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").

Sunday, May 6, 2012

The Physiological Component of Opioid Withdrawal is Mediated Centrally, Not Peripherally

I recently received a comment on the blog; specifically in reference to this older piece about the efficacy of loperamide in suppressing opioid withdrawal. 

"Loperamide will bind to any peripheral opiate sites in the body and the ability [to do so] completely eliminates all physical opiate withdrawal symptoms. As for the CNS and brain, the physical relief of stopping opiate withdrawal is all I needed. When my body tells my brain the withdrawals are over I do not give a crap what it is.."

Let me summarize; the reader is stating how, supposedly, loperamide is able to eliminate the physiological symptoms of opioid withdrawal because of its action on peripheral receptor sites throughout the body. For the record, "peripheral" refers to any receptor site outside of the central nervous system; i.e. throughout muscle tissue, beneath the skin, in the GI tract, etc. Being that I've seen people make many remarks similar to this one before, I'm led to believe there may be a common misconception as to the nature of opioid withdrawal. This entry has little to do with loperamide itself, and more to do with opioid withdrawal.

Let me first clarify, there are two primary components to the aversive experience of withdrawal from opioid use; these being a) the physical discomfort or sickness, and b) the dysphoric psychological state of anxiety, depression, drug craving, and perceived impending doom. 

It's common for the layperson (i.e. the average drug user) to think in literal terms in regard to the mechanisms underlying his/her opioid withdrawal sickness - to put it simply, it seems to make sense to some people that the physical symptoms of withdrawal are mediated throughout the body ("physically"), while the psychological symptoms are mediated within the brain ("psychologically"). This isn't the case - the physical symptoms of opioid abstinence are not mediated by the peripheral structures of the body, but instead by the brain (with the exception of diarrhea). 

The emotional symptoms of withdrawal and the physical symptoms of withdrawal are not as clearly distinguished in their physiological origins as has traditionally been believed. The brain regulates far more than emotions and psychological state. The brain regulates every function of every organ, tissue, and vessel of the body; it controls perspiration, salivation, tears of the eye, heartbeat, movement of the diaphragm, libido, erection and ejactulation, pupil size, bowel tone, body temperature, sense of body temperature, skin texture, voluntary and involuntary muscle movements, bladder control, and almost any other bodily function imaginable. The peripheral pathways innervating the organs, muscles, and skin are all directed by orders from the brain to which they connect. 

The physical component of opioid withdrawal is characterized by a state of autonomic arousal. The key areas of the brain and brainstem which narcotics typically suppress become hyperactive (running at a level above normal) when the inhibitory action of the opioids is suddenly reduced or withdrawn. 

Most affected is the sympathetic branch of the autonomic nervous system. The structures of the sympathetic branch modulate the body's "fight or flight" response to stress or environmental threats. When opioids are withdrawn; the normally suppressed structures of the hypothalamus, the pituitary gland, and the locus coeruleus begin working at levels above what is normal. 

With the exception of diarrhea, functional changes in certain areas of the sympathetic brain can account for nearly all of the physical symptoms attributed to opioid withdrawal.

Dysregulation of the hypothalamus leads to an excess of many bodily functions normally inhibited by narcotics. Pinpoint pupils (miosis) become abnormally large (mydriasis), the dry mouth begins overproducing saliva, dry skin begins to perspire, the dry nose begins to run, while the insensitivity to temperature gives way to hot/cold flashes and chills. 

Dysregulation of the hypothalamic-pituitary-adrenal axis contributes to an excess of hormone release, a state of stress, emotional vulnerability, and an inability to fall asleep.

Dysregulation of the locus coeruleus leads to an excess of noradrenergic tone; this manifests as anxiety, agitation, panic attacks, increased heart rate and blood pressure, muscle tension, tremors, restlessness or akathisia, involuntary movements of the limbs, nausea, vomiting, and stomach discomfort.

Loperamide, in high doses, ameliorates more than diarrhea and bowel discomfort. High dose loperamide will suppress most if not all of the physiological discomfort associated with opioid withdrawal, depending on individual tolerance level and drug history - This, along with its documented ability to induce respiratory depression and miosis under certain conditions, leads me to conclude that high dose loperamide does indeed exert an affect on the central nervous system (i.e. brain). But the question of whether loperamide exhibits central activity is not even the point.

The real point is this - there is no known compound capable of alleviating the physical component of opioid withdrawal through its peripheral action alone. The physical symptoms of withdrawal are synonymous with the psychological symptoms of withdrawal, if only in the sense that both are predominantly mediated by the brain; not peripheral tissues.


  1. thedevilinatlanta@yahoo.comMay 7, 2012 at 10:56 PM

    Is Loperamide addictive or found in any medications?

    1. Loperamide is the active ingredient in many over the counter anti-diarrheal medications (Immodium AD, etc). As for its addiction potential, it does produce a mild physical dependence when taken consistently in high doses, particularly when used for extended periods as a maintenance aid to prevent withdrawal.

  2. PGP Pumps move lope back accross the BBB. Take OTC Prilosec and then in ~1 hours dose lope and tagamet. I usually chew one prilosec on day one since they are extended release and swallow one whole. After day 1 I only swallow the prilosec in the morning and take 10-20mg lope 2x daily depending on how I feel with tagamet at every lope dose. This method has allowed me to decrease lope doses. Without the added CYP inhibit from tagamet and pgp pump down regulation from prilosec I needed at least 80mg lope daily to stay 75% well. With this cocktail I generally take no more than 20-30mg daily and have no withdrawal usually much less unless I had a particularly heavy binge. Extended lope administration does cause some damage to some bodily systems evident from elevated amylase/lipase levels but I can generally taper down to 0 within 7 days with hardly no ill effects/withdrawal. The first day after a few day 50-100mg iv daily oxym binge I might dose 40mg the first day but usually I have it tapered to 10-16mg daily lope within 3 days.

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