In a Heroin User, Negative Reinforcement of Drug-taking Behavior Can Occur When

Sci Pract Perspect. 2002 Jul; ane(1): 13–xx.

The Neurobiology of Opioid Dependence: Implications for Treatment

Thomas R. Kosten

ⁱ Yale Academy School of Medicine New Haven, Connecticut

² VA Connecticut Healthcare Arrangement W Oasis, Connecticut

Tony P. George

¹ Yale Academy Schoolhouse of Medicine New Haven, Connecticut

³ Connecticut Mental Health Center New Oasis, Connecticut

Abstract

Opioid tolerance, dependence, and addiction are all manifestations of encephalon changes resulting from chronic opioid abuse. The opioid abuser'south struggle for recovery is in peachy role a struggle to overcome the effects of these changes. Medications such equally methadone, LAAM, buprenorphine, and naltrexone human action on the same brain structures and processes as addictive opioids, just with protective or normalizing effects. Despite the effectiveness of medications, they must be used in conjunction with appropriate psychosocial treatments.

While the individual patient, rather than his or her disease, is the appropriate focus of treatment for opioid abuse, an understanding of the neurobiology of dependence and addiction tin be invaluable to the clinician. It can provide insight well-nigh patient behaviors and problems, help ascertain realistic expectations, and analyze the rationales for treatment methods and goals. Also, patients who are informed about the brain origins of addiction can benefit from understanding that their illness has a biological ground and does non mean they are "bad" people.

Brain abnormalities resulting from chronic utilise of heroin, oxycodone, and other morphine-derived drugs are underlying causes of opioid dependence (the demand to keep taking drugs to avert a withdrawal syndrome) and addiction (intense drug craving and compulsive use). The abnormalities that produce dependence, well understood by scientific discipline, appear to resolve after detoxification, within days or weeks after opioid use stops. The abnormalities that produce addiction, however, are more wide-ranging, circuitous, and long-lasting. They may involve an interaction of environmental effects—for example, stress, the social context of initial opiate utilise, and psychological workout—and a genetic predisposition in the form of encephalon pathways that were aberrant even before the starting time dose of opioid was taken. Such abnormalities tin produce craving that leads to relapse months or years after the individual is no longer opioid dependent.

In this commodity nosotros describe how opioids affect encephalon processes to produce drug liking, tolerance, dependence, and addiction. While these processes, similar everything else that happens in the brain, are highly circuitous, nosotros try to explicate them in terms that tin can be easily understood and explained to patients. We also hash out the handling implications of these concepts. Pharmacological therapy with methadone, LAAM (levoalpha-acetylmethadol), naltrexone, or other medications directly offsets or reverses some of the brain changes associated with addiction, profoundly enhancing the effectiveness of behavioral therapies. Although researchers do not still know everything near how these medications piece of work, it is clear that they are all truly active treatments, rather than simply substitutes for the addictive opioids.

ORIGINS OF DRUG LIKING

Many factors, both private and environmental, influence whether a particular person who experiments with opioid drugs volition continue taking them long plenty to go dependent or addicted. For individuals who do continue, the opioids' ability to provide intense feelings of pleasure is a critical reason.

When heroin, oxycodone, or any other opiate travels through the bloodstream to the encephalon, the chemicals adhere to specialized proteins, called mu opioid receptors, on the surfaces of opiate-sensitive neurons (brain cells). The linkage of these chemicals with the receptors triggers the aforementioned biochemical encephalon processes that reward people with feelings of pleasure when they engage in activities that promote basic life functions, such as eating and sex activity. Opioids are prescribed therapeutically to relieve pain, but when opioids activate these reward processes in the absenteeism of pregnant hurting, they tin motivate repeated use of the drug simply for pleasure.

One of the brain circuits that is activated past opioids is the mesolimbic (midbrain) reward system. This system generates signals in a part of the brain called the ventral tegmental expanse (VTA) that consequence in the release of the chemical dopamine (DA) in another part of the encephalon, the nucleus accumbens (NAc) (Figure 1). This release of DA into the NAc causes feelings of pleasure. Other areas of the brain create a lasting record or memory that associates these good feelings with the circumstances and environment in which they occur. These memories, chosen conditioned associations, often lead to the craving for drugs when the abuser reen-counters those persons, places, or things, and they bulldoze abusers to seek out more drugs in spite of many obstacles.

