NIH Scientists Identify a Potential New Treatment for Depression: A Metabolite of Ketamine

In a remarkable example of scientific collaboration, a new study produced by scientists at various research centers at the National Institutes of Health (NIH) have identified how ketamine works as powerful and fast-acting anti-depressant. This discovery may lead to an effective and potent new treatment for depression.

Ketamine is normally used as an anesthetic but at low doses, it has been shown to have rapid acting and long-lasting anti-depressant effects in humans. Fast relief of depression is incredibly important because most anti-depressant medications are not very effective or can take weeks (or even months in some cases) for maximal effect, which hurts the recovery of patients suffering from this crippling psychiatric disorder. However, despite its rapid action, ketamine has many side effects such as euphoria (a “high” feeling), dissociative effects (a type of hallucination involving a sense of detachment or separation from the environment and the self), and it is addictive.

If ketamine could be made safe to use without any of its other more dangerous properties, it would be a powerful anti-depressant medication.

With this goal in mind, scientists at the National Institute of Mental Health (NIMH), National Institute on Aging (NIA), National Center for Advancing Translational Sciences (NCATS), University of Maryland, and University of North Carolina-Chapel Hill sought to unravel the mystery of how ketamine works.

When ketamine enters the body it is broken down (metabolized) into many other chemical byproducts (metabolites). The team of scientists identified that it’s not ketamine itself but one of it’s metabolites, called HNK, that is responsible for ketamine’s anti-depressant action Most importantly HNK does not have any of the addictive or hallucinogenic properties of ketamine. What does this mean? This special metabolite can now be produced and can be given to patients while ketamine (and all its unwanted negative side effects) can be bypassed.

depressionOf course, many tests still need to be done in humans to confirm the effectiveness of HNK, but the study is an amazing example of how an observation can be made in the clinic, brought in the lab for detailed analysis, and then brought back to the clinic as a potential effective treatment.

But how did the scientist’s do it and how do they know that this HNK is what’s responsible for ketamine’s depression-fighting power? Keep reading below to find out.

Also, check out the NIH’s press release on the study.

The original study can be found here.

What is ketamine?

(±)-Ketamine_Structural_Formula_V1.svg
Chemical structure of ketamine (wikimedia.org).

Ketamine has traditionally been used an as anesthetic due to it’s pain relieving and consciousness-altering properties [1]. However, at doses too low to induce anesthesia, it has been shown that ketamine has the ability to relieve depression [2]. Even more remarkably, the anti-depressant effects of ketamine occur within a few hours and can last for a week with only a single dose. Most anti-depressant medications can take weeks before they start relieving the symptoms of depression (this is due to how those medications work in the brain).

However, ketamine also has unwanted psychoactive properties, which limits its usefulness in the treatment of depression. Ketamine causes an intense high or sense of euphoria as well as hallucinogenic effects such as dissociation, a bizarre sense of separation of the mind from the self and environment. Ketamine is also addictive and is an abused party drug [3].

A debate has been going about whether ketamine should be used for the treatment of depression and if its risks outweigh its benefits [4]. However, what if ketamine itself is not responsible for the anti-depressant function but a chemical byproduct of ketamine? This is what the scientist’s in this study reported: it’s HNK and not ketamine that are responsible for the powerful anti-depressant functions. This discovery was made in mice but how do scientists even study depression in a mouse?

 

How do scientists study depression in rodents?

mice-162163_960_720

Depression is a complex psychological state that is difficult to study but scientists have developed a number of tests to measure depressive-like behavior in rodents. While any one particular test is probably not good enough to measure depression, the combination of multiple tests—especially if similar results are found for each test—provide an accurate measurement of depression in rodents.

Some of the tests include:

Forced Swim Test

As the name reveals, in this test rodents are place in a cylinder of water in which they cannot escape are a forced to swim. Mice and rats are very good swimmers and when placed in the water will swim around for a while, searching for a way to escape. However, after a certain amount of time, the mouse will “give up” and simply stop swimming and will just float there. This “giving up” is used as a proxy for depression, similar to how people that are depressed often lack perseverance or motivation to keep trying. If you a give drug and the mice swim for much longer than without the drug, then you can make the argument that the drug had an anti-depressant effect. See this video of a Forced Swim Test.

Learned Helplessness Test

One theory of depression is that it can result from being placed in a bad situation in which we have no control over. This test models this type of scenario.

First, mice are place in chamber where they experience random foot shocks (the learning about the bad, hopeless situation). Next, they are place in a chamber that has two compartments. When a foot shock occurs, a door opens to a “safe” chamber, which gives the mouse an opportunity to escape the bad situation. One measure of depression is that some mice won’t try to escape or will fail to escape. In essence, they’ve given up at trying to escape the bad situation (learned helplessness). You can then take these “depressed” mice, and run the experiment again but this time with the anti-depressant drug you want to test and see how they do at escaping the foot shocks. Read more here.

Chronic Social Defeat Stress

Imagine you had a bully that would beat you up every day but the bully lived next door to you and would stare at you through his bedroom window? It would probably make you feel pretty crummy, wouldn’t it? Well, in essence, that’s what chronic social defeat stress test is all about [5].

A male mouse is placed in a cage with a much larger, older, and meaner male mouse that then attacks it. After the attack session, the “victim” mouse is housed in a cage where it can see and smell the bigger mouse. This induces a sense of hopelessness or depression in the “victim” mouse and it will not try to interact with a “stranger”” mouse if given a choice between the stranger and an empty cage (mice are pretty curious animals and will usually sniff around a cage with a unfamiliar mouse in it). This social avoidance is a measure of depression. In contrast, some mice will be resilient or resistant to this type of stress and will interact normally with the “stranger” mouse. Similar to above, you can test an anti-depressant drug in the “resilient” mice and the “depressed” mice.

There are a few others but these are three of the main ones used in this paper.

How did the NIH scientists figure out how Ketamine works to fight depression?

It was believed that ketamine’s anti-depressant function was due to its ability to inhibit the activity of the neurotransmitter glutamate. Specifically, ketamine inhibits a special target of glutamate called the NMDA receptor [6].

The first thing done is this paper was to study ketamine’s effects in rodent models of depression and sure enough, it was effective at relieving depression-like behavior in the mice.

Ketamine comes in two different chemical varieties or enantiomers, R-ketamine and S-ketamine. Interestingly, the R-version was more effective than the S-version (this will be more important later).

Recall that ketamine is though to work because it inhibits the NMDA receptor, but the scientists found that another drug, MK-801, that also directly inhibits the NMDA receptor, did have the same anti-depressant effects. So what is it about ketamine that makes it a useful anti-depressant then if not it’s ability to inhibit the NMDA receptor?

Ketamine is broken down into multiple different other chemical byproducts or metabolites once it enters the body. The scientists were able to isolate and measure these different metabolites from the brains of mice. For some reason one of the metabolites, (2S,6S;2R,6R)-hydroxynorketamine (HNK) was found to be three times higher in females compared to males. Ketamine was also more effective at relieving depression in female mice compared to male mice and the scientists wondered: could it be because of the difference in the levels of the ketamine metabolite HNK?

To test this, a chemically modified version of ketamine was produced that can’t be metabolized. Amazingly the ketamine that couldn’t be broken down did not have any anti-depressant effects. This finding strongly suggests that it’s really is one of the metabolites, and not ketamine itself, that’s responsible for the anti-depressant activity. The most likely candidate? The HNK compound that showed the unusual elevation in females vs males.

