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Lucemyra

Generic Name: Lofexidine Hydrochloride
Class: alpha-Adrenergic Agonists
Chemical Name: 2-[1-(2,6-dichlorophenoxy)ethyl]-4,5 dihydro-1H- imidazole monohydrochloride
Molecular Formula: C11H12Cl2N2O•HCl
CAS Number: 21498-08-8

Medically reviewed by Drugs.com. Last updated on Oct 7, 2019.

Introduction

Selective central α2-adrenergic agonist.1 9

Uses for Lucemyra

Opiate Withdrawal

Used for mitigation of opiate withdrawal symptoms to facilitate abrupt opiate discontinuance.1 2 12 20

Not a treatment for opiate use disorder (OUD); use in patients with OUD only in conjunction with a comprehensive treatment program.1

In patients with OUD, opiate withdrawal management (i.e., detoxification) generally involves short-term use of tapering dosages of buprenorphine (opiate partial agonist) or methadone (full opiate agonist) to reduce withdrawal symptoms.12 16 21 1300 1301 1302 However, α2-adrenergic agonists (e.g., lofexidine, clonidine) also used for symptomatic relief of noradrenergic-mediated opiate withdrawal symptoms (e.g., lacrimation, sweating, shivering, rhinorrhea) in inpatient and outpatient settings and may allow for withdrawal over a shorter period of time.1 5 6 12

α2-Adrenergic agonists appear to be less effective than buprenorphine or methadone for management of opiate withdrawal;16 1300 1301 1302 1303 some experts suggest α2-adrenergic agonists may be most useful in withdrawal management as adjuncts to opiate agonists or partial agonists,16 1302 to facilitate transition to opiate antagonist (naltrexone) treatment for relapse prevention,12 13 14 1302 1303 or when opiate agonist or partial agonist therapy is contraindicated, unacceptable, or unavailable.14 16 21 1300 1302 1303

Concomitant supportive therapy for other withdrawal symptoms (e.g., abdominal cramping, diarrhea, nausea and vomiting, muscle spasms, anxiety or restlessness, insomnia) often used.5 12 16 1300 1301 1303

Several small comparative studies suggest lofexidine and clonidine have similar efficacy in managing opiate withdrawal symptoms but lofexidine may cause less hypotension.5 6 9 12 13 17 Must also consider greater cost of lofexidine compared with off-label clonidine use.17 21

Because of potential for hypotension and bradycardia, some experts state that α2-adrenergic agonists are not drugs of choice for opiate withdrawal management in geriatric patients or patients with coronary insufficiency, ischemic heart disease, bradycardia, or cerebrovascular disease.12

In patients receiving long-term opiate analgesia, withdrawal symptoms generally managed by slow tapering of the opiate analgesic dosage.14

Lucemyra Dosage and Administration

General

  • Monitor vital signs prior to dosing.1 Monitor ECG in certain patients at risk for QT interval prolongation.1 (See Hypotension, Bradycardia, and Syncope and also see QT Interval Prolongation under Cautions.)

Administration

Oral Administration

Administer orally 4 times daily (i.e., every 5–6 hours) without regard to meals.1

Dosage

Available as lofexidine hydrochloride; dosage expressed in terms of lofexidine.1 Dosage also has been expressed in terms of the salt; 0.18 mg of lofexidine is equivalent to 0.2 mg of lofexidine hydrochloride.1 14

Adults

Opiate Withdrawal
Oral

Manufacturer states usual initial dosage is 2.16 mg daily administered in 4 divided doses of 0.54 mg every 5–6 hours during period of peak withdrawal symptoms (generally the first 5–7 days following last use of opiates), with dosage guided by symptoms and adverse effects.1 Administer for up to 14 days with dosage guided by symptoms.1 Do not exceed single dose of 0.72 mg or total daily dosage of 2.88 mg.1

Some experts recommend initial dosage of 0.36–0.54 mg twice daily; increase as necessary and tolerated to maximum of 2.16 mg daily in 2–4 divided doses for a total duration of 7–10 days.12

Reduce dosage or withhold or discontinue drug in individuals demonstrating greater sensitivity to its adverse effects.1 12 As opiate withdrawal symptoms wane, lower dosages may be appropriate.1

When discontinuing lofexidine, gradually reduce dosage (e.g., by 0.18 mg per dose every 1–2 days) over 2–4 days to mitigate lofexidine withdrawal symptoms and rebound elevations in BP.1 12 (See Symptoms Resulting from Abrupt Lofexidine Discontinuance under Cautions.)

