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, October 5, 2011

Understanding Opioid Withdrawal: Origins, Symptoms, Remedies

(I've completely watered this down for easy reading)

Primer: Tolerance & Dependence

For a regular opioid agonist such as morphine, subjective effects (including analgesia), for all practical purposes, are dose dependent; however, the agonist effect at opioid receptors which underlies these subjective effects, is concentration dependent. As the concentration of opioid in the blood increases, more receptors become filled, thus increasing the overall narcotic effect.

Over a period of time with consistent use, a level of tolerance begins to develop for a number of pharmacological effects; namely euphoria, analgesia, nausea, sedation, and respiratory depression. Receptors become desensitized, and begin requiring increasing blood concentrations of opioid in order to activate.

Once significant tolerance has developed, the body's natural opioid system - essential in modulating sensitivity to pain and emotional affective states - has adapted to the presence of narcotics by producing less of its own. The endogenous (i.e. natural) opioids which are available are no longer sufficient to satisfy opioid receptors, which have become desensitized with increasing tolerance (not to mention potentiated by an upregulation of cAMP). If narcotic use becomes interrupted in a dependent individual, leading opioid-blood concentration to fall below the required level; the now opioid tolerant central nervous system throws a fucking tantrum - With no inhibitive stimulation to satisfy receptors, not to mention to simply neutralize the ever increasing neuroexcitatory potential, the pathways of the CNS fire signals vigourously, working at a level far above pre-dependence levels. The locus coeruleus responds triggering the autonomic fight or flight response. Such responses to the lack of an opioid manifests as an acute withdrawal syndrome: panic & anxiety, agitation, tension, spasms, sensitivity to pain & touch, and a raw state of general pain & discomfort, these are all symptoms of opioid withdrawal.

Early Signs of Impending Opioid Withdrawal

An experienced user can spot withdrawal from a mile away (or rather, an hour or more away). Slight signs will begin to surface as blood concentrations of opioid begin nearing the level-off point known as the tolerance threshhold. This generally occurs when approaching the time for one's next scheduled dose.

Foods have slightly unusual taste.

Lesser desire for cigarettes, Cigarettes taste unusually disgusting.

Bowels movements increase, Stool comes easier and softer, often after some time of no "stooling" at all.

Pulse rate quickens, Muscles become tense.

Frequent yawning.

Frequent stretching needed to allay slight sensations of restlessness.

Increased salivation, Eyes begin to moisten, Nose begins to run.

Slight sense of impending distress, causing anxiety (anxiety leads to worsening symptoms)

Full Blown Acute Withdrawal

Full blown withdrawal surfaces at or shortly after the time of the next scheduled dose; which varies with the duration of the opioid used. With short acting narcotics such as traditional fentanyl, IV heroin and hydromorphone this may be 4 to 8 hours after the last dose. With intermediate acting narcotics such as morphine or oxycodone it may be up to 12 hours after the last dose. For longer acting opioids such as slow-release morphine, OxyContin, oxymorphone ER, transdermal fentanyl and methadone, withdrawal may surface after as little as 12 hours or as much as 24 to 36 hours. Full blown withdrawal with buprenorphine or LAAM may take days to manifest. Full blown acute opioid withdrawal will manifest with the following symptoms; note that drug craving or other psycho-symptoms may appear only in "addicted" users with psycho-dependencies.

Anxiety & anxiety/panic attacks; anxiety or agitation may precipitate a worsening of other withdrawal symptoms. Often begins with a sense of impending doom.

Depressive symptoms; dysphoria, sadness, amotivation, sense of impending doom.

Strong or obsessive drug craving in cases of psycho-dependence.

Loose bowels progressing to severe diarrhea and GI distress.

Increase in biliary secretions

Spontaneous crying.

Lacrimation, watery eyes.

Hot and cold flashes

Sweating, or sleep sweats.

Severe insomnia.

Thermal sensitivity and shivering.

Pupil dilation.

Body aches, particularly severe in the legs.

Involuntary leg movements resembling kicking.

Restless limbs which further make sleep unattainable.

Severe fatigue.

Nausea & vomiting.

Sensory hyperactivity and/or raw physical pain.

Tachycardia, rapid pulse, palpitations.

Gooseflesh, fever, and chills.

Violent and uncontrollable yawning.

Intensity and Duration of Symptoms

The duration of acute opioid withdrawal again will be dependent on properties of the individual opioid and route of administration, while intensity of withdrawal symptoms is dependent upon the potency of the narcotic used, the duration of its acute withdrawal, the level and duration of one's use, and whether a psycho-dependence exists (psychological symptoms often exponentiate physiological symptoms).

Generally, withdrawal from IV use of fast acting opioids is the shortest in duration. In addition, shorter lived withdrawal syndromes are generally the most severe, with a rapid onset, intense peak, and rapid offset.

Users of short acting fentanyl, heroin and hydromorphone by any route (but especially IV) will likely experience an intense withdrawal syndrome which peaks within 1-2 days and lasts from 3 to 4 days.

Morphine or oxycodone withdrawal will generally be moderately intense, depending upon one's tolerance and dose level, peaking around day 2 to 3, lasting 5 to 7 days.

Long acting opioids such as methadone and buprenorphine are sometimes said to be of a slightly lesser intensity than withdrawal from shorter acting narcotics, but with methadone this is questionable. The worst of the acute stage with methadone or buprenorphine detox may take anywhere from several days to 2 or 3 weeks (peaking at 4 to 7 days), after which time "addicted" users often experience a protracted state of depression, dysphoria, anxiety, insomnia, and certain physical symptoms such as pain or loose bowels. Protracted symptoms for chronic, heavily dependent users may linger months to years.