The Mesolimbic Reward Arrangement

When drugs stimulate mu opioid receptors in the encephalon, cells in the ventral tegmental area (VTA) produce dopamine and release it into the nucleus accumbens (NAc), giving ascension to feelings of pleasure. Feedback from the prefrontal cortex (PFC) to the VTA helps us overcome drives to obtain pleasure through actions that may be unsafe or unwise, but this feedback appears to be compromised in individuals who become addicted to drugs. The locus ceruleus (LC) is an area of the brain that plays an important role in drug dependence.

Specially in the early stages of abuse, the opioid's stimulation of the brain's advantage system is a principal reason that some people accept drugs repeatedly. However, the compulsion to apply opioids builds over fourth dimension to extend beyond a simple drive for pleasure. This increased compulsion is related to tolerance and dependence.

OPIOID TOLERANCE, DEPENDENCE, AND WITHDRAWAL

From a clinical standpoint, opioid withdrawal is ane of the most powerful factors driving opioid dependence and addictive behaviors. Treatment of the patient's withdrawal symptoms is based on agreement how withdrawal is related to the brain'southward adjustment to opioids.

Repeated exposure to escalating dosages of opioids alters the brain so that it functions more or less normally when the drugs are nowadays and abnormally when they are non. Two clinically important results of this alteration are opioid tolerance (the demand to have higher and higher dosages of drugs to achieve the same opioid effect) and drug dependence (susceptibility to withdrawal symptoms). Withdrawal symptoms occur only in patients who have developed tolerance.

Opioid tolerance occurs because the encephalon cells that take opioid receptors on them gradually go less responsive to the opioid stimulation. For example, more opioid is needed to stimulate the VTA brain cells of the mesolimbic reward arrangement to release the same corporeality of DA in the NAc. Therefore, more opioid is needed to produce pleasure comparable to that provided in previous drug-taking episodes.

Opioid dependence and some of the most lamentable opioid withdrawal symptoms stem from changes in some other important brain system, involving an area at the base of operations of the brain—the locus ceruleus (LC) (Figure ii). Neurons in the LC produce a chemical, noradrenaline (NA), and distribute it to other parts of the brain where it stimulates wakefulness, animate, blood pressure level, and full general alertness, among other functions. When opioid molecules link to mu receptors on encephalon cells in the LC, they suppress the neurons' release of NA, resulting in drowsiness, slowed respiration, depression blood force per unit area—familiar furnishings of opioid intoxication. With repeated exposure to opioids, still, the LC neurons conform past increasing their level of activity. At present, when opioids are present, their suppressive impact is get-go by this heightened activity, with the consequence that roughly normal amounts of NA are released and the patient feels more or less normal. When opioids are non present to suppress the LC encephalon cells' enhanced activity, however, the neurons release excessive amounts of NA, triggering jitters, feet, musculus cramps, and diarrhea.

The Neurobiological Basis of Dependence and Withdrawal

The locus ceruleus (LC) is an area of the brain that is critically involved in the production of opioid dependence and withdrawal. The diagrams bear witness how opioid drugs affect processes in the LC that control the release of noradrenaline (NA), a brain chemic that stimulates wakefulness, muscle tone, and respiration, among other functions.

A. Unremarkably, natural opiatelike chemicals produced by the body link to mu opioid receptors on the surface of neurons. This linkage activates an enzyme that converts a chemical chosen adenosine triphosphate (ATP) into another chemical, called circadian adenosine monophosphate (cAMP), which in plow triggers the release of NA. Prior to initiation of opioid drug abuse, the neuron produces enough NA to maintain normal levels of alertness, musculus tone, respiration, etc.

B. When heroin or some other opioid drug links to the mu opioid receptors, it inhibits the enzyme that converts ATP to camp. As a result, less military camp is produced, less NA is released. Alertness, muscle tone, and respiration driblet, and the astute opioid effects of sedation, shallow breathing, etc., appear.