Prescribing Limits

Adults

Opiate Withdrawal
Oral

Manufacturer recommends maximum of 0.72 mg as a single dose and 2.88 mg as total daily dosage.1

Some experts state maximum total daily dosage is 2.16 mg.12

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh score 5–6): 0.54 mg 4 times daily.1

Moderate hepatic impairment (Child-Pugh score 7–9): 0.36 mg 4 times daily.1

Severe hepatic impairment (Child-Pugh score >9): 0.18 mg 4 times daily.1

Renal Impairment

Mild renal impairment: No specific dosage recommendations at this time.1

Moderate renal impairment (eGFR 30–89.9 mL/minute per 1.73 m2): 0.36 mg 4 times daily.1

Severe renal impairment or end-stage renal disease (eGFR <30 mL/minute per 1.73 m2): 0.18 mg 4 times daily.1

Patients receiving dialysis: 0.18 mg 4 times daily administered without regard to timing of dialysis; no supplemental dose required after dialysis session.1

Geriatric Patients

Consider dosage adjustments similar to those recommended for patients with renal impairment.1

Cautions for Lucemyra

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Hypotension, Bradycardia, and Syncope

Risk of hypotension, bradycardia, and syncope.1

Assess vital signs prior to lofexidine dosing.1 Monitor for symptoms of bradycardia and orthostatic hypotension.1

Patients receiving lofexidine in the outpatient setting should be capable of self-monitoring for hypotension, orthostasis, bradycardia, and associated symptoms.1 (See Advice to Patients.) Reduce, delay, or omit dose following clinically important or symptomatic hypotension and/or bradycardia.1

Avoid use in patients with severe coronary insufficiency, recent MI, cerebrovascular disease, chronic renal failure, or marked bradycardia.1 12 Also avoid concomitant use with drugs known to decrease heart rate or BP.1

QT Interval Prolongation

Lofexidine prolongs the QT interval.1 3 Clinically important QT interval prolongation may occur in patients with hepatic or renal impairment, particularly in those with severe impairment.1

Monitor ECG in patients with heart failure, bradyarrhythmias, or hepatic or renal impairment, and in those receiving other drugs known to prolong the QT interval (e.g., methadone).1 (See Drugs that Prolong QT Interval under Interactions.)

In patients with electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia), correct existing abnormalities prior to administration of lofexidine and monitor ECG upon initiation of the drug.1

Avoid use in patients with congenital long QT syndrome.1

Concomitant Use of CNS Depressants

Lofexidine potentiates CNS depressive effects of benzodiazepines and is expected to potentiate such effects of alcohol and other sedating drugs.1 (See Specific Drugs under Interactions.)

Risk of Opiate Overdosage following Relapse to Opiate Use

Patients who complete opiate discontinuance are likely to have reduced tolerance to opiates and are at an increased risk of fatal opiate overdosage if they resume opiate use.1

Lofexidine is not a treatment for OUD; use for mitigation of opiate withdrawal symptoms in patients with OUD only in conjunction with a comprehensive treatment program.1

Symptoms Resulting from Abrupt Lofexidine Discontinuance

Abrupt discontinuance of lofexidine can result in marked increase in BP, diarrhea, insomnia, anxiety, chills, hyperhydrosis, and extremity pain.1

Reduce dosage gradually.1 (See Dosage under Dosage and Administration.) Manage symptoms related to lofexidine discontinuance by resuming previous dosage and subsequently tapering dosage.1

Specific Populations

Pregnancy

Safety not established in pregnant women.1

In animal studies, reduced fetal weights, increased fetal resorption, loss of litters, increased stillbirths, decreased viability and lactation indices, and developmental delays in offspring (delayed sexual maturation, auditory startle, and surface righting) observed.1

Experts state that the recommended treatment of opiate dependence in pregnant women is maintenance treatment with buprenorphine or methadone; this approach is superior to medically supervised withdrawal because withdrawal is associated with high relapse rates and poorer outcomes.18 19 1302 1303

