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Lofexidine

Discussion in 'Drug Articles' started by davestate, Apr 12, 2012.

  1. davestate

    davestate Gold Member

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    Lofexidine (Britlofex) is an alpha2-adrenergic receptor agonist commonly used to alleviate some of the physical symptoms of opiate withdrawal by decreasing the release of norepinephine and epinephrine. It helps to lessen physical withdrawal symptoms such as chills, sweating and cramps, but will not eliminate the symptoms. It will not stop cravings either.[footnote]http://www.patient.co.uk/medicine/Lofexidine.htm[/footnote] Lofexidine effects blood pressure less than clonidine[FOOTNOTE]http://www.ncbi.nlm.nih.gov/pubmed/6890374[/FOOTNOTE], so is safer for detox outside of an inpatient setting I.E. home detox. [footnote]http://www.drugs-forum.com/forum/local_links.php?action=jump&catid=133&id=4559[/footnote][FOOTNOTE]http://www.sciencedirect.com/science/article/pii/S0376871698000404[/FOOTNOTE]

    [h="1"]Introduction to [VAR]PAGENAME[/VAR][/h]
    [imgr=white]https://www.drugs-forum.com/forum/attachment.php?attachmentid=25606&stc=1&d=1334302258[/imgr]

    [h="1"]Using [VAR]PAGENAME[/VAR][/h]

    THe initial dosage should be 0.8mg per day in divided doses. The dosage may be increased by increments of 0.4 to 0.8mg per day up to a max of 2.4mg daily. Max single dose should not exceed 0.8mg. [FOOTNOTE]http://www.medicines.org.uk/emc/medicine/7119/SPC/BritLofex+Tablets+0.2mg/#POSOLOGY[/FOOTNOTE]The amount required will depend on a number of factors. For example, those who are undergoing an acute detox (cold turkey) will need a higher dose than those commencing lofexidine treatment at the end of a taper. The typical duration of treatment for a detox without opiate substitution is 7-10 days, however some user made guides recommend is use for a longer duration, especially with "cold turkey" or steep taper detoxes [FOOTNOTE]http://www.drugs-forum.com/forum/showthread.php?t=76991[/FOOTNOTE] It is recommended to gradually reduce the dose, rather than stopping suddenly, to avoid the risk of rebound hypertension, which not only could be unpleasant, but potentially harmful to health

    [h="2"]Ways of Administration[/h]

    Lofexidine is administered orally, as the hydrochloride salt and is available as 0.2mg tablets.


    [h="2"]Effects of [VAR]PAGENAME[/VAR] [/h]

    [h="2"]Combinations with [VAR]PAGENAME[/VAR][/h]
    Naltrexone may be used in combination with lofexidine as part of an inpatient detoxification treatment. In one study, lofexidine was compared to a combination of lofexidine and nalrexone for detox purposes. Withdrawal symptoms were significantly less severe on days 4–7, and 9–13, in the naltrexone/lofexidine combination group than lofexidine alone[FOOTNOTE]http://www.sciencedirect.com/science/article/pii/S0376871699001167[/FOOTNOTE] Lofexidine in combination with naltrexone also reduced post detox relapses and reduced the effect of cravings caused by stress, stress-induced opiate craving, and negative emotions [FOOTNOTE]http://www.drugs-forum.com/forum/showthread.php?t=91820[/FOOTNOTE]
    Naloxone has also been used, with similar results. Overall abstenance rates were not different for naloxone/lofexidine versus lofexidine alone, but reported/subjective withdrawal symptoms were lower for the combination group[FOOTNOTE]Bearn J, Bennet J, Martin T, Gossop M, Strang J The impact of naloxone/lofexidine combination
    treatment of the opiate withdrawal syndrome. Addiction Biology 2001; 6(2): 147-156[/FOOTNOTE]

    Lofexidine may also be user in conjunction with opiates as part of a taper [FOOTNOTE]http://www.drugs-forum.com/forum/showthread.php?t=76991&highlight=lofexidine[/FOOTNOTE] however when used as part of a slow taper is not shown to significantly increase success rates, and appears to be more useful for quick tapers or cold turkey detoxes. Useful guides to utilising lofexidine in methadone/buprenorphine tapers can be found in the thread: http://www.drugs-forum.com/forum/showthread.php?t=76991


