{{Short description|Medication used for opioid withdrawal}} {{Infobox drug | Verifiedfields = changed | verifiedrevid = 408579887 | IUPAC_name = (''RS'')-2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1''H''-imidazole | image = Lofexidine.svg | image_class = skin-invert-image | width = 175 | chirality = Racemic mixture

<!--Clinical data-->| tradename = Britlofex, Lucemyra, others | Drugs.com = {{drugs.com|monograph|lofexidine-hydrochloride}} | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_US = N | pregnancy_category = | legal_AU = S4 | legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_UK = POM | legal_US = Rx-only | legal_status = Rx-only | routes_of_administration = By mouth

<!--Pharmacokinetic data-->| bioavailability = >90% | protein_bound = 80–90% | metabolism = Liver (glucuronidation) | elimination_half-life = 11 hours | excretion = Kidney

<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 31036-80-3 | ATC_prefix = N07 | ATC_suffix = BC04 | PubChem = 30668 | DrugBank_Ref = {{drugbankcite|changed|drugbank}} | DrugBank = DB04948 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 28460 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = UI82K0T627 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D08141 | ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI = 51368 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 17860

<!--Chemical data-->| C = 11 | H = 12 | Cl = 2 | N = 2 | O = 1 | smiles = Clc2c(OC(C/1=N/CCN\1)C)c(Cl)ccc2 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C11H12Cl2N2O/c1-7(11-14-5-6-15-11)16-10-8(12)3-2-4-9(10)13/h2-4,7H,5-6H2,1H3,(H,14,15) | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = KSMAGQUYOIHWFS-UHFFFAOYSA-N }}

'''Lofexidine''', sold under the brand name '''Lucemyra''' among others,<ref name="FDA Approval"/> is a medication historically used to treat high blood pressure; today, it is more commonly used to help with the physical symptoms of opioid withdrawal.<ref name = BNF/> It is taken by mouth.<ref name=FDA2018/> It is an α<sub>2A</sub>-adrenergic receptor agonist.<ref name=FDA2018/> It was approved for use by the Food and Drug Administration in the United States in 2018,<ref name=FDA2018>{{cite press release|title=FDA approves the first non-opioid treatment for management of opioid withdrawal symptoms in adults|url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-non-opioid-treatment-management-opioid-withdrawal-symptoms-adults |archive-url=https://web.archive.org/web/20190902074109/https://www.fda.gov/news-events/press-announcements/fda-approves-first-non-opioid-treatment-management-opioid-withdrawal-symptoms-adults |url-status=dead |archive-date=September 2, 2019 |website=U.S. Food and Drug Administration (FDA)|access-date=18 May 2018 }}</ref> considering it to be a first-in-class medication.<ref>{{cite report | title=New Drug Therapy Approvals 2018 | website=U.S. Food and Drug Administration (FDA) | date=January 2019 | url=https://www.fda.gov/media/120357/download | archive-url=https://web.archive.org/web/20190826114431/https://www.fda.gov/media/120357/download | url-status=dead | archive-date=August 26, 2019 | format=PDF | access-date=16 September 2020}}</ref>

==Medical uses== In the United States, lofexidine is approved for the "mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults," for a treatment duration of 14 days.<ref name="FDA Approval">{{cite web|title=Press Announcements - FDA approves the first non-opioid treatment for management of opioid withdrawal symptoms in adults|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm607884.htm|archive-url=https://web.archive.org/web/20180517030156/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm607884.htm|url-status=dead|archive-date=May 17, 2018|website=www.fda.gov|publisher=U.S. Food and Drug Administration|access-date=16 May 2018|language=en}}</ref> In the United Kingdom, lofexidine is commonly used in conjunction with the opioid receptor antagonist naltrexone in rapid detoxification cases. When these two drugs are paired, naltrexone is administered to induce an opioid receptor blockade, sending the subject into immediate withdrawal and accelerating the detoxification process, while lofexidine is given to relieve the symptoms associated with the withdrawal including chills, sweating, stomach cramps, muscle pain, and runny nose.{{Citation needed|date=May 2018}}

===Opioid withdrawal=== The United Kingdom's National Institute for Health and Care Excellence (NICE) guidelines recommend the use of methadone or buprenorphine as first-line agents in the management of opioid use disorder. However, lofexidine is considered an acceptable alternative for people with mild or uncertain opioid dependence in need of short-term detoxification.<ref name="NICE 2007">{{cite web|title=Pharmacological interventions in opioid detoxification for drug misuse in people over 16|url=https://pathways.nice.org.uk/pathways/drug-misuse-management-in-over-16s/pharmacological-interventions-in-opioid-detoxification-for-drug-misuse-in-people-over-16#content=view-node%3Anodes-choice-of-medication|website=pathways.nice.org.uk|publisher=NICE|access-date=16 May 2018|language=en}}</ref>

