One of the great questions in the addiction field is why do some people become full-blown addicts while other people can use drugs occasionally without progressing to anything more serious? One part the answer definitely has to do with the drug itself. For example, heroin causes a more intensely pleasurable high than cocaine and people that try heroin are more likely to become addicted to it than cocaine. But that’s not the whole story.

I’ve written previously about how a negative, stressful environment can have long-lasting negative impacts on the development of a child’s brain (also known as early-life stress of ELS). ELS such as childhood abuse (physical or sexual) and neglect can increase the risk for a whole host of problems as an adult such as depression, bipolar disorder, PTSD, and of course drug and alcohol abuse. There’s even a risk for more physical ailments like obesity, migraines, cardiovascular disease, diabetes, and more.

Childhood abuse/neglect = psychological and physical problems as an adult.

This idea doesn’t sound too controversial but believe it or not, the idea that a bad or stressful situation as a child would do anything to you as an adult was laughed away as not possible. It’s only within the last decade or so that a wealth of research has supported this idea that ELS can physically change the brain and that these changes can last through the abused child’s entire life.

This recent review paper (published in the journal Neuron) is an excellent, albeit technical, summary of dozens research papers done on this subject and the underlying biology behind their findings.

I especially love the quotes the author included at the beginning of the article:

And even more recently, yet another research paper has come out that highlights how important childhood is for the development of the brain and how a stressful childhood environment can impact the function of a person as an adult.

This most recent report, published in the journal Neuropscyhopharmacology concludes that early childhood abuse affects male and females differently. That is to say that the physical changes that occur in the brain are distinct for men and women who were abused as children.

Studies like this one are done by examining the brains of adults who were abused as kids and then comparing the activity or structure of different parts of the brain to the brains of adults who were not abused. The general technique of examining the structure or activity of the brain in a living human being is called neuroimaging and includes a range of techniques such as MRI, PET, fMRI, and others. (I’ve written about some of these techniques before. In fact, the development of better methods to image the brain is a huge are of research in the neuroscience field).

However, this study did not examine behavioral differences in the subjects, but as I said above, a great number of many other studies have looked at the psychological consequences of ELS. But this paper is really primarily interested in the gender differences in the brains of adults that have been abused as kids.

*Note: the following discussion is entirely my own and is not mentioned or alluded to by the author’s of this study at all.

This work—and the many studies that preceded it—has important implications because as a society, we have to realize that part of our personality/intelligence/character/etc. is determined by our genetics while the other part totally depends on the environment we are born into. I don’t want to extrapolate too much but the idea that childhood abuse can increase the risk of psychological problems as an adult also supports the broader notion that a great deal of a person’s success is determined by entirely random circumstances.

The science shows that a child born into a household rife with abuse will have more chance of suffering from a psychological problem (such as addiction) as an adult than someone who was born into a more stable life. The psychological problem could hurt that person’s ability to study in school or to hold down a job. And the tragic irony, of course, is that no child gets to choose the conditions under which they are born. A child, born completely without a choice of any kind over whether or not he or she will be abused, can still suffer the consequences of it (and blame for it) as an adult.

As a society, we often always blame a person’s failures as brought on by his or her own personal failings, but what if a person’s childhood plays an important role in why that person might have failed? How, as a society, do we incorporate this information into the idea of ourselves as having complete control over our minds and our destinies, when we very clearly do not? As an adult, how much of a person’s personality is really “their own problem” when research like this clearly show that ELS impacts a person well after the abuse has ended?

If the environment a child is born into has a tangible, physical effect on how the brain functions as an adult, than this problem is more than a social or an economic one: this is a matter of public health. Studies that support findings such as these provide empirical significance for public policy and public services for child care such as universal pre-K, increased availability of daycare, health insurance/medical access for children, increased and equitable funding for all public schools regardless of the economic situation of the district that school happens to be located in, etc.

One of our goals as a society (if indeed we believe ourselves to be a functioning society…the success of Donald Trump’s candidacy raises some serious doubts…but I digress) is the improvement of the lives of ALL of our citizens and securing the prosperity of the society for future generations. Reducing childhood poverty and abuse quite literally could help secure the future generations themselves and improve the ability of any child to grow up to become a successful and productive adult.

