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1.  Medical prescription of heroin to treatment resistant heroin addicts: two randomised controlled trials 
BMJ : British Medical Journal  2003;327(7410):310.
Objective To determine whether supervised medical prescription of heroin can successfully treat addicts who do not sufficiently benefit from methadone maintenance treatment.
Design Two open label randomised controlled trials.
Setting Methadone maintenance programmes in six cities in the Netherlands.
Participants 549 heroin addicts.
Interventions Inhalable heroin (n = 375) or injectable heroin (n = 174) prescribed over 12 months. Heroin (maximum 1000 mg per day) plus methadone (maximum 150 mg per day) compared with methadone alone (maximum 150 mg per day). Psychosocial treatment was offered throughout.
Main outcome measures Dichotomous, multidomain response index, including validated indicators of physical health, mental status, and social functioning.
Results Adherence was excellent with 12 month outcome data available for 94% of the randomised participants. With intention to treat analysis, 12 month treatment with heroin plus methadone was significantly more effective than treatment with methadone alone in the trial of inhalable heroin (response rate 49.7% v 26.9%; difference 22.8%, 95% confidence interval 11.0% to 34.6%) and in the trial of injectable heroin (55.5% v 31.2%; difference 24.3%, 9.6% to 39.0%). Discontinuation of the coprescribed heroin resulted in a rapid deterioration in 82% (94/115) of those who responded to the coprescribed heroin. The incidence of serious adverse events was similar across treatment conditions.
Conclusions Supervised coprescription of heroin is feasible, more effective, and probably as safe as methadone alone in reducing the many physical, mental, and social problems of treatment resistant heroin addicts.
PMCID: PMC169643  PMID: 12907482
2.  Randomised trial of heroin maintenance programme for addicts who fail in conventional drug treatments 
BMJ : British Medical Journal  1998;317(7150):13-18.
Objective: To evaluate an experimental heroin maintenance programme.
Design: Randomised trial.
Setting: Outpatient clinic in Geneva, Switzerland.
Subjects: Heroin addicts recruited from the community who were socially marginalised and in poor health and had failed in at least two previous drug treatments.
Intervention: Patients in the experimental programme (n=27) received intravenous heroin and other health and psychosocial services. Control patients (n=24) received any other conventional drug treatment (usually methadone maintenance).
Main outcome measures: Self reported drug use, health status (SF-36), and social functioning.
Results: 25 experimental patients completed 6 months in the programme, receiving a median of 480 mg of heroin daily. One experimental subject and 10 control subjects still used street heroin daily at follow up (difference 44%; 95% confidence interval 16% to 71%). Health status scores that improved significantly more in experimental subjects were mental health (0.58 SD; 0.07 to 1.10), role limitations due to emotional problems (0.95 SD; 0.11 to 1.79), and social functioning (0.65 SD; 0.03 to 1.26). Experimental subjects also significantly reduced their illegal income and drug expenses and committed fewer drug and property related offences. There were no benefits in terms of work, housing situation, somatic health status, and use of other drugs. Unexpectedly, only nine (38%) control subjects entered the heroin maintenance programme at follow up.
Conclusions: A heroin maintenance programme is a feasible and clinically effective treatment for heroin users who fail in conventional drug treatment programmes. Even in this population, however, another attempt at methadone maintenance may be successful and help the patient to stop using injectable opioids.
Key messages A heroin maintenance programme may be a useful treatment option for patients who do not succeed in conventional drug treatment programmes Patients randomly allocated to the Geneva heroin maintenance programme fared better that patients in conventional drug treatments in terms of street drug use, mental health, social functioning, and illegal activities Results of the trial apply only to a subgroup of severely addicted people who failed repeatedly in conventional drug treatments This evaluation does not distinguish between the effects of heroin itself and the effects of other medical and psychosocial services that were provided as part of the programme There was less demand for the heroin maintenance programme than anticipated and most control subjects declined entry into the programme at the end of the study
PMCID: PMC28595  PMID: 9651260
3.  Methodology for the Randomised Injecting Opioid Treatment Trial (RIOTT): evaluating injectable methadone and injectable heroin treatment versus optimised oral methadone treatment in the UK 
Whilst unsupervised injectable methadone and diamorphine treatment has been part of the British treatment system for decades, the numbers receiving injectable opioid treatment (IOT) has been steadily diminishing in recent years. In contrast, there has been a recent expansion of supervised injectable diamorphine programs under trial conditions in a number of European and North American cities, although the evidence regarding the safety, efficacy and cost effectiveness of this treatment approach remains equivocal. Recent British clinical guidance indicates that IOT should be a second-line treatment for those patients in high-quality oral methadone treatment who continue to regularly inject heroin, and that treatment be initiated in newly-developed supervised injecting clinics.
The Randomised Injectable Opioid Treatment Trial (RIOTT) is a multisite, prospective open-label randomised controlled trial (RCT) examining the role of treatment with injected opioids (methadone and heroin) for the management of heroin dependence in patients not responding to conventional substitution treatment. Specifically, the study examines whether efforts should be made to optimise methadone treatment for such patients (e.g. regular attendance, supervised dosing, high oral doses, access to psychosocial services), or whether such patients should be treated with injected methadone or heroin.
