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HomeMy WebLinkAbout2016-08-08 16-290 Council Documents (18) The NEW ENGLAND JOURNAL of MEDICINE • REVIEW ARTICLE Dan L Longo,M.D.,Editor Treatment of Opioid-Use Disorders Marc A. Schuckit, M.D. THIS ARTICLE PROVIDES AN OVERVIEW OF THE CURRENT TREATMENT OF From the Department of Psychiatry,Uni- opioid-related conditions, including treatments provided by general practi- Aeddress California,ireqests Di �r soJolla.t tioners and by specialists in substance-use disorders. The recent dramatic at the University of California,San Diego, increase in misuse of prescription analgesics, the easy accessibility of opioids such 8950 Villa La Jolla Dr.,B-218,La Jolla,CA as heroin on the streets, and the epidemic of opioid overdoses underscore how 92037,or at mschuckit@ucsd.edu. important it is for physicians to understand more about these drugs and to be able N Engl J Med 2016;375:357-68. to tell patients about available treatments for substance-use disorders. DOl:10.1056/NEJMra1604339 Copyright©2016 Massachusetts Medical Society. Opioids include most prescription analgesics as well as products of the poppy plant (e.g., opium, morphine, and codeine)." Although opioids usually are pre- scribed to control pain, diminish cough, or relieve diarrhea, they also produce feelings of euphoria, tranquility, and sedation that may lead the patient to con- tinue to take these drugs despite the development of serious related problems. These problems include the need to escalate doses in order to achieve these desired effects; such levels of opioids can overwhelm respiratory drive and lead to death"'2 Opioid-use disorders are seen in persons from all educational and socioeconomic backgrounds. Recognition of such disorders has contributed to efforts to change • physicians' prescribing practices and to train first responders regarding the parenteral administration of naloxone (Narcan or Evzio), a mu-opioid receptor antagonist.2 In the United States,an estimated 400,000 persons have used heroin in the past month and 4 million have reported nonmedical use of prescription pain relievers 3-5 By some estimates, almost 17,000 deaths per year are related to opioids; drug poisoning is one of the leading causes of accidental death in the United States. Approximately 3 million persons in the United States and almost 16 million world- wide have a current or past opioid-use disorder.6 The global burden of disease from opioid-related conditions approaches 11 million life-years lost from health prob- lems, disabilities, and early death.' In the 2013 Diagnostic and Statistical Manual of Mental Disorders of the American Psy- chiatric Association (Table 1), an opioid-use disorder is defined as the repeated oc- currence within a 12-month period of 2 or more of 11 problems, including with- drawal, giving up important life events in order to use opioids, and excessive time spent using opioids. A cluster of 6 or more items indicates a severe condition.'"$ The clinical course of opioid-use disorders involves periods of exacerbation and remission,but the underlying vulnerability never disappears.'This pattern is similar to that of other chronic relapsing conditions (e.g., diabetes and hypertension) in which perfect control of symptoms is difficult and patient adherence to treatment is often incomplete. Although persons with opioid problems are likely to have extended periods of abstinence from opioids and often do well,' the risk of early death, primarily from an accidental overdose, trauma, suicide, or an infectious disease (e.g., human immunodeficiency virus [HIV] infection), is increased by a factor of 2010-15 Legal problems are especially likely in persons with criminal re- 0 cords and high impulsivity.13 The risk of adverse outcomes decreases markedly with abstinence from opioids 9,16 N ENGLJ MED 375;4 NEJM.ORG JULY 28,2016 357 The New England Journal of Medicine Downloaded from nejm.org on July 29,2016.For personal use only.No other uses without permission. Copyright©2016 Massachusetts Medical Society.All rights reserved. The NEW ENGLAND JOURNAL of MEDICINE Table 1.Diagnostic Criteria for an Opioid-Use Disorder.