Response to the June 2017 New Yorker Article on the Opioid Epidemic

At this point, I would think that knowledge about the vastness and seriousness of the prescription opioid and heroin epidemic, the biggest threat to American health and well being since the HIV/AIDS epidemic, would be common knowledge. Of course, given the abundance of shiny Internet things to tantalize easily distracted Americans, this is unfortunately not necessarily the case. Thankfully the New Yorker, with their characteristic excellence in reporting, has just released a superb and humanizing article on the opioid epidemic in their June 5 & 12, 2017 issue.

Read the article here.

The piece puts a much-needed human face to the horrors and misery of opioid addiction and the too-frequent death by overdose. Margaret Talbot, the article’s author, zeroes in on Berkeley County, West Virginia, in the heart of a region of the country hardest hit by the epidemic. I don’t want to give away much (because you should actually just read the article) except that the stories are heart wrenching yet balanced, and thorough in way that only the New Yorker can deliver. While the article is largely about the lives of people affected by and fighting against the epidemic, I was disappointed with a couple of points that were either made incorrectly, weakly, or not at all.

First, the article barely talks about how the epidemic arose in the first place. It mentions Purdue pharmaceuticals, the bastards behind Oxycontin (drug name: oxycodone), and that prescription opioid abuse led to heroin addiction but does not describe how the surge in addiction to prescription opioids occurred in the first place. The article describes the main problem with Oxycontin is that it can be crushed and snorted but a 2010 formulation of the drug reduced this risk. While this is indeed true, the article neglects to mention that when someone is first prescribed an opioid like Oxycontin for chronic pain (as was the case in the late 90s and early 2000s despite any evidence for the effectiveness of opioids in the treatment of chronic pain), the addictive potential of opioids often led to opioid substance abuse disorder in people who took it as prescribed (see this comprehensive article for more info). This is the big point, many of the people that eventually abused opioids started down that road by taking the drug as prescribed! Talbot incorrectly frames the big picture problem but she then goes on to correctly describe how those addicted to prescription opioids found their way to the cheaper and more abundant heroin.

The article goes on to mention the CDC’s release of guidelines on opioid prescription but fails to cite that this guidance came out as late as March, 2016, well after the epidemic had already taken root and thousands were already addicted and dying of overdose (I wrote an article on the CDC’s guidelines last year and highly recommend you read that article too if you want to learn more). The CDC’s guidance is mainly about the point I made above, that the over-prescription of opioids is the real cause of the epidemic, not just the crushable version of Oxycontin, and the limitation of opioid prescription is one of the huge policy interventions that is needed.

Later in the article, Talbot introduces us to Dr. John Aldis, a retired U.S. Navy Physician and resident of Berkeley County, WV who took it upon himself to educate people on how to use Narcan (generic drug name: naloxone), the treatment for opioid overdose. Dr. Aldis makes the critical point about the importance of medication-assisted treatments such as Suboxone (generic drug name: buprenorphine) and methadone. I appreciated the point made in the article that some patients may need these vital treatments long-term, or even for life, to combat the all-consuming single-mindedness of opioid addiction. However, beyond this passing mention, I felt that medication-assisted treatment was only weakly covered. There is still a great deal of ignorance about these treatments. Indeed, current HHS secretary Tom Price falsely characterized them as “replacing one opioid with another” and was majorly criticized by addiction experts. The reality is that there is overwhelming scientific evidence (I’ve written plenty on this site) describing the effectiveness of methadone and buprenorphine at 1) keeping addicts off of heroin, 2) allowing them to be able to live their lives without suffering from withdrawals and cravings, and 3) most importantly, keeping them alive. Talbot could have done a much better job of really hammering these points home but she seemed reticent, for some reason, to discuss it in detail in this article.

Finally, the article repeatedly emphasizes the importance of rehab clinics and tells the story of a huge victory for Martinsburg, WV (a town in Berkeley County) when the city council agrees to open a clinic in the town itself. I do not want to discount the importance of an addict assessing their addiction and taking an active role to end it, but this article does miss another critical point: rehab clinics only exist because addiction medicine is not part of medical school curricula and most hospitals are ill-equipped to treat those suffering from addiction. I feel this article could have really made the case for the importance of training for doctors in addiction medicine and the necessary shift that needs to happen for addiction treatment, a move away from overpriced (and often ineffective) private rehab facilities, and to public hospitals. Unfortunately, this point was not made.