Eligible patients (in oral substitution treatment and injecting illicit heroin on a regular basis) are randomised to one of three conditions: (1) optimized oral methadone treatment (Control group); (2) injected methadone treatment; or (3) injected heroin treatment (with access to oral methadone doses). Subjects are followed up for 6-months, with between-group comparisons on an intention-to-treat basis across a range of outcome measures. The primary outcome is the proportion of patients who discontinue regular illicit heroin use (operationalised as providing >50% urine drug screens negative for markers of illicit heroin in months 4 to 6). Secondary outcomes include measures of other drug use, injecting practices, health and psychosocial functioning, criminal activity, patient satisfaction and incremental cost effectiveness. The study aims to recruit 150 subjects, with 50 patients per group, and is to be conducted in supervised injecting clinics across England.
doi:10.1186/1477-7517-3-28
PMCID: PMC1613238  PMID: 17002810
4.  Maintenance treatment for opioid dependence with slow-release oral morphine: a randomized cross-over, non-inferiority study versus methadone 
Addiction (Abingdon, England)  2014;109(4):617-626.
Aims
To compare the efficacy of slow-release oral morphine (SROM) and methadone as maintenance medication for opioid dependence in patients previously treated with methadone.
Design
Prospective, multiple-dose, open label, randomized, non-inferiority, cross-over study over two 11-week periods. Methadone treatment was switched to SROM with flexible dosing and vice versa according to period and sequence of treatment.
Setting
Fourteen out-patient addiction treatment centres in Switzerland and Germany.
Participants
Adults with opioid dependence in methadone maintenance programmes (dose ≥50 mg/day) for ≥26 weeks.
Measurements
The efficacy end-point was the proportion of heroin-positive urine samples per patient and period of treatment. Each week, two urine samples were collected, randomly selected and analysed for 6-monoacetyl-morphine and 6-acetylcodeine. Non-inferiority was concluded if the two-sided 95% confidence interval (CI) in the difference of proportions of positive urine samples was below the predefined boundary of 10%.
Findings
One hundred and fifty-seven patients fulfilled criteria to form the per protocol population. The proportion of heroin-positive urine samples under SROM treatment (0.20) was non-inferior to the proportion under methadone treatment (0.15) (least-squares mean difference 0.05; 95% CI = 0.02, 0.08; P > 0.01). The 95% CI fell within the 10% non-inferiority margin, confirming the non-inferiority of SROM to methadone. A dose-dependent effect was shown for SROM (i.e. decreasing proportions of heroin-positive urine samples with increasing SROM doses). Retention in treatment showed no significant differences between treatments (period 1/period 2: SROM: 88.7%/82.1%, methadone: 91.1%/88.0%; period 1: P = 0.50, period 2: P = 0.19). Overall, safety outcomes were similar between the two groups.
Conclusions
Slow-release oral morphine appears to be at least as effective as methadone in treating people with opioid use disorder.
doi:10.1111/add.12440
PMCID: PMC4226326  PMID: 24304412
Dose–response; maintenance treatment; methadone; opioid addiction; retention rate; slow-release oral morphine
5.  A randomized clinical trial of methadone maintenance for prisoners: findings at 6 months post-release 
Addiction (Abingdon, England)  2008;103(8):1333-1342.
Aims
This study examined the effectiveness of methadone maintenance initiated prior to or just after release from prison at 6 months post-release.
Design
A three-group randomized controlled trial was conducted between September 2003 and June 2005.
Setting
A Baltimore pre-release prison.
Participants
Two hundred and eleven adult pre-release inmates who were heroin-dependent during the year prior to incarceration.
Intervention
Participants were assigned randomly to the following: counseling only: counseling in prison, with passive referral to treatment upon release (n = 70); counseling + transfer: counseling in prison with transfer to methadone maintenance treatment upon release (n = 70); and counseling + methadone: methadone maintenance and counseling in prison, continued in a community-based methadone maintenance program upon release (n = 71).
Measurements
Addiction Severity Index at study entry and follow-up. Additional assessments at 6 months post-release were treatment record review; urine drug testing for opioids, cocaine and other illicit drugs.
Findings
Counseling + methadone participants were significantly more likely than both counseling only and counseling + transfer participants to be retained in drug abuse treatment (P = 0.0001) and significantly less likely to have an opioid-positive urine specimen compared to counseling only participants (P = 0.002). Furthermore, counseling + methadone participants reported significantly fewer days of involvement in self-reported heroin use and criminal activity than counseling only participants.
Conclusions
Methadone maintenance, initiated prior to or immediately after release from prison, increases treatment entry and reduces heroin use at 6 months post-release compared to counseling only. This intervention may be able to fill an urgent treatment need for prisoners with heroin addiction histories.
doi:10.1111/j.1360-0443.2008.002238.x
PMCID: PMC2582162  PMID: 18855822
Heroin addiction; methadone maintenance; prisoners; randomized clinical trial; substance abuse treatment
6.  Effectiveness and Cost Effectiveness of Expanding Harm Reduction and Antiretroviral Therapy in a Mixed HIV Epidemic: A Modeling Analysis for Ukraine 
PLoS Medicine  2011;8(3):e1000423.
A cost-effectiveness study by Sabina Alistar and colleagues evaluates the effectiveness and cost effectiveness of different levels of investment in methadone, ART, or both, in the mixed HIV epidemic in Ukraine.
Background
Injection drug use (IDU) and heterosexual virus transmission both contribute to the growing mixed HIV epidemics in Eastern Europe and Central Asia. In Ukraine—chosen in this study as a representative country—IDU-related risk behaviors cause half of new infections, but few injection drug users (IDUs) receive methadone substitution therapy. Only 10% of eligible individuals receive antiretroviral therapy (ART). The appropriate resource allocation between these programs has not been studied. We estimated the effectiveness and cost-effectiveness of strategies for expanding methadone substitution therapy programs and ART in mixed HIV epidemics, using Ukraine as a case study.