* TREATMENT OF OP 101 D- WITHDRAWAL SYNDROMES • Use of an opioid in increased amounts or longer than intended Persistent wish or unsuccessful effort to cut down or control opioid use Treatment of acute withdrawal syndromes (i.e., Excessive time spent to obtain,use,or recover from opioid use medically supervised withdrawal or detoxifica- Strong desire or urge to use an opioid tion)17 can improve the patient's health and fa- cilitate his or her participation in a rehabilita- Interference of opioid use with important obligations tion program. This treatment also may help Continued opioid use despite resulting interpersonal problems,social problems patients better consider abstinence from opioids (e.g.,interference with work),or both because they can think more clearly once the Elimination or reduction of important activities because of opioid use acute withdrawal phase has passed. However, by Use of an opioid in physically hazardous situations(e.g.,while driving) itself, medically supervised withdrawal is usu- Continued opioid use despite resulting physical problems,psychological ally not sufficient to produce long-term recovery, problems,or both and it may increase the risk of overdose among Need for increased doses of an opioid for effects,diminished effect per dose, patients who have lost their tolerance to opioids or botht (i.e., the need for higher doses of the drug to Withdrawal when dose of an opioid is decreased,use of drug to relieve with- produce effects) and resume the use of these drawal,or botht drugs.1°,12 Repeated misuse of opioids produces tolerance as well as long-lasting craving that *If two or three items cluster together in the same 12 months,the disorder is mild;if four or five items cluster,the disorder is moderate;and if six or more usually requires additional treatment in order to items cluster,the disorder is severe.Criteria are from the Diagnostic and avoid a relapse of drug use. Statistical Manual of Mental Disorders,fifth edition.8 The abrupt discontinuation of opioids after t If the opioid is taken only as prescribed,this item does not count toward a diagnosis of an opioid-use disorder. long-term, intense use produces symptoms that are opposite to those of the acute effects that Table 2.Clinical Opiate Withdrawal Scale for Measuring Symptoms.* • Sign or Symptom Score Resting pulse rate measured after patient has been sitting or lying for 1 min—beats/min s80 0 81-100 1 101-120 2 >120 4 Sweating during past half hr not accounted for by room temperature or physical activity No report of chills or flushing 0 Subjective report of chills or flushing 1 Flushed or observable moisture on face 2 Beads of sweat on brow or face 3 Sweat streaming off face 4 Restlessness observed during assessment Patient able to sit still 0 Patient reports difficulty sitting still but is able to do so 1 Frequent shifting or extraneous movements of legs and arms 3 Patient unable to sit still for more than a few seconds 5 Pupil size Normal size for room light 0 Possibly larger than normal for room light 1 Moderately dilated 2 So dilated that only rim of iris is visible 5 • 358 N ENGLJ MED 375;4 NEJM.ORG JULY 28,2016 The New England Journal of Medicine Downloaded from nejm.org on July 29,2016.For personal use only.No other uses without permission. Copyright©2016 Massachusetts Medical Society.All rights reserved. TREATMENT OF OPIOID-USE DISORDERS 4110 Table 2.(Continued.) Sign or Symptom Score Bone or joint achest None 0 Mild,diffuse discomfort 1 Severe diffuse aching of joints,muscles,or both 2 Patient is rubbing joints or muscles and is unable to sit still because of discomfort 4 Runny nose or tearing not accounted for by cold symptoms or allergies None 0 Nasal stuffiness or unusually moist eyes 1 Nose running or tearing 2 Nose constantly running or tears streaming down cheeks 4 Gastrointestinal upset during past half hr None 0 Stomach cramps 1 Nausea or loose stool 2 Vomiting or diarrhea 3 Multiple episodes of diarrhea or vomiting 5 Tremor in outstretched hands None 0 Tremor can be felt but not observed 1 Slight tremor observable 2 Gross tremor or muscle twitching 4 • Yawning observed during assessment None 0 Once or twice during assessment 1 Three or more times during assessment 2 Several times/min 4 Anxiety or irritability None 0 Patient reports increasing irritability or anxiousness 1 Patient obviously irritable or anxious 2 Patient so irritable or anxious that participation in assessment is difficult 4 Piloerection Skin is smooth 0 Piloerection of skin can be felt or hairs standing up on arms 3 Prominent piloerection 5 *For each item,the clinician should record the score that best describes the patient's signs or symptoms.Only signs or symptoms that are related to opiate withdrawal should be rated.For example,if the patient's heart rate is increased be- cause he or she was jogging just before the assessment,the increased pulse rate would not be included in the score. Scores should be entered at time zero,30 minutes after the first dose of buprenorphine,2 hours after the first dose, and so forth.A score of 5-12 indicates mild withdrawal,13-24 moderate withdrawal,25-36 moderately severe with- drawal,and more than 36 severe withdrawal.Data are from Wesson and Ling.18 t Only pain that is directly linked to withdrawal from opiates should be scored. result from physiologic changes during drug use. clature. Withdrawal syndromes include physical These changes result in what might be called symptoms (e.g., diarrhea and dilated pupils), physical dependence, although physical depen- generalized pain, and psychological symptoms dence is