Substance dependence, commonly called drug addiction, is a compulsive need to use drugs in order to function normally. When such substances are unobtainable, the user suffers from withdrawal. ΔFosB, a gene transcription factor, is now known to be the critical component and common factor in the development of virtually all forms of behavioral and drug addictions.
According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), substance dependence is defined as:
When an individual persists in use of alcohol or other drugs despite problems related to use of the substance, substance dependence may be diagnosed. Compulsive and repetitive use may result in tolerance to the effect of the drug and withdrawal symptoms when use is reduced or stopped. This, along with Substance Abuse are considered Substance Use Disorders....
Substance dependence can be diagnosed with physiological dependence, evidence of tolerance or withdrawal, or without physiological dependence. The DSM-IV does not use the word addiction at all.
Causes
Genetic factors
It has long been established that genetic factors along with social and psychological factors are contributors to addiction. A common theory along these lines is the self-medication hypotheses. Epidemiological studies estimate that genetic factors account for 40–60% of the risk factors for alcoholism. Similar rates of heritability for other types of drug addiction have been indicated by other studies. Knestler hypothesized in 1964 that a gene or group of genes might contribute to predisposition to addiction in several ways. For example, altered levels of a normal protein due to environmental factors could then change the structure or functioning of specific brain neurons during development. These altered brain neurons could change the susceptibility of an individual to an initial drug use experience. In support of this hypothesis, animal studies have shown that environmental factors such as stress can affect an animal's genotype.
Overall, the data implicating specific genes in the development of drug dependence is mixed for most genes. One reason this may be the case is due to a focus of current research on common variants. Many addiction studies focus on common variants with an allele frequency of greater than 5% in the general population, however when associated with disease, these only confer a small amount of additional risk with an odds ratio of 1.1-1.3. On the other hand, the rare variant hypothesis states that genes with low frequencies in the population (<1%) confer much greater additional risk in the development of disease.
GWAS studies represent the newest exploration into discovering associations between dependence, addiction, and drug use. These studies employ an unbiased approach to finding genetic associations with specific phenotypes and give equal weight to all regions of DNA, including those with no ostensible relationship to drug metabolism or response. Surprisingly, these studies very infrequently identify genes from proteins previously described via animal knockout models and candidate gene analysis. Instead, large percentages of genes involved in processes such as cell adhesion are commonly identified. This is not to say that previous findings, or the GWAS findings, are erroneous. The important effects of endophenotypes are typically not capable of being captured by these methods. Furthermore, genes identified in GWAS for drug dependence may be involved either in adjusting brain wiring prior to drug experiences, subsequent to them, or both.
Addictive potential
The addictive potential of a drug varies from substance to substance, and from individual to individual. Dose, frequency, pharmacokinetics of a particular substance, route of administration, and time are critical factors for developing a drug addiction.
An article in The Lancet compared the harm and addiction of 20 drugs, using a scale from 0 to 3 for physical addiction, psychological addiction, and pleasure to create a mean score for addiction. Selected results can be seen in the chart below.
| Drug | Mean | Pleasure | Psychological dependence | Physical dependence |
|---|---|---|---|---|
| Heroin | 3.00 | 3.0 | 3.0 | 3.0 |
| Cocaine | 2.39 | 3.0 | 2.8 | 1.3 |
| Tobacco | 2.21 | 2.3 | 2.6 | 1.8 |
| Barbiturates | 2.01 | 2.0 | 2.2 | 1.8 |
| Alcohol | 1.93 | 2.3 | 1.9 | 1.6 |
| Benzodiazepines | 1.83 | 1.7 | 2.1 | 1.8 |
| Amphetamine | 1.67 | 2.0 | 1.9 | 1.1 |
| Cannabis | 1.51 | 10.9 | 1.7 | 0.8 |
| Ecstasy | 1.13 | 1.5 | 1.2 | 0.7 |
Capture rates
The percentage of users who reported that they had become addicted to their respective drug at some point.
| Drug | Average User |
|---|---|
| Alcohol | 15.4% |
| Cannabis | 9% |
| Cocaine | 16.7% |
| Heroin | 23.1% |
| Tobacco | 31.9% |
Stress response
See also: Stress response
In addition to the reward pathway, it is hypothesized that stress mechanisms also play a role in addiction. Koob and Kreek have hypothesized that during drug use, thecorticotropin-releasing factor (CRF) activates the hypothalamic-pituitary-adrenal axis (HPA) and other stress systems in the extended amygdala. This activation influences the dysregulated emotional state associated with drug addiction. They have found that as drug use escalates, so does the presence of CRF in human cerebrospinal fluid (CSF). In rat models, the separate use of CRF antagonists and CRF receptor antagonists both decreased self-administration of the drug of study. Other studies in this review showed a dysregulation in other hormones associated with the HPA axis, including enkephalin which is an endogenous opioid peptide that regulates pain. It also appears that the µ-opioid receptor system, which enkephalin acts on, is influential in the reward system and can regulate the expression of stress hormones.