Methods and Findings
We developed a dynamic compartmental model of the HIV epidemic in a population of non-IDUs, IDUs using opiates, and IDUs on methadone substitution therapy, stratified by HIV status, and populated it with data from the Ukraine. We considered interventions expanding methadone substitution therapy, increasing access to ART, or both. We measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, infections averted, and incremental cost-effectiveness. Without incremental interventions, HIV prevalence reached 67.2% (IDUs) and 0.88% (non-IDUs) after 20 years. Offering methadone substitution therapy to 25% of IDUs reduced prevalence most effectively (to 53.1% IDUs, 0.80% non-IDUs), and was most cost-effective, averting 4,700 infections and adding 76,000 QALYs compared with no intervention at US$530/QALY gained. Expanding both ART (80% coverage of those eligible for ART according to WHO criteria) and methadone substitution therapy (25% coverage) was the next most cost-effective strategy, adding 105,000 QALYs at US$1,120/QALY gained versus the methadone substitution therapy-only strategy and averting 8,300 infections versus no intervention. Expanding only ART (80% coverage) added 38,000 QALYs at US$2,240/QALY gained versus the methadone substitution therapy-only strategy, and averted 4,080 infections versus no intervention. Offering ART to 80% of non-IDUs eligible for treatment by WHO criteria, but only 10% of IDUs, averted only 1,800 infections versus no intervention and was not cost effective.
Conclusions
Methadone substitution therapy is a highly cost-effective option for the growing mixed HIV epidemic in Ukraine. A strategy that expands both methadone substitution therapy and ART to high levels is the most effective intervention, and is very cost effective by WHO criteria. When expanding ART, access to methadone substitution therapy provides additional benefit in infections averted. Our findings are potentially relevant to other settings with mixed HIV epidemics.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
HIV epidemics in Eastern Europe and Central Asia are mainly driven by increasing use of injection drugs combined with heterosexual transmission. In the Ukraine, in 2007, there were 82,000 officially registered people living with HIV—three times the number registered in 1999—and an estimated 395,000 HIV infected adults. The epidemic in Ukraine, like other countries in the region, is concentrated in at-risk populations, particularly people who inject drugs: in 2007, an estimated 390,000 Ukrainians were injecting drugs, an increase in drug use over the previous decade, not only in Ukraine, but in other former USSR states, owing to the easy availability of precursors for injection drugs in a climate of economic collapse.
The common practices of people who inject drugs in Ukraine and in other countries in the region, such as social injecting, syringe sharing, and using common containers, increase the risk of transmitting HIV. Public health interventions such as needle exchange can limit these risk factors and have been gradually implemented in these countries. In 2007, Ukraine approved the use of methadone substitution therapy and the current target is for 11,000 people who inject drugs to be enrolled in substitution therapy by 2011. Furthermore, since treatment for HIV-infected individuals is also necessary, national HIV control plans included a target of 90% antiretroviral therapy (ART) coverage by 2010 but in 2007 less than 10% of the 91,000 eligible people received treatment. Although the number of people who inject drugs and who receive ART is unknown, physicians are often reluctant to treat people who inject drugs using ART owing to alleged poor compliance.
Why Was This Study Done?
As resources for HIV interventions in the region are limited, it is important to investigate the appropriate balance between investments in methadone substitution therapy and ART in order to maximize benefits to public health. Several studies have analyzed the cost effectiveness of methadone substitution therapy in similar settings but have not considered tradeoffs between ART and methadone substitution therapy. Therefore, to provide insights into the appropriate public health investment in methadone substitution therapy and ART in Ukraine, the researchers evaluated the public health effectiveness and cost effectiveness of different strategies for scaling up methadone substitution therapy and/or expanding ART.
What Did the Researchers Do and Find?
The researchers developed a model to accommodate different population groups: people who inject drugs on substitution therapy with methadone; people who inject opiates and do not take any substitution therapy; and people who do not inject any drugs, hence do not need substitution therapy. The researchers inputted Ukraine country-level data into this model and used current HIV trends in Ukraine to make rational assumptions on possible future trends and scenarios. They considered scenarios expanding methadone substitution therapy availability, increasing acces to ART, or both. Then, the researchers measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, infections averted, and incremental cost effectiveness for the different scenarios. They found that after 20 years, HIV prevalence reached 67.2% in people who inject drugs and 0.88% in people who do not inject drugs without further interventions. Offering methadone substitution therapy to 25% of people who inject drugs was the most effective strategy in reducing prevalence of HIV and was also the most cost effective, averting 4,700 infections and adding 75,700 QALYs versus the status quo at $530/QALY gained. Expanding both methadone substitution therapy and ART was also a highly cost effective option, adding 105,000 QALYs at US$1,120/QALY gained versus the methadone substitution therapy-only strategy. Offering ART to 80% of eligible people who did not inject drugs, and 10% of people who injected drugs averted only 1,800 infections, and added 76,400 QALYs at $1,330/QALY gained.
What Do These Findings Mean?
The results show that methadone substitution-focused therapeutic scenarios are the most cost effective, and that benefits increase with the scale of the project, even among people who do not inject drugs. This makes a methadone substitution strategy a highly cost-effective option for addressing the growing HIV epidemic in Ukraine. Therefore, if it is not feasible to invest in large-scale methadone substitution programs for any reason, political circumstances for example, providing as much methadone substitution as is acceptable is still desirable. While substitution therapy appears to avert the most HIV infections, expanded ART provides the largest total increase in QALYs. Thus, methadone substitution therapy and ART offer complementary benefits. Because the HIV epidemic in Ukraine is representative of the HIV epidemic in Eastern Europe and Central Asia, the cost-effective strategies that the researchers have identified may help inform all decision makers faced with a mixed HIV epidemic.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000423.