Lactation

Not known whether lofexidine or its metabolites distribute into milk, affect breast-fed infants, or affect milk production.1 Lofexidine is chemically and pharmacologically related to clonidine, which reaches high concentrations in milk and breast-fed infants.7

Caution if administered to nursing women,1 especially those breast-feeding neonates or preterm infants.7 Consider benefits of breast-feeding and importance of the drug to the woman; also consider potential adverse effects on breast-fed child from drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

Safety and efficacy not established in geriatric patients.1 Use caution in patients >65 years of age.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Hepatic impairment decreases elimination of lofexidine; dosage adjustment recommended depending on degree of hepatic impairment.1 (See Pharmacokinetics and also see Hepatic Impairment under Dosage and Administration.)

ECG monitoring recommended.1 Clinically important prolongation of QT interval may occur, especially in patients with severe hepatic impairment.1

Renal Impairment

Renal impairment decreases elimination of lofexidine; dosage adjustment recommended depending on degree of renal impairment.1 (See Pharmacokinetics and also see Renal Impairment under Dosage and Administration.)

ECG monitoring recommended.1 Clinically important prolongation of QT interval may occur, especially in patients with severe renal impairment.1

Pharmacogenomics and Poor CYP2D6 Metabolizers

Lofexidine exposure in patients with poor CYP2D6 metabolizer phenotype expected to be increased similar to that in individuals receiving lofexidine concomitantly with a potent CYP2D6 inhibitor (e.g., paroxetine).1 (See Specific Drugs under Interactions.) Monitor for adverse effects (e.g., orthostatic hypotension, bradycardia).1

Common Adverse Effects

Insomnia,1 2 20 orthostatic hypotension,1 20 bradycardia,1 2 20 hypotension,1 2 20 dizziness,1 2 20 somnolence,1 2 20 sedation,1 2 20 dry mouth.1 2 20

Interactions for Lucemyra

Metabolized principally by CYPD26 and to lesser extent by CYP1A2 and 2C19.1 14 21

Causes slight CYP2D6 inhibition, but unlikely to inhibit or induce major CYP isoenzymes at clinically relevant concentrations.1 14 Likely not a substrate of P-glycoprotein (P-gp).14

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 inhibitors: Pharmacokinetic interaction (increased lofexidine exposure).1 Monitor for adverse effects (e.g., orthostatic hypotension, bradycardia).1

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2D6 substrates: Clinically important pharmacokinetic interactions not expected.1

Drugs that Prolong QT Interval

Lofexidine prolongs the QT interval.1 3 Monitor ECG when used concomitantly with other drugs known to prolong the QT interval.1 4

Specific Drugs

Drug

Interaction

Comments

Antidepressants, tricyclic (e.g., desipramine)

Possible reduced efficacy of lofexidine8 9 15

Exacerbation of opiate withdrawal symptoms reported in a patient receiving concomitant desipramine8

Buprenorphine

No pharmacokinetic or pharmacodynamic interaction observed,1 but possible additive sedation12

Cardiovascular drugs

Drugs that decrease heart rate or BP: Risk of excessive bradycardia and hypotension1

Drugs that decrease heart rate or BP: Avoid concomitant use1

CNS depressants (e.g., alcohol, barbiturates, benzodiazepines, opiate agonists and partial agonists, other sedating drugs)

Increased CNS depression observed with benzodiazepines; expected with other CNS depressants1

Use concomitantly with caution (see Advice to Patients)1

Methadone

No effect on methadone pharmacokinetics; slight increase in lofexidine concentrations not expected to be clinically important1

QT interval prolongation reported1

Possible additive sedation12

Use concomitantly with caution and monitor ECG1 4

Naltrexone

Oral naltrexone: No clinically important changes in lofexidine pharmacokinetics; peak naltrexone and 6-β-naltrexol concentrations delayed by 2–3 hours and overall exposure to the opiate antagonist reduced slightly at steady state; possible reduced efficacy of oral naltrexone if administered within 2 hours of lofexidine1

Interaction not expected if naltrexone administered by nonoral routes1

Paroxetine

Increased peak plasma concentration and AUC of lofexidine by about 11 and 28%, respectively1