not part of the official diagnostic nomen- (e.g., restlessness and anxiety) (Table 2).18 Symp- N ENGLJ MED 375;4 NEJM.ORG JULY 28,2016 359 The New England Journal of Medicine Downloaded from nejm.org on July 29,2016.For personal use only.No other uses without permission. Copyright©2016 Massachusetts Medical Society.All rights reserved. The NEW ENGLAND JOURNAL of MEDICINE toms of abstinence syndromes after discontinu- symptoms of autonomic overactivity.22 Anxiety ation of shorter-acting opioids such as heroin and insomnia are treated with benzodiazepines • begin within hours after receiving the prior dose or other sedating drugs. Diarrhea, nausea, and and decrease greatly by day 4, whereas with vomiting are addressed with loperamide (Imo- misuse of longer-acting opioids, such as metha- dium), prochlorperazine (Compazine), or both, done (Dolophine), withdrawal begins after sev- along with sports drinks or intravenous fluids. eral days and decreases at approximately day 10. Pain is mitigated with nonsteroidal antiinflam- Opioid antagonist—precipitated withdrawal begins matory agents such as naproxen (Aleve). Such almost immediately and lasts approximately an combination therapies are superior to placebo in hour after intramuscular or subcutaneous admin- alleviating symptoms, but they are not as effec- istration of 0.4 to 2 mg of the short-acting antago- tive in relieving symptoms as a methadone or nist naloxone every 2 to 3 minutes (up to a total buprenorphine taper. dose of 10 mg). Acute withdrawal symptoms are followed by weeks to months of protracted with- OPIOIDS FOR TREATING WITHDRAWAL drawal syndromes that include fatigue, anhedo- Although methadone and buprenorphine for nia, a poor appetite, and insomnia 1,19 withdrawal are administered only in specialty The most effective approach to treating a programs by physicians with special training, it patient who has withdrawal is to prescribe a may be useful for nonspecialists to understand long-acting oral opioid (usually methadone or these approaches in order to explain the treat- buprenorphine [Buprenex]) to relieve symptoms ment process to patients whom they refer to and then gradually reduce the dose to allow the specialty programs. Because opioid-withdrawal patient to adjust to the absence of an opioid. syndromes are caused by rapidly decreasing drug However, only licensed addiction-treatment pro- levels after repeated exposure, symptoms can be grams (both office-based treatments and inpa- reduced by administering other opioids to dimin- tient treatments) and physicians who have com- ish symptoms and then weaning the patient off pleted specific training regarding opioid drugs the new drug.1'4,23 Although any mu-opioid re- can administer opioids to treat opioid-use disor- ceptor agonist that is long-acting (to create a • ders20 Such medically supervised withdrawal can smoother withdrawal) and oral (for ease of ad- also involve the use of nonopioid medications ministration) might work, most studies have that help to control symptoms.21,22 focused on methadone or buprenorphine. This section thus begins with the more gen- erally available but less effective withdrawal Methadone Taper regimen with the use of less closely controlled Methadone, an oral mu-opioid agonist, has a medications than those that are available in spe- half-life of 15 to 40 hours.23 Controlled trials cialty clinics. show that the use of methadone tapers in pa- This review does not describe ultrarapid pro- tients who misuse other opioids is superior to tocols that precipitate withdrawal with the use placebo and a2-adrenergic agonist-based regimens of naltrexone in heavily sedated patients because for managing withdrawal symptoms and retain- the close medical monitoring of heavily sedated ing patients in treatment programs.24 patients is more expensive and more dangerous The condition of patients is first stabilized and produces no better outcomes than the opioid with a dose that mitigates withdrawal but does tapers discussed below. Finally, ultrarapid with- not oversedate (Table 4). Then, in outpatients, drawal protocols by themselves are not likely to doses are decreased by 10 to 20%D every 1 to 2 days increase long-term abstinence from opioids. over 2 to 3 weeks or longer.25 The taper can oc- cur over approximately 1 week in inpatients who DECREASING SYMPTOMS WITH a -ADRENERGIC are going through withdrawal from short-acting AGONISTS AND OTHER NONOPIOID AGENTS drugs such as heroin and, as discussed below, As indicated in Table 3, a2-adrenergic agonists can be as slow as 3% of the dose per week in such as clonidine (Catapres) or tizanidine (Zana- patients who are discontinuing methadone main- flex) can be used on an off-label basis to de- tenance.26 Flexible administration of the drug on crease anxiety, piloerection, and other signs and the basis of a patient's response is important. • 360 N ENGLJ MED 375;4 NEJM.ORG JULY 28,2016 The New England Journal of Medicine Downloaded from nejm.org on July 29,2016.For personal use only.No other uses without permission. Copyright©2016 Massachusetts Medical Society.All rights reserved. TREATMENT OF OPIOID-USE DISORDERS 411, Table 3.Opioid-free Treatment of Opioid Withdrawal.