Alliance provides information on its work supporting community action on AIDS in Ukraine
USAID provides an HIV/AIDS Health Profile for Ukraine
UNICEF provides information about its activities to help Ukraine fight rising HIV/AIDS infection rates
International Harm Reduction Association provides information about the status of harm reduction interventions such as methadone substitution therapy around the world
doi:10.1371/journal.pmed.1000423
PMCID: PMC3046988  PMID: 21390264
7.  Randomized Trial of Standard Methadone Treatment Compared to Initiating Methadone without Counseling: 12-month Findings 
Addiction (Abingdon, England)  2012;107(5):943-952.
Aims
This study aimed to determine the relative effectiveness of 12-months of Interim Methadone (IM; supervised methadone with emergency counseling only for the first 4 months of treatment), Standard Methadone treatment (SM; with routine counseling) and Restored Methadone treatment (RM: routine counseling with smaller caseloads).
Design
A randomized controlled trial was conducted comparing: IM, SM, and RM treatment. IM lasted for 4 months after which participants were transferred to SM.
Setting
The study was conducted in two methadone treatment programs in Baltimore, MD, USA.
Participants
The study included 230 adult methadone patients newly-admitted through waiting lists.
Measurements
We administered the Addiction Severity Index and a supplemental questionnaire at baseline, 4-, and 12-months post- baseline.
Measurements included retention in treatment, self-reported days of heroin and cocaine use, criminal behavior and arrests, and urine tests for heroin and cocaine metabolites.
Findings
At 12 months, on an intent-to-treat basis, there were no significant differences in retention in treatment among the IM, SM and RM groups (60.6%, 54.8% and 37.8%, respectively). Positive urine tests for the three groups declined significantly from baseline (ps<0.001 and 0.003, for heroin and cocaine metabolistes respectively) but there were no significant Group x Time interactions for these measures. Thirty-one percent of the sample reported at least one arrest during the year, but there were no significant between-group effects.
Conclusions
Limited availability of drug counseling services should not be a barrier to providing supervised methadone to adults dependent on heroin - at least for the first 4 months of treatment.
doi:10.1111/j.1360-0443.2011.03700.x
PMCID: PMC3319854  PMID: 22029398
Interim methadone; methadone treatment; counseling; heroin addiction treatment
8.  Optimum Methadone Compliance Testing 
Executive Summary
Objective
The objective of this analysis was to determine the diagnostic utility of oral fluid testing collected with the Intercept oral fluid collection device.
Clinical Need: Target Population and Condition
Opioids (opiates or narcotics) are a class of drugs derived from the opium poppy plant that typically relieve pain and produce a euphoric feeling. Methadone is a long-acting synthetic opioid used to treat opioid dependence and chronic pain. It prevents symptoms of opioid withdrawal, reduces opioid cravings and blocks the euphoric effects of short-acting opioids such as heroin and morphine. Opioid dependence is associated with harms including an increased risk of exposure to Human Immunodeficiency Virus and Hepatitis C as well as other health, social and psychological crises. The goal of methadone treatment is harm reduction. Treatment with methadone for opioid dependence is often a long-term therapy. The Ontario College of Physicians and Surgeons estimates that there are currently 250 physicians qualified to prescribe methadone, and 15,500 people in methadone maintenance programs across Ontario.
Drug testing is a clinical tool whose purpose is to provide objective meaningful information, which will reinforce positive behavioral changes in patients and guide further treatment needs. Such information includes knowledge of whether the patient is taking their methadone as prescribed and reducing or abstaining from using opioid and other drugs of abuse use. The results of drug testing can be used with behavior modification techniques (contingency management techniques) where positive reinforcements such as increased methadone take-home privileges, sustained employment or parole are granted for drug screens negative for opioid use, and negative reinforcement including loss of these privileges for drug screens positive for opioid used.
Body fluids including blood, oral fluid, often referred to as saliva, and urine may contain metabolites and the parent drug of both methadone and drugs of abuse and provide a means for drug testing. Compared with blood which has a widow of detection of several hours, urine has a wider window of detection, approximately 1 to 3 days, and is therefore considered more useful than blood for drug testing. Because of this, and the fact that obtaining a urine specimen is relatively easy, urine drug screening is considered the criterion measure (gold standard) for methadone maintenance monitoring. However, 2 main concerns exist with urine specimens: the possibility of sample tampering by the patient and the necessity for observed urine collection. Urine specimens may be tampered with in 3 ways: dilution, adulteration (contamination) with chemicals, and substitution (patient submits another persons urine specimen). To circumvent sample tampering the supervised collection of urine specimens is a common and recommended practice. However, it has been suggested that this practice may have negative effects including humiliation experienced by patient and staff, and may discourage patients from staying in treatment. Supervised urine specimen collection may also present an operational problem as staff must be available to provide same-sex supervision. Oral fluid testing has been proposed as a replacement for urine because it can be collected easily under direct supervision without infringement of privacy and reduces the likelihood of sample tampering. Generally, the results of oral fluid drug testing are similar to urine drug testing but there are some differences, such as lower concentrations of substances in oral fluid than urine, and some drugs remain detectable for longer periods of time in urine than oral fluid.
The Technology Being Reviewed
The Intercept Oral Specimen Collection Device (Ora-Sure Technologies, Bethlehem, PA) consists of an absorbent pad mounted on a plastic stick. The pad is coated with common salts. The absorbent pad is inserted into the mouth and placed between the cheek and gums for 3 minutes on average. The pad absorbs the oral fluid. After 3 minutes (range 2min-5 min) the collection device is removed from the mouth and the absorbent pad is placed in a small vial which contains 0.8mL of pH-balanced preservative, for transportation to a laboratory for analysis. It is recommended that the person undergoing oral fluid drug testing have nothing to eat or drink for a 10- minute period before the oral fluid specimen is collected. This will remove opportunity for adulteration. Likewise, it is recommended that the person be observed for the duration of the collection period to prevent adulteration of the specimen. An average of 0.4 mL of saliva can be collected. The specimen may be stored at 4C to 37C and tested within 21 days of collection (or within 6 weeks if frozen).
