A Comprehensive Update of Lofexidine for the Management of Opioid Withdrawal Symptoms

Abstract

Purpose of Review

This is a comprehensive review of the literature regarding the use of Lofexidine for opiate withdrawal symptoms. It covers the background and necessity of withdrawal programs and the management of withdrawal symptoms and then covers the existing evidence of the use of Lofexidine for this purpose.

Recent Findings

Opiate abuse leads to significant pain and suffering. However, withdrawal is difficult and often accompanied by withdrawal symptoms and renewed cravings. These symptoms are driven mostly by signaling in the locus coeruleus and the mesolimbic system and a rebound increase in noradrenaline, producing symptoms such as anxiety, gastrointestinal upset, and tension. Lofexidine, an alpha-2 agonist, can be used to manage acute withdrawal symptoms before starting maintenance treatment with either methadone or buprenorphine. Lofexidine, if FDA approved for management of withdrawal symptoms and has been proved to be both effective and safe.

Summary

Opiate addiction is increasing and plaguing the western world and specifically the U.S. It takes a large toll on both a personal and societal level and carries a high cost. Withdrawal is difficult, both related to withdrawal symptoms and renewed cravings. Lofexidine has been shown to be effective in reducing the former and could potentially aid in recovery and withdrawal.

Introduction

Opioid use disorder carries a significant burden, affecting not only the individual but families and communities as well. It is estimated that 10% of the U.S. population has participated in illicit drug use, with 20 million Americans suffering from substance abuse.¹ Factors that have influenced drug use include the availability of synthetic drugs, doctor shopping, and over-prescription of opioids.² Several individuals benefit from the use of opioids for chronic pain. They notably decrease the level of pain, reduce emotional distress, and allow them to perform activities of daily living.³ However, their use is cautioned as they can cause long term physiological effects that ultimately lead to its misuse and abuse.² Over the past few years, the U.S. has experienced an increase in misuse, overdoses, and opioid-related suicide.^1,4,5 Although opioids are not the only factor leading to an overdose death, its long-term use develops tolerance, and abrupt withdrawal causes the development of uncomfortable symptoms triggering the individual to seek more substance.^3,6 Treatment for discontinuation of opioids is a challenging journey for the patient in which individualized plans for slow tapering may be necessary in order to avoid withdrawal symptoms as they are more likely to present in rapid tapering.³ During the process, patients can become anxious and develop cravings that are difficult to control.³ It is essential for patients going through withdrawal to have the proper treatment that keeps them comfortable while reducing their likelihood of returning to opioids.

Opioid Withdrawal Epidemiology

After long term use of prescription opiates, a patient can be alleviated from pain and profound feelings of anxiety and distress. Being removed from their use requires that the patient be informed of the plan to follow. Patients may fear the return of pain or withdrawal and seek illegal opiates as a replacement.³ Obtaining illegal opiates puts the patient at risk of overdose and death. About 50% of opioid-related deaths are caused using prescription opioids.⁷ In July 2019, it was estimated that 67, 508 deaths in the U.S. were related to drug overdose, a noticeable increase from July 2015, where 50, 301 deaths were reported in a 12 month period.⁸ In another report, it was found that about 25% of these deaths were intentional and especially higher for females.⁵ The rates of opioid use disorder are higher among males than females. Non-white Hispanics, Native Americans, and African Americans have disproportionately higher rates of opioid use disorder.⁹ Many people with a substance use disorder have less access to healthcare and therefore are unable to seek treatment for withdrawal. Although we often think of adults going through opioid withdrawal, pediatrics patients in the ICU comprise a large number of withdrawal patients.¹⁰ This further emphasizes the need for opioid withdrawal treatment options to relieve the patients of these symptoms.

Risk Factors

Several factors increase the likelihood of an opioid use disorder. Dependence involves individual genetics, psychological factors, social, and the surrounding environment.⁷ Those of higher risk of developing an opioid use disorder after exposure is young males more than females. Lower education attainment, low income, and diagnosis of a psychiatric disorder have also shown to increase a person’s risk. Anxiety and depression show the strongest association of opioid use and repeated overdoses.¹² The social circle and surrounding environment of the individual can influence their decisions and increase the risk of using when opiates are being used to create a sense of belonging or for continued energy.¹³ The physiological changes that occur with opiate use can encourage the behavior and make it difficult to stop its use, especially once a person begins to experience withdrawal symptoms. Additionally, getting injured from a psychologically and physically demanding job makes a person more likely to develop opioid use disorder after an initial opiate prescription.¹⁴ One or a combination of these factors puts a person at risk. After long term use of opiates, tolerance develops, requiring a higher dose to have the same effect. Eventually, they develop physical dependence increasing their chance of overdose and death.^9,11

