis, and signs or symptoms of

intoxication or withdrawal. Initial investigations shouldalso include urine toxicology testing and screening for

blood-borne viruses (hepatitis B and C, HIV), with referral

for medical treatment if necessary.The initial evaluation should also include screening and

referral for the treatment of other psychiatric disordersbecause problems such as anxiety, depression, and atten-

tion-deficit hyperactivity disorder are common. However,

it is important to keep in mind that patients often report lowmood and anxiety when they present for treatment but that

these symptoms usually improve with cessation of drug use

[52]. Counseling and psychotherapy typically augment theeffects of medication, thus the treatment plan should

include individual and group drug counseling that focuses

on medication adherence, increasing motivation to stay‘clean,’ stopping drug use, and developing a goal-directed

and recovery-oriented lifestyle. In addition, it is important

to meet with family members to enlist their support for theoverall treatment plan because they may feel conflicted

about medication-assisted treatment, and to explore barri-

ers that might interfere with school or work attendance,development of healthy social relationships, and maturing

into an adult social role.

Although there have been no studies to identify types ofpatients who are more or less likely to accept and respond

to any of the three medications that are currently available

for opioid-dependence treatment (methadone, buprenor-phine, extended-release injectable naltrexone), clinical

experience suggests some questions to be considered. One

is whether youth with opioid dependence should be treatedpharmacologically past the point of brief acute detoxifi-

cation; a second is if there should be a ‘fail-first’ expec-

tation of relapse following a previous episode ofpsychosocial treatment without medications; and a third is

the choice of drug class or drug (see Table 1). Because of

the morbidity and mortality associated with opioid depen-dence, the evidence that psychosocial-only treatments are

associated with very high rates of treatment dropout and

relapse, and the emerging evidence for the effectiveness ofcurrently available pharmacological treatments, we suggest

that opioid-dependent youth with physiological features

(DSM-IV-Text Revised [53]) be offered one of the threeFDA-approved medications as a component of the first

episode of care, with the strength of this recommendation

increasing with each subsequent episode. This neither callsfor medications to replace psychosocial interventions nor

for universal, indefinite ‘maintenance’ treatment. Rather,

pharmacologically assisted treatment in this populationshould augment psychosocial treatment as part of a

comprehensive treatment plan, and the use of medications

might range from short-term stabilization followed by aslow taper (i.e., ‘extended’ detoxification), to medium-term

extended treatment with an agonist, to longer-term treat-

ment (but not indefinite maintenance) with an agonist,based on individual response and treatment history, or the

extended-release version of the antagonist naltrexone for

an extended time after detoxification. It is important to notethat none of these variations encompass a ‘lifetime’ dura-

tion of medication use, which is a prospect that raisesunderstandable concerns, and for which there is no evi-

dence in this population.

As for the choice of drug, in terms of agonists, thechoices are methadone or buprenorphine-naloxone

(Suboxone"). At least in the USA, methadone is limited as

an option, because the existing delivery system lacksyouth-specific treatment components, requires parental

permission for persons aged under 18 years, and is gener-

ally not adolescent friendly. For this reason, the recom-mendation of methadone for young adult patients in the

USA is usually reserved for individuals aged 18 years and

above who are more adult-like in their presentations or whohave been refractory to other treatments. Buprenorphine

can be delivered in primary care, has less restrictive take-

home policies than methadone, and is much less likely toproduce a life-threatening overdose than methadone if

taken in excessive doses. A buprenorphine-naloxone sub-

lingual film that has all the above advantages and is easy toadminister because it quickly dissolves when placed under

the tongue has been the only available formulation of Su-

boxone" in the USA since March 18, 2013 [54]. The thirdeffective pharmacotherapy is extended-release injectable

naltrexone (Vivitrol"; XR-NTX). It received FDA

approval for the treatment of opioid-dependent individualsaged 18 years and older in 2010, and its use has been

increasing. It might be more acceptable than methadone or

buprenorphine-naloxone to adolescents and/or their fami-lies because it has no abuse liability, does not interact with

benzodiazepines or other drugs to produce a ‘high,’ and

needs to be administered only once per month. It has beentested primarily in adults, and there is no reason to believe

that its effects or adverse effects will be different in ado-

lescents than adults, but studies have not been done thatfocus on its use with opioid-dependent youth.