The oral fluid specimen must be analyzed in a laboratory setting. There is no point-of-care (POC) oral fluid test kit for drugs of abuse (other than for alcohol). In the laboratory the oral fluid is extracted from the vial after centrifugation and a screening test is completed to eliminate negative specimens. Similar to urinalysis, oral fluid specimens are analyzed first by enzyme immunoassay with positive specimens sent for confirmatory testing. Comparable cut-off values to urinalysis by enzyme immunoassay have been developed for oral fluids
Review Strategy
 
Research Question
What is the diagnostic utility of the Intercept oral specimen device?
Inclusion criteria:
Studies evaluating paired urine and oral fluid specimens from the same individual with the Intercept oral fluid collection device.
The population studied includes drug users.
Exclusion criteria:
Studies testing for marijuana (THC) only.
Outcomes:
Sensitivity and Specificity of oral fluid testing compared to urinalysis for methadone (methadone metabolite), opiates, cocaine, benzodiazepines, and alcohol.
Quality of the Body of Evidence
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the overall quality of the body of evidence (defined as 1 or more studies) supporting the research questions explored in this systematic review. A description of the GRADE system is reported in Appendix 1.
Summary of Findings
A total of 854 potential citations were retrieved. After reviewing titles and abstracts, 2 met the inclusion and exclusion criteria. Two other relevant studies were found after corresponding with the author of the 2 studies retrieved from the literature search. Therefore a total of 4 published studies are included in this analysis. All 4 studies carried out by the same investigator meet the definition of Medical Advisory Secretariat level III (not a-randomized controlled trial with contemporaneous controls) study design. In each of the studies, paired urine and oral fluid specimens where obtained from drug users. Urine collection was not observed in the studies however, laboratory tests for pH and creatinine were used to determine the reliability of the specimen. Urine specimens thought to be diluted and unreliable were removed from the evaluation. Urinalysis was used as the criterion measurement for which to determine the sensitivity and specificity of oral fluid testing by the Intercept oral fluid device for opiates, benzodiazepines, cocaine and marijuana. Alcohol was not tested in any of the 4 studies. From these 4 studies, the following conclusions were drawn:
The evidence indicates that oral fluid testing with the Intercept oral fluid device has better specificity than sensitivity for opiates, benzodiazepines, cocaine and marijuana.
The sensitivity of oral fluids testing with the Intercept oral fluid device seems to be from best to worst: cocaine > benzodiazepines >opiates> marijuana.
The sensitivity and specificity for opiates of the Intercept oral fluid device ranges from 75 to 90% and 97- 100% respectively.
The consequences of opiate false-negatives by oral fluid testing with the Intercept oral fluid device need to be weighed against the disadvantages of urine testing, including invasion of privacy issues and adulteration and substitution of the urine specimen.
The window of detection is narrower for oral fluid drug testing than urinalysis and because of this oral fluid testing may best be applied in situations where there is suspected frequent drug use. When drug use is thought to be less frequent or remote, urinalysis may offer a wider (24-48 hours more than oral fluids) window of detection.
The narrow window of detection for oral fluid testing may mean more frequent testing is needed compared to urinalysis. This may increase the expense for drug testing in general.
POC oral fluid testing is not yet available and may limit the practical utility of this drug testing methodology. POC urinalysis by immunoassay is available.
The possible applications of oral fluid testing may include:
Because of its narrow window of detection compared to urinalysis oral fluid testing may best be used during periods of suspected frequent or recent drug use (within 24 hours of drug testing). This is not to say that oral fluid testing is superior to urinalysis during these time periods.
In situations where an observed urine specimen is difficult to obtain. This may include persons with “shy bladder syndrome” or with other urinary conditions limiting their ability to provide an observed urine specimen.
When the health of the patient would make urine testing unreliable (e,g., renal disease)
As an alternative drug testing method when urine specimen tampering practices are suspected to be affecting the reliability of the urinalysis test.
Possible limiting Factors to Diffusion of Oral Fluid Technology
No oral fluid POC test equivalent to onsite urine dips or POC analyzer reducing immediacy of results for patient care.
Currently, physicians get reimbursed directly for POC urinalysis. Oral fluid must be analyzed in a lab setting removing physician reimbursement, which is a source of program funding for many methadone clinics.
Small amount of oral fluid specimen obtained; repeat testing on same sample will be difficult.
Reliability of positive oral fluid methadone (parent drug) results may decrease because of possible contamination of oral cavity after ingestion of dose. Therefore high methadone levels may not be indicative of compliance with treatment. Oral fluid does not as yet test for methadone metabolite.
There currently is no licensed provincial laboratory that analyses oral fluid specimens.
Abbreviations
2-ethylidene- 1,5-dimethyl-3,3-diphenylpyrrolidine
enzyme immunoassay
Enzyme Linked Immunosorbent Assay (ELISA),
Enzyme Multiplied Immunoassay Test (EMIT)
Gas chromatography
gas chromatography/mass spectrometry
High-performance liquid chromatography
Limit of Detection
Mass spectrometry
Methadone Maintenance Treatment
Oral fluid testing
Phencyclidine
Point of Care Testing
tetrahydrocannabinol
11-nor-delta-9-tetrhydrocannabinol-9-carboxylic acid
urine drug testing
PMCID: PMC3379523  PMID: 23074492
9.  Association between methadone dose and concomitant cocaine use in methadone maintenance treatment: a register-based study 
Background
Concomitant cocaine use is a major problem in clinical practice in methadone maintenance treatment (MMT) and may interfere with successful treatment. Data from European methadone populations is sparse. This register-based study sought to explore the association between prescribed methadone dose and concomitant cocaine and heroin use in the methadone population of Basel City.