Lofexidine is not an opioid.<ref name=FDA2018/> It does not eliminate the symptoms of opioid withdrawal but reduces them.<ref name=FDA2018/> Indeed, one suggested use for lofexidine is to ease withdrawal symptoms of methadone dependence. Its use is approved in the United States for up to 14 days.<ref name=FDA2018/>

===Other clinical uses=== The possibility of using lofexidine to treat alcohol withdrawal symptoms has been investigated, and has not yet been shown to be an effective treatment.<ref>Keaney F, Strang J, Gossop M, Marshall EJ, Farrell M, Welch S, Hahn B, Gonzalez A. A double-blind randomized placebo-controlled trial of lofexidine in alcohol withdrawal: lofexidine is not a useful adjunct to chlordiazepoxide. Alcohol Alcohol (2001) 36:426–30.</ref> It is also used in treatment of cases with postmenopausal hot flashes.

===Special populations=== Lofexidine's safety in pregnancy or in the setting of breastfeeding are unknown.<ref name="BNF Lofexidine" /> Caution is warranted if chronic kidney impairment is present.<ref name="BNF Lofexidine" />

==Adverse effects== Adverse effects that have occurred after taking lofexidine include the following:<ref name="BNF Lofexidine">{{cite web|title=LOFEXIDINE HYDROCHLORIDE|url=http://bnf.nice.org.uk/drug/lofexidine-hydrochloride.html|website=bnf.nice.org.uk|publisher=NICE|access-date=16 May 2018}}</ref> * Slow heart rate * Dizziness * Sleepiness * Dry mouth * Low blood pressure * QT prolongation In addition, people may experience a sudden jump in blood pressure after stopping lofexidine.<ref name="FDA Approval" />

==Overdose== The {{LD50}} of lofexidine is above 77&nbsp;mg/kg in animals. Studies of high-dose, single administrations of lofexidine proved tolerable for animals, but repeat administration induced symptoms consistent with toxicity. In studies on mice, rats, and dogs, these included ataxia, somnolence, and tremors. It is expected that an overdose of lofexidine would result in symptoms akin to its pharmacological side effects in humans, such as bradycardia and hypotension.<ref name="PubChem" />

== Interactions ==

Many drug-drug interactions with lofexidine are possible.<ref name="BNF Lofexidine DDIs">{{cite web|title=<nowiki>Lofexidine | Interactions | BNF</nowiki>|url=http://bnf.nice.org.uk/interaction/lofexidine.html|website=bnf.nice.org.uk|publisher=NICE|access-date=16 May 2018}}</ref>

===QT prolongation=== Lofexidine prolongs the QT interval, which can result in a severe interaction (torsade de pointes) when combined with other drugs that also prolong the QT interval. Patient-specific characteristics that increase the risk for a clinically significant drug-drug interaction include:<ref name="BNF Lofexidine DDIs" /> *increasing age *female sex *cardiac disease *electrolyte disturbances (low blood potassium) As a result, there are many QT-prolonging drugs that may interact with lofexidine. These include medications such as methadone, amiodarone, citalopram, and fluconazole. Other medications may increase the risk for a low level of potassium in the blood, thereby indirectly increasing the risk for QT prolongation. For example, dexamethasone, hydrochlorothiazide, and theophylline can lower the level of potassium in the blood.<ref name="BNF Lofexidine DDIs" />

===CNS depression=== Lofexidine can depress the central nervous system (CNS), which, in combination with other CNS depressants, may reduce a person's ability to perform tasks that require skills and attention. For example, clobazam, gabapentin, and levetiracetam all can depress the CNS.<ref name="BNF Lofexidine DDIs" />

===Hypotension=== The risk of hypotension (low blood pressure) is increased when lofexidine is combined with other drugs that lower blood pressure. These may include losartan, metoprolol, and pramipexole.<ref name="BNF Lofexidine DDIs" />

==Pharmacology== Lofexidine is an agonist at the alpha-2A, 2B, and 2C adrenergic receptor subtypes, with the highest activity at the α<sub>2A</sub>-adrengergic receptor.<ref name="Fulton Book" /> ::{| class="wikitable" |+ K<sub>i</sub> for lofexidine<ref name="Fulton Book" /> ! Adrenergic receptor ! K<sub>i</sub> (nM) |- !α<sub>2A</sub> | 4 |- !α<sub>2B</sub> | 67 |- !α<sub>2C</sub> | 69 |- |} <small>K<sub>i</sub> represents the dissociation constant<ref name="Neubig">{{cite journal | vauthors = Neubig RR, Spedding M, Kenakin T, Christopoulos A | title = International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology | journal = Pharmacological Reviews | volume = 55 | issue = 4 | pages = 597–606 | date = December 2003 | pmid = 14657418 | doi = 10.1124/pr.55.4.4 | s2cid = 1729572 }}</ref> for lofexidine's binding to a specific subtype of α<sub>2</sub> receptor. The smaller the K<sub>i</sub> value, the stronger the drug binds to the receptor to exert its activity.</small>