Acute narcotic withdrawal can be rapidly reversed with the administration of an adequate dose of an appropriate mu opioid agonist. All mu-opioid drugs exhibit a degree of cross tolerance or interchangeability; for instance, morphine withdrawal can be relieved with heroin, and heroin withdrawal is relieved with morphine. Withdrawal from both is relieved by oxycodone, hydrocodone, oxymorphone, hydromorphone, methadone, fentanyl, or buprenorphine, all in the appropriate relative doses. Each of these narcotics and many others are all interchangeable amongst each other in terms of maintaing dependence.

In terms of physical dependence and attenuating withdrawal, appropriate substitution doses will vary depending on the opioid's 'dependence-maintaining' potency. A narcotic's potency in this context is not always the same as its analgesic potency, and is not predetermined by a fixed ratio; therefore when dosing to relieve acute withdrawal, titration to effect is reccomended.


Withdrawal can be managed by treating symptoms supportively with non opioids. Clonidine is a centrally acting alpha-2 agonist which inhibits the autonomic stress response of acute withdrawal - it does so by targeting the locus coeruleus (or LC), an area of the brainstem involved in the physiological 'fight or flight' response, which essentially sends the body into panic mode during stressful events (including withdrawal). Clonidine depresses the LC in a manner similar to opioids, causing a significant reduction in the symptoms of acute withdrawal; relieving the hypertension, palpitations, hot flashes, sweating, muscle spasms, and restless limbs. Clonidine has been shown to reduce symptoms by roughly 1/3; it can be given alone, in conjunction with other non opioid comfort meds, or as an adjunct to opioid assisted detox/taper using methadone or buprenorphine.

Benzodiazepines will lessen or attenuate the psychic distress of narcotic withdrawal; such as the emotional symptoms of anxiety and panic. Barbiturates will do the same, but may also lessen the stomach & GI discomfort. Both may help to a degree with insomnia, though many simply find sleep impossible during withdrawal under any circumstance. Benzodiazepines and barbiturates both target central GABA receptor's to inhibit vigorous excitatory signaling; thereby relieving anxiety, agitation, panic and muscle tension.

Centrally acting muscle relaxants such as carisoprodol (Soma) and Meprobamate (related to the former) can be used to relieve tension and provide sedation when benzodiazepines are unavailable. Both are considered minor tranquilizers, but their mechanism of action remains ambiguous. They are believed to act on multiple CNS pathways; Including GABAa receptors.

Anaesthetic or near-anaesthetic doses of dextromethorphan (DXM) may be useful in opioid withdrawal. As an NMDA antagonist (among other functions) DXM and its major metabolite have dissociative anaesthetic qualities which are often useful during withdrawal. It has also been shown to attenuate tolerance to mu opioid agonists, and may alleviate hyperalgesia during withdrawal. DXM in the sub-anaesthetic dose range (180-300mg) may elevate the otherwise depleted mesolimbic dopamine levels during withdrawal, lessening withdrawal related 'craving' and depression - During this period, mesolimbic dopamine reaches levels as low as 33% of baseline. DXM binds mu opioid receptors in large doses, though not to a significant extent.

A weak opioid such as tramadol or propoxyphene makes a good comfort measure and will alleviate a degree of dysphoria, depression, craving or pain. Both are weak agonists at the mu receptor and may be very effective or mildly effective depending on one's habit & tolerance level. Kratom in any form - especially isolated alkaloid extracts - will be useful to a similar or greater extent. All three compounds will be most effective in those with a mild to moderate habit of oral opioid use.

Loperamide is a peripherally acting opioid of the broad synthetic piperidine class. It is used in the treatment of diarrhea, and available over the counter in most countries. It is known best in the US as the brand name Immodium AD. It acts as an agonist at the mu receptor, but is non lipophilc and in regular doses is unable to effectively penetrate the BBB. Opioid users have found that loperamide significantly alleviates withdrawal when taken in massive quantities - typically in excess of 90mg each day (or 45 tablets). In such doses it saturates peripheral receptors in the gut and elsewhere - at the very least relieving the diarrhea of withdrawal. More importantly however, is that in such large doses, small quantities of loperamide likely overwhelm the body's BBB defense mechanism (the PGP transporter) and reach receptors throughout the central nervous system. Loperamide is a long acting compound and requires time to accumulate to steady state levels. Initial doses (the first 1-3 days) should be high, with lower subsequent doses (about 50% the initial dose) once withdrawal symptoms begins to subside. Once steady state is reached; 1-2x daily dosing is the norm. Loperamide should not be used to maintain for longer than 1 to 2 weeks; it should only be used for short periods of substitution in emergency situations, or as a short term taper/detox aide.

The aches and pains of withdrawal can be treated with regular OTC analgesics; namely ibuprofen or acetaminophen.


  1. This is very interesting information. I am doing research for my health class on methadone withdrawal and I came across your blog. Thank you so much for the great information.

  2. I am a clinical social worker who has treated many opioid addicts. I am also a recovering opioid addict myself. This is one of the best written and most accurate primers on opioid withdrawal and its treatment that I have ever read. Just one note...as buprenorphine is a partial agonist, it can cause a severe precipitated withdrawal itself if administered too soon. Make sure the patient is in at least the beginning stages of withdrawal before administering. Ideally, wait until the patient really begins to feel some symptoms of mid-stage/acute withdrawal (e.g. Diarrhea, muscle cramps, depression). This will not only avoid the problem of precipitated withdrawal but also provide more complete relief of symptoms for the patient.

  3. Accurate and complete.

  4. Stopping opiates is just a difficult fight, however it could be gained using the correct resources. Nowadays we're likely to evaluation the very best techniques to relaxed withdrawal signs brought on by extended opiate habit to help you proceed to an existence located in recuperation.
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