In-patient detoxification procedures, treatment retention, and post-treatment opiate use: comparison of lofexidine + naloxone, lofexidine + placebo, and methadone.

OBJECTIVE: In-treatment and post-treatment outcomes were compared for three detoxification procedures (lofexidine+naloxone, lofexidine+placebo naloxone, and methadone). SAMPLE AND DESIGN: The sample was 137 opiate dependent in-patients. Detoxification treatments were 6-day lofexidine+naloxone (n=45), lofexidine+placebo naloxone (n=46), or 10-day methadone reduction (n=46). A cohort study design was used with double-blind random allocation to lofexidine+naloxone versus lofexidine+placebo. Patients who did not consent to, or who were excluded from randomisation received methadone. RESULTS: Outcome differences between treatment groups at follow-up were generally associated with length of stay post-detoxification rather than detoxification procedure. Among patients who were not opiate abstinent throughout follow-up (n=85), those who received lofexidine+naloxone detoxification reported a longer interval to first heroin use, with an interaction between detoxification medication and subsequent retention in treatment also identified. CONCLUSIONS: Detoxification medication may influence medium-term opiate use outcomes via its effect upon retention in treatment.

Induction of patients with moderately severe methadone dependence onto buprenorphine.

Current clinical practice allows patients with low levels of physiological dependence on opioids (equivalent to methadone doses of 30 mg/d or less) to be transferred to buprenorphine. This study investigated the response of opioid-dependent patients receiving doses of methadone between 30-70 mg/d when transferred to buprenorphine at doses between 12-16 mg/d. Twenty-three patients receiving inpatient opioid detoxification agreed to take part in a trial of facilitated transfer to buprenorphine. Following the last morning dose of methadone, buprenorphine was substituted in doses increasing from 4 mg to a maximum of 16 mg, with adjunctive lofexidine (maximum of 2.4 mg/d). All except two patients successfully completed transfer to buprenorphine. To investigate the effect of initial methadone dose, the group was split into intermediate dose (ID; 30 - 49 mg/d; n = 10) and high dose (HD; 50-70 mg/d; n = 11) groups. Average stabilisation dose of buprenorphine for the sample who completed transfer was 14.0 mg/d (SD 2.3) and average daily lofexidine dose during transfer was 0.57 mg (SD 0.39). The HD group used significantly more lofexidine to complete transfer compared to the ID group. Increased opioid withdrawal symptoms, of mild severity as measured by the Short Opiate Withdrawal Scale (SOWS), were found in the HD group compared with the ID group during the first and last day of buprenorphine stabilisation. However, average SOWS scores for the whole of the period of transfer were not significantly different from those during the period of stabilisation on buprenorphine in either the ID or HD groups. This study suggests that transfer to buprenorphine is relatively uncomplicated from daily methadone doses of 30-70 mg in an inpatient setting and may be facilitated by use of lofexidine. This procedure may allow a larger proportion of opioid-dependent patients access to buprenorphine treatment.

Are the Twelve Steps more acceptable to drug users than to drinkers? A comparison of experiences of and attitudes to Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) among 200 substance misusers attending inpatient detoxification.

The present study is a cross-sectional interview-based investigation comparing experiences of and attitudes towards Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) in a sample of 200 patients attending inpatient substance misuse detoxification services. Two hundred consecutive admissions were recruited; 100 each from one drug and one alcohol in-patient treatment service in which attendance at AA/NA was a voluntary adjunct to a generic treatment programme. Although there were no differences in the history of AA/NA attendance, the drug users (who were on average younger) reported significantly more positive attitudes towards AA/NA, more willingness to attend during their in-patient treatment and greater intention to attend following completion of their detoxification. In particular, despite no differences in spiritual/religious orientation, the drug users reported more positive views of the Twelve Steps. As AA/NA remain popular and accessible forms of substance misuse support, it is critical that we develop a clearer understanding of their impact and of the scope for their integration with generic forms of substance misuse treatment.

Salivary cortisol during opiate dependence and withdrawal.