Pathophysiology

Opiate withdrawal causes significant emotional distress as the neurobiology involved in addiction are undergoing reductions or cessation in substance. The locus coeruleus and mesolimbic system are the driving factors triggering the clinical presentation of withdrawal.¹¹ Upon use of an opiate, it binds to a mu, kappa, or delta receptor, creating a signaling cascade.¹⁵ The locus coeruleus contains numerous mu-receptors. These receptors belong to a family of G-coupled protein receptors that provide intracellular signals inhibiting adenylyl cyclase and decreasing cAMP. This induces a reduction of voltage-gated Ca channels and increase potassium channels traveling inward.¹⁶ These changes cause less production of noradrenaline suppressing excitatory signaling and reducing the feeling of pain.^15,17 The rostral ventromedial medulla and the periaqueductal gray are also involved in suppressing the nervous system for pain control.¹⁶ The amount of noradrenaline being released leads to a different presentation of symptoms. An increase in noradrenaline would show as tension, diarrhea, and anxiety, while a decrease would develop respiratory depression and confusion.¹⁷ Continuous use of opiates eventually prompts an increase in noradrenaline that develops into tolerance.¹⁷ In order to produce the same effects, higher doses are required. At this point, if the drug is no longer used or amount cannot be increased withdrawal begins to occur. Manifestations of withdrawal occur from activation of the nervous system and compensatory mechanisms.¹⁶ Typically this can be managed with a mu-opioid agonist as it can produce the same physiological effects as an opiate.^13,18

Presentation

Chronic use of opiates impairs a person’s ability to control their drug-seeking behaviors despite the consequences. It can be difficult to stop their use as a slight reduction in dose or removal triggers withdrawal.¹³ Opiate withdrawal can be divided into an acute phase and a long-term phase. During the acute phase, symptoms present within 24 hours after the last use of a short-acting opiate and may last between 7 to 10 days.^9,17 Early symptoms include runny nose, insomnia, arthralgias, nausea, vomiting, diarrhea, and hypertension.^11,13,17 The process of withdrawal creates both psychological and physical symptoms that produce anxiety and an intense need to provide relief. Most patients relapse during the acute phase; therefore, needing to be monitored 3 to 4 times daily and be well hydrated to compensate for diarrhea and sweat that occurs during this phase.¹³ Long-acting opiates were creating effects lasting 14 days or greater.⁹ The long term phase can last for six months, presenting with opioid cravings, low body temperature, reduced energy, and bradycardia.^3,13

Current Treatment of Opioid Withdrawal

The treatment of opioid withdrawal has been studied for many years and contains a wide variety of treatment options. There are several opioid and nonopioid based medications available. The use of opioid medications, such as methadone, buprenorphine, and naltrexone, has been widely studied and proven effective. The use of opioids for opioid use disorder (OUD) stems from the idea of combatting withdrawal symptoms and making a patient feel ‘normal.’ There is also a strong fear of withdrawal symptoms among patients with the tapering or cessation of opioids and the use of nonopioid medications.^19–21 For patients with OUD, it is recommended not to abruptly stop opioid use, but rather the use of medication to avoid withdrawal symptoms.²² Two opioid medications, methadone, and buprenorphine have been approved by the Food and Drug Administration (FDA) for use in OUD. However, these medications are typically used for maintenance therapy rather than treating withdrawal symptoms.^23,24 Methadone is a synthetic mu-opioid receptor agonist that acts similarly to morphine. Withdrawal symptoms on methadone typically are much slower than other opioids. Buprenorphine is a partial opioid agonist at the mu-receptor and an antagonist at the kappa-opioid receptor.²⁵ It has similar effects as methadone and issued for opioid dependence. The treatment of withdrawal symptoms is targeted through alpha-2 adrenergic agonists, such as lofexidine and clonidine, and supportive measures. Supportive medications include anticholinergics, antipsychotics, antidepressants, and benzodiazepines.²⁴ In a 2016 Cochrane review, 26 randomized control trials on the use of alpha-2 adrenergic agonists were analyzed. Medications included clonidine, lofexidine, guanfacine, and tizanidine. There was evidence that alpha-2 agonists were more effective in controlling withdrawal symptoms versus the use of a placebo. Additionally, alpha-2 agonists were shown to resolve symptoms quicker and more effectively than reducing doses of methadone; however, hypotension was more common with alpha-2 agonists.²⁶ Clonidine is not currently approved by the FDA for opioid withdrawal, and there is no established dosing regimen. In this regard, clonidine historically has been the main drug utilized in ultra-rapid detoxification techniques that place patients under general anesthesia typically in an intensive care unit setting. In ultra-rapid opioid detoxification, opioid antagonists are administered to acutely precipitate withdrawal. Furthermore, clonidine is typically used as an antihypertensive and attention-deficit/hyperactivity disorder agent and has been used off-label for opioid withdrawal and sedation. Lofexidine is currently approved by the FDA for the treatment of opioid withdrawal and has been proven to have weaker side effects than clonidine.²⁷ The FDA currently states that lofexidine can be used for management of withdrawal symptoms but not as a treatment for OUD. Both clonidine and lofexidine are associated with orthostatic hypotension, syncope, bradycardia and somnolence.