Monitor for adverse effects (e.g., orthostatic hypotension, bradycardia)1

Lucemyra Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability is 72%; approximately 30% of orally administered dose converted to inactive metabolites on first pass through the liver.1

Pharmacokinetics are dose proportional over the lofexidine dosage range of 0.72–2.88 mg daily.1 10 14

Peak plasma concentrations achieved 3–5 hours after oral administration.1 10 14

Pharmacokinetics similar in opiate-dependent patients and healthy individuals.9 11

Food

Administration with a high-fat, high-calorie meal did not alter peak plasma concentration or AUC;1 14 only slightly delayed median time to peak plasma concentration (from 5 hours to 6 hours).14

Special Populations

Renal and hepatic impairment increase exposure, with less effect on peak plasma concentration than AUC.1 (See Table 1 and Table 2.)

Table 1. Lofexidine Exposure in Patients with Hepatic Impairment

Severity of Impairment (Child-Pugh class, score)

Peak Concentration (as percent of normal)

AUC (as percent of normal)

Mild (A, 5–6)

114%

117%

Moderate (B, 7–9)

117%

185%

Severe ©, 10–15)

166%

260%

Table 2. Lofexidine Exposure in Patients with Renal Impairment

Severity of Impairment (eGFR, per 1.73 m2)

Peak Concentration (as percent of normal)

AUC (as percent of normal)

Mild (60–89 mL/minute)

124%

144%

Moderate (30–59 mL/minute)

117%

173%

Severe (15–29 mL/minute)

154%

243%

End-stage renal disease or requiring dialysis (<15 mL/minute)

104%

171%

Dialysis: Transient decrease in lofexidine plasma concentrations during 4-hour dialysis session; concentrations return to near predialysis values within a few hours following completion of dialysis.1

Distribution

Extent

Not known whether distributed into milk.1

Volume of distribution suggests extensive tissue distribution.1 14

Plasma Protein Binding

Approximately 55%.1 14

Elimination

Metabolism

Extensively metabolized, principally by CYP2D6 and to a lesser extent by CYP1A2 and 2C19.1 14 21

Elimination Route

Excreted in urine (93.5%; 15–20% as unchanged drug) and feces (0.9%).1

Half-life

Elimination half-life: Approximately 12 hours.1

Terminal half-life: Following initial dose, approximately 11–13 hours.1 At steady state, approximately 17–22 hours.1

Special Populations

Renal and hepatic impairment decrease lofexidine elimination.1 (See Table 3 and Table 4.)

Table 3. Lofexidine Half-life in Patients with Hepatic Impairment

Severity of Impairment (Child-Pugh class, score)

Half-life (as percent of normal)

Mild (A, 5–6)

139%

Moderate (B, 7–9)

281%

Severe (C, 10–15)

401%

Table 4. Lofexidine Half-life in Patients with Renal Impairment

Severity of Impairment (eGFR, per 1.73 m2)

Half-life (as percent of normal)

Mild (60–89 mL/minute)

111%

Moderate (30–59 mL/minute)

145%

Severe (15–29 mL/minute)

157%

End-stage renal disease or requiring dialysis (<15 mL/minute)

137%

Typical 4-hour dialysis session removes only a negligible fraction of a lofexidine dose.1

CYP2D6 phenotypes conferring poor metabolism may result in increased lofexidine exposure.1 (See Pharmacogenomics and Poor CYP2D6 Metabolizers under Cautions.)

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 Store in original container; protect from excess heat and moisture.1

Actions

  • Centrally acting α2-adrenergic agonist.1 9 14

  • Binds to receptors on adrenergic neurons, reducing release of norepinephrine and decreasing sympathetic tone.1 9 Decreases sympathetic neurotransmission from the locus ceruleus, which is responsible for many opiate withdrawal symptoms during acute withdrawal.9 21

  • Structurally and pharmacologically related to clonidine.9 14 Greater selectivity for the α2A-adrenergic receptor thought to be responsible for lofexidine's improved adverse effect profile (e.g., decreased hypotension and sedation) over clonidine.5 6 9 12 13 15 21