Seventeen inpatients (14 men, three women) with opiate dependence and polysubstance misuse participated in a longitudinal study of salivary cortisol secretion during and after lofexidine detoxification treatment. Both opiate withdrawal symptoms and salivary cortisol were measured every morning for up to 25 days. Results were compared with a control group of 10 normal volunteers. There was an 80% reduction in withdrawal symptom severity between the first 12 days and the subsequent 12 days of treatment. Salivary cortisol fell from a mean of 22.3 nm/l over days 1-12 to 18.5 nm/l during days 13-25, a reduction of 17%. Salivary cortisol concentration correlated significantly with withdrawal symptom severity. Salivary cortisol levels remained significantly higher than controls for the duration of the study. The study supports a role for hypothalamo-pituitary-adrenal (HPA) activation in opiate withdrawal. The contribution of persistant dysregulation of the HPA, found in this study, to the vulnerability for relapse after abstinence has been achieved, is discussed.

The impact of naloxone/lofexidine combination treatment on the opiate withdrawal syndrome.

Clinical studies in opiate-dependent patients suggest that detoxification treatment with opiate antagonists may accelerate the resolution of the opiate withdrawal syndrome, permitting early induction onto naltrexone maintenance treatment. The present open study compared the clinical efficacy of daily naloxone injections in conjunction with lofexidine, with conventional lofexidine monotherapy, in 49 polysubstance-misusing opiate-dependent patients. Overall, the addition of naloxone did not confer substantial benefit over lofexidine monotherapy, although area-under-the-curve analysis showed that withdrawal severity in the naloxone/lofexidine combination group was significantly less than in the lofexidine monotherapy group, who experienced more severe withdrawal symptoms on days 4, 7, 9 and 13 of treatment. There were no significant differences in rates of completion of detoxification. Blood pressure remained within normal limits in both groups. Naltrexone maintenance treatment acceptability was low; only four patients continued with treatment for 5 or more days. The modest benefit of adding naloxone to lofexidine compared to the findings of previous opiate antagonist detoxification treatment studies is discussed in the context of the hypothesis that a critical level of opiate receptor occupancy is required to accelerate resolution of opiate withdrawal; the neurochemical mechanisms which may promote this are discussed.

Effects of methadone on cognition, mood and craving in detoxifying opiate addicts: a dose-response study.

RATIONALE: Methadone is the most widespread pharmacological treatment for opiate dependency but relatively little is known of its effects on cognitive and psychomotor functioning, drug craving and mood. OBJECTIVE: The present study aimed to assess the acute effects of methadone in patients admitted to an opiate detoxification programme. METHODS: Patients were randomly allocated to one of two groups who received either 50% or 100% of their daily stabilisation dose, and a placebo, in a double-blind, cross-over design. Twenty patients completed the study, all were assessed pre- and post-drug on 2 separate testing days. RESULTS: Performance on a task tapping episodic memory (delayed recall of a prose passage) was significantly impaired following the 100% daily dose of methadone. Methadone treatment had no effect on craving or mood. Patients were unable to distinguish between methadone and placebo treatments. CONCLUSIONS: A single dose of methadone can induce episodic memory impairment in patients who have a history of heroin use averaging more than 10 years. Such impairment can be avoided by giving methadone in divided doses.

Health care professionals referred for treatment of alcohol and drug problems.

This study reports on 62 health care professionals referred to a specialist drug and alcohol treatment service. Most patients used more than one type of substance. Health problems were common, but were seldom reasons for referral. Self-referral was infrequent. Referral was often subsequent to intoxication at work or persistent absenteeism. Just over half of admissions completed treatment. Multiple drug use was a poor prognostic indicator with fewer multiple drug users engaging with, or completing, treatment.

Neural responses associated with cue evoked emotional states and heroin in opiate addicts.

