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Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Wednesday, March 7, 2012

The Merits of High Dose Loperamide for Opioid Withdrawal

Basic:

Loperamide, best known as the active compound in Immodium AD, is a synthetic opioid widely used as an over the counter antidiarrheal agent. It was originally controlled under schedule V of the US controlled substance act, due to initial occurences of mild physical dependence and withdrawal symptoms, but is no longer classified as a controlled substance.

Loperamide and other opioids relieve diarrhea by reducing wave-like movements (i.e. peristalsis) of the intestines and allowing time for the body to absorb moisture from intestinal waste. This allows feces to take on a thick, nugget-like form, rather than gooey diarrhea. The constipating action involves the same mechanisms as conventional opioids; loperamide acts as an agonist at mu receptors in the gut. Mu receptor activity in this area produces primarily an anticholinergic response - leading to the inhibition of secretions and smooth muscle functions; or in very high doses, additional side effects such as dry eyes and mouth, sore throat, vision problems, and urinary retention.

Loperamide is highly lipophilic and unable to dissolve in water, which adds to its appeal as a non-prescription compound.  Dissolution of the compound in the gut is very slow. Peak levels are reached in around 5 hours after oral administration. It has a half life of 11 hours. It is metabolized by the liver and excreted via the feces (main kinetic pathway is N-demethylation via cytochrome P450 enzymes).

Use in Preventing Opioid Withdrawal

Loperamide has a limited ability to reach the central compartment when taken in typical doses, so its action on the CNS is insignificant in this setting. Accounting for its limited psychoactivity is its very slow dissolution (~5 hours to reach peak plasma levels), its limited bioavailability (~40%), and a metabolic efflux of loperamide from the CNS (a process in which therapeutic concentrations of loperamide present in central fluid is pumped back out of the central compartment). 

The aforementioned limitations are primarily pharmacokinetic or metabolic in nature and have been overcome with the use of high dosages or the concurrent administration of a metabolic inhibitor of P-glycoprotein (the aforementioned transport protein). Both measures have been found to be somewhat succesful in overwhelming the metabolic function that limits the central activity of the drug. 

With very high doses of loperamide, sufficient to accumulate in the central compartment (spinal cord and brain), marked narcotic effects have been reported. In addition, abstinence suppressing properties have been widely reported in opioid-dependent subjects; who frequently use the drug to reduce, or alleviate altogether, opioid withdrawal syndrome in the abscence of conventional narcotics.

Its effects are unique in some respects but similar to typical opioids in other respects. Most users report a "body buzz" - consisting of a heavy, warm, or weakening sensation in the arms, legs and neck, similar to that produced by poppy tea or plain morphine. Also common is dry and itchy skin, this itching is often particularly intense and may require the use of antihistamines. CNS effects (aside from relief of withdrawal) may include a mild sense of well being or an increase in mood, talkativeness, sedation or sleepiness, analgesia, miosis, emesis and respiratory depression.

It is important to note that loperamide has very limited recreational value; mainly because the risk to benefit ratio in the context of recreational use is extremely unfavorable. The only possibly justified use of such high doses remains temporary alleviation of abstinence symptoms - and even in this case, the risk/benefit merits of this self treatment are questionable.

Risks and Adverse Events:

Such uses of loperamide are not without risk. Loperamine is a synthetic compound of the phenylpiperidine type. Very little is known about its action on CNS and brain tissue, and little is known about the potential for neurotoxicity with either the parent drug or its metabolites, though it shares structural attributes with methadone and meperidine, or more significantly, a neurotoxic meperidine analogue MPTP; a compound linked with irreversible symptoms of parkinsonism. The lack of such known neurotoxic properties with loperamide could very well hinge only on its lack of CNS activity in normal doses - though there have not yet been reports of loperamide-induced parkonsinism to the author's knowledge. However, with its high lipophilicity and slow elimination profile, accumulation of loperamide in the CNS and soft tissue organs could present a real issue, especially in the astronomical dose ranges used in these opioid tolerant & dependent populations; opening up the possibilities of hepatic and renal issues, the aforementioned neurotoxicity, and delayed acute toxicity (overdose). The constipating action itself raises some issues of concern with extended high dose use. 