Behavior
Understanding how learning and behavior work in the mesolimbic pathway can help understand the action of addictive drugs. Drug addiction is characterized by strong, drug seeking behaviors in which the addict persistently craves and seeks out drugs, despite the knowledge of harmful consequences. Addictive drugs produce a reward, which is the euphoric feeling resulting from sustained dopamine concentrations in the synaptic cleft of neurons in the brain. Operant conditioning is exhibited in drug addicts as well as laboratory mice, rats, and primates; they are able to associate an action or behavior, in this case seeking out the drug, with a reward, which is the effect of the drug. Evidence shows that this behavior is most likely a result of the synaptic changes which have occurred due to repeated drug exposure. The drug seeking behavior is induced by glutamatergic projections from the prefrontal cortex to the NAc. This idea is supported with data from experiments showing the drug seeking behavior can be prevented following the inhibition of AMPA glutamate receptors and glutamate release in the NAc.
Psychological drug tolerance
The reward system is partly responsible for the psychological part of drug tolerance.
The CREB protein, a transcription factor activated by cyclic adenosine monophosphate (cAMP) immediately after a high, triggers genes that produce proteins such as dynorphin, which cuts off dopamine release and temporarily inhibits the reward pathway. In chronic drug users, a sustained activation of CREB thus forces a larger dose to be taken to reach the same effect. In addition it leaves the user feeling generally depressed and dissatisfied, and unable to find pleasure in previously enjoyable activities, often leading to a return to the drug for an additional "fix".
A similar mechanism, interfering also with the dopamine system, but relying on a different transcription factor, CEBPB, has also been proposed. In this case dopamine release onto the nucleus accumbens neurons would trigger the increased synthesis of substance P which, in turn, would increase the dopamine synthesis in the VTA. The effect of this positive feedback is suggested to be dampened by repeated substance abuse.
Sensitization
Sensitization is the increase in sensitivity to a drug after prolonged use. The proteins ΔFosB (Delta-FosB)and regulator of G-protein Signaling 9-2 (RGS9-2) are thought to be involved:
The ΔFosB transcription factor is thought to activate genes that, counter to the effects of CREB, actually increase the user's sensitivity to the effects of the substance. ΔFosB slowly builds up with each exposure to the drug and remains activated for weeks after the last exposure—long after the effects of CREB have faded. The hypersensitivity that it causes is thought to be responsible for the intense cravings associated with drug addiction, and is often extended to even the peripheral cues of drug use, such as related behaviors or the sight of drug paraphernalia. There is some evidence that ΔFosB even causes structural changes within the nucleus accumbens, which presumably helps to perpetuate the cravings, and may be responsible for the high incidence of relapses that occur in treated drug addicts.
Regulator of G-protein Signaling 9-2 (RGS9-2) has recently been the subject of several animal knockout studies. Animals lacking RGS9-2 appear to have increased sensitivity to dopamine receptor agonists such as cocaine and amphetamines; over-expression of RGS9-2 causes a lack of responsiveness to these same agonists. RGS9-2 is believed to catalyze inactivation of the G-protein coupled D2 receptor by enhancing the rate of GTP hydrolysis of the G alpha subunit which transmits signals into the interior of the cell.
Management
Treatments for addiction vary widely according to the types of drugs involved, amount of drugs used, duration of the drug addiction, medical complications and the social needs of the individual. Determining the best type of recovery program for an addicted person depends on a number of factors, including: personality, drug(s) of choice, concept of spirituality or religion, mental or physical illness, and local availability and affordability of programs.Addiction is a complex but treatable disease. It is characterized by compulsive drug craving, seeking, and use that persists even if the user is aware of severe adverse consequences. For some people, addiction becomes chronic, having periodic relapses even after long periods of abstinence. As a chronic, relapsing disease, addiction may require continued treatments to increase the intervals between relapses and diminish their intensity. While some with substance issues recover and lead fulfilling lives, others require ongoing additional support. The ultimate goal of addiction treatment is to enable an individual to manage their substance misuse; for some this may mean abstinence. Immediate goals are often to reduce substance abuse, improve the patient's ability to function, and minimize the medical and social complications of substance abuse and their addiction; this is called Harm Reduction.
Many different ideas circulate regarding what is considered a "successful" outcome in the recovery from addiction. Programs that emphasize controlled drinking exist for alcohol addiction. Opiate replacement therapy has been a medical standard of treatment for opioid addiction for many years.
