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Opioid Withdrawal Syndrome- What to expect the first few days

 Opiate drugs include morphine and it's derivatives: heroin and codeine as well as a variety of synthetic chemicals that are widely used for pain relief including methadone, Demerol, fentanyl, dilaudid, Vicodan and Percocet.  Opiates are medications that stimulate opiod receptors and therefore depress function in certain parts of the brain.  Major benefits of the medications are that they can relieve pain and cough.  Of course, the use of these drugs also causes sedation, affect the ability to urinate, slow down the intestinal tract and cause the pupils of the eyes to become pinpoint.  This is because the receptors are widely distributed throughout the brain, intestinal tract as well as other places in the body.  Abusers of the drug describe euphoria as well, which is likely related to the release of dopamine in the brain. This is responsible for causing drug-seeking behavior even in the absence of physical withdrawal.

When there is a constant administration of these medications, tolerance develops.  This means that the drug yields a lesser effect than it previously did and that more of the drug needs to be taken in order to obtain the same effect.  This is why persons using these drugs usually increase their amount used. A popular theory states that tolerance is caused because opiate receptors decrease in activity secondary to constant over stimulation.  While there are other theories, it is clear that the receptor's sensitivity to the drug is diminished and the ability for the drug to depress brain function is reduced.  One important area that becomes depressed and eventually develops tolerance is a certain area of the brain called the LOCUS COERULEUS or LC.  This is a part of the brain intimately involved in mobilizing the various body functions in reaction to pain, fear, blood loss and stress and is important in the fight or flight response.

During withdrawal, those areas that have been chronically depressed become overactive causing multiple problems such as nausea, diarrhea, cramping, yawning, irritability and restlessness, gooseflesh, large pupils. sleep problems, excess eye and nose secretions, high blood pressure,  rapid pulse, muscle spasms and fatigue.  There is also sensitivity to pain resulting in diffuse aches and pains.

The intensity and time course of the withdrawal syndrome is related to the rate at which the opiate receptors become empty of drugs.  This is, in turn,  related to how fast the drug is metabolized.  Drugs that are metabolized faster, such as heroin, cause a more intense withdrawal syndrome since they leave the body and therefore the receptors at a faster rate.  Drugs such as methadone that are metabolized slowly cause a more prolonged but less intense withdrawal syndrome. (This  assumes  the same degree of tolerance. However,  most persons on Methadone maintenance on doses typically prescribed usually  have extremely high levels of tolerance which results in an intense withdrawal syndrome despite its'  relatively slow metabolism.)  Heroin users will usually begin experiencing withdrawal within 3-4 hours.  This peaks in 2-3 days  and begins to resolve in 4-5 days.  Methadone withdrawal will start in 2-3 days, peak in 5-7 days and resolve 1-2 weeks later.  Most other drugs will fall in between.

Hyperactivity in the LC during withdrawal is well recognized and correlates highly with the intensity of the measurable withdrawal syndrome.  The belief now is that most, if not all, physical symptoms of withdrawal originate from over activity in this area of the brain.  Note that the LC is an area distinct from the areas of the brain that are responsible for euphoria and the sedation.  Clonidine, a blood pressure drug, has been shown to reduce this over activity.  It has been a useful medication for controlling the withdrawal syndrome.

Many people who take opiate pain killers would never realize that can even start the withdrawal  process while they take their medication.  Vicodin and Oxycodone are both short acting. Half of the medication is gone from the body in 4-5 hours.  Since these medications are often use four times daily, there are often times that 6 hours elapses between doses.  Mild increases in pain may be the very first symptom of withdrawal.  Depression and irritability are also seen.  This is a major reason while many chronic pain patients have poorly controlled pain.
It must be noted that in addition to physical withdrawal, there is emotional withdrawal as well.  This comprised depression, fatigue, lack of energy and cravings.  It is related to imbalances elsewhere in the brain  (not the LC)such as the nucleus accumbens. It can go on for months or longer.  


What are the General Approaches for treating opioid withdrawal

 Opiates cause depression of activity in certain area of the brain and body.When the opiates are no longer present, these areas become hyperactive.  Hyperactivity of the intestinal tract can cause cramping, bloating, diarrhea.Hyperactivity in the in the area of the brain known as the Locus Coereleus (LC) causes a whole host of symptoms as well.

