Archive for the ‘Tolerance’ Category

Overdose Deaths: Opioids and Benzodiazepines

Any opioid, mixed with any benzodiazepine, alcohol, or barbiturate, can be deadly.

Part of our brainstem, the medulla, tells our bodies to breath while we sleep. Opioids inhibit the neurons (individual nerve cells) of this area of the brain, potentially interfering with this automatic breathing. This is how overdose deaths occur. People go to sleep, stop breathing, and die from lack of oxygen to main organs like the brain and the heart. Even a relatively small dose of opioid can kill a person who isn’t accustomed to taking them, and a larger dose can kill even those who are used to opioids. If you are wondering what constitutes a small or larger dose, that’s unanswerable, because of the considerable differences between individuals.

Benzodiazepines, alcohol, and barbiturates all also inhibit this same brain center, and have the potential to slow breathing, just like opioids. We don’t see many doctors prescribing barbiturates any more, with the possible exception of phenobarbital for seizures, and butalbital for headaches. Sometimes carisoprodol (Soma) is prescribed as muscle relaxant, and it gets metabolized to a barbiturate. We do see a great many people prescribed benzodiazepines, which can be dangerous for a person also taking opioids. And of course, alcohol flows freely in the U.S. society.

When a person with addiction mixes opioids with benzos, alcohol, or barbiturates, he often ends up taking more of the drug than he planned, making it easy to have a fatal overdose. Addiction is all about the loss of control. So for example, an addict may decide to take one Xanax with an opioid, but ultimately take three or four Xanax’s with the opioid. Compounding the problem, the effects of the two drugs together is usually more than would be expected, due to synergy. Synergy means that instead of 1+1=2, suddenly 1+1=4. There’s more of an effect than the person expected.

Some people are able to take both opioids and benzodiazepines without complications, but these people usually don’t have the disease of addiction, and are able to take their medication just as prescribed by their doctor. Even for these patients, benzodiazepines are rarely indicated for use for more than three months (fodder for a future blog).

But benzodiazepines can harm patients with addiction. Except for unusual circumstances, it’s a bad idea to mix any benzodiazepines with any opioid in people with addiction, because of the risk of overdose death. Rarely, a situation may arise that warrants use of benzodiazepines in a patient on opioids, but it’s for a short-term situation, and safer long-term treatments for anxiety usually can be found.

When my patients on methadone or buprenorphine (Suboxone) take benzodiazepines for anxiety, I get anxious. I worry those patients will die from an overdose. It’s a dilemma. Often, patients are clearly benefitting from methadone or buprenorphine, because they’re no longer using illicit opioids, but we now have the risk of an overdose death. So, the methadone or buprenorphine are helping them – unless it kills them… in which case it’s no longer helping.

What to do??

Some doctors say if the patient is benefitting even a small amount, because death rates are so high for opioid addicts who leave treatment, that patient should never be dismissed from a methadone clinic for using benzodiazepines.

I don’t agree with that. The first thing doctors learn in medical school is, “First, do no harm.” In other words, please try to kill as few patients as possible.

And yet, many of these patients can stop using benzodiazepines if they get the right kind of help. I ask my patients “Why do you use benzos?” and base my intervention of what they say. If they’re getting medication from a doctor, I’d like to talk to that doctor, and often a better long-term solution can be found. Benzodiazepines have very few indications for long-term use, because patients develop tolerance to the anti-anxiety properties of these medications fairly quickly. However, it’s dangerous to stop benzodiazepines suddenly in a patient who has been taking them for months or years, because of the risk of withdrawal seizures. We have to decide on the best way to handle the situation. If patients take benzos for the high it produces with methadone, they have to decide if it’s worth risking not only their treatment but their lives. If they take benzos for sleep, often I can prescribe a more suitable medication.

As long a patient has a willing spirit, and does not look like an overdose is imminent, I try to work with him or her. In each case, there are risks in stopping methadone treatment, and risks in continuing methadone treatment. The decision should be made by a physician who is well-educated and well-trained in addiction medicine. We make the best decision we can for the patient in front of us. We are the most qualified to make those – literally – life and death decisions.

New Drug, Old Problems?

The internet is abuzz with dire predictions surrounding the release of a more potent form of hydrocodone. Two drug companies have announced their intent to release a hydrocodone pill with a higher content of hydrocodone, with no acetaminophen. Currently, hydrocodone is available in doses of 5, 10, and 7.5mg per pill, combined with 325 or 500mg of acetaminophen (generic drug name of Tylenol). Teva Pharmaceuticals, based in Israel, has announced their intention to release a newer, higher potency form of hydrocodone that contains 45mg per pill.  If it’s approved by the FDA, it will contain over four times the opioid firepower in one pill that the next highest dose now on the market. Teva pharmaceutical is predicting up to $500 million in sales.

