Focus: Addiction: Prescription Sedative Misuse and Abuse

Sedatives are widely prescribed for anxiety or insomnia and include benzodiazepines, selective benzodiazepine receptor subtype agonists (z-drugs), and barbiturates. These sedatives are controlled substances due to their potential for misuse and abuse. Misuse is often self-medication (chemical coping) of psychological symptoms in ways unauthorized by the prescriber, usually as dose escalation leading to requests for early refills. Sedatives are abused for euphoric effects, which may have dangerous consequences. Some sedative overdoses can be treated with flumazenil, a reversal agent, along with supportive care. Sedative withdrawal syndrome is treated by tapering the sedative and may require hospitalization. Long-term treatment of sedative addiction requires counseling, often with the help of an addiction-treatment professional.     

Clinical pharmacology and therapeutics of benzodiazepines.

Benzodiazepines are among the most commonly prescribed drugs in the world. In contrast to their extensive use, the therapeutic indications and potential of benzodiazepines are limited. All benzodiazepine derivatives available in Canada are similar structurally and in their pharmacologic actions. Few have specific advantages over any others. For example, no benzodiazepine has been shown to be superior to chlordiazepoxide in the treatment of acute anxiety, chronic anxiety neurosis or insomnia. Barbiturates should not be prescribed for these problems since benzodiazepines are just as effective and are safer. Persons more than 70 years old should receive initial doses of benzodiazepines 50% less than those prescribed for younger persons, and individuals with cirrhosis should receive chlordiazepoxide or diazepam in one third the usual dose; oxazepam or lorazepam should be considered for these two groups of patients. Diazepam and chlordiazepoxide should not be given intramuscularly. Benzodiazepines should be prescribed only when clearly indicated and only for the necessary length of time.     

Defensive Thinking in Alcohol Addicts

Every day in Canada and the United States thousands of patients seek medical help for diseases and injuries acquired as a result of excessive alcohol consumption. Unfortunately much of the medical effort expended in this way is wasted. Failure to bridge the gap between initial treatment and a rehabilitation program is the main reason for this waste.Since the power of the abnormal desire in addiction compels the victim to continue to indulge in spite of his awareness of his addiction, he becomes more and more defensive. His thinking is marked by alibis, lying, projection, resentment and suspicion. Resistance to treatment becomes an integral part of the disability.The addict usually cannot stop defending his dependence simply because he is advised to do so. However, a physician can often find ways to interrupt defensive thinking long enough to initiate a treatment and rehabilitation program if he will consider the primary and secondary factors concerned.     

Genetic Markers of a Munc13 Protein Family Member,BAIAP3, Are Gender Specifically Associated with Anxiety and Benzodiazepine Abuse in Mice and Humans

Anxiety disorders and substance abuse, including benzodiazepine use disorder, frequently occur together. Unfortunately, treatment of anxiety disorders still includes benzodiazepines, and patients with an existing comorbid benzodiazepine use disorder or a genetic susceptibility for benzodiazepine use disorder may be at risk of adverse treatment outcomes. The identification of genetic predictors for anxiety disorders, and especially for benzodiazepine use disorder, could aid the selection of the best treatment option and improve clinical outcomes. The brain-specific angiogenesis inhibitor I–associated protein 3 (Baiap3) is a member of the mammalian uncoordinated 13 (Munc13) protein family of synaptic regulators of neurotransmitter exocytosis, with a striking expression pattern in amygdalae, hypothalamus and periaqueductal gray. Deletion of Baiap3 in mice leads to enhanced seizure propensity and increased anxiety, with the latter being more pronounced in female than in male animals. We hypothesized that genetic variation in human BAIAP3 may also be associated with anxiety. By using a phenotype-based genetic association study, we identified two human BAIAP3 single-nucleotide polymorphism risk genotypes (AA for rs2235632, TT for rs1132358) that show a significant association with anxiety in women and, surprisingly, with benzodiazepine abuse in men. Returning to mice, we found that male, but not female, Baiap3 knockout (KO) mice develop tolerance to diazepam more quickly than control animals. Analysis of cultured Baiap3 KO hypothalamus slices revealed an increase in basal network activity and an altered response to diazepam withdrawal. Thus, Baiap3/BAIAP3 is gender specifically associated with anxiety and benzodiazepine use disorder, and the analysis of Baiap3/BAIAP3-related functions may help elucidate mechanisms underlying the development of both disorders.     