Despite these missed opportunities, I commend Talbot and the New Yorker for a well-written article and thank them for this important piece that I encourage all to read.

 

5 Facts on the Opioid Epidemic: National Drug and Alcohol Facts Week

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

Well, I’m a little late to the punch on this one but National Drug and Alcohol Facts week has been going and ends tonight. This public awareness campaign is now in it’s seventh year and is all about shattering the myths about addiction.ndafw_logoI might as well throw my belated hat in the ring and share 5 facts about the opioid epidemic.

Fact #1: The opioid epidemic in the U.S. has hit all demographic groups, regardless of race, gender, age, location, or socioeconomic status.

Fact #2: Prescription opioid pain medications like oxycodone can be just as addictive as heroin, even if taken as prescribed.

Fact #3: There is no scientific evidence that prescription opioids are effective at managing chronic pain; they are extremely effect for short-term, acute pain.

Naloxone_(1)Fact #4: Naloxone is a drug that counters the effects of opioids and can immediately reverse an overdose; you cannot get addicted to naloxone.

Fact #5: Buprenorphine and methadone are opioids that can help a person to fight their heroin addiction by satisfying their craving for the drug.

To learn more, here’s a short “Best of” from Dr. Simon Says Science on the Opioid Epidemic. Check out the posts below for oodles of info on opioids.

  1. What is naloxone? Should it be available over the counter?
  2. The CDC Fights Back Against the Opioid Epidemic
  3. Is Methadone an Effective Treatment for Heroin Addiction? YES!
  4. Morphine and Oxycodone Affect the Brain Differently
  5. Important: CDC Releases Report on Heroin Epidemic
  6. Methadone Maintenance Therapy Works-End of Story
  7. Paper Review-Initiation into Injection Drug Use and Prescription Opioids
  8. New Review Paper-The Prescription Opioid and Heroin Epidemic

 

The CDC Fights Back Against the Opioid Epidemic

2000px-US_CDC_logo.svg

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.)

Morphine and Oxycodone Affect the Brain Differently

(Neurons. Image from Ana Milosevic, Rockefeller University)
(Neurons. Image from Ana Milosevic, Rockefeller University)

Why are some drugs of abuse more addictive than others?

 This is a central question to the addiction field yet it remains largely a mystery. All drugs of abuse have a similar effect on the brain: they all result in increased amounts of the neurotransmitter dopamine (DA) in an important brain region called the mesolimbic pathway (also known as the reward pathway). One of the core components of this pathway is the ventral tegmental area (VTA), which contains many neurons that make and release DA. VTA neurons communicate with neurons in the nucleus accumbens (NAc). This means that the axons of VTA neurons project to and synapse on NAc neurons. When VTA neurons are stimulated, they release DA onto the NAc, and this is a core component of how the brain perceives that something is pleasurable or “feels good.” Many types of pleasurable stimuli (food, sex, drugs, etc.) cause DA to be released from the VTA onto the NAc (See the yellow box in the diagram below). In fact, all drugs of abuse cause this release of DA from VTA neurons onto NAc neurons.

*Important note: many other brain regions are involved in how the brain perceives the pleasurable feelings of drugs besides the VTA and NAc, but these regions represent the core of the pathway.

"Dopamineseratonin". Licensed under Public Domain via Wikipedia.
“Dopamineseratonin”. Licensed under Public Domain via Wikipedia.

Check out these videos for a more detailed discussion of the mesolimbic pathway.

But if all drugs of abuse cause DA release, then why do different drugs make you feel differently? This is a very complicated question but one component of the answer is that different drugs have different mechanisms and dynamics of DA release.

For the opioid drugs like heroin, morphine, and oxycodone, they are able to bind to a special molecule called the Mu Opioid Receptor (MOPR). This action on the MOPR results in an indirect activation of DA neurons in the VTA and a release of DA in the NAc. While all opioid drugs reduce the feeling of pain and induce a pleasurable feeling, they have slightly different properties at the MOPR.

The different properties of the opioids may be a reason why some are more abused than others. For example, a number of studies have suggested that oxycodone may have greater abuse potential than morphine. This means that oxycodone is more likely to be abused morphine.

But do the different properties of morphine and oxycodone on the MOPR affect DA release and is this important to why oxycodone is more likely to be abused than morphine?

Vander Weele et al. 2015 titleThis is the question that scientists at the University of Michigan sought to address. Using several different sophisticated techniques, the scientists looked at differences in DA release in the NAc caused by morphine and oxycodone, two common opioid drugs.