It’s a little early to start saying we’re going to have another OxyContin on our hands. Since 2009, the FDA demands each pharmaceutical company that manufactures powerful opioids have a plan in place, prior to the release of a new medication, to reduce the risk of harm to the public. This program is called “REMS” for “risk evaluation and mitigation strategy.” Before a higher strength hydrocodone can be released, the manufacturer must assure the FDA that all proper precautions are being taken to avoid excessive misuse and addiction.

We will never reduce medication misuse to zero, but we can learn from the past, and use available technologies to reduce the potential for drug misuse, to prevent another version of the OxyContin situation. Teva calls its product “TD” because it’s tamper deterrent, but I can’t find any information on which technology they plan to use. It will be a sustained-release preparation that is taken once every 12 hours.

Another company, Zogenics, is preparing to release Zohydro, their brand of higher dose version of hydrocodone. They say their version contains no tamper-resistant technologies.

Do we need another high potency, long-acting opioid for pain? And do we need it at a time in history when we’re on the crest of an opioid addiction epidemic? Some experts say yes, for a startling reason: We are seeing liver failure from acetaminophen overdoses.

According to one article, the most common cause of acute liver failure is acetaminophen, the generic name of the brand Tylenol. In 1998, liver failure from acetaminophen made up only 23% of the total number of liver failure cases, while in 2003, it rose to 51% of all acute liver failure cases. Of the people with unintentional acetaminophen overdoses, 63% were taking opioids containing acetaminophen, sometimes in combination with other medication that also contained acetaminophen. (1)

There’s not a wide margin of safety with acetaminophen.  The upper limit of what’s considered to be safe is about 3 grams per day of acetaminophen, but if the person has underlying hepatitis B or C, or damage from alcohol ingestion, not even 3grams is a “safe” dose. Some hydrocodone preparations now contain 500mg per tablet, so even at therapeutic doses that’s coming close to a toxic level of acetaminophen.

Opioid addicts often take much more hydrocodone than prescribed, regardless of the amount of acetaminophen. Addicts often take 15 or 20 pills of hydrocodone per day, which could be as much as 10grms of acetaminophen per day. And they take this day after day. An ordinary person might ask, “Why would anyone take the risk of damaging their liver like that?” But that’s addiction. Addiction is about loss of control. I’ve heard dozens of addicts entering treatment voice concerns they’ve damaged their livers because of pain pill use. They describe the curious predicament of taking pills because the addiction compels them to do so, all the while hoping they won’t die from liver failure. It’s a strong statement about the strength of addiction.

While acetaminophen-free hydrocodone may not trash your liver, it can still trash your life, if you become addicted.

  1. Larson AM et al, “Acetaminophen-induced Acute Liver Failure: Results of a U.S. Multicenter, Prospective Study,”  Hepatology, 2005;42:1364-1372.

Methadone Dosing in Opioid Treatment Programs: Use the Evidence

The most successful opioid treatment programs and the most successful patients in those programs use evidence-based dosing of methadone. Many studies over the last 40 years show patients do better on adequate doses of methadone. They have better outcomes when they’re on enough methadone to block physical withdrawal signs and symptoms than when they’re on insufficient doses.

In the past, methadone clinics often had dose caps. Some clinics told their patients they didn’t need any more than 60 or 70mg of methadone per day.  But over the last 40 years, we have multiple studies showing poorer outcomes at clinics with these low dose caps, as opposed to individualized dose determination. Numerous studies show higher drop-out rates in patients on doses less than 60mg, as well as more illicit opioid use and higher rates of HIV infection, as compared to patients on 100mg or more. For most patients, the blocking effect is seen in the neighborhood of 80 to 120mg of methadone per day.

However, there’s a great deal of difference between how patients metabolize methadone. A patient with slow methadone metabolism may do best on 30mg of methadone per day, and a fast metabolizer may need much more than 120mg per day. This rate of methadone metabolism is probably determined by our genetics. When patients ask me how much methadone they should be taking, my answer is, “Enough.” I’m not advocating taking doses higher than they need to be, but if the patient looks like they’re in withdrawal, and they feel like they’re in withdrawal, it’s best to take the dose up. We want to use the lowest effective dose.                                                                                                                                 

There are still misguided opioid treatment programs that try to keep methadone doses low. Sometimes clinic staff can send shaming verbal or nonverbal messages, and imply patients who ask for an increase in their dose are somehow trying to get one over on the clinic. Staff shouldn’t shame patients who ask for a dose increase; staff should defer decisions about methadone dosing to their medical personnel.

Sometimes patients don’t want to increase their dose of methadone because they have mixed feelings about their treatment. If they feel guilty about being in a methadone program, they may want to keep their dose low. Sometimes family members, with the best of intentions, will demand the patient stay on a low dose, not understanding that their loved one is less likely to do well on an inadequate dose.