In choosing a pharmacotherapy, one of the most

important factors is patient and family choice, both becausepeople will usually find a way to get what they want and

even more so because of the general intuition that patient

motivation is enhanced by choice. Because of its morerecent introduction, there is at present much less recogni-

tion of and knowledge about XR-NTX among the public.

Buprenorphine-naloxone has a growing reputation, bothpositive and negative, that precedes it, and many

Treatment of Opioid-Dependent Youth

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Table 1 Comparison of pharmacologic agents used in opioid-dependence treatment

Methadone [55, 56] Buprenorphine [57, 58] Naltrexone [59, 60]

Type Full agonist Partial agonist Antagonist

Dosing Dosing observed for first 3 months.‘Take home’ doses allowed basedon treatment progress

No more than 30 mg on first dosewith additional dosing up to 40 mgallowed based on response

Recommend increases of 5–10 mgevery 3–7 days to maintenancelevel of 80–120 mg/day

Initial dosing typically observed butnot required. ‘Take home’ dosesallowed in first week with up to30 days of ‘take home’ dosesallowed based on progress

First dose typically 6–8 mg withincrease to maintenance doseaveraging 16 mg/day within2–3 days; upper dosing limit of32 mg/day

Patient should be in mild ormoderate opioid withdrawal priorto first dose

Extended-release injectable(Vivitrol") administered monthly;intramuscular injection required,typically in buttocks. US FDAapproved for treatment of opioidand alcohol dependence

Implant (Prodetoxon") approved inRussian Federation. Inserted underskin of abdominal wall bysurgically trained medicalpersonnel. Blocks opioids for2–3 months. Patient must be freeof physiological opioiddependence prior to dosing withany naltrexone product

Used for Detoxification

Maintenance

Detoxification

Maintenance

Relapse prevention afterdetoxification

Formulations used inopioid dependence

Oral concentrate, typically mixedwith Tang

Sublingual tablet or film

Formulated as buprenorphine(Subutex"), or as a combination offour parts of buprenorphine to onepart of naloxone (Suboxone")

Vivitrol" extended-release injection.

Prodetoxon" implant

Contraindications andcautions

Hypersensitivity to methadone

Respiratory depression

Acute bronchial asthma

Known or suspected paralytic ileus

Hypersensitivity to buprenorphine ornaloxone

Respiratory depression

Physiologically dependent onopioids and not in withdrawal priorto first dose

Acute hepatitis or liver failure

Opioid analgesics needed for paincontrol

Physiologically dependent onopioids prior to first dose

Hypersensitivity to naltrexone orother components of the injectionor implant

Patients should be told … Physiological dependence willoccur; will have withdrawal ifstopped

Can result in fatal overdose ifconsumed by a person who is notopioid dependent

Can impair ability to drive or operateheavy machinery if dosing levelexceeds level of opioid tolerance

Overdose deaths have occurredwhen used with high doses ofbenzodiazepines or other centralnervous system depressants,including alcohol

Physiological dependence willoccur; will have withdrawal ifstopped

Can result in fatal overdose ifconsumed by a person who is notopioid dependent

Can impair ability to drive or operateheavy machinery if dosing exceedslevel of opioid tolerance

For preparations containingnaloxone, injecting use bysomeone dependent on heroin orother full opioid agonists willprecipitate withdrawal

Overdose deaths have occurredwhen used with high doses ofbenzodiazepines or other centralnervous system depressants,including alcohol

Blocks opioid effects and protectsfrom relapse if used as directed

Need to inform medical caregiversthat non-opioid alternatives will beneeded for pain relief oranesthesia. Should carryemergency medical notificationcard

Before treatment Medical and addiction history Medical and addiction history Medical and addiction history

Physical examination Physical examination Physical examination

Mental status examination Mental status examination Mental status examination

Screen for psychiatric disorders Screen for psychiatric disorders Screen for psychiatric disorders

Urine drug screen Urine drug screen Urine drug screen

Naloxone challenge

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adolescents may have had a positive previous experience

with it owing to the relief of cravings and withdrawal,either when obtained non-medically (‘on the street’) or

when used for detoxification. This may lead them to prefer

buprenorphine, and such a request should not be rejectedout of hand as ‘drug-seeking.’ However, the next factor, as

in most clinical decision making, is that failure with one

medication should lead to a change in the treatment plan,meaning either a change in the structure of treatment

delivery (e.g., increased or different psychosocial treat-

ment, increased monitoring) or a switch to anothermedication.