Similar to ketamine, HNK comes in two varieties, (2S,6S)-HNK and (2R,6R)-HNK. The scientists knew that the R-version of ketamine was more potent than the S-version so they wondered if the same was true for HNK. Sure enough, (2R,6R)-HNK was able to relieve depression in mice while the S-version did not. The scientists appeared to have identified the “magic ingredient” of ketamine’s depression-relieving power.

These experiments required a great deal of sophisticated and complex analytical chemistry. However, this is beyond my area of expertise so unfortunately cannot discuss it further.

So now the team had what they thought was the “magic ingredient” from ketamine for fighting depression. But could they support their behavior work with more detailed molecular analyses?

The next step was to look at the actual properties of neurons themselves and see if (2R,6R)-HNK changed their function in the short and long term. Using a series of sophisticated electrophysiology experiments in which the activity of individual neurons can be measured, the scientists found that glutamate signaling was indeed disrupted. However, it appeared that a different type of glutamate receptor was involved: the AMPA receptor, and not NMDA receptor. The scientists confirmed this with protein analysis; components of the AMPA receptor increased in concentration in the brain over time. These data suggest that it is alterations in glutamate-AMPA signaling that underlies the long-term effectiveness of HNK.

OK, so great! HNK reduces depression but does it still have all the other nasty side effects of ketamine? If it does, then it’s no better than ketamine itself.

For the final set of experiments, the scientists looked at the psychoactive and addictive properties of ketamine. Using a wide range of behavioral tests that I won’t go into the details of, 2R,6R)-HNK had a much lower profile of side effects than ketamine.

Finally, ketamine is an addictive substance that can and is abused illegally. A standard test of addiction in mouse models is self-administration (I’ve discussed this technique previously). Mouse readily self-administer ketamine, which indicates they want to take more and more of it, just like a human addict. However, rodent’s do not self-administer HNK! This means that HNK is not addictive like ketamine.

mental health

In conclusion, (2R,6R)-HNK appears to be extremely effective at relieving depression in humans, has less side-effects than ketamine, and is not effective. Sounds pretty good to me!

Next step: does HNK work in humans? To be continued….

Selected References

  1. Peltoniemi MA, et al. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clinical pharmacokinetics. 2016.
  1. Newport DJ, et al. Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. The American journal of psychiatry. 2015;172(10):950-66.
  1. Morgan CJ, et al. Ketamine use: a review. Addiction. 2012;107(1):27-38.
  1. Sanacora G, Schatzberg AF. Ketamine: promising path or false prophecy in the development of novel therapeutics for mood disorders? Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2015;40(5):1307.
  1. Hollis F, Kabbaj M. Social defeat as an animal model for depression. ILAR journal / National Research Council, Institute of Laboratory Animal Resources. 2014;55(2):221-32.
  1. Abdallah CG, et al. Ketamine’s Mechanism of Action: A Path to Rapid-Acting Antidepressants. Depression and anxiety. 2016.

 

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Methadone vs Buprenorphine: Which is Better for Treating Heroin Addiction?

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The CDC Fights Back Against the Opioid Epidemic

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The CDC has released important information on dealing with the prescription opioid pain medication and heroin epidemic. Opioids are a class of drugs that include pain medications such as morphine, oxycodone, hydrocodone, methadone, fentanyl and others and the illegal drug heroin. I’ve spoken a great deal about this problem in various other posts (see here here here and especially here and here). Just to summarize some of most disturbing trends: the US is experiencing a surge in deaths due to overdose on opioids (overdoses/year due to opioids are now greater than fatalities from car crashes), virtually all demographics (age groups, income levels, gender, race) are affected, and many people addicted to opioid pain pills transition to heroin and as such, a huge increase in heroin abuse is also occurring; teenagers and adolescents are especially hard hit. The CDC’s report, released on Friday, March 18 provides a thorough review of the clinical evidence around prescription opioid pain medications and makes 12 recommendations to help control the over-prescription of these powerful drugs in attempt to reduce the amount of overdose deaths and addiction.

Read the full report.

I finally got around to reading the whole thing and am happy to summarize its main analyses and findings. While the report is intended for primary health care providers and clinicians, the report’s findings are important for anyone suffering from short or long-term pain and the risks vs benefits posed by opioids.

But before I dive into the meat of the report, I wanted to clarify an important issue about addiction to prescription opioids. A false narrative exists that those suffering from addiction are “drug seekers” and it is this group of people that is duping doctors in prescribing them too many opioids while good patients that take opioids as directed are not over dosing or becoming addicted. It’s important to remember that opioids are so powerful anyone that takes them runs the risk of overdosing or becoming addicted after repeated use. Most people suffering from addiction and overdoses during the current prescription opioid epidemic are people that used opioids medically and not for recreation. This is true for youths prescribed opioids for a high-school sports injury, and older patients prescribed opioids for chronic back pain, and many other “regular” people. The CDC released this report to help fight back against the over-prescription of opioids and the severe risks that accompany their use. Doctors and patients alike need to be aware of the risks vs benefits of opioids if they decide to use them for pain therapy.

Hydrocodone (wikimedia.org)
Hydrocodone (wikimedia.org)

The CDC’s report had three primary goals:

  1. Identify relevant clinical questions related to prescribing of opioid pain medications.
  2. Evaluate the clinical and contextual evidence that addresses these questions
  3. Prepare recommendations based on the evidence.

Two types of evidence were used in preparation of the report: direct clinical evidence and indirect evidence that supports various aspects of the clinical evidence (contextual evidence). Studies included in the analysis ranged from high quality randomized control studies (the gold standard for evaluating clinical effectiveness) to more observational studies (not strong, direct evidence but useful information nonetheless).

The report identified five central questions regarding the concerns over opioids:

  1. Is there evidence of effectiveness of opioid therapy in long-term treatment of chronic pain?
  2. What are the risks of opioids?
  3. What differences in effectiveness between different dosing strategies (immediate release versus long-acting/extended release)?
  4. How effective are the existing systems for predicting the risks of opioids (overdose, addiction, abuse or misuse) and assessing those risks in patients?
  5. What is the effect of prescribing opioids for acute pain on long-term use?

Based on a close examination of the clinical evidence from a number of published studies, the CDC found the following answer to these questions.

  1. There is no evidence supporting the benefits of opioids at managing chronic pain. Opioids are only useful for acute (less than 3 days) pain and for cancer pain or end-or-life pain treatment.
  2. Opioids have numerous risks such as abuse and addiction, overdose, fractures due to falling in some older patients, car crashes due to impairments, and other problems. The longer opioids are used the greater these risks.
  3. There is no difference in effectiveness between immediate release opioids and long-acting or extended release formulation. The evidence suggests the risk for overdose is greater with long-acting and extended-release opioids.
  4. No currently available monitoring methods or systems are capable of completely predicting or identifying risk for overdose, dependence, abuse, or addiction but severak methods may be effective at helping to evaluate these risk factors.
  5. The use of opioids for treating acute pain increases the likelihood that they will be sued long-term (most likely because of tolerance and dependence).
Oxycodone (wikimedia.org)
Oxycodone (wikimedia.org)

The CDC also examined what they called contextual evidence or studies that didn’t directly answer the primary clinical questions but still provided valuable, if indirect, information about treatment of pain with/without opioids.