    According to NHS guidlines, the following medications may also be prescribed to offer further symptomatic relief, for no longer than 21 days[FOOTNOTE]http://www.nhft.nhs.uk/mediaFiles/downloads/30503881/MMG025.pdf.pdf[/FOOTNOTE]:
    • Diazepam: For agitation
    • Zopiclone: For insomnia
    • Buscopan: For stomach cramps
    • Ibuprofen: For analgesia
    • Loperamide: For diarrhoea


    [h="2"]Different Uses for [VAR]PAGENAME[/VAR][/h]


    [h="1"]Pharmacology of [VAR]PAGENAME[/VAR][/h]
    During opiate withdrawal, levels of catacholeamines like adrenaline and noradrenaline are significantly elevated, and are responsible for some of the physical effects of opiate withdrawal. Lofexidine stimulates receptors in the brain that monitor the levels of adrenaline and noradrenaline in the blood. The brain believes that catecholamine levels are higher than they really are, causing signals to be sent to the adrenal medulla, which is part of the adrenal glands that sit above the kidneys. The signals cause the adrenal glands to lower catecholamine production, which lowers the amount in the bloodstream. This lowers the heart rate and blood pressure, offering some relief from the physical withdrawal symptoms

    Lofexidine is a structural analogue of clonidine. It is an imidazoline with a high affinity for α2-adrenergic receptor subtypes. This makes it less likely to cause hypotension than non-selective α2-adrenergic agonists [FOOTNOTE]Cox, S. and Alcorn, A. (1995) Lofexidine and opioid withdrawal. Lancet, 345, 1385–1386.[/FOOTNOTE]
    When taken orally lofexidine has a very high bioavailability, in the range of around 90%. Average time to peak plasma concentration is 3 hours, but can vary from 2-5. Half life is approximately 11 hours, meaning that a steady state for plasma concentration is reached after approx 2 days (55hours)[FOOTNOTE]http://www.ncbi.nlm.nih.gov/pubmed/18393298[/FOOTNOTE][FOOTNOTE]http://www.medicines.org.uk/emc/medicine/7119/SPC/BritLofex+Tablets+0.2mg/#PHARMACOKINETIC_PROPS[/FOOTNOTE]
    There are few studies available on the metabolism and excretion of lofexidine, but one study using radiolabeled C[sup]14[/sup] showed "significant
    hepatic metabolism [glucuronidation] with four metabolites detected. The glucuronide metabolites accounted for 50% of those identified. Approximately 10% of the drug appears unchanged in the urine."[FOOTNOTE]http://www.nacd.ie/publications/LofexidineReport.pdf[/FOOTNOTE]The main metabolite found was 2,6-dichlorophenol, which was excreted in urine as "two O-glucuronic acid conjugates" [FOOTNOTE]http://www.ncbi.nlm.nih.gov/pubmed/6880242[/FOOTNOTE]

    LD[sub]50[/sub] (mg/kg) (as the hydrochloride) [1] :
    74-147 orally (rat, mice, dog); 8-18 intravenously (rat, mice, dog)

    [h="1"]Chemistry of [VAR]PAGENAME[/VAR][/h]
    Column 1 Column 2
    0 Systematic (IUPAC) name: (RS)-2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1H-imidazole
    1 Synonyms: 2-[1-(2,6-dichlorophenoxy)ethyl]-2-imidazoline; MDL-14042A, Ba-168, BritLofex, Lofetensin (hydrochloride)
    2 Molecular Formula: C[sub]11[/sub]H[sub]12[/sub]Cl[sub]2[/sub]N[sub]2[/sub]O, C[sub]11[/sub]H[sub]12[/sub]Cl[sub]2[/sub]N[sub]2[/sub]O.HCl
    3 Molar mass: 259.13 g/mol, 295.59 g/mol (hydrochloride)
    4 CAS Registry Number: 31036-80-3, 21498-08-8 (hydrochloride)
    5 Melting Point: 126-128°C; 221-223°C, also reported 230-232°C (hydrochloride)
    6 Boiling Point: no data
    7 Flash Point: no data
    8 Solubility: Hydrochloride very soluble in water, ethanol; sligthly soluble in isopropanol; practically insoluble in ether
    9 Additionnal data: none
    10 Notes: Hydrochloride crystallized from ethanol + ether or isopropanol
    [1]