C. With repeated heroin exposure, the neuron increases its supply of enzyme and ATP molecules. Using these extra raw materials, the neuron can produce enough cAMP to offset the inhibitory result of the drug and release roughly normal amounts of NA despite the presence of the drug. At this phase, the individual no longer experiences the same intensity of acute opioid effects as in earlier stages of abuse.

D. When heroin is discontinued after chronic corruption, the drug's inhibitory touch is lost. Operating at normal efficiency merely with enhanced supplies of converting enzyme and ATP, the neuron produces abnormally high levels of camp, leading to excessive release of NA. The patient experiences the clinical symptoms of withdrawal—jitters, anxiety, muscle cramps, etc. If no further drugs are taken, the neuron volition largely revert to its predrug status (console A) within days or weeks.

Other brain areas in addition to the LC also contribute to the production of withdrawal symptoms, including the mesolimbic reward system. For instance, opioid tolerance that reduces the VTA'southward release of DA into the NAc may forbid the patient from obtaining pleasure from normally rewarding activities such as eating. These changes in the VTA and the DA advantage systems, though not fully understood, grade an important brain system underlying craving and compulsive drug use.

TRANSITION TO ADDICTION

As we have seen, the pleasure derived from opioids' activation of the brain's natural reward system promotes continued drug use during the initial stages of opioid addiction. Subsequently, repeated exposure to opioid drugs induces the brain mechanisms of dependence, which leads to daily drug use to avert the unpleasant symptoms of drug withdrawal. Further prolonged use produces more long-lasting changes in the brain that may underlie the compulsive drug-seeking behavior and related adverse consequences that are the hallmarks of addiction. Recent scientific research has generated several models to explain how habitual drug utilize produces changes in the brain that may atomic number 82 to drug addiction. In reality, the process of addiction probably involves components from each of these models, besides as other features.

Definitions of Key Terms

dopamine (DA): A neurotransmitter nowadays in brain regions that regulate movement, emotion, motivation, and the feeling of pleasure.

GABA (gamma-amino butyric acid): A neurotransmitter in the brain whose master function is to inhibit the firing of neurons.

locus ceruleus (LC): A region of the brain that receives and processes sensory signals from all areas of the body; involved in arousal and vigilance.

noradrenaline (NA): A neurotransmitter produced in the brain and peripheral nervous system; involved in arousal and regulation of blood pressure, sleep, and mood; also chosen norepinephrine.

nucleus accumbens (NAc): A structure in the forebrain that plays an important part in dopamine release and stimulant action; one of the brain's fundamental pleasance centers.

prefrontal cortex (PFC): The frontmost part of the encephalon; involved in higher cognitive functions, including foresight and planning.

ventral tegmental expanse (VTA): The group of dopamine-containing neurons that make up a key part of the encephalon reward organization; fundamental targets of these neurons include the nucleus accumbens and the prefrontal cortex

The "Changed Fix Signal" Model

The "changed set point" model of drug addiction has several variants based on the altered neurobiology of the DA neurons in the VTA and of the NA neurons of the LC during the early phases of withdrawal and abstinence. The basic idea is that drug corruption alters a biological or physiological setting or baseline. One variant, by Koob and LeMoal (2001), is based on the thought that neurons of the mesolimbic reward pathways are naturally "ready" to release plenty DA in the NAc to produce a normal level of pleasure. Koob and LeMoal suggest that opioids cause addiction by initiating a cruel cycle of changing this set signal such that the release of DA is reduced when usually pleasurable activities occur and opioids are non present. Similarly, a alter in gear up betoken occurs in the LC, but in the opposite direction, such that NA release is increased during withdrawal, equally described above. Under this model, both the positive (drug liking) and negative (drug withdrawal) aspects of drug addiction are accounted for.

A specific style that the DA neurons tin can get dysfunctional relates to an alteration in their baseline ("resting") levels of electrical activeness and DA release (Grace, 2000). In this second variant of the changed fix point model, this resting level is the result of two factors that influence the amount of resting DA release in the NAc: cortical excitatory (glutamate) neurons that drive the VTA DA neurons to release DA, and autoreceptors ("brakes") that close down further release when DA concentrations become excessive. Activation of opioid receptors past heroin and heroin-like drugs initially bypasses these brakes and leads to a large release of DA in the NAc. Withal, with repeated heroin apply, the brain responds to these successive large DA releases by increasing the number and strength of the brakes on the VTA DA neurons. Eventually, these enhanced "braking" autoreceptors inhibit the neurons' resting DA release. When this happens, the dependent addict volition take fifty-fifty more than heroin to offset the reduction of normal resting DA release. When he or she stops the heroin utilize, a state of DA deprivation will result, manifesting in dysphoria (pain, agitation, malaise) and other withdrawal symptoms, which can pb to a cycle of relapse to drug use.