* Medication j Target Symptoms Dose: a2-Adrenergic agonist Clonidine(Catapres)g Increased pulse rate and blood pres- 0.1-0.2 mg orally every 4 hr up to 1 mg/day;hold dose if blood sure,anxiety,chills,piloerection pressure<80 mm Hg systolic or<50 mm Hg diastolic;by day 5,start to decrease dose by 0.2 mg/day Clonidine patch Increased pulse rate and blood pres- The patch is an alternative for patients 100-200 lb(45.4-90.7 kg), sure,anxiety,chills,piloerection with oral dose augmentation,but few data are available Benzodiazepine Temazepam(Restoril) Insomnia 15-30 mg orally at bedtime Diazepam(Valium) Anxiety 2-10 mg orally as needed every 4 hr,up to 20 mg/day Gut-acting opioid:loperamide Diarrhea 4 mg orally initially,then 2 mg as needed for loose stools,up to (Imodium) 16 mg/day NSAID:naproxen (Aleve) Bone,muscle,joint,or other pain 500 mg orally twice daily as needed(take with food) Antiemetic Prochlorperazine(Compazine) Nausea and vomiting 5-10 mg orally every 4 hr as needed Ondansetron (Zofran) Nausea and vomiting8 mgorallyevery8 hr as needed *A physical examination should be performed,and abscesses from injections and related conditions should be treated.Human immunodefi- ciency virus infection,hepatitis,and other infections should be ruled out or treated.The patient should be screened for his or her willingness to participate in a rehabilitation program. NSAID denotes nonsteroidal antiinflammatory drug. t Medications are administered according to symptoms;not all medications are administered to every patient.Also,there are few definitive data indicating that any drug of a class (e.g.,naproxen as an example of an NSAID) is superior to any other drug of the class.The medica- tions listed are examples of only one possible medication.Data are from Kowalczyk et al.21 and Gowing et al.22 *Doses are approximate. S Clonidine is used on an off-label basis for opioid withdrawal.Tizanidine(Zanaflex) is an alternative a2-adrenergic agonist cited in the litera- ture and used en an off label basis for opioid withdrawal,and outsidc the United States,lofcxidinc at a dose of 0.1 mg every 1 hours (up to III2 mg per day) has been used. I Buprenorphine Taper precipitating more intense withdrawal, buprenor- Buprenorphine is an analgesic that is available phine should be initiated 12 to 18 hours after as a sublingual monotherapy or in combination the last administration of opioids in patients with naloxone as a film strip for sublingual use who misuse shorter-acting opioids (48 hours in (e.g., Suboxone or as a generic formulation) or in patients who are receiving long-acting drugs such a buccal dissolving film (Bunavail). This review as methadone), with initial doses of 4 to 8 mg. focuses on buprenorphine itself, which is a mu- Additional doses up to 16 mg may be adminis- opioid receptor partial agonist (binding only tered, depending on the patient's response.After partially to the mu-opioid receptor with result- the patient's condition is stabilized for 3 to 5 days, ing competitive antagonism of concomitantly the dose is often decreased over 2 or more administered full agonist drugs), an agonist of weeks; more opioid-free urine samples are seen delta and opioid-like receptor-1 (or nociceptin) with a 4-week reduction protocol than with a opioid receptors, and a kappa-receptor antago- shorter reduction protocol. nist.27-29 Like methadone, it has advantages of oral administration and a long"functional"half- APPROACHES TO REHABILITATION life. (With a half-life of 3 hours, buprenorphine AND MAINTENANCE does not easily disassociate from mu-opioid re- ceptors.) BACKGROUND Methadone and buprenorphine produce simi- Once patients express interest in discontinuing lar improvements during opioid withdrawal, or diminishing drug use,the core of care depends although buprenorphine is associated with less on the same kinds of cognitive behavioral ap- sedation and respiratory depression. To avoid proaches that are used for other chronic, relaps- • N ENGLJ MED 375;4 NEJM.ORG JULY 28,2016 361 The New England Journal of Medicine Downloaded from nejm.org on July 29,2016.For personal use only.No other uses without permission. Copyright©2016 Massachusetts Medical Society.All rights reserved. The NEW ENGLAND JOURNAL of MEDICINE Table 4.Treatment for Symptoms of Opioid Withdrawal with the Use of a Taper with Long-Acting Opioid Agonists or Partial Agonists.