Rats were injected with either morphine or oxycodone and then DA release was measured using either fast-scan cyclic voltammetry or microdialysis. I’ve discussed microdialysis in a previous post but in brief, it involves drawing fluid from a particular brain region at different time points in an experiment and then measuring the neurotransmitters present (using advanced chemistry tools that I won’t explain here).

Voltammetry is a more technically complicated technique. In brief, it uses electrodes to measure sensitive voltage changes. Since a molecule has specific electrochemical properties, these voltage changes can be related back to a specific molecule, such as the neurotransmitter DA as in this study. Voltammetry may even allow greater temporal resolution (easier to detect very precise changes at very short time frames, like seconds), which may make it more accurate than microdialysis (which can only measure neurotransmitter release on the scale of minutes).

Because each technology has its own limitations and potential problems, the authors used both of these techniques to show that they are observing the same changes regardless of the technology being used. Showing the same observation multiple times but in different ways is a common practice in scientific papers: it increases your confidence that your experiment is actually working and what you are observing is real and not just some random fluke.

The authors administered a single dose of either morphine or oxycodone to rats and then measured the DA release in the NAc as described above. What they found were very different patterns!

Morphine resulted in a rapid increase in DA (less than 30 seconds) but by 60 seconds had returned to normal. In contrast, oxycodone took longer to rise (about 20-30 sec before a significant increase was detected) but remained high for the entire 2 minutes that it was measured. The difference in DA release caused by morphine and oxycodone is striking!

Many other changes were observed such as differences in DA release in different sub-regions of the NAc, different effects on phasic release of DA (DA is often released in bursts), and differences in the other neurotransmitters such as GABA (morphine caused an increase in GABA release too while oxycodone did not). I won’t discuss these details here but check out the paper for more details.

Of course, do these differences in DA release explain why oxycodone is more often abused than morphine? Unfortunately no, there are many other factors (for example, oxycodone is more widely available than morphine) to consider. Nevertheless, this is some intriguing neuroscientific evidence that adds one more piece to the addiction puzzle.

Paper Review-Initiation into Injection Drug Use and Prescription Opioids

Lankenau SE, 2012

It’s been a few weeks since my last post. Apologies! Just finished up a big experiment and grant proposal. My goal is to release a few small posts over the next few days and here’s the first:

Numerous reported the dramatic increase in opioid addiction and death’s due to overdose over the past decade. Abuse of prescription opioid pain medication, such as oxycodone and hydrocodone, has skyrocketed. Even more disturbing is the surge in addiction to heroin, which was in decline during the 80s and 90s. I already reviewed an article that cites some of the statistics. Read it here.

Some key facts cited in today’s paper:

  • Abuse of prescription opioid drugs has been increasing dramatically over the past decade, especially amongst young people (18-26)
  • Opioids, such as hydrocodone and oxycodone, are the second most abused drug amongst young adults, after cannabis.
  • Very little data exists on initiation of drug abuse (i.e. first drugs abused) among injection drug users.

This study is a epidemiology/public health study that recruited 50 young (under 30), active injection drug users (e.g. heroin users) from New York and Los Angeles and interviewed them about their drug use. Note that this is a small study as far as epidemiology studies go, and the authors admit this and describe it as an exploratory study, but the trends they find are consistent with other studies (see the National Survey on Drug Use and Health).

The conclusions are simple: the majority of injection drug users began by abusing prescription opioids.

The average age for first use of prescription opioids was 12.6 years old and 41/50 reported swallowing (compared to 8 that snorted or 1 injecting). And 30/50 reported getting the prescription opioids from the homes of either immediate or extended family members that had a prescription.

Even more disturbing is that 36/50 injection drug users reported having a prescription for opioid pain medications during their lifetime, which occurred on average at 14.6 years of age. 8 of these 36 reported their opioid abuse began from their own prescriptions.

Several other interesting trends can be found in this study but the conclusions are pretty stark: injection of heroin began with abuse of pain pills.

Clearly tighter control of available prescriptions and careful monitoring of prescription opioids is required to help control their abuse among adolescents. However, the specific policy recommendations and medical attitude changes necessary are complex. Hopefully the more knowledge about the topic will provide an impetus for this important and necessary discussion.