  • Non-medication based therapies like physical therapy, exercise therapy, psychological therapies, etc. can be effective at treating chronic pain for a number of conditions.
  • Non-opioid pain medications such as acetaminophen, NSAIDs, Cox-2 inhibitors, anti-convulsants, and anti-depressants (in some instances) were also effective in treating chronic pain for various conditions and have fewer dangers than opioids.
  • Long-acting opioids increase the risk for overdose and addiction. Higher doses of opioids also increase the risk for overdose.
  • Co-prescription of opioids with benzodiazepines greatly increases the risk of overdoses.
  • Many doctors are unsure of how to talk to their patients about opioids and their benefits vs risks and most patients don’t know what opioids even are.
  • The opioid epidemic costs billions of dollars in medical and associated costs. Its estimated  costs due to treatment of overdose alone is $20.4 billion.

Many other findings and important pieces are information were reported but too many to list here.

Based on all results of the analysis the CDC came up with 12 recommendations in three broad categories. I’ll briefly discuss each recommendation.

Category 1: Determining when to initiate or continue opioids for chronic pain.

  • Recommendation 1: Non-pharmacologic (medication-based) therapy and non-opioid pharmacologic therapy are preferred for chronic pain.
    • The risks of overdose and addiction from long-term use of opioids is very high and benefits for actually treating pain are very low for most people. Therefore, other safer and more-effective treatments should be use first. The discussion of the risks vs benefits needs to be made clear by the patient’s doctor.
  • Recommendation 2: Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function
    • Opioids should be used for the shortest amount of time possible but if used for a long-term treatment, at the lowest effective dose.
    • If a patient suffers from an overdose or seems as if dependence or addiction is developing, a patient may need to be tapered off of opioids.
  • Recommendation 3: Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy.
    • The risks are high for the use of opioids and it is necessary for doctors to keep their patients informed about these risks.
    • Doctors should be “be explicit and realistic about expected benefits from opioids, explaining that while opioids can reduce pain during short-term use, there is no good evidence that opioids improve pain or function with long-term use, and that complete relief of pain is unlikely.”

Category 2: Opioid selection, dosage, duration, follow-up, and discontinuation.

  • Recommendation 4: When starting opioid therapy, clinicians should prescribe immediate-release opioids instead of extended-release or long-acting opioids.
    • There appears to be no difference in effectiveness at treating pain between the different types of opioids but the long-acting opioids come with a greater risk for overdose and dependence.
    • Long-acting opioids should be reserved for cancer pain or end-of-life pain.
    • It’s important to note that “abuse-deterrent” does not mean that there is no risk for abuse, dependence, or addiction. These types of formulations are generally to prevent intravenous use (shooting up with a needle) but most problems with opioids occur as a result of normal, oral use.
  • Recommendation 5: When opioids are started, clinicians should prescribe the lowest effective dosage.
    • The higher the dose the greater the risk. A low dose may be sufficient to control the pain without risk for overdose or the development of dependence.
    • Opioids are often most effective in the short-term and may not need to be continued after 3 days.
    • If dosage needs to be increased, changes in pain and function in the patient should be re-evaluated afterwards to determine if a benefit has occurred.
    • Patients currently on high-dose long-term opioids for chronic pain may want to consider tapering down their dosage.
      • Tapering opioids can be challenging can take a long-time due to the physical and psychological dependence. Tapering should be done slowly to and the best course of dosage should be determined specifically for the patient.
    • Recommendation 6: Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed.
      • Evidence suggests that using an opioid for acute pain can start a patient down a path of long-term use. This should attempted to be avoided by using a low dose if opioid is selected to treat acute pain.
      • Acute pain can often be effectively managed without opioids with non-medication-based therapies (like exercise, water aerobics, physical therapy, etc.) or non-opioid medications (like acetaminophen or NSAIDs).
    • Recommendation 7: Clinicians should evaluate benefits and harms with patients within 1-4 weeks of starting opioid therapy for chronic pain or of dose escalation.
      • Opioids are most effective for the first three days and possible up to a week. If long-term therapy is decided upon, treatment should regularly be reassessed and reevaluated (at least every 3 months for long-term therapy).

Category 3: Assessing risks and addressing harms of opioid use.

  • Recommendation 8: Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone.
    • Specific risk factors for the specific condition that patient is using opioids for should be considered when developing the treatment plan.
    • Naloxone blocks the effects of opioids and can immediately revive someone that has experienced an overdose. Naloxone should be offered to patients if a patient is using opioids at high-dose for long-term therapy or previously suffered an overdose.
  • Recommendation 9: Clinicians should review the patient’s history of controlled substance prescription using state prescription drug monitoring program (PDMP) data to determine whether a patient is receive opioid dosages or dangerous combinations that put him or her at risk for overdose.
    • PDMPs are state-run databases that collect information on controlled prescription drugs dispensed by pharmacies and in some states, physicians too.
    • While the clinical evidence was unclear if PDMPs were accurate at predicting overdose or addiction, the contextual evidence supported that “most fatal overdoses were associated with patients receiving opioids from multiple prescribers and/or with patients receiving high total daily opioid dosage.”
    • PDMP should be consulted before beginning opioid therapy and during the course of treatment if used for long-term therapy and this data should be discussed with the patient.
    • However, PDMP data must be used cautiously as some patients are turned away from treatment that would otherwise have benefited.
  • Recommendation 10: (not a general recommendation but to be considered on a patient-by-patient basis) When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs.
    • Urine drug tests can reveal information about potential risks due to combinations with other drugs not reported by the patient (e.g. benzodiazepines, heroin).
    • Urine testing should become standard practice and should be done prior to starting opioids for chronic therapy.
    • Clinicians should make it clear that testing is intended for patient safety and is not intended to deprive the patient of therapy unnecessarily.
  • Recommendation 11: Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible.
    • Strong evidence suggests that many overdoses occurred in patients prescribed both benzodiazepines and opioids. The two should never be prescribed together if at all possible.
  • Recommendation 12: Clinicians should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies) for patients with opioid abuse disorder (addiction).
    • Many patients using opioids for chronic pain now may have become physically and psychologically addicted to them and should be offered treatment (estimated at 3-26% of patients using opioids for chronic pain therapy).
    • Methadone and buprenorphine are proven, safe, and effective-treatments that retain patients in treatment and that satisfy an opioid addict’s cravings, prevent relapse to abusing opioids/heroin, and allow the patient to live a normal life (read my blog post on methadone).
    • Behavioral therapy/individual counseling in combination with medication-based treatment may improve positive benefits of treatment even further.
    • However, access to these medications can be extremely limited in some communities due to availability (methadone is restricted to clinics and clinicians need certification in order to prescribe buprenorphine) or cost (treatment often is not covered by insurance).
    • Urine testing or PDMP data may help to reveal if a patient has become addicted and if so, treatment should be arranged.

In Summary, the main takeaways from the report are:

  • Opioids are associated with many risks such as overdose, abuse, dependence, addiction, and others (e.g. fractures from falling or car-crashes due to impairment).
  • No evidence exists that opioids are effective for treatment of chronic pain (with the exception of cancer and end-of-life pain).
  • Opioids are most effective for short term (3-7 days) and in immediate-release formulations.
  • Non-medication based therapies and non-opioid medications are preferred for treatment of chronic pain.
  • Doctors need to clearly explain the risks vs benefits of opioid therapy with their patients.
  • If decided as the best course of action for a particular patient, opioid therapy needs to be repeated re-evaluated to make sure it is still working to alleviate pain.
  • The prescription drug monitoring programs are useful tools that should be consulted prior to beginning therapy in order to help determine a patient’s history with opioids and risk for abuse or overdose.
  • Naloxone should be made available to patients using opioids for long-term therapy in order to prevent possible overdoses.
  • Access to medication-based treatments (methadone or buprenorphine) for dependent individuals should be provided.