Ten male opiate addicts, who were current heroin injectors, underwent positron emission tomographic (PET) scanning during exposure to a sequence of six alternating drug related and neutral video cues, on two occasions. After the second scan, each subject received heroin or placebo using a randomised single-blind procedure. This design allowed the investigation of patterns of brain activity during a range of self-reported cue evoked emotional states, both in the presence and absence of heroin. Self-reports of 'urge to use' correlated strongly with increased regional blood flow (rCBF) in the inferior frontal and orbitofrontal cortex target regions of the mesolimbic dopaminergic system, implicated in conditioning and reward. 'Urge to use' was also associated with highly significant increased rCBF in the right pre-cuneus, an area associated with episodic memory retrieval, and in the left insula, implicated in the processing of the emotional components of stimuli. Self-reports of feeling 'high' correlated with rCBF activation in the hippocampus, an area relevant to the acquisition of stimulus-associated reinforcement.

Naltrexone and lofexidine combination treatment compared with conventional lofexidine treatment for in-patient opiate detoxification.

This study compares a naltrexone/lofexidine combination treatment with a 7-day course of lofexidine alone in the treatment of opiate withdrawal in 22 opiate-dependent patients. Withdrawal symptoms were significantly less severe on days 4-7, and 9-13, in the naltrexone/lofexidine combination group. There were no significant differences in the percentage of patients completing detoxification or in the mean length of stay for the two groups. Both treatments had similar, minimal effects on blood pressure. The naltrexone/lofexidine combination was associated with a more rapid resolution of the opiate withdrawal syndrome than a 7-day lofexidine-only treatment schedule, without substantial increases in withdrawal symptoms or hypotensive side-effects.

Lofexidine for opiate detoxification: review of recent randomised and open controlled trials.

The objective of this article was to review the data from recently published trials of lofexidine in the treatment of opiate withdrawal, with particular attention to evidence on efficacy, side-effects (particularly hypotension), and the acceptability of this new treatment to the patient population. The authors reviewed data contained within peer-reviewed published reports of clinical trials of lofexidine compared with detoxification using reducing doses of the opiate agonist methadone or the alpha-adrenergic agonist clonidine. Five published reports of clinical trials of lofexidine have been identified from peer-reviewed journals in the eight years between 1990 and 1998--all published within the last three years. Three of the reports compare lofexidine with clonidine, while the remaining two compare it with methadone detoxification. The three comparisons with clonidine find lofexidine to be similar in its moderating effect on the withdrawal syndrome, but without the same extent of problems with hypotension. Comparisons with methadone show a more rapid resolution of withdrawal symptoms with lofexidine--particularly with the accelerated 5-day lofexidine protocol. Such problems of hypotension as were encountered with lofexidine were adequately managed with dose reduction. Acceptability of the treatment to the patient (as measured by retention in treatment) appears to be greater with lofexidine than clonidine, although possibly less than with methadone. Lofexidine is an alpha-2 adrenergic agonist that is increasingly used in the management of opiate withdrawal--notably in the UK. The available data indicate that it is a useful new addition to the armamentarium of the clinician. Future studies should explore its application with improved protocols and in new treatment settings. This article reviews the recent advances in the study of lofexidine as a new treatment for opiate detoxification. It examines the background of the development and introduction of lofexidine into the U.K., with data on the extent to which it is now used in the U.K. in the treatment of opiate addiction. A review is then provided of the published evidence on the use of lofexidine in the management of opiate detoxification, mainly concentrating on the data from recent double-blind randomised trials. Finally, the possible future role of lofexidine in this field is considered.

Activation of reward circuitry in human opiate addicts.

The neurobiological mechanisms of opiate addictive behaviour in humans are unknown. A proposed model of addiction implicates ascending brainstem neuromodulatory systems, particularly dopamine. Using functional neuroimaging, we assessed the neural response to heroin and heroin-related cues in established opiate addicts. We show that the effect of both heroin and heroin-related visual cues are maximally expressed in the sites of origin of ascending midbrain neuromodulatory systems. These context-specific midbrain activations predict responses to salient visual cues in cortical and subcortical regions implicated in reward-related behaviour. These findings implicate common neurobiological processes underlying drug and drug-cue-related effects.