The Scientist’s Toolbox: Techniques in Addiction Research, Part 1

Lab Mice IMG_4102
(Image © Derek Simon 2015)

One of the most important questions that every scientist learns to ask is “How do you know that…?” As scientists, we are trained to be skeptical. When we consider a bit of research done by a colleague, before we are inclined to believe the data,  we need to be sure that they conducted the right experiments and that those experiments were done correctly. This doesn’t mean that scientists are stubborn or closed-minded. The reality is quite the opposite. Scientists are ready to incorporate new ideas and new results but first we need to know that the data are real. That’s what being a skeptic is all about: reserving judgment until you know all the facts.

The question “How do you know that..?” is one of the intellectual tools we use when considering whether or not data are real or not. This question has two parts: 1) how do you measure the thing that you interested in and 2) how do you know the effect you are seeing is actually based on what you think it is? What type of comparisons do you need to make in order to test the effect you’re interested in?

The first point of the question relies on special tools, equipment/technology, and experimental setups that are used to take measurements. For example, if you want to know how much a mouse likes taking a drug, then you need a way to measure how much drug it takes and how often it takes the drug (more on this in a bit). Today, I’ll go over a few of the tools that we use in addiction research.

The second part is more important (and more difficult to explain) but is really at the heart of the scientific method. It is all about experimental design and making sure you make the proper comparisons and analyses. I won’t discuss these details any more right now but will save this discussion for a future post.

Instead, let’s take a look at a few of the tools a scientist studying drug addiction has in his/her toolbox.

Locomotor Activity Test

The psychostimulants amphetamine and cocaine act in very similar ways and have very similar effects on the brain. We know that stimulants sort of “amp you up” or make you feel like you have more energy. Think of how you feel after drinking too much coffee. And what do you do when you have more energy? You tend to move around more (maybe you feel a little twitchy/antsy after too much of that coffee…). The same thing happens to mice and rats.

Locomotor Activity Test Chamber with a mouse. Image from UC-Davis Mind Institute (http://www.ucdmc.ucdavis.edu/mindinstitute/).
Locomotor Activity Test Chamber with a mouse. Image from UC-Davis Mind Institute (http://www.ucdmc.ucdavis.edu/mindinstitute/).

We can measure the amount of movement using a locomotor activity test. This test uses a special piece of equipment that uses light beams and a light-sensitive detector. Whenever the animal moves around the test box, the light beams are broken and the detector records that information. One way to analyze the data is by simply plotting beam-breaks (photo-cell counts are the same thing) that occur over the time of the test period. This way you have a measure of how much the animal moves around in a certain amount of time (more beam-breaks/time unit equals greater movement). A more sophisticated analysis of this same data can actually give you information on where in the box the animal spends its time. Does is just pace back and forth in a small area of the box or does it explore the entire chamber? This type of exploratory behavior data is valuable information and can be useful to other fields that may or may not study drug addiction. The general test for this exploratory behavioral analysis, regardless of speed of the movement caused by drugs, is the open field test.

 

Multiple test boxes with a computer that collects the data. Image from Douglas Mental Health Institute (http://www.douglas.qc.ca/page/neurophenotyping-motor-function).
Multiple test boxes with a computer that collects the data. Image from Douglas Mental Health Institute (http://www.douglas.qc.ca/page/neurophenotyping-motor-function).

An interesting phenomenon has been identified with psychostimulants. If you give an animal an injection of cocaine it will move around more compared to regular animals. But if you give it another dose of cocaine the next day it will move around even more than it did on the first day. This is called locomotor sensitization and is an important property of psychostimulants like amphetamine and cocaine.

The graphs below are real data that I took from a figure from one of our lab’s papers so you can see what locomotor sensitization looks like.

Cocaine-induced locomotor sensitization. Unterwald EM et al. J. Pharmacol. Expt. Ther. 1994.
Cocaine-induced locomotor sensitization. (Unterwald EM et al. J. Pharmacol. Expt. Ther. 1994.)

It’s a little hard to read but there are two groups of animals: one that receives cocaine injections (the top line) and the other that receives saline injections (the bottom line). Saline is a saltwater solution that is a standard control solution that has no biological effects. Each data point represents an average of several animals from each group. The baseline graph shows the locomotor activity before injections (no differences). As you can see, at day 1 the cocaine animals are already moving more than the saline group. This increase in movement continues over the 14 days of the experiment, evidence of locomotor sensitization.

This video shows an analysis of locomotor activity using video tracking software instead of light-beam breaks.