Table 1 continued

Methadone [55, 56] Buprenorphine [57, 58] Naltrexone [59, 60]

Induction Be sure patient not sedated orintoxicated before dosing

No more than 30 mg on initial dose;can increase to 40 mg on first dayif initial dose does not suppresswithdrawal

Check for withdrawal, intoxication,or respiratory depression after firstdose

Slowly titrate up in increments of5–10 mg every 3–5 days untilwithdrawal suppressed for 24 h

Patients must be in mild withdrawal(Clinical Opiate Withdrawal Scalescore of 5 or more often used toverify)

Initial dose typically 4–8 mg

Titrate in increments of 2–8 mg overfirst 2–4 days until withdrawalsuppressed for 24 h

Confirm absence of opioidphysiologic dependence withnaloxone challenge or by closeobservation, preferably on secureinpatient unit prior to dosing

Maintenance Recommended dose 80–120 mg/day Usual dose 16 mg; maximumrecommended dose is 32 mg/day

Withdrawal Variable; based on symptoms andpatient’s level of comfort. Mostrecommend 5–10 % reduction1–7 days

Variable; based on symptoms andpatient’s level of comfort. Mostrecommend 5–10 % reduction1–7 days

No withdrawal

Non-medicationinterventions (usedduring or aftermedication treatment)

Urine drug screens

Counseling/psychotherapy

Evaluate for emergence of medical,psychiatric, social, legal, andfamily problems; respond asneeded

Consider changing medication ortreatment approach if notresponding

Encourage participation in self-helpgroups

Urine drug screens

Counseling/psychotherapy

Evaluate for emergence of medical,psychiatric, social, legal, andfamily problems; respond asneeded

Consider changing medication ortreatment approach if notresponding

Encourage participation in self-helpgroups

Urine drug screens

Counseling/psychotherapy

Evaluate for emergence of medical,psychiatric, social, legal, andfamily problems; respond asneeded

Consider changing medication ortreatment approach if notresponding

Encourage participation in self-helpgroups

Potential adverse effects Sedation, cognitive impairment,poor coordination, respiratorydepression, or overdose iftolerance exceeded, particularly ifused with high doses ofbenzodiazepines, alcohol, or othersedatives

Prolonged QT interval

Constipation

Fluid retention

Allergic reactions

Sedation, cognitive impairment,poor coordination, respiratorydepression, or overdose iftolerance exceeded, particularly ifused with high doses ofbenzodiazepines, alcohol, or othersedatives

Allergic reactions

Hepatotoxicity if more thanrecommended doses used

Eosinophilic pneumonia

Nausea

Anxiety

Injection- or implant-site reactions

Allergic reactions

Warnings Possible adverse events listed above Possible adverse events listed above Possible adverse events listed above

Opioid overdose at the end of adosing interval, after missing adose, or in an attempt to overcomeopioid blockade

Not all medications and formulations are universally available. This table does not contain all contraindications, warnings, adverse effects, orother information necessary to prescribe these drugs; clinicians are advised to consult complete prescribing information and all applicable lawsand regulations in force in their locale

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Compliance enhances the success of any treatment, and

XR-NTX has the advantage of once-monthly dosing andeasy verification of dose delivery. Parents may have a sense

(though perhaps somewhat exaggerated) of protection and

the prospect of relief from worries, and their enthusiasmand motivation may be a reason to select XR-NTX.