Methods
The study included 613 methadone patients between April 1, 2003 and March 31, 2004. Anonymized data was taken from the methadone register of Basel City. For analysis of the prescribed methadone dose distribution, the patient sample was split into three methadone dosage groups: a low dose group (LDG) (n = 200; < 60 mg/day), a medium dose group (MDG) (n = 273; 60 to 100 mg/day), and a high dose group (HDG) (n = 140; > 100 mg/day). Concomitant drug use was based on self-report.
Results
Analysis showed a significant difference in self-reported cocaine use between groups (p < 0.001). Patients in the LDG reported significantly fewer cocaine consumption days compared to the MDG (p < 0.001) and the HDG (p < 0.05). Patients in the HDG reported significantly fewer heroin consumption days than those in the LDG (p < 0.01) and the MDG (p < 0.001). In logistic regression analysis, cocaine use was significantly associated with heroin use (OR 4.9).
Conclusions
Cocaine use in methadone patients may be associated with heroin use, which indicates the importance of prescribing appropriate methadone dosages in order to indirectly reduce cocaine use.
doi:10.1186/1747-597X-9-46
PMCID: PMC4280704  PMID: 25472871
Cocaine use; Methadone dose; Methadone maintenance treatment; Opioid dependence
10.  Buprenorphine Outpatient Outcomes Project: can Suboxone be a viable outpatient option for heroin addiction? 
Background
Opioid dependence treatment traditionally involves methadone clinics, for which dispensing schedules can be cumbersome. Buprenorphine, a partial agonist of the mu receptor and antagonist of the kappa receptor, is a potential outpatient alternative to methadone. Funded by a grant from the State of Maryland's Community Health Resources Commission (CHRC), the Buprenorphine Outpatient Outcomes Project (BOOP) evaluates the outcome of Suboxone (buprenorphine/naloxone) treatment on abstinence from heroin use, rates of emergency room visits and hospitalizations, legal issues, and quality of life.
Methods
Active heroin users were recruited between June 2007 and June 2010 and induction therapy with Suboxone was instituted during hospitalization. Once discharged, patients were followed as outpatients for maintenance treatment and counseling. Data were collected from electronic medical records, Maryland state legal records, and SF-36® Health Surveys regarding several parameters and patients were categorized according to duration of treatment with Suboxone into one of three groups: <1 month, 1–3 months, and >3 months.
Results
A total of 220 participants were included in the study. The age range of participants was 18–67 years with most being African American males. Eighty-three (38%) remained in the study for at least 1 month, with 37 of the 83 (45%) remaining in treatment for >3 months. Ten of the 37 (27%) never relapsed after their longest period of abstinence from heroin. During the first year after initiating treatment with Suboxone, hospitalization and emergency room visit rates for all 220 participants decreased by 45 and 23%, respectively, as compared to the year prior to starting treatment. The number of legal charges for drug possession decreased from 70 to 62. Anecdotally, the quality of life seemed to improve in those who were treated with Suboxone for longer periods of time and received regular counseling.
Conclusion
Overall, Suboxone is an effective treatment method for heroin addiction and is a viable outpatient therapy option. Individualized treatment plans and counseling must be implemented for maximum benefits to be seen. Retention of patients for a long duration of therapy was difficult, but for those who did remain, benefits were seen in overall health, abstinence from heroin use, cognition, and quality of life.
doi:10.3402/jchimp.v4.22902
PMCID: PMC3992357  PMID: 24765257
Suboxone; heroin abuse; substance abuse treatment; quality of life
11.  Substitution treatment for opioid addicts in Germany 
Background
After a long and controversial debate methadone maintenance treatment (MMT) was first introduced in Germany in 1987. The number of patients in MMT – first low because of strict admission criteria – increased considerably since the 1990s up to some 65,000 at the end of 2006. In Germany each general practitioner (GP), who has completed an additional training in addiction medicine, is allowed to prescribe substitution drugs to opioid dependent patients. Currently 2,700 GPs prescribe substitution drugs. Psychosocial care should be made available to all MMT patients.
Results
The results of research studies and practical experiences clearly indicate that patients benefit substantially from MMT with improvements in physical and psychological health. MMT proves successful in attaining high retention rates (65 % to 85 % in the first years, up to 50 % after more than seven years) and plays a major role in accessing and maintaining ongoing medical treatment for HIV and hepatitis. MMT is also seen as a vital factor in the process of social re-integration and it contributes to the reduction of drug related harms such as mortality and morbidity and to the prevention of infectious diseases. Some 10 % of MMT patients become drug-free in the long run. Methadone is the most commonly prescribed substitution medication in Germany, although buprenorphine is attaining rising importance. Access to MMT in rural areas is very patchy and still constitutes a problem. There are only few employment opportunities for patients participating in MMT, although regular employment is considered unanimously as a positive factor of treatment success. Substitution treatment in German prisons is heterogeneous in access and treatment modalities. Access is very patchy and the number of inmates in treatment is limited. Nevertheless, substitution treatment plays a substantial part in the health care system provided to drug users in Germany.