* • Step Oral Methadone Sublingual Buprenorphine Preparation Perform physical examination Perform physical examination.Administer bu- prenorphine approximately 12-48 hr after most recent opioid use and while patient is having early withdrawal symptoms(e.g., score>10 on the Clinical Opiate Withdrawal Scalet) Initial dose If patient is participating in a metha- 4-8 mg done program,verify dose;start taper 10 mg below that level;if pa- tient is not participating in a meth- adone program,start at 10-30 mg administered in divided doses Stabilization at effective 7-14 days 2-5 days dose Taper Administer 10-20%of initial dose Decrease dose to 0 by reducing dose 10-20% every 1-2 days over 2-3 wk or more every 1-2 days over 2 wk or more *To ensure the patient's health and to relieve withdrawal symptoms,a long-acting opioid agonist or partial agonist can be administered and then slowly tapered.If possible,the patient should be cared for in an inpatient or outpatient reha- bilitation program.All doses are approximate for an average patient and vary according to the patient's condition and additional medications.It is very important to check the patient 1 to 3 hours after the medication is administered in order to adjust the dose and avoid doses that are too high or too low for the individual person. t Scores on the Clinical Opiate Withdrawal Scale range from 0 to more than 36,with higher scores indicating a greater severity of withdrawal. ing conditions, such as hypertension and dia- NALTREXONE FOR ABSTINENCE-ORIENTED OPIOID • betes mellitus.1,3o These approaches include REHABILITATION working with patients to encourage motivation Naltrexone is a mu-opioid receptor antagonist to change, enhance adherence to medication that blocks opioid effects and helps maintain through education, reward cooperation with abstinence from opioids in highly motivated pa- treatment guidelines,30,31 keep motivation high, tients.23,28 It is available in 50-mg daily tablets and teach ways to minimize relapses to drug with effects lasting 24 to 36 hours. To help use. Most of these elements are part of motiva- maintain adherence to treatment when used as tional interviewing.32 part of an outpatient rehabilitation program, it Unlike some rehabilitation approaches for is also available as an extended-release inject- some other disorders, patients with substance- able formulation containing 380 mg of nal- use disorders are encouraged to participate in trexone (Vivitrol) that blocks opioid effects for self-help programs such as Alcoholics Anony- 1 month.34-36 mous and Narcotics Anonymous 30'33 The combi- Medication treatment is most effective when nation of education, motivational enhancement, it is administered as part of a cognitive behav- and self-help groups, which are incorporated ioral approach (to enhance motivation, work to- into individual and group counseling approach- ward behavioral changes, and prevent relapse) es in inpatient and outpatient programs, helps with patient participation in a self-help group. patients change how they think about the ways Side effects of these medications include gastro- that opioids affect their lives, recognize that intestinal upset, fatigue, and insomnia, as well change is possible, and work to decrease behav- as elevated levels on liver-function tests at higher iors that perpetuate illicit-drug use while devel- doses, although naltrexone is relatively safe in oping new behaviors that diminish drug-related persons who consume large amounts of alcohol problems 1'30 and those with hepatitis C or HIV infection.23,36,37 Patients who initiate naltrexone treatment must be free of physiological opioid dependence • 362 N ENGLJ MED 375;4 NEJM.ORG JULY 28,2016 The New England Journal of Medicine Downloaded from nejm.org on July 29,2016.For personal use only.No other uses without permission. Copyright©2016 Massachusetts Medical Society.All rights reserved. I TREATMENT OF OPIOID-USE DISORDERS • (e.g., >7 days without acute withdrawal symp- m y R T 1 toms) (Table 5). Opioid-free status can be estab- 0 lished by an opioid free urine sample and a o 8 T E v s R c " E co X E „ ' •- challenge with 0.8 to 1.6 mg of intravenous or u .... .1 =4-- L- N .'CL v o intramuscular naloxone with no withdrawal ° E▪ 0 0 3 • g s,, Ra, £ m symptoms over the next 15 to 30 minutes before 1- =� >7..--->.,---...t29'13 '` O O O c t0 0c L .D.,- -E receiving naltrexone (at a dose of 50 mg) that :. - ao_ o bA7-0.