Concluding Thoughts

In 1995 Purdue pharmaceuticals released OxyContin (oxycodone, one of the most common prescription opioid pain medications) and launched an enormous push for doctors to use opioids as the primary treatment for chronic pain. The enormous surge in in prescriptions of oxycodone (500% increase from 1999-2011) followed this marketing campaign. One of the most disturbing aspects revealed by the CDC’s report is that despite this surge in prescriptions, there is a complete lack of data on the effectiveness of opioids for long-term chronic pain therapy.

To be fair though, “Big Pharma” is not the sole culprit in this crisis. One argument is that pharma was responding to the need of clinicians for an increased demand by patients for management of chronic pain. It is very disturbing though that the push for the use of opioids for long-term management was initiated without any supporting evidence. This is another example of how medicine must be guided by evidence-based principles and not on personal beliefs and values or medical tradition and culture.

It’s important to remember that some patients do tolerate opioids well and these patients may find them beneficial at treating their chronic pain condition. The guidelines do stress frequent reevaluation of the benefits vs risks of opioids and for some patients benefits will outweigh the risks.

Finally, the CDC’s guidelines are not legally binding. These are recommendations and not laws or regulations. This means no doctors are not legally required to comply with any of the CDC’s recommendations. Hopefully some or all of these recommendations will be formalized into formal laws and regulations because many of them are extremely important in regulating these powerful and potentially dangerous drugs.

(Also check out the Diane Rehm Show’s hour-long discussion of the report. As usual, the show offers a high quality analysis and discussion from a panel of experts.)

Is Methadone an Effective Treatment for Heroin Addiction? YES!

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Response to HuffPost Marc Lewis Interview on Addiction

So the Huffington Post runs a sub-blog on Addiction and Recovery and sometimes they present excellent reporting (for example, the piece on opioid addiction by Jason Cherkis who actually interviewed my boss, Dr. Mary Jeanne Kreek, for the article). But more often than not, they present quite variable reporting on addiction.  A recent interview with psychologist Marc Lewis, PhD is one such example.

Based on my own neuroscience of addiction background, I unfortunately find a number of Dr. Lewis’s claims not supported by scientific evidence and I believe the spread of such false statements can have the exact opposite of his intended effect—hurting more addicts rather than helping them. I do not claim to be the consensus voice of the addiction field but present my own arguments based on my own research and work done in the field. I also admit have not read any of Dr. Lewis’s books and am merely responding to the statements made in his interview. I include references at the end of the post.

The original interview between Carolyn Gregoire, Senior Health and Science Writer for Huffington Post and psychologist Marc Lewis, PhD

The questions (Q) by Carolyn Gregoire in the original interview are in bold, Dr. Lewis’s response (L) is italicized, and my response (S) is the un-italicized larger-size text.

Q: What’s wrong with the disease model of addiction? 

L: I know what scientists are looking at when they say addiction is a disease. I don’t dispute the findings, but I dispute the interpretation of them. They see addiction as a chronic brain disease — that’s how they define it in very explicit terms. 

My training is in emotional and personality development. I see addiction as a developmental process. So the brain changes that people talk about and have shown reliably in research can be seen as changes that are due to learning, to recurrent and deep learning experiences. But it’s not an abnormal experience and there’s nothing static or chronic about it, because people continue to change when they recover and come out of addiction. So the chronic label doesn’t make much sense.

S: The brain is a physical organ that operates under defined molecular biological principles. Drugs are physical chemical substances that perturb the molecular function of the brain. It is true that addiction is a process that can take months or even years to develop but the end result is a physical neurobiological change in how the brain functions [1, 2]. And when neuroscientists say chronic brain disease—or what my lab says A disease of the brain with behavioral manifestations—what we mean is that repeated drug use has caused a change is brain function which in turn results in a change in behavior. That doesn’t mean that this change is irreversible but, like other diseases, the first step to treatment is recognizing the underlying biological cause. Defining addiction as a chronic brain disease is not a judgment or interpretation of the development of addiction (which definitely does involve a learning and memory component [3, 4]) but is a statement asserting that drug addiction and drug cravings, compulsive drug use, and relapse are ultimately based on physical changes in the brain. It is important that we recognize this because otherwise we would not be able to treat it with effective and safe medications, in combination with other behavioral and psychological therapies.

Q: What’s problematic about the way we treat addiction, based on the disease model? 

L: Well, lots. The rehab industry is a terrible mess — you either wait on a long list for state-sponsored rehabs that are poorly run or almost entirely 12-Step, or else you pay vast amounts of money for residential rehabs that usually last for 30-90 days and people often go about five to six times. It’s very difficult to maintain your sobriety when you go home and you’re back in your lonely little apartment. 

What I emphasize is that the disease label makes it worse. You have experts saying, “You have a chronic brain disease and you need to get it treated. Why don’t you come here and spend $100,000 and we’ll help you treat it?” There’s a very strong motivation from the family, if not the individual, to go through this process, and then the treatments offered in these places are very seldom evidence-based, and the success rates are low. 

S: I strongly agree with this assessment. The rehab industry and many 12-step programs are ineffective, expensive, and rarely based on scientific evidence. The primary reason is that for decades addiction was thought of a problem of “spiritual weakness” or “lack of will power”. In reality addiction is a medical disorder based on physical neurobiological processes that make it seem like an addict has no “will power”, when in reality that addict’s brain has been hijacked to crave the drug compulsively and practically uncontrollably. However, again, I disagree that calling addiction a disease is what funnels people into rehab clinics. I believe it is the stigmatization of addiction that precludes treatment by doctors (unlike for every other disease), which in turn fuels admission into the rehab industry. Sadly, effective medications exist (such as methadone and buprenorphine for opioid addicts) that can flick a switch off in an addicts brain, satisfying their craving and allow them to live a normal live [5, 6]. Or medications such as naltrexone may be effective at reducing drinking in alcohol addicts but is not widely used [7, 8]. It is only recently that public acknowledgement of the biological basis of addiction and appropriate shifts in public policy are beginning to take place. Importantly, addiction medicine is beginning to become incorporated into medical school education and the first accredited residency programs in addiction medicine have been announced.

Q: There are lots of ways to trigger a humanistic response besides calling something a disease. So you would say that telling people who are in recovery for addiction that they have a “chronic disease” is actually doing them a disservice? 

L: Well, the chronic part is really a yoke that people carry around their necks. [Proponents of the disease model] say that this is important because this is how to prevent the stigmatization of addicts, which has been a standard part of our culture since Victorian times. 

But I think that’s just bullshit. I don’t think it feels good when someone tells you that you have a chronic disease that makes you do bad things. There are ways to reduce stigmatization by recognizing the humanity involved in addiction, the fact that it happens to many people and the fact that people really do try to get better — and most of them do. There are lots of ways to trigger a humanistic response besides calling something a disease.  