Conclusion
In Germany, a history of substitution treatment spanning 20 years has meanwhile accumulated a wealth of experience, e.g. in the development of research on health care services, guidelines and the implementation of quality assurance measures. Implementing substitution treatment with concomitant effects and treatment elements such as drug history-taking, dosage setting, co-use of other psychoactive substances (alcohol, benzodiazepines, cocaine), management of 'difficult patient populations', and integration into the social environment has been arranged successfully. Also psychosocial counseling programmes adjuvant to substitution treatment have been established and, in the framework of a pilot project on heroin-based treatment, standardised manuals were developed. Research on allocating opioid users to the 'right' form of therapy at the 'right' point in time is still a challenge, though the pilot project 'heroin-based treatment' brought experience with patients who do not benefit from methadone treatment. There is also expertise in the treatment of specific co-morbidity such as HIV/AIDS, hepatitis and psychiatric disorders. The promotion and involvement of self-help groups plays an important part in the process of successful substitution treatment.
doi:10.1186/1477-7517-4-5
PMCID: PMC1797169  PMID: 17270059
12.  30-Year Trajectories of Heroin and Other Drug Use Among Men and Women Sampled From Methadone Treatment in California* 
Drug and alcohol dependence  2011;118(2-3):251-258.
Background
This study examines 30-year trajectories of heroin and other drug use among men and women who were in methadone maintenance treatment in California in the late1970s and interviewed in 1978–1981.
Methods
Nearly half (n = 428; 46.8%) of the original study sample (N = 914) was deceased. Of the remaining 486 subjects, 343 (44.3% female) completed a follow-up interview in 2005-09 (70.6% of those not deceased). Average age at follow-up was 58.3 (SD = 4.9) years for males and 55.0 (SD = 4.1) years for females. Longitudinal data was obtained on their drug use, treatment participation, and criminal justice status over the follow-up period. Trajectory group modeling was used to identify distinctive trajectory groups based on monthly averages of heroin and other drug use per year; group differences were examined.
Results
Four heroin and five alcohol and other drug (AOD) trajectory groups were identified. A greater proportion of women (60%) were in the “rapid decrease” heroin group (odds of use less than 10% by 10 years following initiation of use) as compared with the other groups. More rapid decrease of heroin use was associated with increases in AOD use, whereas a gradual decrease in heroin use was associated with a gradual decrease in AOD use. More school problems and earlier age at onset of heroin use and first arrest were associated with more persistent heroin use.
Conclusion
Heroin-use trajectories were linked with changes in AOD use. Childhood antecedents of heroin-use trajectories were identified as well as gender differences.
doi:10.1016/j.drugalcdep.2011.04.004
PMCID: PMC3156933  PMID: 21549528
longitudinal research; gender; heroin dependence; trajectory group models
13.  Heroin Dependence Treatment in Malaysia: A randomized, double-blind placebo-controlled comparison of buprenorphine and naltrexone maintenance treatment 
Lancet  2008;371(9631):2192-2200.
Background
Expanding access to effective treatments for heroin dependence is a global health priority that will also reduce HIV transmission. This study compares the efficacy for maintaining heroin abstinence, preventing relapse, and reducing HIV risk behaviors of three common treatments: detoxification followed by drug counseling only or drug counseling combined with opioid antagonist (naltrexone) or agonist (buprenorphine) maintenance treatment.
Methods
126 detoxified heroin dependent patients in Malaysia were randomly assigned to 24 weeks of medication maintenance with naltrexone, buprenorphine, or placebo, provided double-blind and double-dummy. All patients received manual-guided drug counseling. Primary outcomes, assessed by three times per week urine testing, were days to first heroin use, days to heroin relapse (3 consecutive opioid-positive urine tests), maximum consecutive days heroin abstinence, and, assessed by self-report at baseline, 3- and 6-months, reductions in HIV risk behaviors. The study was terminated after 22 months of enrolment, based on findings of superior buprenorphine efficacy in an interim safety analysis and the recommendation of the Data and Safety Monitoring Board. This study is registered with ClinicalTrials.gov, with the number NCT00383045.
Findings
We observed consistent, significant linear contrasts in days to first heroin use (p<0.001), days to heroin relapse (p<0.001), maximum consecutive days heroin abstinence (p<0.01), and retention (p<0.001), with all results best for buprenorphine, intermediate for naltrexone, and worst for placebo. Buprenorphine was associated with significantly greater time to first heroin use and retention compared to naltrexone (p<0.01 for both measures) or placebo (p<0.001 for both measures) and also significantly greater time to heroin relapse (p<0.01) and maximum consecutive weeks abstinent (p<0.01) compared to placebo. There were no significant differences between naltrexone and placebo on these measures. HIV risk behaviors were significantly reduced from baseline across all 3 treatments (p<0.001), but the reductions did not differ significantly among the 3 treatments.
Interpretation
The effectiveness of buprenorphine for maintaining prolonged periods of abstinence, delaying the time to resumption of heroin use or relapse, and retaining patients in treatment supports widespread dissemination of opioid agonist maintenance treatment.
doi:10.1016/S0140-6736(08)60954-X
PMCID: PMC4041792  PMID: 18586174
Heroin Dependence; Buprenorphine; Naltrexone; Randomized Clinical Trial; HIV/AIDS
14.  Use of general practice by intravenous heroin users on a methadone programme. 
Users of intravenous heroin represent a major challenge for general practice. A study was undertaken in a general practice in central London in 1990 to investigate the use of general practice made by intravenous heroin users who were on a methadone programme. Using information recorded in the patients' notes, 29 intravenous heroin users on a methadone programme were identified; 58 non-drug users (two controls per case) were matched for age, sex and general practitioner. A study of the number of routine consultations, missed appointments, emergency appointments and prescribed items showed that during the study period, those on a methadone programme made a larger number of routine consultations than the control subjects (median number of consultations 14 versus 0). When consultations at which only a prescription was issued were excluded this difference disappeared. Appointments were missed by 14 drug abusers (48%) but by none of the control group (P < 0.001). Emergency appointments were made by seven drug abusers (24%) compared with only two controls (3%) (P < 0.01). Even after prescriptions for methadone hydrochloride had been excluded from the analysis, patients on the methadone programme were prescribed significantly more items than patients in the control group (P < 0.001). This research has shown that intravenous heroin users on a methadone programme used general practice to a greater extent than non-drug users, according to the criteria used in the study. The implications that this may have in discouraging budget holding practices from running such schemes are discussed.