A third variation on the ready-betoken change emphasizes the sensitivity to environmental cues that leads to drug wanting or craving rather than merely reinforcement and withdrawal (Breiter et al., 1997; Robinson and Berridge, 2000). During periods when the drug is non available to addicts, their brains can remember the drug, and desire or peckish for the drug can be a major gene leading to drug use relapse. This peckish may stand for increased activity of the cortical excitatory (glutamate) neurotransmitters, which drive the resting action of the DA-containing VTA neurons, equally mentioned, and also drive the LC NA neurons. As the glutamate activity increases, DA will be released from the VTA, leading to drug wanting or craving, and NA will be released from the LC, leading to increased opioid withdrawal symptoms. This theory suggests that these cortical excitatory brain pathways are overactive in heroin addiction and that reducing their activity would be therapeutic. Scientists are currently researching a medication called lamotrigene and related compounds called excitatory amino acid antagonists to see whether this potential handling strategy really can work.

Thus, several mechanisms in the LC and VTA-NAc encephalon pathways may exist operating during addiction and relapse. The excitatory cortical pathways may produce little response in the VTA during the resting state, leading to reductions in DA. Withal, when the addicted individual is exposed to cues that produce craving, the glutamate pathways may get sufficiently agile to enhance DA and stimulate desire for a greater high. This aforementioned increase in glutamate activity will raise NA release from the LC to produce a dysphoric land predisposing to relapse and continued addiction.

Cognitive Deficits Model

The cognitive deficits model of drug addiction proposes that individuals who develop addictive disorders accept abnormalities in an area of the encephalon chosen the prefrontal cortex (PFC). The PFC is of import for regulation of judgment, planning, and other executive functions. To assistance u.s.a. overcome some of our impulses for immediate gratification in favor of more important or ultimately more rewarding long-term goals, the PFC sends inhibitory signals to the VTA DA neurons of the mesolimbic reward system.

The cerebral deficits model proposes that PFC signaling to the mesolimbic advantage system is compromised in individuals with addictive disorders, and equally a outcome they have reduced ability to use judgment to restrain their impulses and are predisposed to compulsive drug-taking behaviors. Consistent with this model, stimulant drugs such as methamphetamine appear to harm the specific encephalon circuit—the frontostriatal loop—that carries inhibitory signals from the PFC to the mesolimbic reward arrangement. In addition, a recent report using magnetic resonance spectroscopy showed that chronic alcohol abusers have abnormally depression levels of gamma-amino butyric acrid (GABA), the neurochemical that the PFC uses to betoken the reward system to release less DA (Behar et al., 1999). As well, the cognitive deficits model of drug addiction could explain the clinical observation that heroin addiction is more severe in individuals with antisocial personality disorder—a condition that is independently associated with PFC deficits (Raine et al., 2000).

In contrast to stimulants, heroin plain dam-ages the PFC but not the frontostriatal loop. Therefore, individuals who become heroin addicts may take some PFC damage that is independent of their opioid abuse, either inherited genetically or caused by another factor or event in their lives. This preexisting PFC impairment predisposes these individuals to impulsivity and lack of command, and the additional PFC impairment from chronic repeated heroin abuse increases the severity of these problems (Kosten, 1998).

STRESS AND DRUG CRAVING

That drug corruption patients are more vulnerable to stress than the full general population is a clinical truism. In the enquiry arena, numerous studies have documented that concrete stressors (such as footshock or restraint stress) and psychological stressors can cause animals to reinstate drug use and that stressors can trigger drug peckish in addicted humans (east.g., Shaham et al., 2000). The probable explanation for these observations is that opioids raise levels of cortisol, a hormone that plays a primary role in stress responses; and cortisol, in turn, raises the level of activity in the mesolimbic advantage arrangement (Kreek and Koob, 1998). By these mechanisms, stress may contribute to the abuser's desire to take drugs in the first place and to his or her subsequent compulsion to keep taking them.