Although the month-long duration is a plus, the need for

strategies to ensure subsequent dosing adherence shouldnot be trivialized. Buprenorphine, as a partial agonist, has

the advantage of intrinsic self-reinforcing properties suchthat patients may like it for the way it makes them feel, in

advance of later learning to be reinforced by the natural

rewards of abstinence. Conversely, buprenorphine requiresdaily dosing, which limits its effectiveness if the patient

skips doses. Strategies to overcome this include parental

supervision, daily program medication administration, andothers, but these entail burdens themselves.

Because of the requirements of naltrexone induction (post-

detoxification opioid-free washout period of approximately7 days to avoid precipitated withdrawal), it is generally easier

to accomplish in an inpatient or residential setting where

access to opioids can be limited by confinement. In this way,XR-NTX has the potential to become a more natural or

organic feature of inpatient treatment, which is often the

preferred entry point for opioid-dependence treatment inadolescents because of the complexity of their presentations

in broad life crises beyond simple opioid withdrawal. How-

ever, inpatient/residential treatment is not always available,and because of this, buprenorphine may have the advantage

of being more easily available in outpatient settings where

induction can be accomplished without delay. Of course,adherence must be monitored with buprenorphine-naloxone

treatment, and the occurrence of a diversion should be a

reason to consider switching to XR-NTX.While there can be stigma associated with any medication-

assisted treatment, it tends to be more prominent with agonists

and partial agonists than with antagonists. One example of aculture in which there is often a particular stigma associated

with pharmacologically assisted treatment is that of Alco-

holics Anonymous and Narcotics Anonymous. While 12-stepmutual and self-help groups can be a vital force in recovery,

many harbor skepticism, even antipathy, towards pharmaco-

logically assisted treatment, particularly agonists [46]. Inthese and other settings where buprenorphine may have less

acceptability, there may be a preference for XR-NTX.

4 Conclusions

Evidence demonstrates the inefficacy of detoxification-only

treatments and high rates of dropout from psychosocial-

only treatment for opioid-dependent youth. Although moreresearch needs to be done to establish safety and efficacy of

medication-assisted treatment with youth, there is

increasing evidence that agonist and antagonist medica-tions are effective and can be easily combined with psy-

chosocial treatment. The implementation of medications

(i.e., buprenorphine-naloxone and XR-NTX) as standardpractice is feasible in specialty care settings, easily inte-

grated with counseling or psychotherapy, and has the

potential to greatly improve treatment outcomes. Metha-done is another option, but access is limited because of

regulatory barriers and unavailability in many locations,and program environments may not be suited to youth. Of

course, unresolved concerns about the safety and efficacy

of these medications with young people need to beaddressed with more research specific to them, and more

work needs to be done on articulating and testing youth-

specific models of care. However, given the growingproblem of opioid dependence in this underserved popu-

lation, it would be wise to adopt medication-assisted

treatment more broadly by advocating for its integrationinto treatment programs, building program capacity, and

addressing the problem with the urgency that it deserves.

Acknowledgments No funding sources were used to prepare thisarticle, but MF is a member of the Clinical Advisory Board forOrexo, which manufactures a buprenorphine product for which it isseeking FDA approval. MF has an equity interest in a communitytreatment provider (Maryland Treatment Centers) at which youthopioid treatment is delivered, including medications. GW and APreceived salary support from NIDA U10 DA-13043, and GW receivedsalary support from NIDA KO5 DA-17009. GW was the principalinvestigator of a Clinical Trials Network (CTN) study on buprenor-phine among adolescents in which the medication was supplied byReckitt-Benckiser, and Alkermes has provided XR-NTX for a studyin which he is a co-investigator. MF received salary support fromNIDA R01 DA02455301, NIDA-VA CS #1030, and NIDA-VA CS#1031. MF participated in a CTN study on buprenorphine amongadolescents in which the medication was supplied by Reckitt-Benckiser, and Alkermes has provided XR-NTX for a study in whichhe is a co-investigator. GP is a co-investigator of a study of Subox-one" and methadone for HIV risk reduction, funded by NationalInstitute on Drug Abuse grants R21-DA-026754, U10 DA-13043, andKO5 DA-17009. Reckitt Benckiser supplied Suboxone" for the trial.MM and AP report no conflicts of interest.

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