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19 Articles in Volume 20, Issue #4
20/20 with Dr. Nathaniel Katz: Pain Research and Future Therapeutics
A 20-Year Timeline: Pain Therapeutics and Regulations
A Comparison of the Alpha-2-Adrenergic Receptor Agonists for Managing Opioid Withdrawal
A Pain Assessment Primer
After the Task Force: A Conversation with Vanila A. Singh, MD
Ask the PharmD: Can opioids and benzodiazepines ever be used together?
Cognitive Strategies and Mindful Awareness for Integrative Pain Care
COVID: Clinical Considerations for Acute and Post-Infection Symptoms
Editorial: Fudin and Gudin Tackle Pain Care History – Asking, Have We Done a 180?
From Hands-On to Home-Based Care: Physical Therapy Undergoes a Paradigm Shift Due to Pandemic
MS-Related Pain and Spasticity: Are Cannabinoids an Option?
New Biological Agents for Psoriatic Arthritis: A Monoclonal Antibody Primer
Pandemic Presents Unexpected Opportunity to Embrace Multimodal Analgesia and the Integrative Care Team
Provider Perspective on Knee OA: Injections and RFA Options
Redefining the “Pain Specialist” of Today
Resident’s Corner: Climbing the Learning Curve in Pain Management
The Evolution of Pain Management: Experts Weigh In
Tips from the Field: How to Enhance Practice Efficiency
Tumor Necrosis Factor (TNF) Inhibitors: A Clinical Primer

A Comparison of the Alpha-2-Adrenergic Receptor Agonists for Managing Opioid Withdrawal

When abrupt opioid discontinuation is indicated, lofexidine may reduce autonomic symptoms of withdrawal with a better risk profile than clonidine.

Lofexidine is an alpha-2-adrenergic receptor agonist distributed in the United States by US WorldMeds under license from Britannia Pharmaceuticals Limited (brand name: Lucemyra). Lofexidine was approved by the FDA in 2018 for the mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults1 and is the only non-opioid medication FDA approved for the management of opioid withdrawal. Lofexidine is not indicated for treatment of opioid use disorder (OUD, formerly known as opioid addiction).

Prior to approval in the US, lofexidine was licensed as an anti-hypertensive agent in Germany before its removal from the market due to inefficacy.2 Lofexidine has been approved in the United Kingdom since 1992 as a non-opioid agent for management of opioid withdrawal symptoms.2

Lofexidine is composed of two isomers, dexlofexidine and levlofexidine, and is a structural analog of clonidine with high alpha-2a-receptor affinity (see Table I).4

Clonidine is an alpha-2-adrenergic receptor agonist FDA approved in 2010 for the management of hypertension that is widely used off-label for management of autonomic symptoms of acute opioid withdrawal.5,6

Acute opioid withdrawal symptoms may include hypertension, tachycardia, myoclonus, sweating, nausea, diarrhea, irritability, anxiety, and insomnia. Many acute opioid withdrawal symptoms are caused by overactive sympathetic outflow via increase in norepinephrine and adrenergic neuron activity. Alpha-2-adrenergic receptor agonists work to reduce sympathetic outflow and may reduce autonomic symptoms of opioid withdrawal.3

Lofexidine Compared to Clonidine: What the Data Show

Numerous studies have been conducted comparing lofexidine to clonidine for management of opioid withdrawal symptoms, many finding similar efficacy for withdrawal symptoms but less adverse effects with lofexidine versus clonidine (see Table II).7-12

Lofexidine and clonidine share similar warnings for use, including monitoring vital signs and avoiding abrupt discontinuation to avoid rebound hypertension.1,13

In comparison to placebo, the most common adverse effects reported with lofexidine use have been orthostatic hypotension, bradycardia, hypotension, dizziness, somnolence, sedation, and dry mouth.1