Lofexidine Drug Info

Lofexidine, sold under the brand name Lucemyra, is an alpha-2 adrenergic receptor agonist used for the opioid withdrawal symptoms. It is typically used when opioids are stopped abruptly, helping reduce symptoms significantly.²⁸ Lofexidine was approved by the FDA in May 2018 and was the first nonopioid treatment for opioid withdrawal symptoms.²⁹ It has historically been used to treat high blood pressure; however, it is now more commonly used for opioid withdrawal. It has been proven to be more effective, and with fewer side effects than clonidine, an alpha-2 adrenergic receptor used off-label for opioid withdrawal. Studies show that that there was a less hypotensive effect when using lofexidine over clonidine, however no other significant side effects were noted.²⁷ A double-blind study comparing lofexidine and placebo in opioid-dependent patients demonstrated that the drug was tolerated and highly effective.³⁰ Using the Modified Himmelsbach Opiate Withdrawal Scale (MHOWS), subjects treated with lofexidine had significantly lower scores, forcing the study to be terminated early. Side effects were significant compared to the placebo and included asthenia, dizziness, hypotension, and insomnia. The FDA currently cites that potential adverse effects include the risk of syncope, hypotension and bradycardia, risk of Q.T. prolongation, increased risk of central nervous system depression, increased risk of opioid overdose after opioid discontinuation and risk of discontinuation symptoms. Due to these risks, there are a few drug interactions that must be monitored, including methadone, oral naltrexone, CNS depressant drugs, and paroxetine. Currently, there are no studies on the effect of lofexidine in pregnancy, fertility, children, geriatric patients, or patients with hepatic or renal impairments.²⁸ It is currently offered in an oral tablet form, containing 0.18 mg of lofexidine. Starting dosage for patients without renal impairment is typically three tablets taken four times a day while a patient is actively withdrawing. Dosing is guided by patient improvement, tolerance, and side effects with treatment lasting up to 14 days. Studies have shown that lofexidine may be dosed with methadone, buprenorphine, or naltrexone. Lofexidine has been used internationally for many years with reported success; however, hypotension remains one of the most consistent side effects of drug usage.²⁹

Mechanism of Action, Pharmacokinetics, and Pharmacodynamics

The primary mechanism of lofexidine is the same as that of many alpha-2 agonists. The alpha-2 agonist has been identified as a target for a multitude of conditions such as hypertension, ADHD, opioid and alcohol withdrawal, and nicotine addiction. It has also been targeted for use as sedation and anesthetic medication. These drugs activate the alpha-2 receptor, which targets the medulla oblongata at a post-synaptic location acting within the lateral reticular nucleus. The hallmark of opioid withdrawal is increased central noradrenergic activity. Both opioids and alpha-2 agonists act on the locus coeruleus. Opioids and opiates act on the opioid receptor, which is antagonized by naloxone, while alpha-2 agonists are not antagonized by opioid antagonists.³¹ Three subtypes have been identified for the alpha-2 receptor; alpha-2A, alpha-2B, and alpha-2C.³² The central nervous system is thought to consist of alpha-2B and -2C, potentiating antihypertensive effects, and sedation.³³ The alpha-2 receptor is known to inhibit adenyl cyclase, which decreases cyclic adenosine monophosphate levels. In turn, intercellular cAMP levels are decreased. Neural firing is then suppressed due to an increase of potassium, preventing calcium from entering the nerve terminal. Norepinephrine is suppressed, causing a decrease in sympathetic stress response. This process is a negative feedback loop that results in analgesia, sedation, and antihypertensive effects.^34,35 The increase in norepinephrine turnover causes a decrease in opioid withdrawal symptoms, but adverse effects such as hypotension and sedation remain prevalent.

The pharmacokinetic profile of lofexidine has been well documented in the literature, both preclinically and clinically. In one study, the maximum plasma concentration was seen in doses of 1.2 and 2.0 mg and was observed at approximately 3 hours.³⁶ The area under the curve was shown to be dose-proportional, showing a 1.72-fold increase when the dose was increased by 1.67. For both doses, the elimination rates were not statistically significant. The reported rate for the 1.2 and 2.0 mg dose was 0.063 and 0.065 h⁻¹, respectively. The half-life of lofexidine is approximately 11 hours.^36,37 The FDA label reports that maximum plasma concentration is between 3 to 5 hours and protein binding at approximately 55% of its dose. After its first pass after oral administration, 30% of the drug is converted to inactive metabolites and lost. The bioavailability does not increase or decrease with food consumption. Lofexidine is primarily metabolized by CYP2D6; however, CYP1A2 and CYP2C16 have also been reported to have small effects on metabolization. The half-life was reported at approximately 12 hours in its initial dose with a mean clearance of 17.6 L/h when administered intravenously. Steady-state is reached two days.^28,36,38