° '" a t, a„ 2- - .2 I:07 0c ^ a„ s same day. An alternative challenge is to adminis- o 3 -o v N W o N o 0. o R j._ ter a small dose of naltrexone(e.g., 12.5 to 25 mg) ,,i_, 8 N v g s N Y R a '8 s 3 „ r� o orally, and if no withdrawal is seen over the next m =° v c R T'3 Y-° ° 2'1' 'o 2 0 y U .0 R c c 2 fC c N y•H 4 hours, administer 50 mg orally. After the pa- _ - -6 ;;_ „ go o Lb• 1-▪ 13 „ o E E c 73 tient's condition is stable and he or she is absti- E .E '..i 0 a 5 E_• 0 3 „ E N c3 v, c -0-1.,-.0•E.O •• c O '^ > „ nent from opioids, it may be possible to switch • Y b0 N Y t o „E n a 0-61)s -i- to 100 mg orally on Monday and Wednesday and 80° E 3 = °-a 0 3-0 E o ca _2 ” 150 mg on Friday, or to monthly depot injec- _ Z .FS tions. If naltrexone is used following abstinence m a E T from opioids after methadone or buprenorphine o - 0 •.,71 L a3 ” o." maintenance, the induction might be slower(e.g., 0 o o N -C d E v G o x V E 12.5 mg orally on day 1; 25 mg on days 2 and 3; • U -. o.E `°V o a-0 oh • 34,38 O �c „ >.._ „d „ pn and then 50 to 100 mg thereafter). N E 0 3 2 7 2 oo E 8 N c :° bD a „ O m C Efficacy studies have generally used oral „ Y N >,a c c E � v 3 0 0 rather than intramuscular doses of naltrexone ° o ;°o ° ° o _ n ;, " v. ' 8 v s v °' R cd� v 3 0-070 v but both forms are superior to placebo for main- t 3 A " �" o g= • '� . .z! taming abstinence from opioids, with some evi- E „ v • " ° g „ �`.0 3 u �p 2 V1▪ c.- to O n.N „ c T„ t- 0 c dence that monthly injections are superior to v a a R 0 T E.3 o V 3, 3 . > >. 35,39 m. E' °. „ u c w O o a v s c6-0 „"7„' m c oral doses. However, in most studies of oral ;, -� b -0 o tgg r,-° „ 0 E •7,s „ •E • naltrexone, approximately 50% of patients dis- 4,2 E V M-° 0 • `g cu E continued the drugby6 weeks, with only15% n v •N ° E co� ”:=.CU aY' „ ao. E. bD 3-n N i=,M . E 00 V 0 > 3 remaining in the study at 25 weeks in some c o 0 2 v E N evaluations 40 Higher rates of adherence are seen I'D Z U- -n with opioid maintenance,as described below.11,41is: 0 ° OO v N ti >. - _ O O-- T '� :2 c 6p •c E 5 In addition, because of the loss of tolerance that 8 200E a o ° E o E O T. bA U•v „ occurs with abstinence from opioids, the danger 03 a �� o 8 00 E 0 0 of overdoses that may lead to death is enhanced o s o among patients who discontinue naltrexone and o p c o Y -0 o -0 c Y a r return to opioid use 11 = E 0 3 �u�3 3 °A o o o'3^ s w E .6 4• x O of `,, ,a O 0 E, „ ° ut O is „ v Q - w E-aw0 E vi c• £ v. x y OPIOID MAINTENANCE APPROACHES a f, m 0 3 2 m u z:d .E y o u u2 22 Opioid-dependent persons who are reluctant to z _o 3 0 `o 0 0co,0 - a C O or unable to discontinue opioids but want to E OS a 00 `° ``` d0 y •- u as " ° a' " �v: E = '^-0 m A t co 0->0 improve their health and life situation can _ LL co Y v N m 2 7_ E 8 0 c-o markedly improve their daily functioning with Y "- o o > _t cs O c „ R In a, U R °_N .A O 3 R Lb LA eN-° „• „ .D a = O v„i opioid treatment. Oral opioids to avoid past = = -T o •� 0 0 U- R v bD reinforcement associated with needles, as well U a v °-' as relatively inexpensive, long-lasting opioids to a0 0 avoid daily withdrawal symptoms and enhance `~° c E c o adherence,are available 10,11,42 Maintenance goals . c •X 800 O c o c c include improving health, avoiding contami- 2 -o 0 „ a nated needles and risks of HIV or hepatitis C 3 LL c co N c U U ° `° 0 o c— co v O E infection, improving interpersonal relation- o C ° , E 0 ships and the ability to work, decreasing crav- R 0 v CU 0 s U III ing and the rewarding effects of illicit opioids, I- '" a Ce •s .a++ N ENGLJ MED 375;4 NEJM.ORG JULY 28,2016 363 The New England Journal of Medicine Downloaded from nejm.org on July 29,2016.For personal use only.No other uses without permission. Copyright©2016 Massachusetts Medical Society.All rights reserved. The NEW ENGLAND JOURNAL of MEDICINE and diminishing crimes committed to pay for initial oral doses of 15 to 30 mg, increasing by illicit drugs. 10 to 15 mg every 3 to 5 days to 50 to 80 mg per • Maintenance programs should include psy- day. During the late stabilization phase (at ap- chological support, require participants to take proximately weeks 3 to 6), doses are increased part in counseling, offer education about how to as tolerance develops and craving decreases.The deal with pain syndromes without misusing most effective dose is 80 to 100 mg per day.47.50 prescription opioids, and warn patients to avoid Patients who receive more than 100 mg per day misuse of other drugs such as benzodiazepines must be closely monitored for side effects 44,46,50 and gabapentin (Neurontin) that they might use The maintenance phase begins at approxi- to create a high while receiving opioid-agonist mately 6 weeks, with doses adjusted to avoid treatment.It is important to carefully monitor the drug-related euphoria, sedation, or opioid crav- use of illicit drugs and diversion of the medica- ing. Methadone clinics must be open on week- dons eektions for opioid treatment to other users 43 Al- ends in order to meet the needs of most pa- though,theoretically,any long-acting oral opioid tients,51 and weekend take-home doses are based might be used for maintenance, the only ap- on the patient's progress in treatment and deter- proved drugs for this use in the United States mination that he or she is unlikely to divert are methadone and buprenorphine. medications to other persons.The length of the maintenance phase, which depends on the pa- METHADONE MAINTENANCE APPROACHES tient's progress in treatment and his or her Maintenance treatment