Lofexidine: Difference between revisions

{{Short description|Medication used for opioid withdrawal}}

{{Drugbox

| Verifiedfields = changed

| verifiedrevid = 408579887

| image = Lofexidine.svg

| width = 175

| chirality = [[Racemic mixture]]

<!--Clinical data-->

| tradename = Britlofex, Lucemyra, Kai Er Ding, 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 = [[Oral administration|By mouth]] ([[Tablet (pharmacy)|tablets]])

<!--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

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D08141

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 51368

<!--Chemical data-->

| C=11 | H=12 | Cl=2 | N=2 | O=1

| smiles = Clc2c(OC(C/1=N/CCN\1)C)c(Cl)ccc2

'''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 [[alpha-2A adrenergic receptor|α_2A 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 |website=U.S. [[Food and Drug Administration]] (FDA)|access-date=18 May 2018 }}</ref>

The U.S. [[Food and Drug Administration]] (FDA) considers 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 | format=PDF | access-date=16 September 2020}}</ref>

==Medical uses==

In the [[United States]], the brand name Lucemyra (lofexidine HCl) 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|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 [[Drug detoxification|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 flash]]es.

===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 disease|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>

* [[Bradycardia|Slow heart rate]]

* [[Dizziness]]

* [[Somnolence|Sleepiness]]

* [[Xerostomia|Mouth dryness]]

* [[Hypotension|Low blood pressure]]

* [[QT prolongation]]

In addition, people may experience [[rebound hypertension|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 interaction|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 ([[hypokalemia|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 α-2A, 2B, and 2C adrenergic receptor subtypes, with the highest activity at the α_2A receptor.<ref name="Fulton Book" />

::{| class="wikitable"

|+ [[Dissociation constant|K_i]] for lofexidine<ref name="Fulton Book" />

! [[Adrenergic receptor]]

! K_i (nM)

|-

!α_2A

| 4

|-

!α_2B

| 67

|-

!α_2C

| 69

|-

|}

<small>K_i 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 α₂ receptor. The smaller the K_i 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 (withdrawal)|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. [[Cmax (pharmacology)|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 [[Arene substitution pattern|ortho]] [[chlorine]] (Cl⁻) atoms on the [[phenyl]] ring are necessary for lofexidine's agonism at the α_2A 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===

[[Image:Clonidine and lofexidine.svg|thumb|350px|right|Structure of clonidine and lofexidine]]

Lofexidine is structurally analogous to [[clonidine]], another α₂ 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 [[Opioid use disorder|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 [[Hypertension|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 [[medical prescription|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:Alpha-2 adrenergic receptor agonists]]

[[Category:Chloroarenes]]