Use of Lofexidine for the Management of Hypertension

Lofexidine was first studied for its use in hypertension. It is a drug comparable to clonidine as an alpha-2 adrenergic agonist. In a study that looked at the use of lofexidine and clonidine for mild to moderate hypertension, it found there were no significant changes in blood pressure between both drugs.³⁹ When used in short-term lofexidine, adequately controlled blood pressure without the need of hydrochlorothiazide as an additive. During its long-term use, blood pressure increased, and the addition of hydrochlorothiazide, as well as larger doses of lofexidine, was necessary to maintain blood pressure control. Both lofexidine and clonidine produced severe adverse effects that required patients to discontinue participation in the study.³⁹ Significant adverse effects recorded over the course of two years were chest pain, rash, eosinophilia, headache, fatigue, and sexual dysfunction.³⁹ In a different study by Vlachakis ND et al., Lofexidine reduced both systolic and diastolic pressure; however, it resulted in a decrease of cardiac output from a reduction in contractility.⁴⁰ Similar results were found in the study by Lopez LM and Mehta JL, where lofexidine produced a reduction in cardiac output and heart rate but had lower rates of toxicity than clonidine.⁴¹ Another study determined that large doses of lofexidine are necessary in order to provide effective blood pressure control and, at lower doses, produce uncomfortable side effects of dry mouth and drowsiness.^42,43 Many of the studies examining lofexidine for treatment of hypertension express their concerns on the cardiovascular effects with conflicting information on the exact changes and dosing. In some patients, it demonstrated to both reduce heart rate and cardiac output without an increase in total peripheral resistance resulting in orthostatic hypotension.⁴⁴ Each additional dose of lofexidine decreased systolic and diastolic pressure, with more significant changes to systolic pressure.⁴⁵ The antihypertensive effects occurred within 2 to 4 hours after administration lasting 15 hours. It was also found that levels of noradrenaline excretion decreased while plasma expansion occurred in some patients.^44,45 In another comparison study, plasma renin and catecholamine levels decreased with clonidine, while lofexidine produced no changes.⁴⁶ Many of the differences in antihypertensive effects of clonidine and lofexidine are due to their distinct α₁-adrenergic agonist and α₂-adrenergic agonist receptor affinity.^45,46 Despite lofexidine being studied for its use of hypertension, its effectiveness in reducing blood pressure was not as significant as the reduction produced by clonidine and has shown to result in adverse effects over long-term use in hypertension. In these studies, lofexidine repeatedly showed to be safer a drug than clonidine based on dosing and side effects.

Clinical Studies: Safety and Efficacy

The treatment of opioid withdrawal using lofexidine is generally safe, well-tolerated, and effective. Lofexidine is used to decrease the sympathetic tone that drives the major symptoms of opiate withdrawal. The potential adverse effects of lofexidine include but are not limited to bradycardia, hypotension, orthostatic hypotension, xerostomia, and increase in the QTcF interval.⁴⁷ In the clinical trials described below, severe adverse events were rare.

A randomized control trial evaluated the safety and efficacy of lofexidine.⁴⁸ A sample size of 603 subjects was randomly assigned into three different groups: placebo, lofexidine 0.54 mg four times daily (2.16 mg/day), and lofexidine 0.72 mg four times daily (2.88 mg/day). The primary outcomes measured were the Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) and the Clinical Opiate Withdrawal Scale (COWS). The SOWS-Gossop and COWS scores were both significantly lower from days 1 through 5 in the lofexidine groups, indicating less severe withdrawal symptoms. There was no significant difference in SOWS-Gosspop scores and COWS scores from days 1–5 between the 2.16 mg/day and 2.88 mg/day treatment groups.⁴⁸ The rate of adverse effects was slightly higher in the lofexidine treatment groups. Adverse effects included dizziness, orthostatic hypotension, and bradycardia. Treatment was stopped for one subject receiving 2.88 mg/day after experiencing a syncopal episode. Subjects who received lofexidine versus placebo were significantly more likely to complete the treatment. In the placebo group, 72.2% (109/151) of patients dropped out of the study, whereas 59% (135/229) and 60.4% (134/222) did not finish the study for the 2.16 mg/day group and the 2.88 mg/day group respectively.⁴⁸ Darpö et al. used data from the randomized control trial above and analyzed the effect of lofexidine on the QTcF interval.⁴⁹ The largest increase in the QTcF interval was on day 1 of lofexidine administration. Once lofexidine reached steady-state levels on day 3 or 4, the QTcF interval returned to baseline or below baseline values.⁴⁹