S: I agree that stigma is a huge problem with the treatment of drug addiction and mental health. Admitting you are an addict or depressed or know someone who suffers from these disorders is accompanied with unnecessary shame and fear of admission of the problem. I disagree that acknowledgement of medical/neurobiological basis of these disorders (ie calling them diseases) increases stigma but in fact do humanize patients. It helps alleviates shaming–both public and self–and can help an addict to seek evidence-based, medical treatment. Acknowledging the chronic nature of the disorder is not intended to make people feel bad but is merely truthfully stating the nature of the problem in hopes that it can be properly treated; denial can be lead to false and ineffective treatments.

Q: It can be difficult to comprehend the idea that something as severe as a heroin addiction is a developmental process. Can you explain that? 

L: First of all, let’s include the whole bouquet of addictions. So there’s substances — drugs and alcohol — and there’s gambling, sex, porn and some eating disorders. The main brain changes that we see in addiction are common to all of them, so they’re not specific to taking a drug like heroin, which creates a physical dependence. We see similar brain changes in a region called the striatum, which is an area that’s very central to addiction, which is involved in attraction and motivational drive. You see that with gambling as much as you do with cocaine or heroin. So that’s the first step of the argument — it’s not drugs, per se. 

From there, it’s important to recognize that certain drugs, like opiates, create physical dependency. There’s a double whammy there. They’re hard to get off because they’re addictive, like sex or porn is, but they also make you uncomfortable when you stop taking them. People try to go off of them and get extremely uncomfortable and then they’re drawn back to it — now for physical as well as psychological reasons. 

S: It is true that all addictions involve the striatum and there are similarities between the different addictions but to say that ALL addictions affect the brain in the exact same way is an absurd simplification. Different drugs absolutely DO affect the brain differently and have differences in addiction potential and relapse potential. To say addiction to heroin is identical to addiction to alcohol is identical to gambling addiction and therefore has nothing to do with the specific drug or behavior is just plain wrong. A wealth of evidence is gathering that addictions to different drugs progress differently and effect different brain systems, despite certain changes common to all [9]. For example, even opioids such as morphine and oxycodone, whose pharmacology are probably the best understood of any drug of abuse (they interact with mu opioid receptors [10]), have different behavioral and neurobiological effects that may affect addictions to the individual drugs (see my blog post). In a paper published by the lab I work for, the Kreek lab, cocaine administration in drug naïve mice (mice that have never had cocaine in their system) results in a rapid release of dopamine [11]. In contrast, some studies show that self-administration of an opioid drug only increases dopamine in rats that have already been exposed to the drug and not naïve animals [10]. The differences in the dopamine profiles between cocaine and opioids obviously means that how these two drugs affect the brain is different and is drug-specific! These are just a few small examples demonstrating the scientific inaccuracy of lumping all addictions into one general category or making the false claim that addiction has “nothing to do with the drug” (just as reducing cancer to a single disease is entirely inaccurate and harmful for its treatment).

Q: In the case of any type of addiction, what’s going on in the brain? 

L: The main region of interest is the striatum, and the nucleus accumbens, which is a part of the striatum. That region is responsible for goal pursuit, and it’s been around since before mammals. When we are attracted to goals, that region becomes activated by cues that tell you that the goal is available, in response to a stimulus. So you feel attraction, excitement and anticipation in response to this stimulus, and then you keep going after it. The more you go after that stimulus, the more you activate the system and the more you build and then refine synaptic pathways within the system. 

The other part of the brain here that’s very important is the prefrontal cortex, which is involved in conscious, deliberate control — reflection, judgment and decision-making. Usually there’s a balance between the prefrontal cortex and the striatum, so that you don’t get carried away by your impulses. With all kinds of addictions — drugs, behavior, people — the prefrontal system becomes less involved in the behavior because the behavior is repeated so many times. It becomes automatic, like riding a bike. 

S: Dr. Lewis’s assessment is basically correct. The core of the reward circuit involves dopamine-releasing neurons of the ventral tegmental area (VTA) projecting to the nucleus accumbens (NAc; a part of the ventral striatum), which primarily drives motivated behavior and is involved in reinforcement of drug taking behavior. Conversely, the prefrontal cortex acts as a “stop” against this system and one model of addiction is the motivated-drive to seek the drug overpowers the “stop” signal from the prefrontal cortex. However, addiction is far more complex beyond just this basic system. Numerous other circuits and systems (hippocampus, amygdala, hypothalamus, just to name a few) are also involved and each individual drug or rewarding stimuli can affect these circuits in disparate ways [12].

Q: What would a scientifically informed approach to addiction look like? 

L: That’s a really hard question because the fact that we know what’s happening in the brain doesn’t mean that we know what to do about it. 

A lot of recent voices have emphasized that addiction tends to be a social problem. Often addicts are isolated; they very often have difficult backgrounds in terms of childhood trauma, stress, abuse or neglect — so they’re struggling with some degree of depression or anxiety — and then they are socially isolated, they don’t know how to make friends and they don’t know how to feel good without their addiction. 

S: As I’ve stated above, a scientifically informed approach to addiction treatment already exists but is not widely used. However, one day an addict will hopefully be able to consult with a medical doctor to receive appropriate medications specific to their addiction, which will be combined with individual counseling by a psychiatrist or psychologist and a specific cognitive behavioral therapy or other psychological/behavioral therapy. The combination of medications and psychological therapy administered by trained medical professionals will be the future of evidence-based addiction medicine. Development of additional medications and/or psychological therapies for future treatment absolutely requires solid scientific evidence supporting their efficacy, which includes use of randomized control trials,  prior to widespread implementation.

But to call addiction primarily a social problem once again ignores all the basic neuroscience research that shows the powerful effects drugs have on the brain. It also ignores the prominent effect of genetics and how, due to a random role of the dice, an individual’s risk of becoming an addict can drastically increase [2, 13]. Plus the opioid epidemic that is currently sweeping the nation effects nearly every strata of society regardless of socioeconomic status, age, gender or race, and therefore cannot be explained simply by the hypothesis that addicts are people that are socially isolated. Why someone starts using drugs in the first place and how exactly they progress from a casual drug user to an addict are incredibly complex questions that scientists all over the world are attempting to answer through rigorous research. Being socially isolated or experiencing childhood trauma may certainly be factors that eschew some people towards the development of addiction but are definitely not the only ones.

Q: So what can we do about that?

L: Other than certain drugs that can reduce withdrawal symptoms, there’s nothing much medicine can offer, so we have to turn to psychology, and psychology actually offers a fair bit. There’s cognitive behavioral therapy, motivational interviewing, dialectic behavioral therapy, and now there are mindfulness-based approaches, which I think are really exciting. 

There’s been good research from Sarah Bowen in Seattle [on Mindfulness-Based Relapse Prevention] showing that mindfulness practices can have a significant impact on people, even on people who are deeply addicted to opiates. 

S: This is a completely false statement: medications for treatment of addictions exist [14]! Once again, comprehensive systematic reviews of methadone and buprenorphine, two medications used for treatment of opioid cravings, have indisputably shown that these medications are effective at keeping addicts off of heroin compared to no medication [5, 6]. Furthermore, a number of other drugs are currently being explored for treatments to alcohol and cocaine addiction [15, 16]. Some people may consider methadone or buprenorphine replacing “one drug with another” but this is naïve view of how powerfully addictive opioid drugs can be and how use of these FDA-approved medications in combination with individual psychological counseling, can lead to gradual dose reduction and amelioration of cravings. Medication-assisted addiction treatment is designed to help addicts fight their craving so that they can live a normal life. With time, dose can be reduced and cravings can become less intense.