There are a number of strategies for the treatment of opiate withdrawal.   An Opioid free strategy involves treating the symptoms of withdrawal without substituting other opiates.  In this case, withdrawal from short acting drugs such as heroin begins in 12 hours, peaks 48-72 hours and has almost completely resolved by 5-7 days.  Of course, the discomfort can be rather intense but there are drugs are available to alleviate the symptoms. 

 Clonidine is a blood pressure medication that is useful in treating opiate withdrawal.  It can directly lessen the degree of over activity in the LC.  Numerous studies have demonstrated that it reduces the subjective symptoms of withdrawal.  It has side effects such as sedation and low blood pressure.  These can be a problem at times but the side effects can often be minimized by careful dose adjustment.  In addition, there is still a great deal of irritability and insomnia that can be treated with sedatives and sleeping pills.  Aches and pains, nausea, vomiting, diarrhea and cramping can all be treated with commonly available medications.  Lofexidine (Lucymyra) is a relatively new drug that has a mechanism of action similar to Clonidine.  It has been used in Europe for years and it seems to be  more effective and have fewer side effects.  Unfortunately, it is expensive so we usually have to go through a prior authorization process with variable success.  

There are other medications that I use which  are not generally used by other physicians.

Opioid substitution and weaning involves the gradual reduction of opiates so that the intensity of withdrawal never becomes intolerable.  Many programs, both inpatient and outpatient, will substitute a long acting drug, such as Methadone, for the shorter acting drugs which constitute most of the abused opiates.  This results in two benefits.  The course of withdrawal with Methadone is easier to control, as there are fewer variations in drug levels and therefore fewer variations in the intensity of the withdrawal syndrome.  Additionally, the continued use of the drug of choice can be detected, since methadone will show up in drug testing as distinct from other opiates.  That makes it easier to evaluate the success of treatment. 

The problem with methadone is the legal restrictions on its use since it can only be given in a hospital setting or on site at a methadone clinic.  Many private doctors who are trying to perform an outpatient detox prescribe other opiates such as Darvon or Vicodan.  These are widely available but they are short acting.  Therefore, the withdrawal syndrome is more difficult to control and the patient is often under medicated.  In addition, these drugs are also more likely to be abused.  Therefore, the use of these drugs alone is more likely to result in treatment failure.

Buprenorphine has been approved for office based opioid maintenance.  The doctors allowed to prescribe this have to have a special certification and licensure from the DEA and state.  Buprenorphine is a long acting drug like Methadone.  This allows for more control of symptoms.  It is also a safer drug than Methadone .  However, Methadone is a more powerful medication.

It is important to remember that the use of opiate substitution will prolong the duration of the withdrawal syndrome.  This is because the receptors do not empty of drugs as quickly.  Also, many addicts will want their time on medication prolonged because of fear and because most opiates are inherently addictive.  In my own personal experience, when the duration of the detoxification regimen exceeds some critical time (which varies for each patient), the patient’s motivation to complete the detox regimen is lost and there is a treatment failure.  This is especially true in an outpatient setting.

Traditionally, detoxification has occurred in an inpatient setting.  This is a result of several factors including a reluctance to give a substance abuser addictive medication to take home. There is also a belief that the symptoms of withdrawal are too intense for outpatient detoxification to be of much value.  These concerns are valid and certainly result in treatment failure in some patients.  However, the restrictions placed on treatment providers by the HMO’s are making us rethink outpatient detoxification.  I have developed an experience with thousands of patients undergoing outpatient detoxification of opiates using a combination of the above strategies.  I rely on Clonidine as well as sedatives and other medications.  I have treated persons using more than 25 bags of heroin and others on an excess of 80 pills daily.  I have found that about a third accomplish the detoxification easily and another third complete this with a course marked by temporary relapses.  I will refer the last third to inpatient detoxification if they are not lost to follow-up.  I have found that the most important factors are the desire to get clean as well as the presence of a social support system.

In another article, I will talk about Precipitated  Opioid Withdrawal where withdrawal is hastened by the addition of antagonist medication.