PHARMACOLOGICAL INTERVENTIONS AND TREATMENT IMPLICATIONS

In summary, the various biological models of drug habit are complementary and broadly applicative to chemic addictions. Long-term pharmacotherapies for opioid dependence and addiction counteract or reverse the abnormalities underlying those conditions, thereby enhancing programs of psychological rehabilitation. Short-term treatments for relieving withdrawal symptoms and increasing abstinence are beyond the scope of this article; instead, we refer readers elsewhere for detailed neurobiological explanations of the various nonopioid-based abstinence initiation approaches such as clonidine and clonidine-naltrex-one for rapid detoxification (come across O'Connor and Kosten, 1998, and O'Connor et al., 1997).

The medications nearly unremarkably used to treat opioid corruption attach to the brain cells' mu opioid receptors, like the addictive opioids themselves. Methadone and LAAM stimulate the cells much as the illicit opioids exercise, merely they have different furnishings because of their different durations of activeness. Naltrexone and buprenorphine stimulate the cells in means quite distinct from the addictive opioids. Each medication tin can play a role in comprehensive treatment for opioid addiction.

Methadone

Methadone is a long-interim opioid medication. Unlike morphine, heroin, oxycodone, and other addictive opioids that remain in the brain and trunk for but a short time, methadone has effects that last for days. Methadone causes dependence, simply—considering of its steadier influence on the mu opioid receptors—it produces minimal tolerance and alleviates craving and compulsive drug apply. In addition, methadone therapy tends to normalize many aspects of the hormonal disruptions plant in fond individuals (Kling et al., 2000; Kreek, 2000; Schluger et al., 2001). For example, it moderates the exaggerated cortisol stress response (discussed in a higher place) that increases the danger of relapse in stressful situations.

Methadone handling reduces relapse rates, facilitates behavioral therapy, and enables patients to concentrate on life tasks such as maintaining relationships and holding jobs. Pioneering studies past Dole, Nyswander, and Kreek in 1964 to 1966 established methadone's efficacy (Dole et al., 1966). As a Drug Enforcement Administration schedule II controlled substance, the medication is administered primarily in federally regulated methadone programs, where careful monitoring of patients' urine and regular drug counseling are critical components of rehabilitation. Patients are generally started on a daily dose of 20 mg to 30 mg, with increases of 5 mg to 10 mg until a dose of sixty mg to 100 mg per mean solar day is achieved. The college doses produce full suppression of opioid craving and, consequently, opioid-free urine tests (Judd et al., 1998). Patients mostly stay on methadone for 6 months to 3 years, some much longer. Relapse is mutual amidst patients who discontinue methadone after simply 2 years or less, and many patients accept benefited from lifelong methadone maintenance.

LAAM

A longer acting derivative of methadone, LAAM can exist given three times per week. Recent concerns virtually heart rhythm problems (specifically, prolonged QT interval) have express LAAM's use (U.S. Nutrient and Drug Administration, 2001). Nevertheless, long-term maintenance on moderate to high doses of LAAM can, like methadone maintenance, normalize physiological functions such as the cortisol stress response (Kling et al., 2000; Kreek, 1992, 2000; Schluger et al., 2001). Dosing with LAAM is highly individualized, and three-times-weekly doses range from 40 mg to 140 mg.

Naltrexone

Naltrexone is used to assistance patients avoid relapse subsequently they have been detoxified from opioid dependence. Its main therapeutic action is to monopolize mu opioid receptors in the brain so that addictive opioids cannot link upward with them and stimulate the encephalon's reward system. Naltrexone clings to the mu opioid receptors 100 times more than strongly than opioids do, only it does not promote the brain processes that produce feelings of pleasure (Kosten and Kleber, 1984). An individual who is fairly dosed with naltrex-one does not obtain any pleasure from addictive opioids and is less motivated to utilize them.