The study Dr. Lewis cites regarding mindfulness is well designed and intriguing. However, the study did not compare mindfulness-based approaches to medication-based approaches and is therefore incomplete [17]. Nevertheless, it is an interesting approach that may be able to be combined with medication-based treatment but definitely requires more research before its efficacy can be confirmed.

References

  1. Koob GF, Le Moal M. Addiction and the brain antireward system. Annual review of psychology. 2008;59:29-53.
  1. Kreek MJ, et al. Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics. The Journal of clinical investigation. 2012;122(10):3387-93.
  1. Kelley AE. Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron. 2004;44(1):161-79.
  1. Tronson NC, Taylor JR. Addiction: a drug-induced disorder of memory reconsolidation. Current opinion in neurobiology. 2013;23(4):573-80.
  1. Mattick RP, et al. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. The Cochrane database of systematic reviews. 2009(3):CD002209.
  1. Mattick RP, et al. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. The Cochrane database of systematic reviews. 2014;2:CD002207.
  1. Anderson P, et al. Effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol. Lancet. 2009;373(9682):2234-46.
  1. Hartung DM, et al. Extended-release naltrexone for alcohol and opioid dependence: a meta-analysis of healthcare utilization studies. Journal of substance abuse treatment. 2014;47(2):113-21.
  1. Badiani A, et al. Opiate versus psychostimulant addiction: the differences do matter. Nature reviews Neuroscience. 2011;12(11):685-700.
  1. Fields HL, Margolis EB. Understanding opioid reward. Trends in neurosciences. 2015;38(4):217-25.
  1. Zhang Y, et al. Effect of acute binge cocaine on levels of extracellular dopamine in the caudate putamen and nucleus accumbens in male C57BL/6J and 129/J mice. Brain research. 2001;923(1-2):172-7.
  1. Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nature reviews Neuroscience. 2013;14(9):609-25.
  1. Kreek MJ, et al. Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nature neuroscience. 2005;8(11):1450-7.
  1. Kreek MJ, et al. Pharmacotherapy of addictions. Nature reviews Drug discovery. 2002;1(9):710-26.
  1. Addolorato G, et al. Novel therapeutic strategies for alcohol and drug addiction: focus on GABA, ion channels and transcranial magnetic stimulation. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2012;37(1):163-77.
  1. Bidlack JM. Mixed kappa/mu partial opioid agonists as potential treatments for cocaine dependence. Advances in pharmacology. 2014;69:387-418.
  1. Bowen S, et al. Relative efficacy of mindfulness-based relapse prevention, standard relapse prevention, and treatment as usual for substance use disorders: a randomized clinical trial. JAMA psychiatry. 2014;71(5):547-56.

Promising Shifts in Policy Towards Addiction Prevention and Treament

Spilled prescription medication --- Image by © Mark Weiss/Corbis
Spilled prescription medication — Image by © Mark Weiss/Corbis

 

Normally a search for drug addiction in Google news pulls up a similar thread of articles: arrests of dealers and addicts, big drug busts, a crime committed by a user or dealer, somebodies mug shot. Basically, the news tends to cover only the drug enforcement and criminal aspects of the drug addiction problem. This is unsurprising since for the past few decades the lens in which we view addicts and addiction has been smeared by the “War on Drugs”, which views drug users as criminals and deviants and seeks to punish rather than treat. However, with advances in medical technology, advances in neuroscience, cognitive psychology, and a host of related fields, we understand addiction at the neurochemical and physiological level better than we ever have before. A shift in attitude that acknowledges addiction as a medical disease that needs to be treated as such (well established in the scientific community) is finally making its way into public consciousness, and most importantly, public policy.

SFN 2015 LogoI was recently at the 2015 Society for Neuroscience Conference, an enormous gathering of neuroscientist from around the world, held Oct 17-21 in Chicago. The conference hosts an overwhelming number of lectures, symposia, and workshops for scientists to share the latest developments in research in Alzheimer’s, Parkinson’s, stroke, learning and memory, brain development, addiction, and many others neuroscience sub-disciplines. Several special lectures on neuroscience related-topics are also held and I had the pleasure of attending one of these special lectures given by the Honorable Jed S. Rakoff, Senior US District Judge for the Southern District of New York and founding member of the MacArthur Foundation Project on Law and Neuroscience, which researches issues on the intersection of law and neuroscience. Judge Rakoff spoke on how new advances in neuroscience research such as improved neuroimaging technologies and greater understanding into human cognition and decision-making, is changing how the law treats defendants. Significantly, Judge Rakoff spoke frequently about addiction, and he acknowledges what many do, that those arrested for non-violent offenses should be treated, not brutalized. However, he explained that many judge’s hands are tied when it comes to sentencing due to laws in place that set mandatory minimums for drug offenders. Judge Rakoff believes these mandatory minimum laws should be eliminated if progress is to be made toward providing treatment, rather than prison sentences, for drug addicts. It was refreshing to hear this come from such a distinguished judge and I hope it is a bellwether for changes in our legal system.

Of course, laws cannot changes without lawmakers to change them. But we may be seeing the beginning of shift in drug addiction policy for the first time in years.

The epidemic of addiction to prescription opioids and heroin has been making news for months now. I’ve blogged about this epidemic in several posts. One covering a review article describing the epidemic, another sharing an excellent article in the Huffington Post about the epidemic and available treatments for opioid addiction, and most recently, an important report released by the Centers for Disease Control that names opioid addiction as one of the counties top public health crises. Following this latter groundbreaking report by the CDC, policy-makers are finally starting to wake up to the problem.

In a speech in on October 21 in Charleston, West Virginia, one of the areas in the country worst hit by the opioid problem, President Obama held an hour-long public forum in which he promised $133 million dollars to combating the prescription opioid and heroin problem. The President gave about a 15-minute introduction to the event, which entailed some of the most refreshing comments about addiction to ever come from a US President.

Watch the full speech here:

President Obama began by citing shocking statistics stated in the CDC report concerning the surge in deaths due to prescription opioids, “More Americans now die from drug overdoses than from motor vehicle crashes…The majority involve legal prescription drugs.” He went on to talk about heroin as an extension of prescription opioid abuse, “4 out of 5 heroin users start with prescription opioids”.

Of special significance was the shift in language he used to describe addiction and addicts, which contrasts strongly with the “War on Drugs” rhetoric of the previous administration. Obama said, “This is an illness and we have to treat is as such. We have to change our mindset”, which is something that scientists have been arguing for years but is just now being acknowledged by a US President.

Progress towards treating addiction cannot be made unless the biological and medical realities of the illness are understood and addicts are treated as patients rather than criminals. Indeed, stigma towards addicts is one of the biggest hurdles towards reforming public health policy and attitudes towards addiction and President Obama admitted this, “We can’t fight this epidemic without eliminating stigma.”