Accelerated lofexidine treatment regimen compared with conventional lofexidine and methadone treatment for in-patient opiate detoxification.

This open study compares an accelerated 5-day lofexidine regimen with orthodox 10-day lofexidine and methadone regimens in the treatment of opiate withdrawal in 61 polysubstance abusing opiate addicts. Significant differences in levels of withdrawal symptoms were found on days 11, 13-15 and 17-20, symptoms resolving most rapidly in the 5-day lofexidine treatment group, whilst withdrawal responses in the 10-day lofexidine treatment group were intermediate between the 5-day lofexidine and standard methadone treatment conditions. When the two lofexidine regimens were separately compared with methadone the 5-day lofexidine treatment was significantly more effective on day 10, 11 and 13-20, whilst the 10-day lofexidine treatment was not significantly different from methadone. There were no significant differences in rates of completion of detoxification between the three treatments. Both the lofexidine treatment regimens had a similar effect on blood pressure. Five patients experienced side effects which resolved with dose reduction, all remaining in the study. An accelerated 5-day lofexidine regimen may attenuate opiate withdrawal symptoms more rapidly than conventional 10-day lofexidine or methadone treatment schedules without exacerbating hypotensive side effects.

Route of drug use and its implications for drug effect, risk of dependence and health consequences.

Route of administration has a profound, but often overlooked, influence on the actual experience of the drug use itself, on the risk of resulting development of dependence, and on the nature of the harms to which drug users are exposing themselves. These three areas are reviewed. The influence of route of administration on drug effect is considered first with regard to overall effectiveness of absorption, and also with regard to speed of onset of effect. The implications for risk of dependence cover animal and human laboratory studies of reinforcement schedules, epidemiological studies, the attitudes of drug users themselves to the different routes of possible drug use and associated dependence risk and the postulated influences on progression to dependence. Finally, the relationship between route of drug use and health sequelae is explored for the three most widely used routes of administration of illicit drugs-snorting, smoking and injecting.

Changes in growth hormone, insulin, insulinlike growth factors (IGFs), and IGF-binding protein-1 in chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is characterized by severe physical and mental fatigue of central origin. Similar clinical features may occur in disorders of the hypothalamopituitary axis. The aim of the study was to determine whether patients with CFS have abnormalities of the growth hormone/insulinlike growth factor (GH-IGF) axis basally or following hypothalamic stimulation with insulin-induced hypoglycemia. We compared levels of GH, IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), insulin, and C-peptide in nondepressed CFS patients and normal controls. We found attenuated basal levels of IGF-I (214 +/- 17 vs. 263.4 +/- 13.4 micrograms/L, p = .036) and IGF-II (420 +/- 19.8 vs. 536 +/- 24.3 micrograms/L, p = .02) in CFS patients and a reduced GH response to hypoglycemia (peak GH; 41.9 +/- 11.5 vs. 106.0 +/- 25.6 mU/L, p = .017). Insulin levels were higher (7.6 +/- 1.0 vs. 4.3 +/- 0.8 mU/L, p = .02) and IGFBP-1 levels were lower (19.7 +/- 4.6 vs. 43.2 +/- 2.7 mg/L, p = .004) in CFS patients compared with controls. This study provides preliminary data abnormalities of the GH-IGF axis in CFS. It is not apparent whether these changes are components of a primary pathological process or are acquired secondary to behavioral aspects of CFS such as reduced physical activity.

Randomised double-blind comparison of lofexidine and methadone in the in-patient treatment of opiate withdrawal.

This study compares the clinical responses to methadone and lofexidine in the treatment of opiate withdrawal in 86 polydrug-abusing opiate addicts, using a randomised double-blind study design. The lofexidine treatment more severe symptoms from day 3 to 7 and again on day 10 (the last day of treatment), but thereafter both groups showed a similar progressive symptom decline. There was no significant difference in rates of treatment completion. Both treatments had similar effects on blood pressure. Lofexidine is broadly clinically equivalent to methadone, and appears to be a non-opiate treatment of opiate withdrawal without serious limiting hypotensive side effects.