Another randomized, double-blind, placebo-controlled trial analyzed the safety and efficacy of lofexidine for the relief of opiate withdrawal symptoms.⁵⁰ Subjects selected for the study had to score ≥ 2 on the Handelsman Objective Opiate Withdrawal Scale (OOWS-Handelsman). The treatment group was given lofexidine 3.2 mg/day for five days and received a placebo for days 6 and 7. The primary outcomes used were the SOWS-Gossop score on day three, and the study dropout rate. On day 3, the mean SOWS-Gossop score on day 3 for subjects in the lofexidine group and the placebo group was 6.32 and 8.67, respectively (p = 0.0212). Also, more patients finished treatment in the lofexidine group compared to the placebo group. Subjects who received lofexidine had a 37.3% trial completion rate (50/134) compared to the placebo group, which had a 26.9% trial completion rate (35/130).⁵⁰ In patients receiving lofexidine, there was a significant decrease in systolic, diastolic, and orthostatic blood pressure measurements. Both groups reported adverse events at a high rate, but most were secondary to opiate withdrawal symptoms. There was no clinically significant difference between the lofexidine and placebo groups in the mean QTc values. The most common adverse events in the lofexidine group were hypotension, dizziness, bradycardia, and xerostomia. Four patients treated with lofexidine had serious adverse effects related to bradycardia or hypotension, but all were discharged in stable condition after one day of inpatient monitoring.⁵⁰

Methadone maintenance therapy can potentially cause QTc prolongation.⁵¹ Some data suggest alpha2-adrenergic agonists also cause QTc prolongation. A prospective, double-blind safety study examined electrocardiographic effects on patients receiving both methadone and lofexidine for opiate withdrawal.⁵² After being stabilized on methadone 80 mg/day for three weeks, fourteen subjects were administered increasing doses of lofexidine for five weeks in duration. EKGs were obtained before and after each dose of lofexidine. When comparing the primary outcomes for patients receiving methadone alone versus after the coadministration of methadone and lofexidine, there was a statistically significant decrease in heart rate as well as statistically significant increases in the P.R. interval, QRS interval, and QTc interval.⁵² The combination of methadone and lofexidine can cause QTc prolongation and put patients at risk of developing torsades de pointes.

Schroeder et al. used data from the above trial and observed the cardiovascular and cognitive effects of treating opiate withdrawal with methadone and lofexidine.⁵³ There were statistically significant decreases in both sitting systolic and diastolic blood pressure in patients receiving lofexidine 0.4 mg/day compared to placebo. There was a mean decrease of 27 mmHg and 15 mmHg for sitting systolic and diastolic blood pressures, respectively. There was no significant change in orthostatic blood pressure measurements. Subjects were asked to perform tasks to assess the cognitive effects of lofexidine. Patients receiving lofexidine performed worse on mathematical processing.⁵³

Five articles were included in a review comparing the use of clonidine and lofexidine for the treatment of opiate withdrawal.⁵⁴ Only one study demonstrated a statistically significant advantage in using lofexidine over clonidine.⁵⁵ In this study, patients received either clonidine or lofexidine for three days, but both groups also received oxazepam, baclofen, ketoprofen, as well as naltrexone. In this study, clonidine caused significant changes in systolic blood pressure, whereas lofexidine did not. Subjects treated with lofexidine also had significant improvement in withdrawal symptoms during detoxification than those treated with clonidine. The study was limited by small sample size (N = 35). Although the other studies did not show a significant difference in efficacy between clonidine and lofexidine, four of the five articles did show statistically significant more adverse effects in the clonidine treatment groups.^27,55–57 Studies suggest that clonidine and lofexidine have similar efficacy, but lofexidine is better tolerated for treating opiate withdrawal.

Naltrexone is an opiate antagonist used to treat opiate withdrawal. It competitively binds to the opiate receptor and blunts the effects of opiates as well as drug craving behavior.⁵⁸ A pilot randomized, the double-blind placebo-controlled study explored the combination of naltrexone and lofexidine for treating opiate withdrawal 14. All patients were started on naltrexone, and on day 2 of treatment, patients were either given placebo or lofexidine in addition to naltrexone. Patients were titrated up to 2.4 mg/day of lofexidine, but some doses were decreased due to adverse effects.⁵⁹ In the lofexidine group, 5 of the 22 subjects were withdrawn due to medication side effects such as dizziness or hypotension. The lofexidine group completed the trial at a significantly higher rate than the placebo group. Opiate craving was evaluated by a subjective scale, and patients in the lofexidine group reported decreased drug craving each week throughout the twelve-week period compared to placebo.⁵⁹

A preliminary study evaluated stress-induced and cue-induced opiate craving and opiate abstinence rates in patients receiving lofexidine-naltrexone for opiate withdrawal.⁶⁰ All eighteen patients were stabilized on naltrexone 50 mg daily and lofexidine 2.4 mg bid over four weeks. Some patients were then tapered off of lofexidine over a three days course and treated with placebo for an additional four weeks.⁶⁰ Of patients that completed the trial, the naltrexone-lofexidine group had more negative urine drug screens for opiates. Patients were asked to use their personal experiences to imagine a stressful, opiate-related, and relaxing event. Scripts were created based on these experiences, and subjects used a scale to assess opiate craving behavior. Patients receiving naltrexone-lofexidine had significantly lower opiate craving scores when presented with stressful and drug-related cues.⁶⁰