Treatments and attitudes toward addiction vary widely among different countries. In the USA and developing countries, the goal of commissioners of treatment for drug dependence is generally total abstinence from all drugs. Other countries, particularly in Europe, argue the aims of treatment for drug dependence are more complex, with treatment aims including reduction in use to the point that drug use no longer interferes with normal activities such as work and family commitments; shifting the addict away from more dangerous routes of drug administration such as injecting to safer routes such as oral administration; reduction in crime committed by drug addicts; and treatment of other comorbid conditions such as AIDS, hepatitis and mental health disorders. These kinds of outcomes can be achieved without eliminating drug use completely. Drug treatment programs in Europe often report more favourable outcomes than those in the USA because the criteria for measuring success are functional rather than abstinence-based.The supporters of programs with total abstinence from drugs as a goal believe that enabling further drug use just means prolonged drug use and risks an increase in addiction and complications from addiction.
It is sometimes difficult to convince people with substance dependencies to engage in any form of treatment. Family Interventions have been highly successful in helping these people accept the help they need.
Residential
Residential drug treatment can be broadly divided into two camps: 12 step programs or Therapeutic Communities. 12 step programs have the advantage of coming with an instant social support network, though some find the spiritual context not to their taste. In the UK drug treatment is generally moving towards a more integrated approach with rehabs offering a variety of approaches. These other programs may use a Cognitive-Behavioral Therapy approach, such as SMART Recovery, that looks at the relationship between thoughts, feelings and behaviors, recognizing that a change in any of these areas can affect the whole. CBT sees addiction as a behavior rather than a disease and subsequently curable, or rather, unlearnable. CBT programs recognize that for some individuals controlled use is a more realistic possibility.
One of many recovery methods is the 12 step recovery program, with prominent examples including Alcoholics Anonymous, Narcotics Anonymous, Drug Addicts Anonymous[54]and Pills Anonymous. They are commonly known and used for a variety of addictions for the individual addicted and the family of the individual. Substance-abuse rehabilitation (or "rehab") centers offer a residential treatment program for some of the more seriously addicted in order to isolate the patient from drugs and interactions with other users and dealers. Outpatient clinics usually offer a combination of individual counseling and group counseling. Frequently a physician or psychiatrist will prescribe medications in order to help patients cope with the side effects of their addiction. Medications can help immensely with anxiety and insomnia, can treat underlying mental disorders (cf. Self-medication hypothesis, Khantzian 1997) such as (manic-)depression, and can help reduce or eliminate withdrawal symptomology when withdrawing from physiologically addictive drugs. Some examples are using benzodiazepines for alcohol detoxification, which prevents delirium tremens and complications; using a slow taper of benzodiazepines or a taper ofphenobarbital, sometimes including another antiepileptic agent such as gabapentin, pregabalin, or valproate, for withdrawal from barbiturates or benzodiazepines; using drugs such as baclofen to reduce cravings and propensity for relapse amongst addicts to any drug, especially effective in stimulant users, and alcoholics (in which it is nearly as effective as benzodiazepines in preventing complications); using clonidine, an alpha-agonist, and loperamide for opioid detoxification, for first-time users or those who wish to attempt an abstinence-based recovery (90% of opioid users relapse to active addiction within 8 months and/or are "multiple relapse patients"); or replacing an opioid that is interfering with or destructive to a user's life, such as illicitly-obtained heroin, Dilaudid, or oxycodone, with an opioid that can be administered legally, reduces or eliminates drug cravings, and does not produce a high, such as methadone or buprenorphine - opioid replacement therapy - which is the gold standard for treatment of opioid dependence in developed countries, reducing the risk and cost to both user and society more effectively than any other treatment modality (for opioid dependence), and shows the best short-term and long-term gains for the user, with the greatest longevity, least risk of fatality, greatest quality of life, and lowest risk of relapse and/or legal issues including arrest and incarceration.
In a survey of treatment providers from three separate institutions (the National Association of Alcoholism and Drug Abuse Counselors, Rational Recovery Systems and the Society of Psychologists in Addictive Behaviors) measuring the treatment provider's responses on the Spiritual Belief Scale (a scale measuring belief in the four spiritual characteristics AA identified by Ernest Kurtz); the scores were found to explain 41% of the variance in the treatment provider's responses on the Addiction Belief Scale (a scale measuring adherence to the disease model or the free-will model addiction).