Public programs are essential because the unfortunate reality for many people born into poverty is that they must work all the time at low paying jobs in order to simply survive and may not be able to give their children all the advantages of a wealthier family. And this is where government and public policy step in, to correct the imbalances and unfairness inherent to the randomness of life and level the playing field for all peoples. Of course, the specific programs and policies to reduce childhood poverty and abuse would need to be evaluated empirically themselves to guarantee an important improvement in development of the brain and health of the child when he/she grows up.

And this is the real power of neuroscience and basic scientific research papers like this one. Research into how our brains operate in real-life situations reveal a side of our minds and our personalities that we never may have considered before and the huge implications this can have for society. The brain is a complex machine and just like other machines it can be broken.

Of course, we shouldn’t extrapolate too much and say that, for example, a drug addict who was abused as a child is not responsible for anything they’ve ever done in between. But is important to recognize all the mitigating factors at play in a person’s success and simply dismiss someone’s problems as “their own personal responsibility.” As a neuroscientist, I might argue that that phrase and the issues behind it are way more nuanced than the how certain politicians like to use it.

Special endnote Due to some recent shifts in my career, Dr. Simon Says Science will be expanding the content that I write about. Addiction and neuroscience will still be prominently featured but I plan to delve into a variety of other topics that I find interesting and sharing opinions that I think are important. I hope you will enjoy the changes! Thanks very much!

 

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.

Of 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 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?

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.

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.

2. 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.

3. Morgan CJ, et al. Ketamine use: a review. Addiction. 2012;107(1):27-38.

4. 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.

5. 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.

6. Abdallah CG, et al. Ketamine’s Mechanism of Action: A Path to Rapid-Acting Antidepressants. Depression and anxiety. 2016.

 

New blog post for addictionblog on naloxone, an antidote for opioid overdoses.

Read my post at addictionblog here!

 

 

Check out my new post for addictionblog!

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.

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).

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.)

NEW BLOG POST FOR ADDICTIONBLOG IS UP NOW! ALL ABOUT METHADONE.

CHECK IT OUT!

A new review article published in the prestigious New England Journal of Medicine highlights the importance of treatment of addiction as a medical disease and calls for a change in public health policy towards addiction. Written by several leaders in the addiction field including Nora Volkow, MD, the director of NIDA, and George Koob, PhD, the director of NIAAA, the article does a superb job at outlining the underlying biology of addiction and clearly explains why addiction is a disease of the brain that needs to be treated medically.

Read the full article here.

In fact, I also covered most of the points made in the article in my own post for Addiction Blog on “Why Addiction is a Brain Disease?”

However, when it comes to public health policy towards addiction, this is where the article fell short. While treatments for opioid addiction such as methadone and buprenorphine were briefly mentioned in the article, there was no call for a national effort to be made to increase access to these vital medications. The authors had a potential to increase awareness of the opioid epidemic and the treatments already on hand to fight it but failed to make a stronger case for this critical improvement.

Nevertheless, the article is well written and a great introduction to the neuroscience of addiction and why it is a disease of the brain.

I started as a contributor for the blog network addictionblog.org.

Read my first post, published today!

WHY IS ADDICTION A BRAIN DISEASE?

After alcohol, marijuana is the most widely used illegal drug in the United States (I mean seriously, who hasn’t smoked up at least once? According to Pew Research Center, half of the country) But pot laws are rapidly changing in many parts of the country and soon it may be as ubiquitous as alcohol. Four states in the US have legalized marijuana for recreational use and 23 total states have some form of legal marijuana use (including D.C.). While the health effects of alcohol have been well studied and are significant (some 88,000 deaths/year, the third highest cause of preventable death in the US, according to the CDC and NIAAA), little is known how this shifting trend in marijuana use will affect the country. Another important trend is the amount of THC (Δ-9-tetrohydrocannabinol, the chemical that is primarily responsible for the psychoactive effects of marijuana) in marijuana strains has been steadily increasing over the past few decades [1, 2]. The big question that researchers are asking themselves is if legal marijuana use drastically increases, what are the long-term personal and public health consequences of marijuana use? Of course, this is a huge question with many complexities.