Meta-analysis of benzodiazepine use in the treatment of insomnia

OBJECTIVE: To systematically review the benefits and risks associated with the use of benzodiazepines to treat insomnia in adults. DATA SOURCES: MEDLINE and the Cochrane Controlled Trials Registry were searched for English-language articles published from 1966 to December 1998 that described randomized controlled trials of benzodiazepines for the treatment of insomnia. Key words included "benzodiazepines" (exploded), "randomized controlled trial" and "insomnia." Bibliographies of relevant articles were reviewed for additional studies and manufacturers of benzodiazepines were asked to submit additional randomized controlled trial reports not in the literature. STUDY SELECTION: Articles were considered for the meta-analysis if they were randomized controlled trials involving patients with insomnia and compared a benzodiazepine with placebo or another active agent. Of the 89 trials originally identified, 45 met our criteria, representing a total of 2672 patients. DATA EXTRACTION: Data were extracted regarding the participants, the setting, details of the intervention, the outcomes (including adverse effects) and the methodologic quality of the studies. DATA SYNTHESIS: The meta-analyses of sleep records indicated that, when compared with placebo, benzodiazepines decreased sleep latency by 4.2 minutes (non-significant; 95% confidence interval (CI -0.7 to 9.2) and significantly increased total sleep duration by 61.8 minutes (95% CI 37.4 to 86.2). Patient-reported outcomes were more optimistic for sleep latency; those randomized to benzodiazepine treatment estimated a sleep latency decrease of 14.3 minutes (95% CI 10.6 to 18.0). Although more patients receiving benzodiazepine treatment reported adverse effects, especially daytime drowsiness and dizziness or light-headedness (common odds ratio 1.8, 95% CI 1.4 to 2.4), dropout rates for the benzodiazepine and placebo groups were similar. Cognitive function decline including memory impairment was reported in several of the studies. Zopiclone was not found to be superior to benzodiazepines on any of the outcome measures examined. INTERPRETATION: The use of benzodiazepines in the treatment of insomnia is associated with an increase in sleep duration, but this is countered by a number of adverse effects. Additional studies evaluating the efficacy of nonpharmacological interventions would be valuable.     

Penile curvatures

Penile curvatures are common. They are caused by tethering inelastic tissues that can be from the skin externally, from the congenital fibrous tissue of hypospadias and epispadias, and from inelastic tunica albuginea as in fractures, trauma, or Peyronie's disease. At the present time, with sexual organs exposed in photographs, human sexuality talked about with more freedom, and sexual experiences more open, a great deal of mental stress and anxiety can be produced by penile curvatures. Adjunct to this are impotency and other sexual problems. Surgical treatment is generally curative with grafts, flaps, excision of tunica albuginea, or repositioning and coaptation of the corporal bodies. Also, the use of a sex therapist can offer additional aid to the physician and realistic acceptance by the patient. More attention should be given to the patient with this problem. It is not well recognized by most physicians, and therefore, patients may suffer needlessly in silence without adequate help.     

Temperature dependence and GABA modulation of [3H]triazolam binding in the rat brain

The hypnotic triazolam (TZ), a triazolobenzodiazepine displays a short physiological half life and has been used for the treatment of insomnia related to anxiety states. Our major objectives were the direct measurement of the temperature dependence and the gamma-aminobutyric acid (GABA) effect of [3H]TZ binding in the rat brain. Saturation studies showed a shift to lower affinity with increasing temperatures (Kd = 0.27 +/- 08 nM at 0 degree C; Kd = 1.96 +/- 0.85 nM at 37 degrees C) while the Bmax values remained unchanged (1220 +/- 176 fmoles/mg protein at 0 degree C and 1160 +/- 383 fmoles/mg protein at 37 degrees C). Saturation studies of [3H]TZ binding in the presence or absence of GABA (100 microM) showed a GABA-shift. At 0 degrees C the Kd values were (Kd = 0.24 +/- 0.03 nM/-GABA; Kd = 0.16 +/- 0.04/+GABA) and at 37 degrees C the Kd values were (Kd = 1.84 +/- 0.44 nM/-GABA; Kd = 0.95 +/- 0.29 nM/+GABA). In contrast to reported literature, our findings show that TZ interacts with benzodiazepine receptors with a temperature dependence and GABA-shift consistent with predicted behavior for benzodiazepine agonists.     

Cigarette smoking,nicotine dependence,and treatment.