  • Not an effective antihypertensive agent.9 14

  • Does not suppress psychological cravings.9

Advice to Patients

  • Importance of reading patient information provided by manufacturer.1

  • Inform patients that lofexidine may lessen, but not completely prevent, symptoms associated with opiate withdrawal syndrome (e.g., feeling sick, stomach cramps, muscle spasms or twitching, feeling cold, palpitations, muscular tension, aches and pains, yawning, runny eyes, sleep disturbances).1 Recommend additional supportive measures as needed.1

  • Risk of hypotension and bradycardia.1 Advise patients to be alert for any symptoms of hypotension, orthostasis, or bradycardia (e.g., dizziness, lightheadedness, feelings of faintness at rest or on abrupt standing); to avoid dehydration and overheating; and to rise carefully from a seated or supine position.1 Instruct patients on how to reduce the risk of serious consequences if hypotension occurs (e.g., by sitting or lying down).1 Advise patients in the outpatient setting experiencing symptomatic episodes of hypotension, orthostasis, or bradycardia to withhold lofexidine and contact their clinician for instructions.1

  • Advise patients receiving lofexidine in the outpatient setting to avoid driving, operating heavy machinery, or performing other hazardous activities until they know how the drug will affect them.1 Risk of increased CNS depression with concomitant use of benzodiazepines, alcohol, barbiturates, or other drugs with sedative effects.1

  • Advise patients to avoid abrupt discontinuance of therapy and to consult a clinician prior to discontinuing therapy.1

  • Risk of opiate overdosage if opiate use is resumed following a period of nonuse (i.e., relapse).1 Inform patients that they may be more sensitive to the effects of opiates and at greater risk of fatal overdosage if they resume opiate use after a period of nonuse.1

  • Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., renal or hepatic impairment, cerebrovascular or cardiovascular disease).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Lofexidine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

0.18 mg (of lofexidine)

Lucemyra

US WorldMeds

AHFS DI Essentials™. © Copyright 2020, Selected Revisions October 7, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. US WorldMeds. Lucemyra (lofexidine hydrochloride) tablets prescribing information. Louisville, KY; 2018 May.

2. Gorodetzky CW, Walsh SL, Martin PR et al. A phase III, randomized, multi-center, double blind, placebo controlled study of safety and efficacy of lofexidine for relief of symptoms in individuals undergoing inpatient opioid withdrawal. Drug Alcohol Depend. 2017; 176:79-88. http://www.ncbi.nlm.nih.gov/pubmed/28527421?dopt=AbstractPlus

3. Schmittner J, Schroeder JR, Epstein DH et al. QT interval increased after single dose of lofexidine. BMJ. 2004; 329:1075. http://www.ncbi.nlm.nih.gov/pubmed/15528619?dopt=AbstractPlus

4. Schmittner J, Schroeder JR, Epstein DH et al. Electrocardiographic effects of lofexidine and methadone coadministration: secondary findings from a safety study. Pharmacotherapy. 2009; 29:495-502. http://www.ncbi.nlm.nih.gov/pubmed/19397459?dopt=AbstractPlus

5. National Collaborating Centre for Mental Health (UK), National Institute for Health and Clinical Excellence. Drug misuse: opioid detoxification, national clinical practice guideline number 52. Leicester (UK): The British Psychological Society and The Royal College of Psychiatrists; 2008.

6. Gowing L, Farrell M, Ali R et al. Alpha2-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev. 2016; :CD002024. http://www.ncbi.nlm.nih.gov/pubmed/27140827?dopt=AbstractPlus

7. Lofexidine. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-. Updated 2018 Jun 4. Accessed 2018 Aug 7.

8. Keaney F, Crimlisk H, Bearn J. Lofexidine and desipramine: Interaction results in breakthrough opioid withdrawal symptoms. Int J Psychiatry Clin Pract. 2002; 6:179-81. http://www.ncbi.nlm.nih.gov/pubmed/24945207?dopt=AbstractPlus

9. Gish EC, Miller JL, Honey BL et al. Lofexidine, an {alpha}2-receptor agonist for opioid detoxification. Ann Pharmacother. 2010; 44:343-51. http://www.ncbi.nlm.nih.gov/pubmed/20040696?dopt=AbstractPlus

10. Al-Ghananeem AM. Pharmacokinetics of lofexidine hydrochloride in healthy volunteers. J Pharm Sci. 2009; 98:319-26. http://www.ncbi.nlm.nih.gov/pubmed/18393298?dopt=AbstractPlus