    [​IMG]

    [h="1"]The Dangers of [VAR]PAGENAME[/VAR][/h]
    Lofexidine should be used with caution if you suffer from severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease or chronic renal failure and in patients with bradycardia or hypotension.[FOOTNOTE]http://www.medicines.org.uk/emc/medicine/7119/SPC/BritLofex+Tablets+0.2mg/#INTERACTIONS[/FOOTNOTE]
    Lofexidine should not be taken if you are pregnant or breast feeding or have underlying psychosis or mental health[FOOTNOTE]http://www.nhft.nhs.uk/mediaFiles/downloads/30503881/MMG025.pdf.pdf[/FOOTNOTE]

    Lofexidine can cause hypotension and bradycardia, though not as severely as clonidine, so caution should be taken when standing up quickly, getting out of a hot bath, or any situation in which you are chaning posture quickly. If you feel dizzy, light headed or faint, do not drive or operate machinery.

    As Lofexidine may cause drowsiness and sedation, interactions may occur when taken in combination with
    alcohol, sedatives, anti-hypertensive agents and tricyclic antidepressants. Particular risk arises when pharmacokinetic and pharmacodynamic interactions may occur e.g. concurrent use of alcohol or sedatives.[FOOTNOTE]http://alcalc.oxfordjournals.org/content/36/5/426.full[/FOOTNOTE]

    Overdosage may cause hypotension, bradycardia and sedation.[FOOTNOTE]http://www.drugbank.ca/drugs/DB04948[/FOOTNOTE]
    [h="2"]Summary of side effects[/h]
    BritLofex tablets may sometimes cause the following:
    – dry mouth or throat
    – dry nose
    – sleepiness
    – light-headedness or dizzyness upon standing
    – slow heart beat
    [FOOTNOTE]http://www.drugs-forum.com/forum/showthread.php?t=92535[/FOOTNOTE]
    [h="1"]Legal Status of [VAR]PAGENAME[/VAR][/h]
    Not controlled. Prescription only medicine

    [h="2"]USA[/h]
    Lofexidine has not yet been approved by the FDA for use in the USA, however it is undergoing phase III trials [FOOTNOTE]http://www.solsticeneuro.com/docs/USW%20RELEASE%20-%20FINAL%20REV%2010.10.pdf[/FOOTNOTE]
    [h="2"]EU[/h]
    [h="3"]UK[/h]
    Lofexidine has been used in an estimated 20 000[FOOTNOTE] Strang, J., Bearn, J. and Gossop, M. (1999) Lofexidine for opiate detoxification: review of recent randomised and open controlled trials. American Journal on Addictions 8, 337–348.
    [/FOOTNOTE] detoxifications over 13 years in the UK, where it is marketed by Britannia Pharmaceuticals as Britlofex. It is a prescription only medication and is approved for home and inpatient detox
    [h="3"]Ireland[/h]






    [h="1"] Popularity of lofexidine over time[/h]
    [insights]lofexidine[/insights]



    [h="2"]The Latest [VAR]PAGENAME[/VAR] Threads[/h]
    [showthreads=8]281[/showthreads]

    [CAT]Anti-hypertensive[/CAT]
    [CAT]Alpha2-adrenergic receptor agonist[/CAT]

    [h="1"]References[/h]
    [REFLIST][/REFLIST]
    [1] Merck Index, fifteenth edition (2013)
     
  2. Docta

    Docta Idiot Savant

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    Standardized Drugs Wiki image with stereogenic center bold wedge orientation (coming out toward you)

    In your face Wikipedia, sometimes I think there's a trained monkey drawing the isomers for um over their.

    [​IMG]
     

    Attached Files:

  3. davestate

    davestate Gold Member

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    Nice one docta cheers! Can I request more standardised images for you to do (if it's not too much trouble, I only have ISISdraw now and it's shite compared to chemdraw)
     
  4. Docta

    Docta Idiot Savant

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    Yep that's fine just leave your request at the Wiki image task thread I tent to get them done quickly if its just a single isomer.

    Chemical synthesis and compound production diagrams take a little longer.
     
  5. John_bob

    John_bob Titanium Member

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    I added chem data. It seems lofexidine is racemic (from what I see in wikipedia and merck index). It would be good to change the image.