neurobiology of opiate addiction and neural circuitries involved

Running head: NEUROBIOLOGY OF OPIATE ADDICTION 1

Neurobiology of Opiate Addiction: Neural Circuits and Opiate Treatment Methodologies

Charlie Mayer

University of San Francisco

NEUROBIOLOGY OF OPIATE ADDICTION 2

In 2002, over 3.7 million Americans had abused opiate medications or illicit narcotics at

least once in their lifetime (Gruber et al., 2007). This number surpassed 4.5 million in 2008, and

has become an alarmingly problematic public health problem. Opiates are classified into

different groups depending on their binding affinity to specific receptor sites in the brain. These

groups include: agonists, antagonists, partial agonists, and mixed agonist/antagonists. The

affinity for binding defines the nature of the drug and its abuse potential; agonists fully bind to

receptor sites and antagonists bind to the receptor sites preventing agonist responses rather than

provoking a chemical response. There are receptor sites located throughout the body, as some

are located in the spinal cord and scattered throughout the peripheral nervous system. Each

natural or synthetic opiate will bind to a specific receptor(s), as each variation shows binding

affinity to different receptors. According to the Substance Abuse and Mental Health Services

Administration (SAMHSA), the abuse of opiate agonists has risen dramatically in the past

decade, and can be measured by the rate of heroin use which has recently reached levels not seen

since the 1970s (SAMHSA, 2010).

Opiate addiction, as defined by the Diagnostic and Statistical Manual for Mental

Disorders (5th ed.; DSM-5; American Psychiatric Association, 2013) must meet at least one or

more of the following criteria: "1) Recurrent use that results in failure to fulfill obligations at

work, school, or home; 2) recurrent use in situations that are physically hazardous, such as

driving or operating machinery; 3) legal problems resulting from recurrent use; 4) continued use

despite social or interpersonal problems caused or exacerbated by use" (American Psychiatric

Association, 2013). Opiate addiction can lead to a rapid onset of both mental and physical

dependency which can be gained after only a short period of daily use.


In 2008, more than 36,000 people died from overdose or accident (intentional and

accidental). The vast majority of these accidental overdoses resulted from drug interactions and

comorbidities resulting from excess use (Centers for Disease Control and Prevention [CDC],

2008). The two main treatment options for opiate addiction currently are methadone

maintenance treatment (MMT) and buprenorphine maintenance treatment (BMT). These

medications differ in the way they interact with the brain circuitry (functional and structural

comparison of neural circuitry is discussed later), bind to receptor sites, and the way in which

they activate specific neurotransmitters in the brain. MMT has been used for over forty five

years in specified clinics while BMT was approved for clinical use under the brand name

Suboxone in 2002 after clearing clinical trials (SAMHSA, 2010). MMT is the favored treatment

option nationally due to the low cost of clinical treatment, but has its own unique set of

problems. It is beyond the scope of this article to discuss the psycho-social factors relating to

treatment successes, which often lead to decisions on which treatment method to begin. Before

detailing the neurological affects of methadone and buprenorphine, a fuller picture of the neural

circuitry involved in opiate addiction must be discussed.

Drugs of abuse alter different neural circuits and act upon different neurotransmitters

depending on their chemical structure. Mimicking the action of endogenous opioids, they bind

to three specific receptor sites; µ, ĸ, and δ-opioid receptors. Each receptor site displays different

behavioral effects when stimulated. Agonists which bind to the µ-opioid (MOR) receptors are

thought to be responsible for the pleasurable effects of narcotics, and the δ-opioid receptors

(DOR) contribute to opiate reinforcement. The ĸ-opioid receptors (KOR) are believed to be

responsible for the aversive effects of opiates such as perspiration or hypoventilation. Receptor

sites for MOR are spread throughout the body, but are most concentrated in the ventral tegmental


area (VTA) and the nucleus accumbens (NAc) (Pierce & Kumaresan, 2006). In the NAc, opiates

act by inhibiting GABAergic NAc neurons or inhibiting neurotransmitter release in the NAc

glutamatergic terminals (Jiang & North, 1992). Results from Jiang & North (1992) indicate that

main function of opioids on neurotransmitter excitation/inhibition was the presynaptic inhibition

of excitatory input in the corticostriate pathways. However, in trials the NAc dopaminergic

pathway was destroyed in rats, and the rats still maintained their propensity for self-injection of

heroin and interestingly showed a marked decrease for cocaine self-administration (Pettit et al.,

