Tuesday, February 15, 2022

Addiction Case File

Posted By: Medical Group - 2/15/2022 Post Author : Medical Group Post Date : Tuesday, February 15, 2022 Post Time : 2/15/2022
Addiction Case File
EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 36
A 30-year-old male presents to the emergency room (ER) with a chief complaint of painful priapism. He estimates the time of onset to be about 8 hours prior to admission to the ER. The patient also complains of severe muscle cramps in his arms and legs and seems anxious and irritable.

Upon physical examination, no signs of trauma to the spinal cord are found. Patient denies having injected any sort of substance into his penis, but visible track marks can be found on both his arms. He admits to sustained heroin use, but claims to have been clean for several days. Based on this history, you inform the patient that these symptoms are most likely secondary to heroin withdrawal.
  • What receptors does heroin act on?
  • What would be an appropriate treatment for the patient’s symptoms?


ANSWERS TO CASE 36: ADDICTION

Summary: A 30-year-old male presents with priapism and severe muscle cramps in limbs. Patient has a history of sustained heroin use but claims to have ceased usage.
  • Receptors: Opioid receptors.
  • Treatment: Because the elapsed time since onset has exceeded 6 hours, treatment of patient’s priapism through medication is no longer an option. Surgical shunt and aspiration of the penis are the most viable procedures. Buprenorphine is recommended as a substitute opioid to help ease other symptoms of heroin withdrawal.


CLINICAL CORRELATION

Heroin withdrawal syndrome may manifest in the patient within 6-24 hours of discontinuation of sustained use of the drug. This time frame may vary depending on the degree of tolerance of the patient, as well as the amount of heroin consumed in the last dose. Symptoms of heroin withdrawal include sweating, malaise, anxiety, depression, priapism in men, extra sensitivity of the genitals in females, general feeling of heaviness, cramplike pains, yawning, insomnia, cold sweats, chills, severe muscle and bone aches, nausea and vomiting, diarrhea, goose bumps, and fever. Many symptoms of opioid withdrawal are caused by rebound hyperactivity of the sympathetic nervous system, which can be suppressed using clonidine, a centrally acting α2 agonist primarily used to treat hypertension. Baclofen, a muscle relaxant, is often used to treat leg twitches, another symptom of withdrawal. Diarrhea can be treated with the peripherally active opioid drug loperamide. One of the most widely used opioid substitutes in the treatment of heroin withdrawal is buprenorphine, a partial opioid agonist/antagonist. Buprenorphine develops a lower grade of tolerance than heroin and results in less severe withdrawal symptoms when discontinued abruptly. Buprenorphine acts as a κ-opioid receptor antagonist, while simultaneously acting as a partial agonist at the same μ-receptor where opioids like heroin exhibit their action. Because of the effects of buprenorphine on this receptor, patients with high tolerances are unable to achieve any euphoric effects from other opioids while using buprenorphine. There are three known opioid antagonists currently being utilized in the treatment of opioid addiction: naxolone and the longer acting naltrexone and nalmefene. These medications act by blocking the effects of heroin and other opioids at the receptor sites.


APPROACH TO ADDICTION

Objectives
  1. Describe the development of addiction.
  2. Identify the mesolimbic dopaminergic system and its role in rewardrelated learning.
  3. Describe the nature of drug tolerance and its implications in the withdrawal symptoms that occur upon discontinuation of the drug.


Definitions

Buprenorphine: A semisynthetic opioid analgesic used for the relief of moderate-to-severe pain.
Opioid antagonist: A receptor antagonist that acts on opioid receptors, blocking the effects of opioids.


DISCUSSION

The development of addiction is thought to be a simultaneous process of increased focus on and engagement in a particular behavior and the simultaneous attenuation or shutting down of other behaviors. For instance, in certain experimental circumstances, test animals are allowed the ability to selfadminister certain psychoactive drugs. Given an unlimited supply of the drug, the animals will show an extremely strong preference for it, forgoing food, sleep, and sexual intercourse in order to maintain access to the drug. From a neuroanatomical standpoint, it can be argued that the mechanisms involved in driving goal-directed behavior become gradually more selective for certain stimuli and rewards, exceeding the point at which the mechanisms involved in behavior inhibition can effectively preclude the action. In this case, the limbic system is thought to be the major driving force and the orbitofrontal cortex is the substrate of the top-down inhibition.

The portion of the limbic system responsible for the translation of motivation to motor behavior–learning and reward-related learning is the mesolimbic dopaminergic system. This system is comprised of the ventral tegmental area (VTA), the nucleus accumbens, and the bundle of dopamine-containing fibers that connect them. Located on the anterior cingulated circuit, the portion of the frontal lobe that incorporates much of the brain’s motivational pathways, is the ventral striatum. This locus is of importance because it is where the nucleus accumbens are situated and where the release of dopamine takes place, a process that is believed to be a critical mediator of the reinforcing effects of stimuli, including drugs of abuse. This system is commonly implicated in the seeking out and consumption of rewarding stimuli or events, such as sweet-tasting foods or sexual interaction. However, its importance to addiction research goes beyond its role in “natural” motivation: while the specific site or mechanism of action may differ, all known drugs of abuse have the common effect in that they elevate the level of dopamine in the nucleus accumbens. This may happen directly, via the blockade of the dopamine reuptake mechanism, as is the case with cocaine use. Or it may also happen indirectly, such as through stimulation of the dopaminecontaining neurons of the VTA that synapse onto neurons in the accumbens, which occurs during opiate use. The euphoric effects of drugs of abuse are a direct result of the acute increase in accumbal dopamine.