Some progress has been made under Obama’s watch and he and Health and Human Services Secretary Sylvia Burwell outlined several addiction reforms. One important change already in place is a stipulation of the Affordable Care Act that requires insurance to cover treatment for substance abuse disorders. Secretary Burwell outlined three points at the forum in West Virgina for an “evidence-based strategy” towards addiction prevention and treatment:

  • Point 1: Changing prescribing practices. This is necessary to stem the over prescription of opioids and the dependence to the drugs that develops in some patients as result.
  • Point 2: Expand medication-assisted treatment programs and to make sure patients can have access to treatment and behavioral counseling that can help them.
  • Point 3: Increased access to naloxone. Naloxone counteracts the effects of opioids and should be a standard medication on hand for any first responder that deals with overdoses.

The details about implementing these strategies were not provided though.

However, Obama’s speech may be coming too late, as Dr. Andrew Kolodny, founder of the Phoenix House Treatment facilities in New York, believes. As reported in New York Times, Dr. Kolodyn is disappointed with Obama’s progress and thinks he has waited too long to take action and says that opioid epidemic problem has gotten considerably worse over under Obama’s watch.

I am anxious to see what changes may occur within the last year of Obama’s presidency in respect to the opioid epidemic. However, if more permanent changes are not made in the law, a conservative Republican president could easily over turn any changes made and revert to a failed Reagan-era “War on Drugs” approach.

Methadone Maintenance Therapy Works-End of Story

helping hands (pixbay.com)

I hate to be condescending but how the scientific community perceives a phenomena and how the public at large perceive the exact same thing can be starkly different.

For example, there is still a debate over the scientific legitimacy of global warming and climate change. Of course, this flies in the face of reality. In the scientific community, there is no more doubt over climate change than there is over heliocentricity (the theory that states the Earth revolves around the Sun). Study after study comes to the came conclusion, the scientific evidence is overwhelmingly in favor. But I’m not writing to debate climate change.

The same type of dichotomy exists for replacement/maintenance therapies for addiction. Methadone and the related compound buprenorphine (Suboxone, one of its formulations) are still considered controversial or ineffective or “replacing one drug for another.”

(wikipedia.com)
Methadone pills. (wikipedia.com)

In brief, methadone is a compound that acts on the same target as heroin (the mu opioid receptor) but unlike heroin, it acts for a very long time (24hrs). Dr. Vincent Dole, a doctor at the Rockefeller University in New York, and his colleague, Dr. Marie Nyswander, had the brilliant idea of using this very long-acting opioid compound as a way of treating heroin addiction. Indeed, methadone has the advantage of not producing the intense, pleasurable high that heroin produces but is still effective at curbing cravings for heroin and eliminating withdrawal symptoms. Dole and Nyswander published their first study in 1967 and methadone has been an approved—and effective—treatment for heroin addiction worldwide ever since.

However, controversy over the use of methadone exists. Even the opening of a methadone clinic can incite protests. The persistence of negative attitudes towards methadone and the stigma against treating addiction as a medical disease has prevented addicts from receiving proven medical treatments that are effective at curbing cravings and actually keeping them off of heroin and in treatment programs.

So just for a moment, let’s suspend our preconceived notions about what methadone is or how it works and let’s just ask our selves two simple questions:

 Does methadone work?

Does methadone keep addicts off of heroin and in treatment?

The answer is a resounding YES!

 

Mattick JP et al. Methaodone. 2009 title

Many controlled, clinical studies have examined the effectiveness of methadone. But a comprehensive comparison of methadone versus control, non-medication based treatments has not been considered amongst the various studies.

Researchers at the Cochrane Library performed this type of comprehensive analysis. Data was considered from 14 unique, previous clinical studies conducted over the past 40 years. Researchers compared methadone treatment versus control, non-medication based treatment approaches (placebo medication, withdrawal or detoxification, drug-free rehabilitation clinics, no treatment, or waitlist).

11 studies and 1,969 subjects were included in their final analysis.

 Read the full paper, published in 2009, here.

The results were clear. Methadone was found to keep people off of heroin and in treatment more effectively than control treatments. Urine analysis confirmed methadone-treated addicts were more likely to be heroin-free and regularly seeking treatment.

Of course, as I stated above, this is nothing new. But it’s important to note that abstinence therapies or treatments that encourage addicts to go “cold turkey” don’t really work; inevitably, relapse will occur. A medical treatment exists to help addicts fight their cravings so their brains are not fixated on obtaining heroin and these people are able to regain normal daily functions. And in time, methadone doses can be tapered down as intensity and frequency of cravings decrease.

The debate now should not be on whether methadone works, but on how to use it effectively and how to expand its use so that as many people as possible can benefit from it.

Most importantly, methadone helps an addict to return to normal life. End of story.

New York City’s Failure to Care for Recovering Addicts

(From wikipedia.com)
(From wikipedia.com)

A new investigative report in the New York Times reveals a corrupt and virtually unregulated system of housing that preys on those that suffer from addiction and mental disease. Called “three-quarter” homes, there may be as many as 600 of these privately owned residences in NYC that act as a limbo between inpatient hospital care and shelters. The article tells the story of a group of homes owned by a single landlord and a few of the unfortunate residents trapped within this system. Disturbingly, reputable hospitals and treatment centers often refer patients to these homes. Landlord’s profit off of their tenant’s state-provided subsidies, which are insufficient for any other type of housing. The landlord collects the government assistance checks provided to the tenants provided that they regularly attend treatment centers. This has the unexpected consequence of incentivizing a landlord to encourage his tenants to relapse and thus remain in treatment…and in the three-quarter home. This vicious cycle is perfectly encapsulated in the articles headline “A Choice for Recovering Addicts: Relapse of Homelessness.” Read the full article for more details.

However, the article neglects the opportunity to elucidate the root cause of the existence of these three-quarter homes: lack of a sufficient, standardized and coordinated health care system for the treatment of addiction and other mental diseases. A critical problem in the American healthcare system is the lack of adequate inpatient medical treatment for people suffering from addiction, and is why people get referred to the three-quarter homes in the first place.

Addiction is a complex mental health disorder that requires an individual treatment plan that may involve medication, counseling, group and/or individual therapy, and other options. Without a well-funded, evidence-based, medical treatment program formulated for an individual’s addiction, they are likely to fall into the purgatory of three-quarter homes or even worse, the streets or prison. Ultimately homes likes these are allowed to exist due to the lack of adequate treatment options and facilities for addicts.

 And of course, the medical and treatment culture of addiction cannot be changed until the stigma against addicts and addiction is changed. Addiction is a medical disease and needs to be treated as such.

 

New Study-Treatment of Opioid Addicts in Prison and Effect on Relapse After Release

JD Lee et al. 2015. Title

There are many stigmas about addiction that are prevalent in society but the underlying cause of them all is that addiction is moral failing, even though we know addiction is a biological disease of the brain (with behavioral symptoms). In addition to being scientifically unfounded, stigmas about addiction can actually affect policy and public health decisions that have a real impact on people’s lives. In the perfect world, every decision we made would be based on concrete evidence and controlled, experimental studies. Unfortunately, this seems to be the exact opposite case for our attitudes as a society and our public policy towards drugs—ignorance, assumptions, and misconceptions seem to dominate. Nevertheless, as scientists, all we can do is the best work we can, explain and communicate the science to as many people as possible, and help to promote and support the work of others. Which brings me to today’s paper: a small pilot study that may have a wide impact on the treatment of addicts in the criminal justice system.

The paper, released in the journal Addiction, looks at how treatment for opioid addiction while in prison can affect the rate of relapse to opioid abuse once inmates are released. The study recruited opioid-dependent male inmates incarcerated in New York City jails that were not interested in maintenance therapy (methadone or buprenorphine). The treatment tested is a new medication, an extended-release naltrexone (XR-NTX), a compound that blocks opioid receptors.

