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

JD Lee et al. 2015. Title

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

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

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

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

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

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

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

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

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

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

 

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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.

Stress and Addiction Part 3: Molecular Changes

Stress-BrainThis is part three on my series of posts looking at Stress and Addiction. To recap: we’ve seen that, in laboratory studies, stress increases susceptibility to drug addiction. Stress not only increases the self-administration of drugs in adult rats but stress during an early age can have a long-lasting effect on drug-taking behavior. Today, we’ll wrap up by looking at some molecular changes that might help to explain why this effect exists. I’ll conclude by addressing some questions that might have occurred during the course of this discussion.

Paper #1 Sorg 1991. Title

The first paper is examining the effects of stress and cocaine on dopamine. Dopamine is a very important neurotransmitter. All drugs of abuse cause increases in dopamine in an important region of the brain called the mesolimbic pathway. I will discuss this system in detail in the next post but for now don’t worry about the details. All you need to know is that drugs can increase dopamine.

Dopamine levels can be measured directly in the brain using the technique microdialysis (I discuss this technique in more detail in my post The Scientist’s Toolbox: Techniques in Addiction). In this first paper, the scientists use a type of stress called foot-shock stress. It is very similar to tail-pinch stress (see Part 1). The animals are placed on a grid that is connected to an electrical supply. The scientists administer a small amount of electric current to the grid, which gives the animals feet a little shock and stresses them out.

Figure 1.
Figure 1.

The microdialysis technique was used on rats that underwent foot shock stress in order to measure dopamine levels (in a region of the brain called the striatum) after the stress test. As you can see in the top graph of Figure 1, foot shock stress causes an immediate increase in the amount of dopamine released and this eventually returns to normal. The different symbols mean different stress intensity with the most intense stress represented as black squares. Interestingly, as you can see in the lower graph of Figure 1, a more intense foot shock (ie a more intense stress) causes more dopamine to be released.

Remember that I said that cocaine also causes dopamine release? So maybe stress makes cocaine feel better because it works together with cocaine to create a larger release in dopamine than cocaine would by itself. Next, the investigators decided to test this idea.

Sorg 1991. Figure 2
Figure 2.

In this experiment, mice were exposed to a weak foot-shock stress then given an injection of cocaine and the amount of dopamine released was measured. Figure 2 shows much more dopamine was released in the striatum in rats that received cocaine + stress (black squares) compared to cocaine + no stress (white squares) or just stress by itself (black circles). Perhaps the hypothesis that stress makes cocaine more pleasurable because its boosts dopamine released might be true?

Paper #2

Zhou 1996. Title

Recall from Part 1, that stress activates the HPA axis, which results in release of the stress hormone cortisol (corticosterone in rats and mice). But do drugs of abuse also activate the HPA axis? This next paper—done in lab that I work in—takes a look at this question.

Figure 1.
Figure 1.

Cocaine was given to rats under a number of different conditions. In the first experiment, cocaine effects on the HPA axis were examined in the short term (acute cocaine use). Rats were injected with either saline for two days, cocaine for 1 day, cocaine for 1 day and saline for 1 day, or cocaine for 2 days. After the injections, blood was drawn from the animals and the corticosterone in the serum was measured.

*Technical notes: 1) Serum is the liquid part of blood and it does not contain the red blood cells and clotting proteins. Serum is often used when measuring hormones in the blood. 2) Corticosterone can be measured multiple ways but this experiment used something called a radioimmunoassay (RIA). I’ll save the explanation of it for a future Scientist’s Toolbox post.

As you can see in Figure 1, immediately after the rats receive cocaine (either 1 day or 2 days) corticosterone increases. This means that cocaine has resulted in activation of the HPA axis. Interestingly, the animals received 1 day of cocaine and 1 day of saline did not show high corticosterone levels which means that the levels have returned to normal after the cocaine.

But what happens with repeated cocaine use (chronic cocaine use)? Addiction develops because of chronic use of the drug so are any changes occurring after many days of cocaine use?

Figure 2.
Figure 2.

Interestingly, in Figure 2, corticosterone is high after 3 days of cocaine but after 14 days of cocaine corticosterone levels are much lower! What’s going on here? What these data suggest is that 14 days of cocaine use has caused a change in the HPA axis activity. The cocaine has activated the HPA axis so frequently the axis has compensated for this over activation. The activity of the HPA axis response has been blunted because of the repeated cocaine use.

This one small example of how drugs can cause long lasting molecular adaptations and changes in the brain. Perhaps this is why stress helps to make someone more vulnerable to addiction, because changes occur both at the level of dopamine release (paper #1) and in HPA axis activity (paper #2). Both drugs and stress have similar molecular effects that may work together! I’d like to very briefly discuss one more paper that combines both of these concepts.

