A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users.

RATIONALE: Preclinical studies of the benzodiazepine antagonist flumazenil (Romazicon) have contributed to the understanding of the physical dependence associated with chronic benzodiazepine use; when administered to animals chronically pretreated with benzodiazepines, flumazenil precipitates a withdrawal syndrome. However, few controlled clinical studies have been conducted. OBJECTIVES: The objective was to characterize the effects of flumazenil in long-term users of therapeutic doses of benzodiazepines. METHODS: The acute physiological, participant-rated, and observer-rated effects of intravenously administered flumazenil (1 mg/70 kg) and caffeine (300 mg/70 kg; active drug control) were evaluated in an experimental group of 13 long-term users (mean 4.6 years) of low therapeutic doses (mean 11.2 mg/day diazepam equivalent) relative to a matched group of 13 volunteers without prior exposure to benzodiazepines in a double-blind, placebo-controlled, mixed design. RESULTS: Whereas the experimental group did not differ from the control group with respect to the effects of placebo, and both groups showed some changes in response to caffeine (e.g., increased blood pressure and anxiety scores), only the experimental group showed considerable changes in physiological measures, participant ratings (e.g., increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch), and observer ratings in response to flumazenil; in addition, four participants developed panic attacks. CONCLUSIONS: This study clearly demonstrates that flumazenil can precipitate symptoms commonly associated with benzodiazepine withdrawal in chronic low-dose benzodiazepine users.

Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers.

RATIONALE: Buprenorphine is an opioid agonist-antagonist under development in the United States as a sublingual medication for treatment of opioid dependence. Buprenorphine may be abused; therefore, tablets combining buprenorphine with naloxone have been developed with the intent of reducing the abuse risk in people physically dependent upon opioids. The characteristics and abuse potential of buprenorphine and buprenorphine/naloxone tablets in non-dependent opioid abusers have not been determined. Non-parenteral abuse of opioids such as buprenorphine may be more likely in people who have less severe substance abuse disorders (e.g., are not physically dependent upon opioids). OBJECTIVES: To assess the abuse potential of sublingual buprenorphine and buprenorphine/naloxone tablets in non-dependent opioid abusers. METHODS: Subjects (n=7) were tested with sublingual buprenorphine (4, 8, 16 mg), sublingual buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg), as well as intramuscular hydromorphone as an opioid agonist control (2, 4 mg) and placebo in laboratory sessions conducted twice per week. Dosing was double-blind and double-dummy. RESULTS: The higher doses of both buprenorphine and buprenorphine/naloxone produced similar opioid agonist-like effects. The onset of these effects was slowed, consistent with the sublingual route of administration, and the magnitude of effects was moderate. There was no evidence to suggest the addition of naloxone attenuated buprenorphine's opioid agonist effects in this population when buprenorphine was delivered by the sublingual route. CONCLUSIONS: These results suggest that sublingual buprenorphine and buprenorphine/naloxone may both be abused by opioid users who are not physically dependent upon opioids.

Effects of buprenorphine/naloxone in opioid-dependent humans.

RATIONALE: Buprenorphine is a partial mu opioid agonist under development as a sublingual (SL) medication for opioid dependence treatment in the United States. Because buprenorphine may be abused, tablets combining buprenorphine with naloxone in a 4:1 ratio have been developed to reduce that risk. Low doses of injected buprenorphine/naloxone have been tested in opioid-dependent subjects, but higher doses (more than 2 mg of either medication) and direct comparisons to SL buprenorphine/naloxone have not been examined. OBJECTIVES: To assess and compare the effects of intramuscular (i.m.) versus SL buprenorphine/naloxone in opioid-dependent volunteers. METHODS: Opioid-dependent volunteers were maintained on 40 mg per day of oral hydromorphone while on a residential research ward. After safety testing in two pilot subjects, participants (n = 8) were tested with both i.m. and SL buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg); i.m. hydromorphone (10 mg) and naloxone (0.25 mg); both i.m. and SL buprenorphine alone (8 mg); and placebo. Test sessions were twice per week; dosing was double-blind. RESULTS: Intramuscular buprenorphine/naloxone produced dose-related increases on indices of opioid antagonist effects. Effects were consistent with naloxone-precipitated withdrawal, and were short-lived. As withdrawal effects dissipated, euphoric opioid agonist effects from buprenorphine did not appear. Sublingual buprenorphine/naloxone produced neither opioid agonist nor antagonist effects. CONCLUSIONS: Intramuscular injection of buprenorphine/naloxone precipitates withdrawal in opioid dependent persons; therefore, the combination has a low abuse potential by the injection route in this population. Sublingual buprenorphine/naloxone by tablet is well tolerated in opioid dependent subjects, and shows neither adverse effects (i.e., precipitated withdrawal) nor a high abuse potential (i.e., opioid agonist effects).