1984). The significance of dopamine (DA) in the mesolimbic pathway has been demonstrated

repeatedly in experimentation although it acts indirectly. This has been seen by rats self-

administering opioids directly into the NAc and VTA. Opioids have an indirect effect on the

dopaminergic neurons while hyperpolarizing neurons along the GABAergic pathways (Pierce &

Kumaresan, 2006). Although the limbic system includes several other critical neural structures,

the NAc and VTA are believed to play the most critical role due to their concentration of

dopaminergic neurons and indirect DA release mechanisms (Koob & Volkow, 2010). Other

neural circuitry involved include: Prefrontal cortex (PFC) which activates glutamate along

glutamatergic pathways leading to the NAc and VTA, the Amygdala and Hippocampus which

send and receive input/output to the NAc and VTA, and the Dorsal Striatum and Motor Cortex

which receive input along GABAergic pathways (Volkow et al., 2011). The neural circuitry

involved is complex, but having some introductory information will be necessary in

understanding how MMT and BMT work effectively.

Opiate withdrawal effects are important to understand for the inability to discontinue

daily using. All major drugs of abuse demonstrate decrease in serotonergic pathways and

decrease in the activity of the dopaminergic pathways in the NAc (Koob & Volkow, 2010). The


result of this rapid change in brain levels (brought on by withdrawal onset) is a large change in

neurotransmitter excitation and inhibition. One change that is unique to opiate withdrawal is the

chemical dynorphin. Dynorphin is an opioid peptide which is increased in the NAc when

responding to activation by dopaminergic neurons, and plays a large role in the physical and

mental pain associated with withdrawal. After dynorphin production reaches critical mass in the

NAc, drug tolerance to opiates reaches saturation. When this occurs, dynorphin is overly

produced and quickly will precipitate acute withdrawal in the addict by decreasing DA function

and activating the KOR (Pierce & Kumaresan, 2006). The KOR sites are known to cause the

unpleasant effects of withdrawal when activated. These symptoms include; bone and muscle

aches, sweating, nausea, diarrhea and dysphoria. Withdrawal is a complicated neurological

process and not all of the processes are understood, but dynorphin is not the only perpetrator for

onset. Neurons in the locus ceruleus (LC) which typically secrete norepinephrine (NE) have

shown in studies utilizing imagery to be responsible for part of the discomfort of withdrawal, as

the cessation of opiate use results in NE mass-secretion out of the LC (Stimmel & Kreek, 2000).

Chronic opiate addiction leads to the dynorphin overproduction, which activates certain KOR

sites in the VTA. These KOR sites in the VTA are responsible for decreasing the DA release in

the NAc (Chu & Clark, 2009). These neurologic changes are partially the reason for increasing

use of opiates during addiction and the anhedonia and dysphoria associated with withdrawal as

well (DA levels are already decreased in chronic opiate addiction, withdrawal causes these levels

to drop even lower). Methadone and buprenorphine medications were synthesized to counteract

the withdrawal effects from use cessation, to prevent acute withdrawal and promote healthier

living. Since buprenorphine is a relatively new medication, clinical trials to determine the more


effective treatment protocol have not been sufficiently completed. The data that exists now is

often contradictory.

Methadone is a MOR full agonist which acts as a N-methyl-D-aspartic acid (NMDA)

antagonist (Bart, 2012). It acts as a glutamate receptor antagonist in the NMDA receptors,

demonstrating inhibitory effects directly and indirectly. It differs from buprenorphine by

maintaining its full agonistic properties and primarily attaches to the MOR, and generally

promotes the same neural activation as opiates such as heroin (the difference in effect is due to

chemical structure and inability to rapidly cross the blood-brain barrier[BBB]). Methadone

reduces cravings to short acting opiates (diacetylmorphine and other synthetic opioids), but is

still maintains a dangerously low ld50 (ld50 may fluctuate depending on other medications/drugs

ingested) and has to be closely monitored in clinical settings. The mechanism for craving

reduction is by finding and maintaining the tolerance According to a meta-analysis conducted by

Bart (2012), methadone maintains a one year retention rate of 60%, dependent on appropriate

dosing. It is believed that at least 15% of patients undergoing MMT will be abusing illicit

opiates at any given time. Methadone's full agonist properties make it a drug of abuse, and is

used recreationally by opiate addicts.

Buprenorphine is a µ-opioid receptor partial agonist and a ĸ-opioid receptor antagonist.

The partial-agonistic behavior combined with its antagonistic properties on the KOR sites make

it less likely for abuse and more likely to reduce cravings for other opiates. It has a long duration

of action (27+/- 12 hours), similar to that of methadone. One important function buprenorphine

produces is its blocking ability of other opiates. Because it is a partial agonist-antagonist, it has

the ability to block larger amounts of more powerful opiates and prevent receptor binding

(Bickel et al., 1988), effectively preventing users from achieving a high on drugs such as heroin.