The central nervous system, like the rest of the human body, has a natural tendency to maintain an internal equilibrium, or homeostasis. Prolonged elevated levels of dopamine will spur a decrease in the number of dopamine receptors. This process, known as downregulation, causes a change in postsynaptic cell membrane permeability. This in turn makes the postsynaptic neuron less excitable and less responsive to chemical signaling with an electrical impulse, or action potential. The resultant unresponsiveness of the brain’s reward pathways contributes to an inability to feel pleasure, known as anhedonia, a phenomenon often observed in addicts. Upon onset of anhedonia, a greater amount of dopamine is required to maintain the same electrical activity. This is the basis of physiological tolerance of a drug, as well as the withdrawal associated with addiction.

Contrary to popular belief, drug overdoses are generally not the result of a user taking a higher dose than is typical but rather administering the same dose in a new environment. If a behavior occurs repeatedly and consistently in the same environment or contingently with a particular cue, the brain will adjust to the presence of these cues by decreasing the number of available receptors in the absence of said behavior.

Withdrawal symptoms occur in the absence of substances that the body has become physically dependent on. These substances include depressants of the central nervous system such as opioids, barbiturates, and alcohol. Withdrawal from alcohol or sedatives like barbiturates or benzodiazepines can cause seizures and may result in death. However, withdrawal from opioids, while still extremely uncomfortable, is rarely life threatening. In situations of particularly severe anhedonia, the body is so accustomed to high concentrations of a substance that it no longer produces its own natural versions. Instead, it produces opposing chemicals. When delivery of the substance is halted, the effects of the
opposing chemicals can be devastating. For example, in instances of chronic sedative use, the body counters by producing chronic levels of stimulating neurotransmitters such as glutamate. High concentrations of glutamate can be toxic to nerve cells. This scenario is called excitatory neurotoxicity.


COMPREHENSION QUESTIONS

Refer to the following case scenario to answer questions 36.1-36.3:

You are working in a rehabilitation clinic, performing counseling for patients who are trying to stop using drugs of abuse, particularly heroin. A 33- year-old man is telling his story, about how his use of heroin cost him his job, his wife, his kids, his house, essentially everything he had. He says he knew it was destroying his life, but he just could not stop. He describes the amazing euphoric feeling he got whenever he used, and says that without the drug, he just cannot get that feeling anywhere.

[36.1] Release of what neurotransmitter into the nucleus accumbens is most commonly associated with the euphoric effect common to almost all drugs of abuse?
A. Norepinephrine
B. Acetylcholine
C. Serotonin
D. Dopamine

[36.2] What neural tract that connects the VTA to the nucleus accumbens is commonly thought of as the “pleasure center of the brain?”
A. Medial longitudinal fasciculus
B. Medial forebrain bundle (MFB)
C. Mammillothalamic tract
D. Spinothalamic tract

[36.3] What is the molecular mechanism that causes more and more drug to be needed to achieve the same euphoric effect each time the drug is used and that also accounts at least in part for the withdrawal symptoms following cessation of a drug?
A. Receptor downregulation
B. Decreased receptor sensitivity
C. Exhaustion of dopamine stores
D. Depletion of acetyl choline


Answers

[36.1] D. The neurotransmitter most frequently associated with euphoria from drugs is dopamine. In a normal brain, this dopamine release onto the nucleus accumbens is associated with reward, and helps to drive behavior. It can be naturally released through things like sexual activity and sweet foods.

[36.2] B. The MFB is a tract of dopaminergic axons that project from the VTA to the nucleus accumbens. When stimulated, this tract releases dopamine onto the nucleus accumbens, which results in a euphoric feeling. In experimental animals, it has been shown that animals will autostimulate the MFB with an electrode to the detriment of everything to the point that they actually starve to death. This dopaminergic tract plays a very important role in reward and motivational drive, as well as addiction.

[36.3] A. The phenomenon in which more and more drug is needed each time to achieve the same effect is known as tolerance, and the molecular mechanism responsible for this phenomenon is downregulation of postsynaptic dopamine receptors in the nucleus accumbens. Excessive stimulation by dopamine causes the postsynaptic cells to decrease the amount of dopamine receptors they express, resulting in less effect for the same amount of dopamine release. The individual receptors are just as sensitive, there are simply fewer of them around.


NEUROSCIENCE PEARLS

The portion of the limbic system responsible for the translation of motivation to motor behavior–related and reward-related learning is the mesolimbic dopaminergic system.
The euphoric effects of drugs of abuse are a direct result of the acute increase in dopamine in the nucleus accumbens.
Prolonged elevated levels of dopamine will spur a decrease in the number of dopamine receptors, a process known as downregulation.


REFERENCES

Bear MF, Connors B, Paradiso M, eds. Neuroscience: Exploring the Brain. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006. 

Kandel E, Schwartz J, Jessell T, eds. Principles of Neural Science. 5th ed. New York, NY: McGraw-Hill; 2000. 

Zigmond MJ, Squire LR, Bloom FE, Landis SC, Roberts JL, eds. Fundamental Neuroscience. 2nd ed. San Diego, CA: Academic Press; 1999.

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