Self-Administration

Locomotor activity is all good and well but not all drugs of abuse cause locomotor sensitization. More directly related to addiction in humans, how do we even know if the animal likes the drug or wants to take the drug? Humans addicts crave the drug and compulsively use it, meaning the desire to do the of the drug overpowers the addict’s self-control. Is there a way we can study this type of drug-taking behavior in animals? The answer is yes!

Self-administration is a very versatile and powerful technique used throughout the addiction field. This technique allows the animal to control whenever it takes the drug and however much it wants. We can study many different aspect of drug taking using self-administration.

A diagram for a typical self-administration chamber. Image from Med Associates (http://www.med-associates.com/).
A diagram for a typical self-administration chamber. Image from Med Associates (http://www.med-associates.com/).

 

The basic idea is is simple: The rodent (mouse or rat) is placed in a chamber and presented with two levers. If the mouse the presses one lever (the active lever) it receives a dose of drug but if it presses the other lever (inactive lever) it does not. The self-administration sessions are run for a set period of time and the number of presses is recorded for each lever. Over the course of several days the animal steadily increases the amount of lever presses, thus the amount of drug it takes. Meaning the animal learns how to take drug and then takes more and more of it. Just like a human addict would do!

Alternatively, the mouse can poke its nose at a special hole that acts just like the active lever. I’ll use “lever press” and “nose poke” interchangeably because they essentially mean the same thing.

Here’s a little cartoon I found on YouTube of a rat that is self-administering nicotine.

 

Here’s another video that shows a real mouse self-administering a natural reward (meaning not a drug of abuse but food in this case).

 

There are several important variations to this basic idea that help scientists to not only make the experiments easier to control and data better/easier to analyze, but allow different aspects of drug taking to be studied.

For example if you are studying alcohol addiction, then when the mouse presses the lever a spout may appear that allows the animal to drink the alcohol (the inactive lever produces a bottle of water only). This is perfect for testing alcohol self-administration because both humans and mice drink alcohol. But what if you want to study heroin or cocaine self-administration? Humans (nor mice) drink or eat these drugs. So how does the drug get delivered to the mouse when it presses the lever?

The answer is intravenous self-administration. In this version, a small surgery is performed where a small tube (a cathether) is threaded into the jugular vein of the animal. This tube is fixed to the mouse back and attached to another tube that is part of the self-administration apparatus. This time when the mouse hits the lever, a dose of drug is pumped directly into its vein! See the diagram and videos above for more details.

Intravenous self-administration has several advantages.

  • As explained above, it allows us to deliver drugs to animals that won’t take them orally.
  • It allows the drug to act immediately on the animal because the drug is being delivered directly into the bloodstream.
  • It allows us to control the dose of the drug. When the mouse hits the lever (or nose pokes) it receives a fixed amount of drug that the scientist decides on ahead of time. That way we know how much total drug the mouse takes during a single self-administration session.
  • There is no variability in whether the animal is receiving the full dose or not. For example, if the lever press results in a food pellet, there is no guarantee the animal will eat the whole thing. But if you set the self-administration apparatus to deliver 0.5mg of heroin every time the lever is pressed, then there is no doubt if the full 0.5mg dose is delivered to mouse ever time.

Warning: not for the squeamish! This video shows you how to do the catheter implantation surgery on a mouse that will be used for intravenous self-administration!

Finally, best of all, self-ad can be used to address many different types of questions related to different stages in the addiction cycle. Here I briefly describe some of the more common experimental questions and applications that self-ad can help to address.

  • Initial use and escalation of use. How much will the animal take when it is first exposed to the drug? Will the animal reach a ceiling in the amount of drug it will take in a single session?
  • Maintenance of drug taking. One cool variation is you can make it more difficult for the animal to get the same dose of drug. This is called a progressive ratio self-administration. For example, the animal may need to press the lever 5 times before it receives a dose. You can keep increasing the number of presses during each session to see how hard the animal will work for a dose. One way this experiment can be interpreted is how badly does the animal want the drug? Some animals will press the lever many, many times just to get a small dose. This type of behavior is similar to the intense cravings that human addicts can experience.
  • Extinction and Relapse. You can run a special type of experiment where you run a self-administration experiment like normal and then change it so that the active lever no longer gives the animal a dose of drug. Eventually, the animal presses the lever less and less as it learns that it will no longer get the drug. This is called extinction of self-administration. This is like being in a rehab clinic where you are prevented from taking the drug. However, after the extinction sessions, if the scientist gives the animal another does of drug this will causes animal to start pressing the lever at high rates again. This a called reinstatement of self-administration and is model of relapse. What other types of conditions or factors can cause reinstatement (relapse behavior)? This situation is just like an abstinent cocaine addict who may not be craving cocaine but if he/she takes even a single hit, this can be sufficient for that person to sink back into full-blown addiction.