Earlier naltrexone handling is started, patients must be fully detoxified from all opioids, including methadone and other treatment medications; otherwise, they will be at risk for astringent withdrawal. Naltrexone is given at 50 mg per mean solar day or up to 200 mg twice weekly. Patients' liver role should exist tested before handling starts, as heroin abusers may have experienced elevation of certain liver enzymes (transaminases) caused by infectious complications of intravenous drug utilize, such as hepatitis (Verebey and Mule, 1986).

Unfortunately, medication compliance is a critical problem with naltrexone, because unlike methadone or LAAM, naltrexone does not itself produce pleasurable feelings. Poor compliance limits naltrexone's utility to just nigh 15 pct of heroin addicts (Kosten and Kleber, 1984).

Naltrexone is as well sometimes used to apace detoxify patients from opioid dependence. In this situation, while naltrexone keeps the addictive opioid molecules away from the mu opioid receptors, clonidine may help to suppress the excessive NA output that is a primary cause of withdrawal (Kosten, 1990).

Buprenorphine

Buprenorphine'due south action on the mu opioid receptors elicits two different therapeutic responses within the brain cells, depending on the dose. At low doses buprenorphine has effects like methadone, but at high doses information technology behaves similar naltrexone, blocking the receptors and then strongly that it can precipitate withdrawal in highly dependent patients (that is, those maintained on more 40 mg methadone daily).

Buprenorphine is expected to be approved past the Nutrient and Drug Administration for the handling of opioid dependence in 2002. Several clinical trials have shown that when used in a comprehensive handling programme with psychotherapy, buprenorphine is equally effective as methadone, except for patients with heroin habit then severe they would require a dose of more than than 100 mg daily (Kosten et al., 1993; Oliveto et al., 1999; Schottenfeld et al., 1997). Buprenorphine offers a rubber advantage over methadone and LAAM, since loftier doses precipitate withdrawal rather than the suppression of consciousness and respiration seen in overdoses of methadone, LAAM, and the addictive opioids. Buprenorphine can be given three times per week. Because of its safety and convenient dosing, information technology may be useful for treating opioid addiction in primary care settings, which is peculiarly helpful since most opioid addicts take significant medical problems (for example, hepatitis B or C and HIV infection). Buprenorphine will be bachelor in 4 mg and 8 mg tablets. A combination tablet with naloxone (Suboxone) has been developed to negate the advantage a user would feel if he or she were to illegally divert and inject the medication. The maintenance dose of the combination tablet can be upwards to 24 mg and used for every-other-twenty-four hours dosing.

As office-based treatment of heroin habit becomes available, the highest possible rubber level (that is, minimal side effects) should exist counterbalanced with treatment effectiveness. The patient taking methadone must either visit the medical part daily (not feasible in most cases) or be responsible for taking daily doses at dwelling house, as scheduled. Accordingly, for an opioid-dependent patient who cannot be relied upon to accept the medication equally instructed and thus might overdose, buprenorphine in three doses weekly would be a safer choice than methadone. The patient's office visits could be express to once or twice per calendar week, with remaining buprenorphine doses taken at abode. Also, buprenorphine has less overdose potential than methadone, since it blocks other opioids and even itself equally the dosage increases.

SUMMARY

Opioid dependence and addiction are virtually appropriately understood equally chronic medical disorders, like hypertension, schizophrenia, and diabetes. Equally with those other diseases, a cure for drug habit is unlikely, and frequent recurrences tin can be expected; but long-term treatment can limit the illness's adverse effects and meliorate the patient's day-to-twenty-four hour period functioning.

The mesolimbic reward system appears to be central to the development of the direct clinical consequences of chronic opioid corruption, including tolerance, dependence, and addiction. Other brain areas and neurochemicals, including cortisol, also are relevant to dependence and relapse. Pharmacological interventions for opioid addiction are highly effective; nonetheless, given the circuitous biological, psychological, and social aspects of the disease, they must be accompanied by appropriate psychosocial treatments. Clinician awareness of the neurobiological basis of opioid dependence, and information-sharing with patients, can provide insight into patient behaviors and problems and analyze the rationale for treatment methods and goals.

Acquittance

This work was supported by NIDA grants number P50-DA-1-2762, K05-DA-0-0454, K12-DA-0-0167, R01-DA-1-3672, and R01-DA-1-4039.

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