Deaths have been reported in connection with loperamide, anecdotally and in the literature. One such case described a death in which the cause was ruled as "combined loperamide and ethanol intoxication". There have been anecdotal reports of pancreatitis associated with loperamide. Known adverse events include paralytic ileus or bowel obstruction, toxic megacolon, perforated colon, anaphylaxis, septic shock and death.

Whether or not the short term benefits of high dose loperamide are worth the potential risks, remains up to the individual user. The author however does not reccomend anything of the sort.

10 comments:

  1. what is the incidence of accidental overdose using loperamide moderated doses, combined with a history of tolerating such doses ( 20mg-30mg) est. and would it occur as a cns shut down, with or without seizure, quickly and without other drugs consumed by person.

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  2. The good thing about Loperamide is that once it activates it shuts the withdrawals off for almost two days. You have to experiment with it to find your comfortable dose. It's the best thing to come clean. You may not believe this, but I'm more comfortable on Loperamide than I was on Oxycontin. Oxy would only hold off the withdrawal, demon/flu, for a few hours before I'd have to pop another 40 mg. F..k that! I'm sick of being SICK! Get your old life back, you deserve it! Hey, look at the bright side...you and me sailed off into the sunset where hardly anyone else has been..., or ever will go...it was fun dude...now it's time to respect ourselves and retire. We can always talk about those good 'ol days. They can't take them away.

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  3. Good idea, we've over sailed these waters.

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  4. Currently released case studies are showing a connection between severe heart problems and high dose or mega dose loperamide over the long term. You won't see me doing this. I like my heart!

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  5. I've brought my oxy withdrawl down to tolerate levels with just 8mg of loperamide and an occasional glass of tonic water. The quinine in the tonic water inhibits the action that expels loperamide from the CNS.

    The tonic water tastes pretty nasty, so I use flavoring. If you really can't stand the taste you could probably boil or evaporate it. The quinine is in salt form and should be left behind in the container albeit in small quantity.

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  6. I successfully withdrew from tramadol by using the loperamide on its own for just a few days. I didn't use humongous doses like I've seen, either. I needed 36 mg the first day, 24 the next, 20 the third day. The fourth day I felt fine. I'd been taking 400 mg of tramadol for two years, and I've never seen anyone post they got off it that fast or easily through any other method. I did have zolpidem for three nights as well. I wouldn't push loperamide intake too far or for too many days -- it can carry its own horrid withdrawal. And that seems to happen fairly often from the reading I've done, people trading pain med dependence for loperamide dependence. I took Metamucil and was able to have bowel movement, by the way. I wouldn't take that much loperamide without good stool softeners or the Metamucil.

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    1. It's a long shot, since this is anonymous, but did you have stomach pain or any other negative side effects with the lope dose at 30+mg?

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    2. I usually take 90 mg or more, and I'm in the same boat with the tramadol withdrawals. Yeah, it gets a little uncomfortable, feels like a big bubble inside you. But it goes away after a couple hours. Totally manageable. take it with stool softeners and some fiber supplements, otherwise you'll regret it.

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  7. Please watch this interesting video before even considering loperamide. If it's even mentioned in the same sentence as MPTP, stay away! It may not kill neurons as fast as MPTP but if it leads to parkinson's at some point your life, you will be pretty screwed...

    http://www.youtube.com/watch?v=KsBphHpOfd4&feature=youtube_gdata_player

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  8. I take about 400mg a day... I can see how it starts to weaken the body down.. I have lost a decent amount of muscle strength. To the point where my arm starts to shake when i hold something as light as a cup of coffee too long

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