Dr Wassers approach to Opioid withdrawal


The following is an overview of the clinical approach to office-based opiate detoxification. 

The chronic use of opiates causes abnormalities in the ways our body and brain work.  Opiate withdrawal refers to the physical and emotional symptoms we experience as these drugs leave our body and these abnormalities reverse.  Opiate withdrawal can be expected to peak between two to four days.  The symptoms of this include muscle aches and spasms, irritability and anxiety, sweating, runny nose and eyes, yawning, stomach cramps and diarrhea, goose-flesh and difficulty sleeping.  There is also an elevation of the blood pressure and pulse, temperature and persistent vomiting when severe.  This is caused by over-activity in certain areas of the brain as well as in the intestinal tract.  Treatment is tailored to reduce activity in the affected parts of the brain as well as relieve some of the more distressing symptoms.

The initial part of the treatment is the first three or four days.  Buprenorphine (Subuxone) is substituted for the specific opiate that you are coming off of.  It is administered underneath the tongue.  Whatever is swallowed is wasted. Depending upon the patient and their degree of tolerance, this initial period may be associated with mild withdrawal or no withdrawal.  If your primary goal is to detox, I prefer to keep the use of Subuxone as short as possible (1-3 days).  The longer one stays on it, the more difficult it will be to eventually discontinue it

When the Subuxone is stopped, there will be a secondary withdrawal.  It will have all of the characteristics of typical drug withdrawal but it will usually be much less intense.  Some patients do not experience any withdrawal but they are the minority.  It is easy to panic when you experience the milder withdrawals.  They will remind you of a cold turkey withdrawal.  Such a panic will than magnify the actual intensity of the withdrawal symptoms.  In fact, usually the withdrawal symptoms remain mild and will resolve within a week.  Typically, they are described as “not as bad as I expected.”

After the acute withdrawal period is over, psychiatric symptoms last from weeks to months. Sometimes these symptoms are treated with psychiatric medication but sometimes they do not respond well to treatment.  Sometimes the best alternative is to shorten this delayed withdrawal syndrome via the use of naltrexone.  There are even recent studies to suggest that the naltrexone can be started before the Subuxone is withdrawn.


There are medications that are helpful.  They can be used during the initial few days if withdrawal symptoms are too difficult.  They may be needed during the secondary Subuxone withdrawal.  Some of them may even be useful during the early abstinence period that can last one or two months.

1-Elavil (amitriptyline), Trazadone- These are anti-depressants that are quite sedating.  I use them as sleeping pills.  I regularly give it out for one to two months.  It can be used indefinitely without risk of addiction.


 The medicine reduces activity in the locus coeruleus, the area responsible for a great deal of physical withdrawal symptoms.  Increased activity in this area causes most symptoms of physical withdrawal.  So, the clonidine is able to reduce the intensity of withdrawal.  Unfortunately, it can lower blood pressure significantly and cause sedation and/or dry mouth.  A certain amount of lightheadedness (especially when standing up) is normal.  If lightheadedness is severe, the medicine should be reduced.  Suddenly stopping the medication from a high dose to nothing may cause an elevation in pressure so the medicine will need to be tapered.  The pill is started four times daily.  It may be increased or decreased during the detox.  This medication may not be necessary during the first few days but should be started if any withdrawal is being experienced.

Lucemyra, the brand name for lofexidine, is a new medication for the United States though it has been widely used in Europe for years.  It has a similar mechanism of action as clonidine but seems to be more effective with fewer side effects.  

3-Zofran- (please see article elsewhere on site) This is a useful medication for relieving all types of mental irritability as well nausea and other types of stomach upset.

4-Baclofen- This is a muscle relaxer that helps muscle aches.  It was studied as an aid to withdrawal years ago and found to be effective.  Yet, it is rarely used.  It also works as a mild sedative and reduces the intensity of other withdrawal symptoms in addition to muscle spasms. .  This medication may not be necessary initially, but like clonidine, should be used if there is mild to moderate withdrawal

It also has value in early abstinence as it suppresses brain mechanism underling drug cravings

5-Sedatives (clonazepam, phenobarbital, Ativan) - these are  sedative medications used for symptoms such as anxiety, irritability and inability to sleep, which are not adequately treated by the Subuxone, Clonidine, and Baclofen.  Side effects include sedation but it otherwise well tolerated.