Naloxone is an opiate antagonist that is similar to naltrexone but is more rapidly acting and can precipitate opiate withdrawal more quickly. Bearn et al. compared patients receiving naloxone/lofexidine to lofexidine monotherapy for opiate withdrawal.⁶¹ Patients were stabilized on methadone for three days. Methadone was stopped, and one group received intramuscular naloxone and oral lofexidine while the other group received lofexidine only. The withdrawal severity for the naloxone/lofexidine group was significantly less than the lofexidine monotherapy group.⁶¹

A double-blind, randomized clinical trial in Singapore compared diazepam and lofexidine for treating opiate withdrawal.⁶² The mean OOWS and SOWS scores were lower in the lofexidine group compared to the diazepam group, but there was not a statistically significant difference. More patients withdrew from the study when experiencing peak withdrawal symptoms from the diazepam group, and the lofexidine group was more slightly more likely to complete the trial. Diazepam is addictive and is not superior to lofexidine for treating opiate withdrawal.⁶²

A randomized controlled trial was conducted comparing buprenorphine/naloxone and methadone plus lofexidine for opiate withdrawal.⁶³ Eighty subjects were divided into two groups. One group was stabilized on buprenorphine/naloxone four mg/1 mg while the other was stabilized on methadone 30 mg. During the detoxification phase for the buprenorphine/naloxone group, the buprenorphine was gradually titrated down over 14 days. For the methadone/lofexidine group, methadone was stopped on day 3 of detoxification, and lofexidine was given for 14 days.⁶³ During the induction and stabilization phase, patients receiving methadone/lofexidine had significantly lower scores on the Opiate Craving Scale (OCS). During the detoxification phase, the methadone/lofexidine group had significantly worse withdrawal symptoms, and peak withdrawal came earlier. There was no statistical difference between the number of patients that completed detoxification for the two groups.⁶³

Insomnia is a common symptom of opiate withdrawal. Gossop and Bradley found that methadone is not an effective treatment for sleep disturbances in patients suffering from opiate withdrawal.⁶⁴ A trial was conducted to evaluate sleep disruptions for patients undergoing opiate detoxification.⁶⁵ Patients were initially stabilized with methadone. Patients received up to 1.8 mg of lofexidine for six days or a 10-day methadone taper. Patients treated with lofexidine had significantly increased total sleep time and reduced sleep latency. Total time awake decreased over time for both groups, but patients receiving methadone reported total time awake than the lofexidine group.⁶⁵ The lofexidine group reported significantly fewer withdrawal symptoms than the methadone group—the severity of withdrawal symptoms correlated with sleep disturbance. Total sleep time and sleep latency were statistically significant associations for treatment completion.⁶⁵

A barrier to using lofexidine in the USA is the price. It is FDA approved for treating opiate withdrawal but can cost up to $3000 for a 14-day supply.⁶⁶ Some study limitations included small sample size, high dropout rates, and polysubstance abuse. Many patients concurrently used other illicit drugs or abused alcohol. Although adverse effects are common, they are seldom severe or clinically significant. The most common adverse effects observed were hypotension, dizziness, syncope, and bradycardia. Patients treated with lofexidine should follow up regularly with a medical professional. Overall, most trials concluded that lofexidine is an effective treatment for opiate detoxification. It is better tolerated than clonidine and can be combined with other agents such as naltrexone or methadone to treat opiate withdrawal.

About 20 million Americans suffer from some form of substance abuse, an affliction that creates tremendous personal, familial, and societal suffering and loss. Opiates have documented benefits in the management of acute and chronic pain, though the latter carries a risk of creating dependence and abuse. However, attempts at withdrawal are usually accompanied by withdrawal symptoms and renewed craving. Turning to illegally procured opiates increases the risk of overdose and death; other risk factors include male gender, as well as ethnicity—Non-white Hispanics, Native Americans, and African Americans all have higher risk profiles. Lower education and income and previous psychiatric diagnosis also increase the risk.

The pathophysiology of withdrawal symptoms focuses mainly on the locus coeruleus and the mesolimbic system. Historically, virtually all conventional techniques such as 12 step programs, cold turkey techniques, and inpatient management for opioid withdrawal have been largely unsuccessful.^69–72 Ultra-rapid detoxification techniques have provided an important understanding of alpha 2 agonists role in managing opioid withdrawal and in appreciating opioid related withdrawal symptoms in patients with dependence.^73–76 Opiate signaling reduces the expression of noradrenaline in these areas; the withholding of opiates triggers compensatory mechanisms and a rebound in noradrenaline expression, causing anxiety, diarrhea, cramping, tachycardia, hypertension, and psychological tension.

Conclusion

The current maintenance treatment for opiate withdrawal usually includes using a different, controlled, opiate, either methadone or buprenorphine. Alpha-2 receptor agonists, such as lofexidine, can be used to manage the acute symptoms during withdrawal. Lofexidine is effective and safe and is FDA approved for the management of withdrawal symptoms. It does carry warnings for side effects that relate to its alpha-2 blocking activity-hypotension, bradycardia, syncope, and Q.T. prolongation. It acts directly on the locus coeruleus and reduces the symptoms that would otherwise be associated with opiate withdrawal.