Frequently I see patients who are feeling bad, not sleeping, and achy all over in the mornings, and dosing at 40mg. I ask them if we can increase their dose, and they say something like, “No, I promised myself I wouldn’t go higher than 40mg.” Too often, patients don’t increase their dose for fear that coming off methadone will be harder to do at higher doses. This is partly true. It may not be harder to come off of, but it does take longer to taper off a higher dose. But the patient won’t do as well while they’re in treatment, so what’s the point?

Some patients prefer low doses because they want to have just enough methadone per day to keep them out of terrible opioid withdrawal, but not so much to block the euphoria they get from using an illicit opioid later in the day.

I tell patients that methadone is a little like chemotherapy. For chemo to work, you have to take a big enough dose to do the job. It’s the same way with methadone. It’s not a perfect analogy but patients get what I’m saying.

Let’s turn to the other side of dosing. I’ve seen some clinics with many patients on what I would consider very high methadone dosing. It’s hard to criticize, because I do think there are some patients who need doses higher than 250mg, particularly if they’re on certain medications, or are pregnant. But that’s rare, and at some clinics, many patients seem to be on these big doses. Since these patients have their dose increased slowly, they build a tolerance to the methadone, so such patients aren’t sedated. There’s no long-term damage to the body with very high dose methadone, but higher doses can cause some problems.

It may be hard for a patient on a very high dose to transfer to another clinic. Some methadone clinic medical directors are hesitant to accept a patient in transfer if they’re on 200-plus milligrams of methadone, unless there’s evidence that this dose is required. For example, I was looking over the records of a patient on 290mg, in preparation for transfer. This man was on no other medications and otherwise healthy. When I saw the peak and trough data, I was puzzled, because they were both high, and this was done at 200mg of methadone. So why was the patient taken to 290 milligrams? I know peak and trough levels aren’t the only factor to be considered when determining the right methadone dose, but there was scant information about why the doctor decided to raise the dose, or even if the patient had even seen the doctor recently. I wasn’t particularly concerned the patient would be sedated, because the dose had been raised slowly, over months. But I was concerned that the patient was on more methadone than he needed, especially since many of the patients at this clinic were on doses of more than 200mg per day.

Some studies have shown higher doses of methadone affect the way electrical impulses are transmitted through the heart. In some studies, higher methadone doses are more likely to produce prolongation of the QT interval than lower doses. (2) This QT prolongation does put patients at risk for a potentially fatal heart rhythm problem. The medical literature at present suggests that periodic EKG screening of patients on doses above 100mg is probably a good idea, but there’s still disagreement on this issue.

There is another factor to be considered. This may offend some readers, but we need to acknowledge the nature of addiction. It’s a disease who tells its sufferers, “More is better!”  I think it’s important to acknowledge this point, and discuss it openly, but not in a shaming way. This psychological part of addiction doesn’t always go away within the first few weeks.

My approach to a patient on a relatively high dose, who desires an increase in methadone, is to meet with the patient, preferable prior to dosing. Sometimes I like to meet the patient two hours post-dose if I’m worried about sedation. I ask about withdrawal symptoms and check for pupil size and reaction, and other signs. I check the last drug screen. If the patient doesn’t describe withdrawal symptoms, and I don’t see objective signs of withdrawal, I’ll ask the patient how they expect to feel on an ideal dose of methadone, and if it’s possible their addiction is driving the desire to increase. I’m surprised that most patients aren’t offended, but welcome the opportunity to talk openly. Some patients say they honestly can’t tell if they are in withdrawal, or if their addiction tells them they are in withdrawal. My job is to help decide which it is.

Some patients feel “high” for the first few days after a dose increase, but tolerance builds quickly to this feeling. Some patients mistakenly believe they should always get that high after dosing. If the addiction is driving the patient’s way of thinking, the dose may never be “enough.” When I explain this to patients, most understand.

I could be wrong, but I have an impression that very high doses are seen more frequently in patients enrolled in large, for-profit methadone clinic chains, with numerous facilities scattered across the country. I wonder if the doctors working there talk often with their patients, examine them, and talk about their symptoms and expectations.

I’d like to hear feedback from patients at opioid treatment centers. What do you think? Are clinic doctors too reluctant to order dose increases? Or too quick to increase doses, without talking to the patient?



      2. Krantz, Lewkowlez, Hays,, “Torsade de Pointes Associated with Very-High Dose Methadone, Annals of Internal Medicine, Sept. 17, 2002, Vol 137(6) pp 501-505.

Tolerance and Hyperalgesia: Complications of Opioid Use

Both tolerance and hyperalgesia are difficulties encountered by patients who are prescribed opioids. Both conditions can be seen in pain patients and in people with addiction.