A study comparing lofexidine and clonidine pre-treatment effect on naloxone-precipitated withdrawal found both produced dose-related decreases in cardiovascular measures, blood pressure, and heart rate, but neither drug significantly reduced subjective discomfort or other autonomic symptoms of withdrawal such as rhinorrhea or lacrimation.12  The results of this study may not be generalizable to management of spontaneous withdrawal managed by repeated dosing over a period of several days but does suggest that additional adjunctive medications are needed in combination with lofexidine or clonidine to manage all acute opioid withdrawal symptoms.12

A limitation of available studies is a lack of the evaluation of patients without OUD undergoing taper of opioids or discontinuing long-acting opioids. A study comparing detoxification from buprenorphine/naloxone compared to methadone-with-lofexidine-assisted withdrawal found significantly lower subjective withdrawal effects in the buprenorphine/naloxone versus methadone/lofexidine group.14


Current Guidelines for Managing Opioid Withdrawal

The National Institute for Health Care Excellence (NICE) guidance for opioid detoxification for drug misuse recommends methadone or buprenorphine as first-line treatment for opioid detoxification, but lofexidine may be considered for individuals who prefer not to use first-line agents and detoxify in a short time period or those with uncertain dependence. The NICE guidelines specifically recommend avoidance of routine utilization of clonidine.15

The American Society of Addiction Medicine (ASAM) National Practice Guideline for Use of Medication in the Treatment of Addiction Involving Opioid Use contains recommendations for treating opioid withdrawal in patients with OUD. The ASAM guideline recommends against abrupt discontinuation of opioids, but, if needed, recommends withdrawal management with opioid agonists, methadone or buprenorphine, or alpha-2 adrenergic agonists.16 Of note, the ASAM guidelines were updated in 2015 prior to FDA approval of lofexidine.

The recent HHS Guide for Clinicians on the Appropriate Dosage Reduction or Discontinuation of Long-Term Opioid Analgesics emphasizes avoidance of abrupt withdrawal but suggests utilizing alpha-2 agonists, including both clonidine or lofexidine, if needed to manage autonomic symptoms of withdrawal.17


Lofexidine appears to have a better risk-benefit profile in comparison to clonidine with less hypotension and similar efficacy in both inpatient and outpatient settings7-12 However, other supportive medications to manage gastrointestinal and sleep disturbances from opioid withdrawal may need to be co-prescribed.

Possible patient-centered limitations to utilizing lofexidine include high pill burden (up to 12 pills daily for up to 14 days) and cost, especially in comparison to inexpensive clonidine.1 However, patients with commercial health insurance may be eligible for a commercial access program that reduces the cost of lofexidine. 



The clinical implications of promoting a specific or new drug for opioid withdrawal may mislead providers to offer only opioid detoxification in place of a gradual opioid taper or medication-assisted treatment (MAT) in the case of OUD. MAT with opioid agonist therapy (ie, buprenorphine or methadone) has been proven to suppress opioid withdrawal and cravings.18,19 In comparison to clonidine and lofexidine for the management of acute opioid withdrawal, buprenorphine has been shown to be better tolerated and more effective at relieving symptoms.14,20 However, the reason for opioid withdrawal should be taken into account when determining which management method to utilize as not all patients or providers may want to utilize an opioid agonist for this purpose.

In the authors’ view, the future of opioid withdrawal management should emphasize avoidance of acute opioid detoxification with gradual tapers that minimize withdrawal and encourage engaging those patients meeting criteria for OUD to engage with treatment including medication-assisted treatment.

In patients who require acute opioid detoxification with management of autonomic symptoms who cannot tolerate clonidine, utilizing lofexidine may be beneficial, especially in the outpatient setting due to reduced adverse effects. The more favorable risk-to-benefit profile of lofexidine in comparison to clonidine must be considered within the context of higher expense of lofexidine when considering patient-specific factors. 


Prior Analgesics of the Future columns


Last updated on: May 4, 2021
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