Numerous clinical trials have found lofexidine effective in counteracting withdrawal symptoms. While it does carry appropriate warnings, it potentially can facilitate withdrawal from chronic opiate use and contribute to the recovery from chronic opiate use and opioid use disorder.

Table 1. Clinical Efficacy and Safety.

AUTHOR (YEAR)		GROUPS STUDIED AND INTERVENTION		RESULTS AND FINDINGS		CONCLUSIONS
Yu et al. (2008)30		Sixty-eight opioid-dependent subjects were randomly assigned to lofexidine or placebo. Thirty-five were assigned lofexidine, and 33 were assigned placebo. Primary outcomes were measured using the Modified Himmelsbach Opiate Withdrawal Scale (MHOWS).		Due to significant findings using the MHOWS, on study day 5, the study was terminated. Subjects treated with lofexidine had significantly lower scores than placebo subjects.		Lofexidine is well tolerated and highly effective than the placebo.
Schmittner et al. (2009)52		Fourteen adult participants were administered methadone maintenance therapy reaching a target dose of 80 mg/d for three weeks; then, all participants received 0.4 mg/d of lofexidine with dose-escalating each week in 0.2 mg increments. By the 8th week, participants were receiving lofexidine 1.6 mg/d. Electrocardiograms were used at baseline, after stabilization with methadone and after lofexidine coadministration as the primary outcome.		When comparing the primary outcomes for patients receiving methadone alone versus after the coadministration of methadone and lofexidine, there were statistically significant decrease in heart rate (mean +/− SD −9.6 +/− 5.8 beats/min, p < 0.0001) as well as statistically significant increases in the P.R. interval (+11.1 +/− 19.8 msec, p = 0.026), QRS interval (+3.7 +/− 4.3 msec, p = 0.002), and QTc interval (+21.9 +/− 40.8 msec, p = 0.018).		The study shows that the coadministration of lofexidine and methadone induces QTc interval prolongation. This coadministration should be prescribed cautiously and frequent ECG monitoring. QTc interval was the largest in female subjects; females may be at a higher risk.
Gorodetzky et al. (2017)50		Two hundred sixty-five patients with a score of ≥ 2 on the Handelsman Objective Opiate Withdrawal Scale (OOWS-Handelsman) were randomly assigned to lofexidine hydrochloride or placebo. The treatment group received 3.2 mg/day of lofexidine for five days and placebo days 6 and 7. Primary outcomes were measured using SOWS-Gossop score on day three and the dropout rate.		The mean SOWS-Gossop score on day 3 for subjects in the lofexidine group and the placebo group was 6.32 and 8.67, respectively (p = 0.0212). Also, more patients finished treatment in the lofexidine group compared to the placebo group. Subjects who received lofexidine had a 37.3% trial completion rate (50/134) compared to the placebo group, which had a 26.9% trial completion rate (35/130).		Lofexidine significantly decreases SOWS scores compared to placebo, which led to a better trial completion rate in patients going through opioid withdrawal. Lofexidine, nonopioid, may be useful in treating opioid withdrawal symptoms.
Fishman et al. (2019)48		603 subjects were randomly assigned into three groups: placebo (n = 151), 2.16 mg/d of lofexidine (n = 230), 2.88 mg/d of lofexidine (n = 222). Primary outcomes were measured with the Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) and Clinical Opiate Withdrawal State (COWS) over seven days.		SOWS-Gossop and COWS scores were significantly lower from days 1 through 5 in both lofexidine groups compared to the placebo group. There was no significance between the two, 2.16 mg/d and 2.88 mg/d lofexidine groups. Adverse effects of dizziness, orthostatic hypotension, and bradycardia were slightly higher in lofexidine treatment groups. Fewer subjects dropped out of the lofexidine groups (2.16 mg/d and 2.88 mg/d) compared to the placebo group. 59%, 60.4% and 72.2%, respectively.		Lofexidine significantly reduces symptoms of opioid withdrawal state whether being treated with 2.16 mg/d or 2.88 mg/d compared to placebo. More subjects in the lofexidine groups completed the 7-day study. Lofexidine is a relatively safe and effective nonopioid treatment for opioid withdrawal.
Hermes et al. (2019)59		Fifty-seven individuals were randomly assigned to lofexidine (LFX)/oral naltrexone (NTX)/combination group (n = 26) or the placebo (PBO)/NTX group (n = 31) for 12 weeks of treatment. Naltrexone (NTX) compliance, opioid-free urine samples, opioid cravings, opioid withdrawal symptoms, and vital signs were assessed.		Opioid craving control in the LFX/NTX was better managed over the PBO/NTX group (p < .03). There were no differences in NTX compliance, opioid use, opioid craving. There was higher medication intolerance in LFX/NTX vs. PBO/NTX (p < .01). Study 2 individuals were withdrawn due to acute hepatitis infection. However, of the individuals that were not withdrawn, showed significantly higher rates of treatment completion (p < .05), NTX compliance (p < .01), lower percent opioid urine samples (p < .05), and lower overall opioid craving (p < .05) in the LFX/NTX vs. the PBO/NTX group.		Of those that tolerated the medication, LFX/NTX significantly improved opioid craving, delayed return to opioid use, and improved treatment compliance and completion rates. LFX dose titration should be further studied.
Alam et al. (2020)67		Two randomized placebo control study was conducted. In study 1, 602 opioid-dependent subjects were randomized into 2.88 mg/day, 2.16 mg/day lofexidine group, or placebo. In study 2, 264 opioid-dependent subjects were randomized into 2.16 mg/day lofexidine group or placebo. Primary outcomes were measured using the Short Opioid Withdrawal Scale of Gossop (SOWS-G) daily.		In study 1, SOWS-G score was 6.1 (p < .0001), 6.5 (p < .0001) and 8.8 for lofexidine 2.88 mg/day, 2.16 mg/day and placebo respectively. Study 2, (SOWS-G score was 7.0) and 8.9 for 2.16 mg/day lofexidine and placebo respectively (p = .0037). Significantly more subjects in the lofexidine group completed the studies. There were more adverse effects, such as hypotension and bradycardia, in the lofexidine group.		Lofexidine reduces opioid withdrawal symptoms and increases retention compared to placebo for opioid-dependent individuals.