Effects on visual tracking of delta9-tetrahydrocannabinol and pentobarbital.

Detal-9-tetrahydrocannabinol and pentobarbital both interfered with visual tracking performance. Of these, delta9THC had a statistically significant effect (P less than 0.04) when the first 12 responses for each subject were analyzed at each half-hourly period.

Predictive validity of cocaine, sedative, and alcohol dependence diagnoses.

This study examined the predictive validity of Structured Clinical Interview for DSM-III-R (Spitzer, Williams, Gibbon, & First, 1990) based substance dependence diagnoses (i.e., cocaine, sedative, and alcohol) for 518 opioid-dependent outpatients entering methadone maintenance. Patients were followed over 1 year of treatment, which involved daily methadone substitution supplemented by individual and group counseling. Urine specimens were tested randomly 1-4 times per month. Patients diagnosed with current cocaine, sedative, or alcohol dependence were more likely to use these drugs than were patients with past only or no dependence syndrome. Current cocaine dependence predicted early treatment dropout. The results demonstrate the predictive and discriminant validity of several substance dependence diagnoses common among patients in substance abuse or other psychiatric treatment settings.

Preliminary evidence of good treatment response in antisocial drug abusers.

Antisocial personality disorder (APD) is a chronic debilitating condition strongly associated with the development and maintenance of severe drug and alcohol use disorder. The overlap of these problems is associated with high rates of personal and social suffering. Available literature consistently point to this as a population in need of effective clinical services. The present study reports preliminary data from a controlled clinical trial aimed at improving the treatment outcomes of antisocial drug abusers using an intensive behavioral approach relying upon a highly structured contingency management intervention. Drug abusers in methadone substitution therapy (n = 40) were assessed for APD and other psychiatric and substance use problems. Patients were randomly assigned to an experimental (n = 20) or control (n = 20) condition following stratification on demographic and selected clinical variables (baseline drug use, evidence of other non-substance use psychiatric diagnoses). Treatment outcome data are presented for the first 17 weeks of participation in the study (4 weeks baseline and 13 weeks randomized treatment), including results of weekly urine drug testing and monthly self-reports of drug use and other psychosocial problems. Patients in both study conditions attained generally good outcomes. These early results suggest that antisocial drug abusers can respond positively to drug abuse treatments with a behavioral focus, but fail to support superior effectiveness for the more intensive intervention used in the experimental condition.

Intranasal airway/pack: description of a new device.

We have designed and developed a new intranasal pack which has been found to be most effective in controlling anterior and posterior epistaxis. Its ease of introduction and patient tolerance make it ideal for treating posterior epistaxis on an outpatient basis, and as packing for septal, sinus, or rhinoplastic surgery. The unique features of a breathing cannula and total intranasal tamponade distinguish this device from all preceding ones.

Short-term stability of NEO-PI-R personality trait scores in opioid-dependent outpatients.

The present study examined the short-term stability of personality trait scores from the Revised NEO Personality Inventory (NEO-PI-R) among 230 opioid-dependent outpatients. The NEO-PI-R is a 240-item empirically developed measure of the five-factor model of personality (Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness). Participants completed the NEO-PI-R at admission and again approximately 19 weeks later. Results indicated fair to good stability for all NEO-PI-R factor domain scores, with coefficients ranging from .68 to .74. Stability of NEO-PI-R scores was decreased among potentially invalid response patterns but was not significantly affected by drug-positive versus drug-negative status at follow-up.