Since the 1988 Surgeon General''s report on nicotine addiction, more attention is being given to nicotine dependence as a substantial contributing factor in cigarette smokers'' inability to quit. Many new medications are being investigated for treating nicotine withdrawal and for assisting in long-term smoking abstinence. Medications alone probably will not be helpful; they should be used as adjuncts in comprehensive smoking abstinence programs that address not only the physical dependence on nicotine but also the psychological dependence on cigarette smoking.     

Ten ways to improve the treatment of depression and anxiety in adults

Complaints of depression and anxiety are very common among adult patients seeking treatment in primary care settings, and primary care providers prescribe the majority of medications for these conditions. Psychiatrists are often asked to evaluate and manage patients with major depression or anxiety disorders who have not improved after treatment in primary care.We highlight ten frequently overlooked aspects of the care of patients who present with depression and anxiety in primary care. Chief among these aspects is the consideration of a thorough differential diagnosis, particularly bipolar disorder, psychotic disorders, dementia and substance abuse, each of which requires specific treatment approaches. Additional considerations include avoidance of medications or doses that may aggravate anxiety symptoms and regular follow-ups to assess symptomatic and functional improvement. Finally, it is important to actively manage the treatment through dose escalation, switching medications or employing additional treatment components until remission is achieved.Judicious use of benzodiazepine clonazepam and appropriate referrals to psychotherapy can contribute to optimal treatment outcomes.     

Withdrawal from long-term benzodiazepine treatment.

Long-term, normal-dose benzodiazepine treatment was discontinued in 16 patients who were suspected of being dependent on their medication. The withdrawal was gradual, placebo-controlled, and double-blind. All the patients experienced some form of withdrawal reaction, which ranged from anxiety and dysphoria to moderate affective and perceptual changes. Symptom ratings rose as the drugs were discontinued, but usually subsided to prewithdrawal levels over the next two to four weeks. Other features of the withdrawal included disturbance of sleep and appetite and noticeable weight loss. Electroencephalography showed appreciable reduction in fast-wave activity as the drugs were withdrawn, and an improvement in psychological performance was recorded by the Digit Symbol Substitution Test. Because of the risk of dependence on benzodiazepines these agents should probably not be given as regular daily treatment for chronic anxiety.     

A physician's guide to discontinuing benzodiazepine therapy.

Practicing physicians need to have practical techniques to help patients who want to stop using benzodiazepines. I have developed three approaches that usually work. The first, and most widely applicable, is gradually reducing the dose without adding any other medicine. Failing this, use one of the following two approaches, occasionally combining them: switch to a longer-acting, cross-tolerant medication (usually clonazepam or phenobarbital) or use medications to suppress the withdrawal symptoms, usually carbamazepine, propranolol, or clonidine. If this fails, use inpatient detoxification. Chemically dependent patients, including those abusing alcohol and taking higher than recommended doses of sedative-hypnotics, require special care during discontinuation. Aftercare is important for all long-term benzodiazepine users if they are to remain drug-free and live relatively comfortable lives.     

Exploring subtype selectivity and metabolic stability of a novel series of ligands for the benzodiazepine binding site of the GABAA receptor

A novel series of agonists at the benzodiazepine binding site of the GABA_A receptor was prepared by functionalizing a known template. Adding substituents to the pyrazolone-oxygen of CGS-9896 led to a number of compounds with selectivities for either α2- or α1-containing GABA_A receptor subtypes offering an entry into indications such as anxiety and insomnia. In this communication, structure-activity relationship and efforts to increase in vitro stabilities are discussed.     

Can we help addicts become more autonomous? Inside the mind of an addict

I examine the impact of addiction on autonomy in terms of the standard literature on addiction--referred to also as 'substance dependence.' Then in terms of the criteria for substance dependence, by developing a set of practical strategies to help people with addictions think more clearly, I test the idea of whether addicts can be helped to become more autonomous. Given that unsuccessful attempts to quit constitute part of the criteria of substance dependence, I look at what goes wrong when people try to quit using a substance. The subjective experience of addiction is an important aid in understanding addiction and first person accounts and literary characterisations of addiction provide insight into the addict's mind and assist us in deciding whether addicts can be helped to become more autonomous.     

Can the Chronic Administration of the Combination of Buprenorphine and Naloxone Block Dopaminergic Activity Causing Anti-reward and Relapse Potential?