Table 2. Comparative Studies.

AUTHOR (YEAR)		GROUPS STUDIED AND INTERVENTION		RESULTS AND FINDINGS		CONCLUSIONS
Meader (2010)68		A Meta-Analysis using CENTRAL, CINAHL, Embase, HMIC, Medline, and PsycINFO of RCT that included opioid-dependent participants over the mean age of 16 receiving opioid detoxification using buprenorphine, methadone, clonidine or lofexidine was included in the review. The author and research assistant independently assessed the RCTs.		23 RCTs were included in the systematic review and 20 included in the meta-analysis, with a total of 2112 participants. Buprenorphine and methadone were ranked the most effective, followed by lofexidine and clonidine.		Buprenorphine and methadone seem to be the most effective detoxification treatment. It is uncertain if methadone is more effective than buprenorphine. Lofexidine and clonidine are the next effective.
Law et al. (2017)63		Eighty opiate-dependent individuals that met the DSM-IV criteria for opioid dependency were randomized into methadone 30 mg, or buprenorphine/naloxone 4 mg/1 mg for stabilization then was followed by detoxification. For the Buprenorphine/naloxone group, the buprenorphine was gradually titrated down over 14 days. For the methadone/lofexidine group, methadone was stopped on day 3 of detoxification, and lofexidine was given for 14 days. Primary outcomes that were measured were urine drug screens for opiates and withdrawal and the Opioid craving Scale (OCS) score.		During the induction and stabilization phase, patients receiving methadone/lofexidine had significantly lower scores on the OSC. During the detoxification phase, the methadone/lofexidine group had significantly worse withdrawal symptoms, and peak withdrawal came earlier. There was no statistical difference between the number of patients that completed detoxification for the two groups.		Methadone/lofexidine and buprenorphine/naloxone groups had comparable outcomes for low dose opiate users.
Guo et al. (2018)62		One hundred eleven opioid-dependent patients were randomized to receive a ten-day trial of lofexidine (n = 56) or diazepam (n = 55) to examine the safety and efficacy of lofexidine. Primary outcomes were measured on days 3, and 4 using the Objective Opioid Withdrawal Scale (OOWS) score on days 3 and 4. Secondary outcomes were measured using the Short Opioid Withdrawal Scale (SOWS) score, retention rate, and opiate cravings.		OOWS and SOWS scores were lower in the lofexidine group; however, it was not statistically significant. More patients withdrew from the diazepam group, and the lofexidine group has completed the trial.		Diazepam is addictive and is not superior to lofexidine for treating opioid withdrawal symptoms.
Kuszmaul et al. (2020)54		A literature review of MEDLINE/PubMed, EBSCO, and CENTRAl using the terms “lofexidine,” “clonidine,” and “opioid withdrawal” of articles published between October 1992 and May 2019. Three independent reviewers analyzed the studies of lofexidine and clonidine comparison studies for the treatment of opioid withdrawal symptoms.		Of 110 articles screen, only five articles were included. Four studies showed no significant difference between lofexidine and clonidine. One study had a significant reduction in opioid withdrawal symptoms with lofexidine compared to clonidine. Three studies showed significant adverse effects with clonidine compared to lofexidine.		Studies show that clonidine and lofexidine have similar efficacy, but lofexidine is better tolerated for treating opioid withdrawal symptoms due to less adverse effects in the lofexidine group.