Drug tolerance means the body requires a higher dose of drug to achieve the same effect. In the case of a pain patient, that means it takes more opioid to achieve the same amount of pain control. In an opioid addict, it means the addict requires more of the drug to achieve a “high,” or euphoria. However, as the addiction progresses, many addicts are no longer able to get high, but use opioids to prevent painful withdrawal. Tolerance occurs due to changes that the body makes in response to the presence of the drug.

Scientists think that the presence of opioids results in decreased activation of the mu receptors. One theory is the cell actually “swallows” the opioid receptor so that it’s no longer available, on the outside of the cell, to be stimulated by an opioid.

Hyperalgesia isn’t the same as tolerance, but somewhat similar. Hyperalgesia is an increased sensitivity to pain. In other words, little pains feel like big pains. Allodynia, a related condition, means feeling pain in response to things that aren’t usually painful. For example, a touch on the arm may become painful to someone with allodynia.

Hyperalgesia doesn’t only occur with long-term opioid use. Nerve damage of any kind can cause both hyperalgesia and allodynia. In these cases, anti-convulsant medications are used in an effort to stabilize the nerves that transmit pain messages. 

A recent study compared the pain thresholds of four groups of people: normal controls, chronic pain patients medicated with methadone, chronic pain patients medicated with morphine, and patients on methadone for opioid addiction. All three groups were studied with the cold pressor test. In this test, a subject is asked to submerge a hand in ice water, and record the length of time until the subject feels such bad pain that he must remove his hand from the ice water. Normal controls, not taking any opioids, averaged around 31 seconds. Chronic pain patients on methadone tolerated the pain for 20 seconds. Chronic pain patients on morphine were able to endure the pain about the same length of time at 19 seconds. Methadone-maintained patients with addiction were also able to tolerate an average of 19 seconds. (1) This study seems to indicate that patients on opioids for either pain or addiction treatment both develop hyperalgesia. 

So what’s the difference between hyperalgesia and tolerance? In hyperalgesia, there’s increased sensitivity to pain, but with tolerance, there’s decreased sensitivity to opioids. (2) This difference is important, because if the opioid dose is raised in a patient with hyperalgesia, the patient’s pain may actually worsen. But a patient with tolerance would likely improve with a dose increase.

How many patients on opioids develop hyperalgesia? We don’t know, as there are no controlled studies of this problem as yet. We do know that tolerance often occurs in pain patients. For patients on methadone to treat addiction, tolerance does not seem to develop to the blocking effect of methadone, meaning once a patient is at a dose of methadone sufficient to treat all withdrawal symptoms, he usually doesn’t have to keep increasing the dose over time. Of course, other changes, like new medications, weight fluctuations, and changes in physical activity may change methadone blocking dose requirement in these patients, but this is different from tolerance.

Why does this occur in some people but not others? This may be genetically determined, at least in part. There are three basic opioid receptor types, mu kappa, and delta. To complicate things further, within each of these groups, there are subtypes. Our genes determine which subtype of mu receptor predominates in one person as opposed to another. One opioid may stimulate one sort of mu receptor more than another. (This may be why when switching from one opioid to another, the patient isn’t completely tolerant to the new opioid.) Some scientists believe some configurations of subtypes of opioid receptors make a person more likely to develop hyperalgesia.

What can be done to prevent or treat hyperalgesia? Many patients actually have improved pain control after they are gradually tapered from opioids.

Because the body isn’t completely cross tolerant to different opioids, switching opioids helps some patients. Of course for patients being treated for addiction, there are only two medications that can be legally used: methadone and buprenorphine.

 Some pain medicine doctors advocate using low-dose opioid blockers along with a full opioid. The blockers may have effects at opioid receptors besides just the mu receptor, and these other receptors, like the kappa receptor, may play an important role in hyperalgesia and tolerance since some research shows this improves pain outcomes.

Other types of brain receptors may also play a role in pain and hyperalgesia. For example, there’s evidence that the NMDA receptor is involved in development of tolerance and hyperalgesia.

Some doctors add non-opioid medications like anticonvulsants to opioids in an effort to minimize opioid doses needed. At present there’s a lack of strong evidence to support this practice, though it’s a reasonable method to try.

This is a relatively new area of study, and hopefully in the future we’ll have a better idea of why hyperalgesia, tolerance, and allodynia occur, how to treat them, and even how to prevent them.

  1. Hay JL, White JM, et. al., “Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients.” Journal of Pain, 2009, Mar;10(3):316-22.
  2. DuPen, Anna, Shen, Danny, Ersek, Mary; “Mechanisms of Opioid-Induced Tolerance,” Pain Management Nursing 2007; 8(3):113-121.