After taken sublingually and absorbed by the small intestine into the bloodstream, it is

metabolized by liver enzymes into norbuprenorphine, and its glucuronide metabolites.

Norbuprenorphine is a MOR agonist, DOR agonist, and KOR receptor partial agonist. It is

important to note that norbuprenorphine primarily acts upon the MOR receptors in the lungs

rather than the brain, as experimental trials have shown it does not cross the BBB easily (Huang

et al., 2001). Buprenorphine's partial agonist and antagonist properties, often combined with the

antagonist naloxone (Suboxone), make it ineffective as a recreational drug.

The induction phase of treatment is the most difficult with buprenorphine, as the patient

will have to wait until the short-acting opiates of abuse have detoxified from the brain, otherwise

buprenorphine has the ability to precipitate acute withdrawal symptoms if taken too early and

other opiate agonists are still attached to the MOR sites (if opiates are still activating MOR sites

in the VTA/NAc, buprenorphine's molecular composition and partial agonistic/antagonistic

behavior will overpower the other opiates and pull them off the receptor sites). BMT combines

buprenorphine with naloxone, which is pure opioid antagonist used to combat abuse. When

combined, BMT medications prevent the patient from abuse by the full antagonistic properties of

the naloxone, the KOR antagonist properties of buprenorphine, and the moderate speed at which

it crosses the BBB when taken sublingually (as compared to opiates of abuse).

To compare MMT/BMT therapies, it is necessary to examine results of experimental

trials which have been replicated and validated. In a recent landmark study, MMT and BMT

were compared to determine retention rate, positive urinalysis (UA) for abstinence, Addiction

Severity Index (ASI) scores, and compliance. The study conducted by Kamien, Branstetter, &

Amass (2008) was built upon recent landmark studies and meta-analyses conducted with

MMT/BMT, and fixed the flexible dosing problem. This study was able to properly dose


methadone comparative to buprenorphine so that they were equivalent (flexible dosing was

initially the main problem in comparing these two medications; not enough research had been

conducted on BMT to warrant higher dosing, and this study eliminated this concern by building

on previous dosing methodologies). This study was a double-blind, double dummy trial which

compared four experimental groups: Two groups receiving BMT (one group taking 8mg/2mg

buprenorphine/naloxone, the other receiving 16mg/4mg buprenorphine/naloxone), and two

groups receiving MMT (45mg, and 90mg respectively). A total of 268 participants subjects

started the trial out of the first 300 which were selected. They were randomly selected after

stratified for age and other demographic features. A control group was given water mixed with

blue dye to maintain the appearance of methadone (for MMT), and the other control group

received a placebo which looked and tasted identical to buprenorphine (for BMT).

Patients in this study had to meet the DSM-IV criteria for addiction (current at the time of

the study), and the results from their intake ASI scores were recorded as their baseline. The trial

consisted of 17 consecutive weeks of dosing at a clinic, with UA distribution three times each

week. Demographics were broken down by gender, age, race, ethnicity, and drug history. To

test the effectiveness of MMT/BMT on abstinence, UA's were collected three times a week

before any medications were administered (Kamien et al., 2008), as well as breathalyzers given

to prevent intoxication of any kind. Interviews were held three times a week during the trials,

and the participants were told to self-report any positive drug use and were reassured it would

not get them thrown out of the case. A total of 51 UA's were collected for the presence of

opioids and other drugs of abuse, and the participants results were recorded. Exclusionary

criteria did not include positive initial UA screenings for any drug of abuse. The BMT groups


had a slow induction phase, which was required because buprenorphine/naloxone may

precipitate acute withdrawals in patients still under the influence.

To analyze statistical differences between the baseline scores of the groups, ANOVA and

chi-squared testing were utilized. Because of the longer nature of this study, hierarchical linear

modeling (HLM) testing was utilized to examine the statistical significance of the MMT and

BMT groups for abstinence. Participants receiving the highest doses of BMT and MMT were

the most likely to have twelve consecutive negative UA screenings (a secondary treatment

outcome of this study) than those on the lower doses (p=.02) (Kamien et al., 2008). However,

between the MMT and BMT groups there was no statistical significance in terms of abstinence

throughout the trial. Each group performed relatively equally, as the HLM testing determined

that the participants increased their percentage of negative UA screenings over time, but the

increase was not determined by the drug dosing or group. The findings by Kamien, Branstetter,

& Amass (2008) demonstrate the effectiveness of both the MMT and BMT options.