Significantly, Marijuana is the also the most widely used illegal substance amongst youths. Adolescence (ages 12-17) is an extremely critical period for brain development [3, 4] yet the effects of marijuana on the brains of kids have not been thoroughly studied. A recent paper out of Dr. Steven R. Laviolette’s laboratory at the University of Ontario sought to answer this question: what happens to brains of adolescent and adult rats that have been exposed to THC?

Why was the research done? What is the hypothesis?

 There have been a number of studies published that suggest there might be an association between prolonged marijuana use (especially of high-potency strains) and schizophrenic-like or psychotic-like symptoms [5, 6] although there is disagreement in the scientific community on the evidence [7, 8] (I may write a blog post discussing this issue in the future). It is has even been suggested that youths that smoke marijuana are more at risk for psychotic symptoms as adults [9, 10]. The author’s sought to test this directly by injecting adolescent and adult rats with THC for a number of days, waiting a period of time after the injections, then measuring the long-term effects on the rats. The team hypothesized THC would have induced long-term changes in the brains of adolescent but not adults rats, and subsequent changes in psychotic-like behavior.

How was it done?

Adolescent and adult rats were injected with THC twice daily for 11 days. The dose of THC administered was increased (escalating dose) to account for any tolerance that may occur. As an important control, separate groups of adolescent and adult rats were injected with vehicle (the solution that THC was dissolved in but minus the THC itself). Following a 30-day abstinence period after the last injection, THC-adolescent, control-adolescent, THC-adult, and control-adult rat groups were subjected to number of behavioral and molecular tests to see what effect the drug had on the animals. I need to point out that the 30-day abstinence period is significant in the rat life-span. This is enough time for the adolescent rats to become adults so what the scientists are primarily studying is the long-term effects of THC on adolescents vs adults in adulthood.

In the behavioral neuroscience field, we have devised another of tests to measure various aspects of animal behavior. Obviously we can’t inject humans with THC and see what happens so we have to use rodents and identify behaviors that approximate a similar behavior in humans. Of course, rodent behavior is no where near as complex as humans but rats are remarkably sophisticated animals (ask anyone living in New York) and scientists have developed a number of ways to measure things from motivation to social behavior to anxiety to depression.

In this experiment, a social test was used, two different types of anxiety tests and a motor activity test. The tests measured effects on motivation, exploratory-behavior (another indicator of how motivated rats are), social interaction, and anxiety.

The scientists also measured the activity of dopamine-releasing neurons in the living animal using a technique called in vivo electrophysiology. Recall from my post I am Neuron! that when activated, brain cells (called neurons) conduct an electrical current that results in the release of neurotransmitters onto another neuron. This electrical current is called an action potential and we can measure this by inserting a special probe into the those neurons in the animals brain (the probe measures electrical currents). Therefore, with in vivo electrophysiology we can measure every time a neuron fires (i.e. an action potential is generated) in a specific part of the brain. Using this technique, the scientists measured dopamine neurons in an important region of the brain called the VTA and how often these neurons fire in THC vs control rats. Check out this video for more details on in vivo electrophysiology.

Finally, brains from animals were dissected and a number of protein molecules were studied using a common technique in molecular biology called a Western blot (or known as an immunoblot). A Western blot takes advantage of antibodies that are able to recognize and stick to one specific type of protein. Therefore, this assay can tell you two main things 1) if your protein of interest is present in your sample and 2) approximately how much of your protein there is compared to other samples. In this paper, tissue from a specific brain region is used and the protein is analyzed by Western blots in order to comparing quantities of proteins between the different experimental groups. Of course, the limitation of a Western blot is if you have a good antibody for your protein of interest. Luckily there are many biotech companies such as Cell Signaling that specialize in making and testing reliable antibodies. The scientists used the Western blots to study many proteins in a region of the brain called the prefrontal cortex (PFC), which is believed to be important in self-control and other high-function brain processes. Check out this video for more details on Western Blots.

What did they find?