11. Al Ghananeem AM, Herman BH, Abbassi M et al. Urine and plasma pharmacokinetics of lofexidine after oral delivery in opiate-dependent patients. Am J Drug Alcohol Abuse. 2009; 35:311-5. http://www.ncbi.nlm.nih.gov/pubmed/19637105?dopt=AbstractPlus

12. World Health Organization. Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva: World Health Organization; 2009.

13. Kleber HD, Weiss RD, Anton RF et al. Treatment of patients with substance use disorders, second edition. American Psychiatric Association. Am J Psychiatry. 2007; 164(4 Suppl):5-123. http://www.ncbi.nlm.nih.gov/pubmed/17569411?dopt=AbstractPlus

14. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 209229Orig1s000: Multi-discipline review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209229Orig1s000MultidisciplineR.pdf

15. Britannia Pharmaceuticals. BritLofex 0.2-mg tablets summary of product characteristics. Reading, Berkshire, United Kingdom; 2015 Aug 25. https://www.medicines.org.uk/emc/product/1483/smpc

16. . Management of opioid withdrawal symptoms. Med Lett Drugs Ther. 2018; 60:137-141. http://www.ncbi.nlm.nih.gov/pubmed/30133420?dopt=AbstractPlus

17. . Lofexidine (Lucemyra) for opioid withdrawal. Med Lett Drugs Ther. 2018; 60:115-117. http://www.ncbi.nlm.nih.gov/pubmed/30036346?dopt=AbstractPlus

18. Substance Abuse and Mental Health Services Administration (SAMHSA). Clinical guidance for treating pregnant and parenting women with opioid use disorder and their infants (HHS publication no. [SMA] 18-5054). Rockville, MD: SAMHSA. 2018. From SAMHSA website. https://store.samhsa.gov/shin/content//SMA18-5054c/SMA18-5054.pdf

19. American College of Obstetricians and Gynecologists (ACOG) Committee on Obstetric Practice, in collaboration with the American Society of Addiction Medicine. ACOG committee opinion. No. 711: Opioid use and opioid use disorder in pregnancy. Washington, DC; ACOG: 2017 Aug. From the ACOG website. https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Obstetric-Practice/Opioid-Use-and-Opioid-Use-Disorder-in-Pregnancy

20. Fishman M, Tirado C, Alam D et al. Safety and Efficacy of Lofexidine for Medically Managed Opioid Withdrawal: A Randomized Controlled Clinical Trial. J Addict Med. 2018; http://www.ncbi.nlm.nih.gov/pubmed/30531234?dopt=AbstractPlus

21. Doughty B, Morgenson D, Brooks T. Lofexidine: A Newly FDA-Approved, Nonopioid Treatment for Opioid Withdrawal. Ann Pharmacother. 2019; :1060028019828954. http://www.ncbi.nlm.nih.gov/pubmed/30724094?dopt=AbstractPlus

1300. The Management of Substance Use Disorders Work Group, US Department of Veterans Affairs and Department of Defense. VA/DoD clinical practice guideline for the management of substance use disorders. 2015 Dec.

1301. US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration (SAMHSA), Center for Substance Abuse Treatment. Detoxification and substance abuse treatment. Treatment improvement protocol (TIP) series, No. 45. HHS Publication No. (SMA) 15-4131. Rockville, MD; 2006. http://store.samhsa.gov/system/files/sma15-4131.pdf

1302. US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration (SAMHSA), Center for Substance Abuse Treatment. Medications for opioid use disorder, for healthcare and addiction professionals, policymakers, patients, and families. Treatment improvement protocol (TIP) series, No. 63. HHS Publication No. (SMA) 18-5063. Rockville, MD; 2018. http://store.samhsa.gov/system/files/sma18-5063fulldoc.pdf

1303. American Society of Addiction Medicine (ASAM). ASAM national practice guideline for the use of medications in the treatment of addiction involving opioid use. Chevy Chase, MD: ASAM. 2015 Jun 1. From ASAM website. https://www.asam.org/docs/default-source/practice-support/guidelines-and-consensus-docs/asam-national-practice-guideline-supplement.pdf?sfvrsn=24

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