Let’s take a look at some real data. The graph below is from a paper from our group that looks at oxycodone self-administration in mice.

Oxycodone self-administration by adult and adolescent mice. (Zhang Y et al. Neuropsychopharmacol. 2009.)
Oxycodone self-administration by adult and adolescent mice. (Zhang Y et al. Neuropsychopharmacol. 2009.)

 

This study is interested in comparing oxycodone self-administration between adult mice and adolescent mice. As you can see, the number of nose pokes at the active hole (remember, same thing as a lever presses) increases during the course of the experiment (don’t worry about FR1 vs FR3) while the inactive hole is ignored, because it does not result in drug administration. Note that the nose pokes are plotted over the time of the administration sessions (2 hours) and that 9 sessions are run (one every day).

Microdialysis

The types of experiments I’ve described so far are great ways of studies addictive behaviors but they don’t really tell you about what’s going on in the brain. These behavior experiments are useful in themselves but they are much more powerful if they can be combined with another type of experiment that gives you a window into what’s changing in the brain at the same time as the behaviors.

In my post Synapse to it, I described how neurotransmitters are released by the pre-synaptic neurons into the synaptic cleft so that they can act on receptors located on the post-synaptic neuron. Using microdialysis, you can sample the fluid that exists in the synaptic cleft and actually measure the amount of neurotransmitters being released!

This is an extremely difficult and very technically complicated technique and I will only go into the basics about it. First, the microdialysis probe is surgically placed into a region of the brain that you are interested in studying.

The microdialysis probe itself is like a very thin piece of tubing that allows the experimenter to flow fluid into it one side(inlet) and collect the fluid that flows out of the other side (outlet). At the tip of the probe (the part that’s actually inside the brain) is a special type of material that allows fluid from inside the brain to flow into the tubing (a semi-permeable membrane).

Schematic of a microdialysis probe. Image from Wikipedia.
Schematic of a microdialysis probe. Image from Wikipedia.

After the surgery, you run your behavioral experiment, and while you are doing that you start flowing fluid into the brain. The fluid that the microdialysis probe flows in is of a similar consistency to the fluid that exists naturally in the brain. As the fluid inside the probe moves through the tubing, it causes fluids in the brain to enter into the probe and through the tubing where it can be collected when it flows out of the tubing.

Let’s say you give an animal a drug that causes a neurotransmitter to be released in the brain region you are interested in. Then some of those released neurotransmitters will enter the microdialysis probe because some of the fluid that enters the probe is from the synaptic cleft.

You keep collecting fluid at different time points during your experiment. When the experiment is over, then you can use chemistry to determine what neurotransmitters are in the fluid you collected. Best of all, you can determine how much of those neurotransmitters you have! How you do actually use chemistry to do this is a very technical part of the procedure and is not important to this discussion.

And all that work gives you a nice graph of the neurotransmitters that are released at different times during your experiment.

Now for some real data. Below are figures from a paper that our lab produced that uses microdialysis to study release of the neurotransmitter dopamine.

Evidence of probe placement in the Caudate  Putamen. (Zhang Y et al. Brain Res. 2001.)
Evidence of probe placement in the caudate putamen. (Zhang Y et al. Brain Res. 2001.)

 

Cocaine-induced increase in DA. (Zhang Y et al. Brain Res. 2001.)
Cocaine-induced increase in DA. (Zhang Y et al. Brain Res. 2001.)

 

In this study, the effect of cocaine on dopamine release in a region of the brain called the caudate putamen is being studied. The first image shows you that the microdialysis probe was placed in the right area of the brain (the white line that pierces through the dark area is the tract in the caudate putamen). The graph shows that injection of cocaine (the arrows) causes an increase in dopamine release in this brain region. Interestingly, the dopamine levels have returned to normal by the end of the experiment. Note: C57Bl/6J is the strain of mouse used in this study.

These are just three of the techniques that are used in addiction research. But we scientists have very big toolboxes! I’ll to explain some more in a later post.

Feel free to contact me or comment if you have questions!

Thanks for reading 🙂