THC-adolescent rats exhibited deficits in numerous behavioral experiments compared to controls while THC-adult rats did not appear to have any behavioral changes.

*Recall that these experiments were conducted 30 days after the last THC dose so the author’s show that these are long-term effects of THC on the brain of adolescent rats.

In the social activity test, rats showed little interest in interacting with a stranger rat (normal rats are usually curious about the novel stranger). THC-adolescents also did not walk around or explore a new cage as much. In the two different anxiety tests, THC-rats appeared to have be more anxious (demonstrated more anxiety-like behavior).

In the electrophysiology experiment, VTA DA neurons fired more frequently for some reason in THC-adolescents compared to the other groups.

Finally, numerous protein changes in the PFC were observed in a number of important signaling pathways such as Wnt and mTOR pathways. Interestingly, THC-adolescents vs THC-adults seemed to have opposite effects on this proteins.

Limitations to the study?

1.  The behavioral changes observed were statistically significant (meaning, most likely a real effect and not some kind of fluke of random chance) but were modest changes in some of the tests performed. Would the changes last beyond the 30 days post injection in this study?
2. There are impressive arrays of behavioral tests that rats can perform to measure numerous aspects of cognition (for example, memory and learning) but none of these experiments were performed. A far greater range of behavioral experiments would have made this study more compelling.
3. While the electrophysiology and Western blot data are intriguing, the author’s performed no experiments to determine if these changes are responsible for the difference in behavior (association vs causation). These changes could merely be an incidental change and have nothing to do with the behaviors studies.
4. The doses that the mice were injected with, while based on a previous study, are somewhat arbitrary. Would the changes be more pronounced or less pronounced with higher/lower doses or a shorter/longer dosing regimen?
5. Only male rats were studied. Would the same behavioral and molecular changes occur in female rats?

What does it mean?

Based on the behavioral and molecular data presented, this data paper suggests that adolescent rats (but not adults) exposed to THC have long-lasting changes in the brain. The author’s argue that these effects recapitulate schizophrenia-like symptoms but I am not entirely convinced. Also, THC given to rats is not the same thing as marijuana smoked by human teenagers. So it’s important to keep in mind that this is one study. In science, we never draw grand conclusions about anything based on one study. Nevertheless, several other reports have corroborated these findings (see this review paper for a summary of many of them [11]). Indeed, it does seem that marijuana use can cause long-term deficiencies in human and rodent brains. The results of this paper are certainly intriguing and, if true, a whole host of stricter regulations on marijuana use in states that have legalized it may need to put in place to help curb increasing marijuana abuse amongst youths.

References

1. Cascini F, et al. Increasing delta-9-tetrahydrocannabinol (Delta-9-THC) content in herbal cannabis over time: systematic review and meta-analysis. Current drug abuse reviews. 2012;5(1):32-40.

2. Mehmedic Z, et al. Potency trends of Delta9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. Journal of forensic sciences. 2010;55(5):1209-17.

3. Keshavan MS, et al. Changes in the adolescent brain and the pathophysiology of psychotic disorders. The lancet Psychiatry. 2014;1(7):549-58.

4. Spear LP. The adolescent brain and age-related behavioral manifestations. Neuroscience and biobehavioral reviews. 2000;24(4):417-63.

5. Arseneault L, et al. Causal association between cannabis and psychosis: examination of the evidence. The British journal of psychiatry : the journal of mental science. 2004;184:110-7.

6. Di Forti M, et al. Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users. Schizophrenia bulletin. 2014;40(6):1509-17.

7. Moore TH, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370(9584):319-28.

8. Gage SH, et al. Association Between Cannabis and Psychosis: Epidemiologic Evidence. Biological psychiatry. 2015.

9. Rubino T, Parolaro D. Long lasting consequences of cannabis exposure in adolescence. Molecular and cellular endocrinology. 2008;286(1-2 Suppl 1):S108-13.

10. Stefanis NC, et al. Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction. 2004;99(10):1333-41.

11. Renard J, et al. Long-term consequences of adolescent cannabinoid exposure in adult psychopathology. Frontiers in neuroscience. 2014;8:361.