Note on pharmacology: naltrexone is what’s known as a mu opioid receptor (MOPR) antagonist, meaning it blocks activity at MOPR (the molecular target of opioid drugs). It also has a weaker antagonist effect on kappa opioid receptors (KOPR). The KOPR plays a more complicated role in addiction, but several studies have suggested blockade of KOPR may reduce relapse. Extended release means that these receptors remain blocked for a sustained period of time after receiving the initial dose.

While 152 inmates were initially interviewed, only 34 fit the criteria for the study. Many subjects were excluded from the study for a variety of reasons that would have made the study difficult to perform or the data difficult to interpret. For example, no interest, currently on methadone or buprenorphine, tested positive for opioid prior to treatment, and other reasons.

The 34 subjects were randomly assigned to either the group that would receive the XR-NTX or standard behavioral therapy (i.e. no medication given to the patient). 15 (2 of the 17 refused) patients received a single injection of XR-NTX prior to release (average of 5 days before release) and 17 received no medication. Patients that received the XR-NTX were offered a second injection 4-weeks post release and 12 accepted this second injection.

6 of the 16 (1 remained incarcerated so was excluded) that received the first dose of XR-NTX had relapsed to opioid use at 1-4 weeks post-release while 15 of 17 relapsed for the control group. Urine analysis confirmed whether or a not a subject was on opioids.

Granted that these are very small numbers (the authors described the study as a proof-of-principle pilot study) but the data are statistically significant. This means that the effect the experimenters are observing is most likely real and not due to random chance. The results suggest that inmates that receive the XR-NTX medication are less likely to relapse after being released from prison.

 These results are important because one of the problems of the US criminal justice system is that addicts are not treated while in prison. While they are abstinent while incarcerated, the underlying neurobiology of their addiction is not being treated which results in almost immediate relapse following release from prison. This of course can result in being thrown back into jail 1) if arrested while using the drug or  2) due to criminal activity to support the addiction. This cycle of addiction-arrest-incarceration-relapse-arrest-incarceration is harmful for the criminal justice system, for the addicts themselves, and for society at large (after all, we are paying for it). This study suggests addicts in prisons that are treated with medication are less likely to relapse.

However, this study is extremely limited and needs to be expanded to a much larger group of inmates before any type of changes can be implemented on a large scale. Furthermore, once released, subjects need to be monitored more closely and for a longer period of time to determine if relapse rate remains low. Other medications prior to release, besides XR-NTX, should also be considered in future analyses.

Most importantly, this study is an example of how treating addiction as a medical disease that requires medical treatments can actually help addicts to stay off of drugs, and hopefully, out of prison.

 

New Review Paper-The Prescription Opioid and Heroin Epidemic

(Image by Mark Weiss/Corbis)
(Image by Mark Weiss/Corbis)

A new paper published online in January 2015 by Kolodny et al. provides an overview of the epidemic of addiction to opioid prescription medications and heroin which is sweeping through the United States. Numerous news outlets from the Huffington Post to the New York Times have been covering this disturbing trend. This important review paper is being released at a critical time.

Kolodny et al TitleYou can find the complete article here.

The authors do an excellent job of outlining the epidemic from a public health perspective. I just wanted to summarize some of the paper’s main points and findings:

  • Abuse of prescription opioid pain relievers (OPR) and heroin is reaching epidemic levels
    • From 1999-2011, oxycodone (a common OPR) use has increased by 500%
    • From 1997-2011, there has been a 900% increase in individuals seeking treatment to for opioid addiction
    • From 2004-2011, there has been a doubling in ER visits due to non-medical use of OPR
    • The author’s highlight that there is a disturbing correlation between the rise in opioid sales, opioid overdose deaths, and opioid addiction (See the figure below)
(Figure 1 from Kolodny et al. 2015)
(Figure 1 from Kolodny et al. 2015)
  • The authors contend that the cause of our current epidemic is rooted in:
    • The development of new opioid medications such as OxyContin (an extended release form of oxycodone introduced in 1995)
    • The over-prescription of OPR coupled with a shift in medical attitudes towards the treatment of chronic pain
    • A series of studies suggesting that long-term opioid use does not result in addiction. We now know this to be false.
      • According to a recent study, 25% of chronic pain patients treated with OPR fit criteria for opioid addiction and 35% for opioid abuse disorder
  • The public health issues related to non-medical use of OPR are significant
    • Heroin use has drastically increased over the same period as OPR abuse
    • 4 out of 5 current heroin users report that their addiction began with abuse of OPR (See here for more information).
    • Overdose deaths and hospitalizations as a result of OPR have been strikingly high since 2002. See the graphs below.
(Figure 4 from Kolodny et al. 2015)
(Figure 4 from Kolodny et al. 2015)
  • Using an epidemiologic approach, the authors outline a prevention strategy for opioid addiction broken down into primary, secondary, and tertiary interventions.
    • Primary prevention
      • Reduce the incidence of the disease condition: opioid addiction (ie prevent new addiction cases)
      • Education of prescribers regarding OPR use
        • The risks of chronic OPR use, such as addiction and respiratory depression (difficulty breathing), are high
        • Little data exists for the effectiveness of long-term OPR use in helping chronic pain patients
      • Substitution of OPR for non-opioid pain relievers must be strongly encouraged
      • Prevention of OPR use amongst adolescents
        • Caution in OPR prescribing
          • Most youths that experiment with them get OPR from family or friends who have an OPR prescription
        • Change the perception that OPR use is less risky than heroin use
          • In reality the risk of addiction to OPR is as high as it is for heroin
    • Secondary Prevention
      • Identify and treat opioid addicts early in their disease
        • Identify users of OPR that are detected by prior to more significant health problems or transition to heroin use
        • Difficulty in diagnosing opioid addiction
          • Urine toxicology screens in some cases
          • Use of prescription drug monitoring programs (PDMPs) to identify patients who seek prescriptions from multiple doctors
    • Tertiary prevention
      • Treatment and rehabilitation of opioid addiction
        • The National Survey on Drug Use and Health (NSDUH) estimates 2.1 million Americans are addicted to OPR and 467,000 to heroin.
        • Combination of pharmacologic and psychosocial treatments
          • Psychosocial therapies (residential treatment centers, mutual-help programs, 12-step programs) can be effective for some patients but should be use in combination with pharmacologic treaments
        • Pharmacologic treatments such as methadone and buprenorphine (Suboxone) are safe and highly effective
          • They work by effectively blocking cravings without causing the “high” the OPR and heroin cause
          • However, fewer than 1 million addicts are receiving these treatments
          • Significant federal limitations exist to buprenorphine prescription
            • See my Post on this topic, which links to an important Huffington Post article on the topic
        • Harm-reduction approaches
          • Needle-exchange programs to reduce HIV transmission
          • Naloxone for treatment of overdose deaths
    • Conclusions
      • Prescription opioid and heroin addiction are reaching epidemic levels in the United States
      • A coordinated public health effort of federal and state agencies, health care providers and insurers, treatment/recovery initiatives and the research community is required to deal with this crisis.

For more statistical information, consult the National Survey on Drug Use and Health.

Also, see the data section of the Substance Abuse and Mental Health Services (SAMSHA) for statistics related to non-medical use of OPR and heroin.