with methadone, an oral motivation, can last years to a lifetime. mu agonist, has been widely used and intensively Tapering off methadone is individualized and studied worldwide. In the United States, metha- may take weeks or months.26 During and after done is offered only through approved and tapering, close contact with the patient should closely monitored clinics that initially require be maintained because discontinuation of main- almost daily patient participation in order to tenance carries high risks of relapse to the use receive the drug,although some take-home doses of illicit drugs and overdoses that may lead to are usually allowed for patients who adhere to death 11,52,53 • program guidelines. The effectiveness of methadone maintenance To be eligible for methadone maintenance, is well established,and this drug is listed among patients must have a current opioid-use disorder "essential medications" by the World Health with physiologic features or have high risks as- Organization.11,45 Maintenance programs de- sociated with relapse (e.g., during pregnancy).In crease mortality by approximately 50% among addition, patients cannot be currently participat- persons with opioid-use disorders, decrease ac- ing in another maintenance program and cannot quisition of HIV infection and hepatitis, decrease be especially vulnerable to methadone-related crime and illicit-substance use, improve social medical complications (e.g., they cannot be de- functioning,and increase the rate of retention in pendent on a depressant drug or have severe rehabilitation programs.155054,55 respiratory or cardiac disease). Dangers associ- ated with methadone include overdose if the BUPRENORPHINE MAINTENANCE dose is increased too quickly during the initial In the United States, the restriction of metha- stages of treatment and a potential prolongation done to specialized clinics contributed to a of the QT interval on electrocardiography that search for an alternative oral,long-acting opioid. can contribute to cardiac arrhythmias with This search resulted in buprenorphine mainte- doses higher than 100 mg per day.44-46 Patients nance therapy.6,56,57 must understand their roles and responsibilities Although oral buprenorphine is rapidly de- as well as the benefits that the program can and stroyed in the liver, it is well absorbed as a sub- cannot offer. lingual tablet or buccal film.6,28 Buprenorphine Methadone maintenance treatment occurs in has effects that last for 24 to more than 36 hours. approximately three phases (Table 5)47 The in- It reduces opioid-withdrawal symptoms and par- duction and early stabilization phase (beginning tially blocks intoxication from other opioids.6,28 at week 1 and continuing in week 2)begins with Physicians who are approved to prescribe bu- • 364 N ENGLJ MED 375;4 NEJM.ORG JULY 28,2016 The New England Journal of Medicine Downloaded from nejm.org on July 29,2016.For personal use only.No other uses without permission. Copyright©2016 Massachusetts Medical Society.All rights reserved. TREATMENT OF OPIOID-USE DISORDERS prenorphine for office-based maintenance were tion of most patients stabilizes at 16 to 24 mg. • initially limited to 30 such patients at a time, a At doses of less than 8 mg per day, the pro- number that was increased to 275 patients in gram may not be effective, and higher doses July 2016. They must prescribe buprenorphine may be required to achieve the maximum ef- themselves (e.g., not through a nurse practitio- fect.6,10,62 ner), must offer counseling or be able to refer The maintenance phase begins when the most patients for counseling, and must agree to par- appropriate dose is established. The usual mini- ticipate in Drug Enforcement Administration mum length of treatment is 12 months,although, inspections. as with methadone, risks of relapse and over- The risks associated with buprenorphine in- dose increase when buprenorphine is discontin- dude overdoses, especially if it is taken along ued.G3 If the patient and physician decide that a with depressant drugs,and potential illicit diver- buprenorphine taper should be initiated, doses sion of drugs.5859 However, mortality during in- should be decreased slowly while the dose is duction with buprenorphine is lower than that monitored and adjusted according to the with- during induction with methadone; this finding drawal symptoms observed. contributed to approval for office-based mainte- Strong and consistent data support the effec- nance treatment by physicians with special train- tiveness of buprenorphine maintenance, as com- ing and certification.6 pared with placebo and naltrexone, especially at To discourage the misuse of intravenous bu- a dose of 16 mg or more per day.6,61,62 Initiating prenorphine,maintenance therapy involves a sub- buprenorphine maintenance as soon as possible lingual or buccal combination of buprenorphine (e.g.,while the