Opiate addiction is associated with many adverse health and social harms, fatal overdose, infectious disease transmission, elevated health care costs, public disorder, and crime. Although community-based addiction treatment programs continue to reduce the harms of opiate addiction with narcotic substitution therapy such as methadone maintenance, there remains a need to find a substance that not only blocks opiate-type receptors (mu, delta, etc.) but also provides agonistic activity; hence, the impetus arose for the development of a combination of narcotic antagonism and mu receptor agonist therapy. After three decades of extensive research, the federal Drug Abuse Treatment Act 2000 (DATA) opened a window of opportunity for patients with addiction disorders by providing increased access to options for treatment. DATA allows physicians who complete a brief specialty-training course to become certified to prescribe buprenorphine and buprenorphine/naloxone (Subutex, Suboxone) for treatment of patients with opioid dependence. Clinical studies indicate that buprenorphine maintenance is as effective as methadone maintenance in retaining patients in substance abuse treatment and in reducing illicit opioid use. With that stated, we must consider the long-term benefits or potential toxicity attributed to Subutex or Suboxone. We describe a mechanism whereby chronic blockade of opiate receptors, in spite of only partial opiate agonist action, may ultimately block dopaminergic activity causing anti-reward and relapse potential. While the direct comparison is not as yet available, toxicity to buprenorphine can be found in the scientific literature. In considering our cautionary note in this commentary, we are cognizant that, to date, this is what we have available, and until such a time when the real magic bullet is discovered, we will have to endure. However, more than anything else this commentary should at least encourage the development of thoughtful new strategies to target the specific brain regions responsible for relapse prevention.     

Continuously improving the practice of cardiology

Guidelines for the management of patients with cardiovascular disease are designed to assist cardiologists and other physicians in their practice. Surveys are conducted to assess whether guidelines are followed in practice. The results of surveys on acute coronary syndromes, coronary revascularisation, secondary prevention, valvular heart disease and heart failure are presented. Comparing surveys conducted between 1995 and 2002, a gradual improvement in use of secondary preventive therapy is observed. Nevertheless, important deviations from established guidelines are noted, with a significant variation among different hospitals in the Netherlands and in other European countries. Measures for further improvement of clinical practice include more rapid treatment of patients with evolving myocardial infarction, more frequent use of clopidogrel and glycoprotein IIb/IIIa receptor blockers in patients with acute coronary syndromes, more frequent use of β-blockers in patients with heart failure and more intense measures to encourage patients to stop smoking. Targets for the proportion of patients who might receive specific therapies are presented.     

Development of long term use of psychotropic drugs by general practice patients

From 1984 to 1986 a prospective study was conducted of 104 general practice patients who started treatment with a benzodiazepine or an antidepressant drug. The duration of reported use of the drugs was two months for 45% of patients, four months for 17% of patients, and six months for 15%. Type of drug, age, and level of education were found to be predictive of continuing use.General practitioners have a significant effect on their patients'' use of drugs and, with careful selection and review when prescribing, may help to prevent dependence on psychotropic drugs.     

The role of α-synuclein in the pathophysiology of alcoholism

Alcoholism has complex etiology and there is evidence for both genetic and environmental factors in its pathophysiology. Chronic, long-term alcohol abuse and alcohol dependence are associated with neuronal loss with the prefrontal cortex being particularly susceptible to neurotoxic damage. This brain region is involved in the development and persistence of alcohol addiction and neurotoxic damage is likely to exacerbate the reinforcing effects of alcohol and may hinder treatment. Understanding the mechanism of alcohol’s neurotoxic effects on the brain and the genetic risk factors associated with alcohol abuse are the focus of current research. Because of its well-established role in neurodegenerative and neuropsychological disorders, and its emerging role in the pathophysiology of addiction, here we review the genetic and epigenetic factors involved in regulating α-synuclein expression and its potential role in the pathophysiology of chronic alcohol abuse. Elucidation of the mechanisms of α-synuclein regulation may prove beneficial in understanding the role of this key synaptic protein in disease and its potential for therapeutic modulation in the treatment of substance use disorders as well as other neurodegenerative diseases.     

Death Following Inhalation of Mercury Vapor at Home.

Confusion exists among physicians over the legal requirements and appropriate prescribing of narcotics to addicted or habitual users of narcotics. The result has often been either (1) the deprivation of appropriate treatment for patients who desire detoxification or adequate pain relief, or (2) illegal prescribing by physicians. Because most narcotics are potent and dangerous substances, certain legal restrictions are necessary to protect the general public. State-approved programs have been established to prescribe methadone and propoxyphene napsylate for addiction treatment. Current laws and regulations in California permit every practicing physician to provide effective and safe treatment for addiction and pain relief.