6-Motrin (Ibuprofen)- Muscle aches are extremely common and helped with this medication.  It may cause stomach problems and should not be used if there is a history of ulcers.  Taking the medication with food makes it easier to tolerate.

7-Neurontin, Depakote, Topamax- This are medications that Dr. Wasser has found useful in treating the symptoms of early abstinence.  They are used in just a small percentage of patients who are trying to detox quickly.  There seems to be evidence that chronic opiate use can sensitize certain areas of the brain and spinal cord.  This results in increased pain and irritability.  This effect may be blocked to some extent by these drugs. like Neurontin.  They are safe medications that have no addictive potential.  Since it reduces irritability and anxiety, I will use these medications for extended periods, several months if necessary.  These medications can cause stomach upset, fatigue and a fuzzy head in some patients.  I have to stop it in abut 20- 25% of the patients.  

8-Bentyl (dicyclomine)-This is an effective medication for relief of stomach cramps.

9-Imodium- If diarrhea is a real problem, this over the counter medication will usually relieve symptoms. 

10-Nutritional Supplements- For those patients, who are unable to eat during this time, the use of nutritional drinks may improve their sense of well-being.  This should be used as needed.

11-Vitamins- while vitamin therapy is unlikely to affect the withdrawal procedure, the use of a multi-vitamin is helpful in maintaining optimal health over the next few weeks to months


zofran (ondansetron)

Not just for nausea- Helps opioid withdrawal syndrome

One drug that I have begun to use to aid in opioid withdrawal is ondansetron.  This is the Generic name for Zofran, a medication long used for the treatment of chemotherapy related nausea.  It accomplishes this task by blocking the activity of a certain sub-type of serotonin receptors, the 5HT3 receptor.

Elsewhere on this site, Zofran is discussed in regard to its ability to reduce food, alcohol and other drug cravings.  The dosages of Zofran for opioid withdrawal are at a significant higher level than those used for cravings.  It is almost as if the two dosages were separate drugs.

The development of this idea is recent and really demonstrates how modern science helps us realize the unexpected benefits of commonly used medication.   Dr Chu etal out of Stanford University, did a rather elegant set of experiments that were published in 2009.  They were able measure the intensity of withdrawal in 18 different breeds of lab rats and than rank order those breeds from those that became more ill to those that became less ill.  They wanted to determine if there were any genetic determinants that predicted their withdrawal.

After the genetic studies were done, they determined that there was a correlation,  Those breeds that experienced more withdrawal had a lot of similarity in their 5HT3 receptors .  There was a difference those breeds with less withdrawal.  Ondansetron, a know blocker of these receptors was than given to these rats.  It was found that withdrawal was significantly lessened and the rats were less agitated.  Their sensitivity to pain was reduced.  The medication reduced withdrawal separate and apart from nausea. It may also have reduced nausea but this could not be assessed in rats.

They then examined what happened to these receptors when the mice were exposed to opioids.  Multiple area of the brain were examined including the Amygdala which modulates stress and the Nucleus Accumbens, the pleasure center of the brain.  It turns out that one effect of opioid use is to reduce the number of serotonin receptors in these areas. 

This suggests that during opioid withdrawal, the serotonin receptors will increase in number.  Therefore, it is reasonable to assume that some of the symptoms of opioid withdrawal may be due to increasing activity of this receptor.  Blockade of this receptor with with ondansetron will block this effect.  This underlies its' benefit in reducing symptoms of withdrawal.

As a final experiment, Chu subjected human volunteers to an opioid withdrawal protocol.  These subjects were not opio[d addicted.  They were given about 20 mgs of morphine followed by Narcan a few hours later.  This was done while they were given either ondansetron or placebo.  There was a 75% reduction in the intensity of withdrawal when they were using ondansetron.

I have been using this medication for years.   I use it for patients who are weaning down on Suboxone.  It has easily become the the most valuable adjunctive medication for relieving withdrawal