Lofexidine inhibits the release of norepinephrine in the central and peripheral nervous system, thereby reducing some of the symptoms of opioid withdrawal, but it has no documented effect on drug craving and endogenous opioid levels.<ref name="BNF">{{cite book | isbn = 978-0-85711-084-8 | title = British National Formulary (BNF) | last1 = Joint Formulary Committee | year = 2013 | publisher = Pharmaceutical Press | location = London, UK | edition = 65 | page = [https://archive.org/details/bnf65britishnati0000unse/page/330 330] | url = https://archive.org/details/bnf65britishnati0000unse/page/330 }}</ref>

===Pharmacokinetics=== Lofexidine's oral bioavailability is about 90%, with extensive oral absorption. Peak plasma concentrations occur at 3 hours after a single administration, with a half-life of 11 hours. Lofexidine is extensively metabolized by the liver, and primarily cleared by the kidney. It is 80–90% plasma protein bound.<ref name="PubChem" />

==Chemistry== Lofexidine exists as a solid at room temperature, with a melting point of 127 degrees C.<ref name="PubChem">{{cite web|title=Lofexidine|url=https://pubchem.ncbi.nlm.nih.gov/compound/Lofexidine|website=pubchem.ncbi.nlm.nih.gov|publisher=National Center for Biotechnology Information|access-date=16 May 2018|language=en}}</ref> The pair of ortho chlorine (Cl<sup>−</sup>) atoms on the phenyl ring are necessary for lofexidine's agonism at the α<sub>2A</sub> adrenergic receptor subtype; removal of either chlorine atom results in antagonism at the receptor.<ref name="Fulton Book">{{cite book|last1=Fulton|first1=Brian | name-list-style = vanc |title=Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies|date=2014|publisher=John Wiley & Sons|isbn=978-0470614167|page=151}}</ref>

===Comparison to clonidine=== thumb|350px|right|Structure of clonidine and lofexidine Lofexidine is structurally analogous to clonidine, another α<sub>2</sub> adrenergic receptor agonist used for treatment of opioid withdrawal symptoms. A comparison of the two structures is shown at right. Both contain an imidazoline ring and a 2,6-dichlorinated phenyl ring. The differences in structure are shown in red, while the similarities are in black. In addition to the structural differences, administration of lofexidine to people who abuse opioids has been shown to be more effective for a longer duration, with fewer withdrawal symptoms than clonidine even after one day.<ref name=gerra>{{cite journal | vauthors = Gerra G, Zaimovic A, Giusti F, Di Gennaro C, Zambelli U, Gardini S, Delsignore R | title = Lofexidine versus clonidine in rapid opiate detoxification | journal = Journal of Substance Abuse Treatment | volume = 21 | issue = 1 | pages = 11–7 | date = July 2001 | pmid = 11516922 | doi = 10.1016/s0740-5472(01)00178-7 }}</ref> However, clonidine is often preferred as it is substantially cheaper than lofexidine when purchased with a private (non-NHS) prescription. This factor is exacerbated by the considerable number of and quantities of medications prescribed to alleviate the constellation of withdrawal signs and symptoms. Additionally, clonidine has been shown to significantly lower blood pressure. Therefore, although similar to lofexidine, clonidine is most frequently prescribed to treat high blood pressure.{{Citation needed|date=May 2018}}

==Society and culture== Britannia Pharmaceuticals has licensed lofexidine to be sold by US WorldMeds for sale in North America.<ref>[http://www.britannia-pharm.co.uk/ Britannia Pharmaceuticals Limited<!-- Bot generated title -->]</ref> In the United Kingdom, the hydrochloride form, lofexidine HCl, has been licensed and sold since 1992 for opioid withdrawal relief in tablet form as BritLofex by Britannia Pharmaceuticals.<ref name = BNF/> BritLofex is only available by prescription. Lofexidine was first approved by the US FDA on May 16, 2018, under the brand name Lucemyra, produced by US WorldMeds.<ref name="Drugs.com">{{cite web|title=Lucemyra (lofexidine hydrochloride) FDA Approval History - Drugs.com|url=https://www.drugs.com/history/lucemyra.html|website=Drugs.com|access-date=16 May 2018}}</ref> It was noted as the first non-opioid drug approved in the US for the treatment of opioid withdrawal.<ref name="FDA Approval" />

== See also == * Methadone * Naltrexone * Clonidine

== References == {{Reflist}}

{{Antihypertensives and diuretics}} {{Antiaddictives}} {{Adrenergic receptor modulators}}

Category:Alpha2-adrenergic agonists Category:Antihypertensive agents Category:Chloroarenes Category:Imidazolines Category:Phenol ethers Category:Phenoxyethylamines