The strengths of this study was its ability to fix the dosing equivalency problem between

MMT and BMT, and the scope of the trial itself. It took into account many different variables

and made them part of its secondary treatment outcomes to test for. It was constructed upon the

successes of previous trials after completing thorough reviews of available meta-analyses and

other trials. There were limitations to the study also. While stratifying the demographics, the

computer analysis software crashed and initially left the number of patients in the BMT and

MMT groups to match only based on medication, not dose of medication. After discovery, it

was determined that the outcomes from this would not affect trial data and was left alone. Even

though the methodology for UA collection and interviews for positive self-reports followed APA

guidelines, it is still possible that positive use went undetected. This study shows that BMT and


MMT are roughly equivalent for maintaining abstinence, and has been validated in several more

recent studies. It does not quantitatively test whether MMT or BMT would be ideal for long-

term or short-term option for detoxification or maintenance. Perhaps future studies may focus on

which medication is better suited for long-term maintenance or a shorter maintenance program.

Although few direct BMT/MMT clinical trials have been conducted to determine which

treatment is more effective (the few that have demonstrated them to have no statistical

significance in difference), indirect comparisons can be made. In 2009, there were 1,034 deaths

from methadone overdose and only 20 from buprenorphine, due to the agonist/antagonistic

nature of each (SAMHSA, 2010). A recent retrospective cohort study by Auriacombe, Franques,

& Tignol (2001) investigated MMT/BMT overdose deaths in France over a four year period.

Auriacombe et al. (2001) found that the estimated yearly death rate for methadone is at least

three times greater than that of buprenorphine. It is evident that BMT is a safer alternative to

MMT when comparing to BMT, and is seen globally (Neumann et al., 2013). The ability of

BMT to block the effects of opioid-agonists makes it an attractive counter to MMT, where many

patients continue to use heroin along with methadone (as seen in the toxicology reports to

determine COD of overdose victims). BMT is viewed as a more attractive alternative for several

reasons aside from its antagonistic functions. Daily visits to a clinic are not required, as it is

possible to receive a prescription for 1-3 months.

Neurologic functioning (as defined by the average level of neurotransmitter

release/absorption and neuronal activity) is fundamentally altered by long-term opiate abuse

(Chu & Clark, 2009). Current studies are focusing on mapping neurologic abnormalities that are

directly induced by long-term opiate use utilizing fMRI and other imaging techniques.

Methadone is a low cost easy treatment option for many, which allows the patient to function.


Buprenorphine is a new, safe alternative to other synthetic opiates and allows for normal

cognitive functioning and quality of life. New areas of research are examining how to prevent

limbic system degradation, and potential pharmacologic methods which may help normalize

neurotransmitter activity levels in different parts of the brain. It is difficult because there are

many neurotransmitters involved (activation or inhibition of DA, NE, GABA, glutamate,

serotonin) and they act out more than one function at a time, forming an intricate web of direct or

indirect neurologic action. Recent research has been focusing on examining medications and

peptides, such as oxytocin (hormone), which inhibits the memory and learning component of

addiction, as well as inhibiting CNS activation during withdrawal (Kovacs et al., 1998).

With narcotic addiction being one of the leading causes of death each year (36,000 deaths

due to overdose in 2008 [SAMHSA, 2010]), researchers are exploring new avenues of approach

to addiction. With the evolution of new pharmacologic methods it is expected that the overdose

rate will drop, while leading to a higher quality of life (which in turn prevents criminal activities

associated with narcotic abuse). Medication therapy (especially when combined with a form of

cognitive therapy) has shown great promise in attenuating opiate withdrawal, promoting long-

term abstinence, and decreasing cravings. The medical and popular opinion is beginning to shift

about addiction. The concept of functional abnormalities caused by abuse is gaining more

acceptance. Addicts are less and less seen as people who lack the willpower to avoid use, and

more as patients who need treatment to either correct or mitigate neurologic function. Addiction

not only harms the addict, but the people around the addict (included: criminal activities result in

a 26% higher rate of crime than non-users, and the cost of subsequent incarcerations) (Bimbaum

et al., 2011). The new allostatic theory of addiction describes the exact

neurological/endocrinological patterns which addiction changes, and is mapped with precision


(Koob & Le Moal, 2000). Patterning new treatment therapies off of allostasis and neural

imaging is the next logical step to creating helpful new medications to alleviate problems

associated with addiction.


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neurobiology of opiate addiction and neural circuitries involved

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