patient is hospitalized or after an and the short-acting opioid antagonist naloxone, emergency department visit) can enhance effi- usually in a 4-to-1 ratio across the two drugs.6,60 cacy.G4 Combining maintenance therapy with a Because of the low doses of naloxone adminis- cognitive behavioral approach might improve tered and the low proportion of this drug that is outcomes. absorbed orally, this opioid antagonist does not There are no hard-and-fast rules regarding • precipitate withdrawal unless it is injected intra- whether to refer a patient to a clinic for metha- venously, in which case the withdrawal symp- done maintenance or for buprenorphine mainte- toms can be sudden and severe. nance. Considerations include cost; the avail- Patient selection criteria for buprenorphine ability of methadone clinics and physicians who maintenance resemble the above-mentioned cri- are trained in administering buprenorphine; teria for methadone maintenance.57 Although the match of demographic factors, educational treatment protocols vary depending on specific levels, and socioeconomic backgrounds be- patients' needs, the usual process is briefly dis- tween the patient and treatment programs; the cussed here.56,57,61 The patient must have early patient's coexisting medical and psychiatric signs of withdrawal to avoid precipitating an conditions; and individual clinician and patient abstinence syndrome when he or she is taking preferences 65 high doses of the drug of abuse. Direct comparisons between methadone and The induction phase lasts approximately 7 days buprenorphine show that both approaches im- in patients who are misusing a short-acting opi- prove outcomes, but most studies suggest that oid such as heroin. On day 1, typical patients methadone maintenance might be associated receive 4 to 8 mg of buprenorphine. On day 2, with higher rates of patient retention.10,50,65-67 the dose is increased up to 16 mg, with further Also, buprenorphine is more expensive than daily increases by day 7 but rarely a total of more methadone, and the private-office charges for than 30 mg per day. The stabilization phase (at buprenorphine might exceed the usual costs of approximately 8 weeks) begins when craving is a methadone clinic. However, buprenorphine is markedly reduced, opioid misuse is diminished safer than methadone during induction and or absent, withdrawal symptoms are absent, can be administered in offices of trained cli- and a stable dose has been achieved. If needed, nicians; the availability of treatment in clini- doses can be increased up to 4 mg each week cians' offices improves access to opioid main- up to a daily dose as high as 32 mg; the condi- tenance. N ENGLJ MED 375;4 NEJM.ORG JULY 2S,2016 365 The New England Journal of Medicine Downloaded from nejm.org on July 29,2016.For personal use only.No other uses without permission. Copyright 0 2016 Massachusetts Medical Society.All rights reserved. - i The NEW ENGLAND JOURNAL of MEDICINE Universal agreement on how long a patient CONCLUSIONS should continue to receive maintenance thera- • pies is lacking. Some clinicians prefer to work This review describes one person's view of what with patients to attempt to discontinue their the usual practicing clinician should know about medications after approximately 1 year, and the current state of treatments for opioid-use others emphasize the high rate of relapse and disorders. The topics that are likely to be most overdose deaths after leaving these programs useful to nonexperts in the field are included. and suggest that treatment should be open- The areas that are not covered (e.g., basic phar- ended and potentially lifelong. macologic approaches and potential treatments Finally, just as this article provides a broad that are still in early stages of development, overview of medically supervised withdrawal,this most of which are not likely to progress to overview of rehabilitation focuses only on the clinical implementation soon) are less likely to most widely used approaches. Morphine and have immediate clinical utility. heroin are used less often than methadone No potential conflict of interest was reported. and buprenorphine as maintenance treatments, Disclosure forms provided by the author are available with the full text of this article at NEJM.org. and fewer data are available regarding their use I thank Walter Ling,George Woody,Sarah Book, Steve Gro- for this purpose. ban,and others in the substance-use field for their advice. REFERENCES 1. O'Brien CP.Drug addiction.In:Brun- 9. Darke S, Marel C, Slade T, Ross J, study in primary care. Addiction 2015; ton L, Chabner B, Knollman B, eds. Mills KL,Teesson M. Patterns and cor- 110:1476-83. Goodman&Gilman's the pharmacologi- relates of sustained heroin abstinence: 17. Sigmon SC, Bisaga A, Nunes EV, cal basis of therapeutics. 12th ed. 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