Influence of psychiatric comorbidity on HIV risk behaviors: changes during drug abuse treatment.

This study evaluated whether psychiatric comorbidity is related to change in HIV high risk behaviors during outpatient drug abuse treatment. Participants were opioid abusers entering methadone treatment. Psychiatric and substance use diagnoses were determined at intake. Information on HIV high risk drug use and sexual behaviors, psychosocial functioning, and urine toxicology was assessed at intake and at month six. Subjects were divided into those with versus without a lifetime comorbid non-substance use psychiatric disorder. The comorbid group reported more injection equipment sharing, lower rates of condom use, and higher rates of alcohol use at intake and follow-up. Overall injection drug use behavior decreased over the follow-up period for both groups, however. Methadone treatment had a beneficial effect on HIV risk behaviors, and though some risk behaviors improved signiticantly for both groups, comorbid subjects continued to have higher rates of HIV risk factors than noncomorbid subjects.

Remote physiological sensing: historical perspective, theories and preliminary developments.

Many physiological processes are characterized by the generation and propagation of multiple, dynamic, infinitely variable, and often transient electrical phenomena in the respective tissues and organs where they originate. The purpose of physiological recording is to obtain a record that is an exact facsimile or analog of the events under investigation. However, since it is seldom feasible to attach pickup elements directly to the tissues or organs being investigated, some method of sensing the reflections and projections of the phenomena from the surface of the body must usually be employed. Such methods always introduce measurement errors that result in a distorted picture of the processes being recorded. In spite of this limitation, these techniques have proven highly useful for the medical and allied professions. As a result of the transition of medicine from a descriptive to an analytical science, a wide variety of pickup elements of various sophistication have been developed and are presently available for recording many important phenomena associated with various physiological functions from different anatomical sites. With the exception of the electrocardiogram (ECG), electroencephalogram (EEG), and electromyogram (EMG), other forms of biomonitoring have not yet achieved the acceptance necessary to allow their full development. It would seem that the development of the ECG, EEG, and EMG are reaching toward a plateau, and other forms of biomonitoring techniques are required to interpret physiological changes and parameters.

Attention deficit hyperactivity disorder and treatment outcome in opioid abusers entering treatment.

Symptoms of DSM-IV attention-deficit hyperactivity disorder (ADHD) were determined in patients entering methadone maintenance treatment. The relationship of ADHD to psychiatric and substance abuse comorbidity, attention testing, and treatment outcome was analyzed; 19% of patients had a history of ADHD, and 88% of these had current symptoms. Continuous Performance Testing indicated poorer attention in patients with ADHD. The only substance use disorder more common in the ADHD group was clonidine. There was significantly more current axis I, dysthymic disorder, anxiety disorder (including social phobia), and antisocial personality disorder in the ADHD patients. There was no difference between groups at the 1-year follow-up for illicit drug use, treatment retention, or treatment performance. The ADHD diagnosis did not convey significant prognostic implications for methadone maintenance treatment. A strong psychiatric assessment and treatment focus in the treatment program may help to explain the good treatment outcome.

Influence of antisocial personality subtypes on drug abuse treatment response.

This methodological study examined the impact of antisocial personality disorder (APD) and other psychiatric comorbidity on drug use and treatment retention in 513 new admissions to methadone maintenance treatment. Patients were classified into one of four groups: APD ONLY, APD plus other psychiatric disorder (APD MIXED), other psychiatric disorder, and no psychiatric disorder. Patients completed research assessments and were then followed for 1 year of treatment. Patients with APD had longer histories of heroin and cocaine use than non-APD patients and were more likely to meet criteria for cocaine dependence. Distinct clinical profiles emerged that differentiated APD ONLY from APD MIXED. APD ONLY patients exhibited higher rates of cocaine and heroin use, whereas those with APD MIXED exhibited higher rates of benzodiazepine use. Self-report measures supported urinalysis results, but group differences did not affect treatment retention. These differences in clinical profiles should be considered when evaluating treatment performance in substance abusers with APD.