Paper #3

Boyson 2014. Title

This paper is complicated but I’m just going to present a small amount of the data. The key points you need to know is that the scientists are using social stress (see Part 1) in this paper for two key experiments 1) self-administration to measure cocaine taking behavior and 2) microdialysis to measure dopamine release. However, they also inject a chemical compound directly into the rat’s brain that blocks HPA axis activity. This chemical acts at the starting point in the HPA axis: the activity of CRF is blocked (the chemical name is abbreviated as CP). Let’s see what happens in this experiment!

*Technical notes: 1) the drug actually prevents the action of CRF interacting with its receptor. Chemicals that do this are called antagonists. Therefore, the scientists are injecting a CRF Receptor antagonist into the rat brains. 2) as a control, an inactive solution is also injected into some animals. This is called artificial cerebral spinal fluid (aCSF). For the drug studies, the correct comparision is CP vs aCSF.

Figure 1.
Figure 1.

Like we saw in other papers, stress increases self-administration (Figure 1, black circles) compared to no stress (white triangles). However, when you give the CP at a high dose (light grey circles) compared to a low dose (dark grey circles) it reduces the self-administration! This means that blocking HPA axis activity reduces the effects of the stress on the cocaine self-administration. Cool!

Figure 2.
Figure 2.

Next, they did a very similar experiment but only this time measure the interaction between stress, cocaine, and the CRF antagonist on dopamine release. The results are presented in Figure 2. Animals that were stressed and than given a dose of cocaine but not the CP (stress + cocaine + aCSF, black circles) released a large amount of dopamine compared to animals that were only given the cocaine injection (white triangles), which is consistent with findings from Paper #1. Amazingly animals that were stressed and then given cocaine + the anti-HPA axis drug CP showed reduced amounts of dopamine released at bot a low dose of CP (dark grey circles) and high dose (light grey circles). These experiments show that the effect of stress on cocaine taking behavior might be because the stress activates the HPA axis which causes more dopamine to be released.

*Technical note: I described this experiments very briefly but they are extremely technically challenging and probably required months of hard work just to make the two little graphs!

Summary

Finally, if we summarize the papers from Part 1, 2 and 3 we can come up with a little mechanism to help explain the different results from the different papers. Based on the data, stress can contribute to the vulnerability of becoming an addict because it activates the HPA axis and increase the dopamine released, which may cause the drug to feel better to a person and make them want to take more of it. There may be a synergy between stress and drugs that changes brain function so that addictive drugs feel more addictive.

You probably noticed I used the word “may” many times and this is because our proposed mechanism requires a lot more testing. In fact, we barely even scratched the surface with this discussion! There are literally hundreds more papers looking at many other details just on stress and addiction. Hopefully this post and the previous two can give you a little appreciation for the difficultly in learning anything about how addiction really works and what specific changes occur in the brain from drug use! Science is a challenging and time-consuming pursuit but also totally worth it!

To wrap up our discussion on stress and addiction, I’ll address some questions/criticisms that you might have with the research papers in this and previous two posts.

Q & A

Some questions about the research you might have and my answers:

Q: Only the psychostimulants cocaine and amphetamine were looked at in these papers. Does stress have the same effects on other drugs of abuse?

A: Yes. The effect of stress is the same with nearly all drugs of abuse tested including the opioid morphine and heroin, alcohol, and nicotine. The neural machinery that is responsible for enhancing the addictive powers of drugs is common to all drugs of abuse.

Q: Only the initial stages of drug taking were looked at in these papers. That is to say, the role of stress was only discussed in the initiation of addiction. How does this translate into progression to full blown addiction?

A: The effect of stress is consistent regardless of where you are on the addiction continuum: stress enhances the reinforcing properties of drugs of abuse. That is to say, stress makes the pleasurable feeling from drugs more pleasurable. However, in humans, you will never get as clear of an effect (that means, easily testable) as you will in laboratory animals. Humans experience many different types of stress throughout a single day and the specific effect of stress on drug taking depends on the type/length/frequency of the stress and other environmental factors. Nevertheless, in controlled clinical studies, changes in HPA axis function as a result of drug use have been widely reported. A feed-forward mechanism exists in which stress promotes drug taking and then drug effects the stress response so that the next stressor has a greater effect on drug taking, etc.

Q: Can stress trigger relapse?

A: Yes, this is one of the most well studied effects of stress on drug taking: stress can trigger drug cravings in abstinent individuals. In the laboratory, an animal can be taught to lose its self-administration behavior by switching the drug to a neutral substance like saline. Therefore, when the animal nose pokes it does not get drug and eventually it doesn’t nose poke at all. This is called extinction. Amazingly, if you stress an animal with foot-shocks or some other phase and then test it’s self-administration behavior the animal will go back to lever pressing again!

Thanks again for reading! If you stuck through all three of Stress and Addiction posts please comment or email me. I would love to know!

Next time: Doping on Dopamine.