Anti-addictive drugs
Other forms of treatment include replacement drugs such as suboxone/subutex (both containing the active ingredient buprenorphine) and methadone; these are used as substitutes for illicit opiate drugs. Although these drugs perpetuate physical dependence, the goal of opiate maintenance is to provide a clinically supervised, stable dose of a particular opioid in order to provide a measure of control to both pain and cravings. This provides a chance for the addict to function normally and to reduce the negative consequences associated with obtaining sufficient quantities of controlled substances illicitly, by both reducing opioid cravings and withdrawal symptomology. Once a prescribed dosage is stabilized, treatment enters maintenance or tapering phases. In the United States, opiate replacement therapy is tightly regulated in methadone clinics and under theDATA 2000 legislation. In some countries, other opioid derivatives such as levomethadyl acetate, dihydrocodeine, dihydroetorphine and even heroin are used as substitute drugs for illegal street opiates, with different drugs being used depending on the needs of the individual patient. Baclofen has been shown successful in attenuating cravings for most drugs of abuse - stimulants, ethanol, and opioids - and also attenuates the actual withdrawal syndrome of ethanol. Many patients have stated they "became indifferent to alcohol" or "indifferent to cocaine" overnight after starting baclofen therapy. It is possible that one of the best, albeit relatively unexplored, treatment modalities for opioid addiction - notoriously the most difficult addiction to treat (and to recover from), having relapse rates of around 23% at four weeks and 57% at twelve months if not on maintenance therapy with a mu-opioid agonist - would be to combine an opioid maintenance agent, such as methadone or buprenorphine, to block withdrawal symptomology, with baclofen, to attenuate cravings and the desire to use, in people who find that they are still using or still craving drugs while on methadone or buprenorphine maintenance.
Substitute drugs for other forms of drug dependence have historically been less successful than opioid substitute treatment, but some limited success has been seen with drugs such as dextroamphetamine to treat stimulant addiction, and clomethiazole to treat alcohol addiction. Bromocriptine and desipramine have been reported to be effective for treatment of cocaine but not amphetamine addiction.
Other pharmacological treatments for alcohol addiction include drugs like naltrexone, disulfiram, acamprosate and topiramate, but rather than substituting for alcohol, these drugs are intended to reduce the desire to drink, either by directly reducing cravings as with acamprosate and topiramate, or by producing unpleasant effects when alcohol is consumed, as with disulfiram. These drugs can be effective if treatment is maintained, but compliance can be an issue as alcoholic patients often forget to take their medication, or discontinue use because of excessive side effects. Additional drugs acting on glutamate neurotransmission such as modafinil, lamotrigine, gabapentin and memantine have also been proposed for use in treating addiction to alcohol and other drugs.
Opioid antagonists such as naltrexone and nalmefene have also been used successfully in the treatment of alcohol addiction, which is often particularly challenging to treat. Some have also attempted to use these drugs for maintenance treatment of former opiate addicts with little success. They cannot be started until the patient has been abstinent for an extended period - unlikely with opioid addicts who are not on maintenance with a full or partial mu-opioid agonist - or they will trigger acute opioid withdrawal symptoms. No study has found them to be efficacious treatments in preventing relapse. They do nothing to block craving, and block endorphin and enkephalin, two natural neurotransmitters that regulate one's sense of well-being. An addict must discontinue the drug for just eighteen hours in order to use again.
Treatment of stimulant addiction can often be difficult, with substitute drugs often being ineffective, although newer drugs such as nocaine, vanoxerine and modafinil may have more promise in this area, as well as the GABAB agonist baclofen. Another strategy that has recently been successfully trialled used a combination of the benzodiazepineantagonist flumazenil with hydroxyzine and gabapentin for the treatment of methamphetamine addiction.
Another area in which drug treatment has been widely used is in the treatment of nicotine addiction. Various drugs have been used for this purpose such as bupropion,mecamylamine and the more recently developed varenicline. The cannaboinoid antagonist rimonabant has also been trialled for treatment of nicotine addiction but has not been widely adopted for this purpose.
Ibogaine is a hallucinogen (psychotomimetic) that some claim interrupts addiction and reduces or eliminates withdrawal syndromes, specifically in regards to opioids. Its mechanism of action is unknown, but likely linked to nAchR α3ß4 antagonism. In one animal trial, it was shown to slightly reduce self-administration of cocaine. Another uncontrolled trial showed it reduced tremor by a mild to moderate degree during morphine withdrawal in rats.These finding can not be extrapolated to human beings with any certainty. Research is complicated by the fact that ibogaine is illegal in many developed countries, and a Schedule I substance in the US, and as a result no controlled human trials have ever been performed. A semi-synthetic analogue of ibogaine, 18-methoxycoronaridine was developed, in an attempt to reduce the toxic (ibogaine is significantly cardiotoxic, and several deaths have been reported from its use; because of its illegal, underground nature, it is impossible to know how toxic the drug is) and psychotomimetic effects of the drug.
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