PMCID: PMC1372269  PMID: 1472393
15.  A Randomized Clinical Trial of Methadone Maintenance for Prisoners: Results at One-Month Post- Release 
Drug and alcohol dependence  2007;91(2-3):220-227.
Background
Despite its effectiveness, methadone maintenance is rarely provided in American correctional facilities. This study is the first randomized clinical trial in the US to examine the effectiveness of methadone maintenance treatment provided to prisoners with pre-incarceration heroin addiction.
Methods
A three-group randomized controlled trial was conducted between September 2003 and June 2005. Two hundred-eleven Baltimore pre-release inmates who were heroin dependent during the year prior to incarceration were enrolled in this study. Participants were randomly assigned to the following: Counseling Only: counseling in prison, with passive referral to treatment upon release (n = 70); Counseling + Transfer: counseling in prison with transfer to methadone maintenance treatment upon release (n = 70); and Counseling + Methadone: methadone maintenance and counseling in prison, continued in a community-based methadone maintenance program upon release (n = 71).
Results
Two hundred participants were located for follow-up interviews and included in the current analysis. The percentages of participants in each condition that entered community-based treatment were, respectively, Counseling Only 7.8%, Counseling + Transfer 50.0%, and Counseling + Methadone 68.6%, p < .05. All pairwise comparisons were statistically significant, (all ps < .05). The percentage of participants in each condition that tested positive for opioids at one month post-release were, respectively, Counseling Only 62.9%, Counseling + Transfer 41.0%, and Counseling + Methadone 27.6%, p < .05, with the Counseling Only group significantly more likely to test positive than the Counseling + Methadone group.
Conclusions
Methadone maintenance initiated prior to or immediately after release from prison appears to have beneficial short-term impact on community treatment entry and heroin use. This intervention may be able to fill an urgent treatment need for prisoners with heroin addiction histories.
doi:10.1016/j.drugalcdep.2007.05.022
PMCID: PMC2423344  PMID: 17628351
methadone maintenance; drug abuse treatment; prisoners; heroin addiction
16.  Concurrent heroin use among methadone maintenance clients in China 
Addictive Behaviors  2011;37(3):264-268.
Background
The study examined concurrent illicit heroin use among methadone maintenance clients in China and its association with clients’ demographic characteristics, treatment experience, and personal social network.
Methods
Face-to-face surveys were conducted with 178 clients randomly recruited from six methadone maintenance treatment (MMT) clinics in Sichuan, China. Concurrent heroin use was measured based on self-report of heroin use during the past 30 days and a confirmatory urine morphine test. The participants’ demographic characteristics and treatment factors were measured and examined. The drug use status of their family members and friends was also assessed.
Results
A total of 80 participants (44.9%) who either reported illicit heroin use in the past 30 days or had a positive urine test were defined as using heroin concurrently. Having drug-using friends was significantly associated with increased concurrent heroin use. Longer length of treatment (2 years or longer) was associated with increased concurrent heroin use. Among those who had both drug-using family members and friends, more women (71.4%) than men (50.0%) used heroin. For those who had no drug-using family members or friends, more men (34.8%) than women (20.8%) used heroin.
Discussion
Study findings indicate an urgent need to address concurrent illicit heroin use among MMT clients. Further examination of the influence of social networks on concurrent drug abuse behavior is encouraged. Results also highlight the importance of understanding gender differences in treatment seeking and behavioral changes, which is crucial to the development of gender-specific treatment strategies.
doi:10.1016/j.addbeh.2011.11.004
PMCID: PMC3258322  PMID: 22100548
Drug use; Methadone maintenance therapy; China
17.  Differences in sociodemographic, drug use and health characteristics between never, former and current injecting, problematic hard-drug users in the Netherlands 
Background
Injecting drug users are at increased risk for harmful effects compared to non-injecting drug users. Some studies have focused on differences in characteristics between these two groups (e.g., housing, overall health). However, no study has investigated the specific Dutch situation which in the last years has seen a decrease in homelessness among problematic hard-drug users and an increasing focus on physical health in low-threshold addiction care. The purpose of this study was to determine differences in sociodemographic, drug use and health characteristics between never-injecting (NIDUs), former-injecting (FIDUs) and current-injecting drug users (IDUs) and describe injecting practices.
Methods
A total of 202 problematic hard-drug users (NIDU = 64; FIDU = 76; IDU = 62) were recruited from 22 low-threshold care facilities, including drug consumption rooms, methadone maintenance treatment, heroin-assisted therapy, day shelter and/or night shelter, supported housing and day activity centres. Data were collected on-site through structured face-to-face interviews.
Results
Results indicate that IDUs represented a separate group of problematic hard-drug users, with distinct sociodemographic and drug use characteristics. Overall, IDUs appeared to be the group with least favourable characteristics (unstable housing/homelessness, illegal activities, polydrug use) and NIDUs appeared to have the most favourable characteristics (stable housing, help with debts, less polydrug use). The FIDU group lies somewhere in between. The three groups did not differ significantly in terms of health. Regarding injecting practices, results showed that majority of IDUs had injected drugs for over 10 years and IDUs injected heroin, cocaine, amphetamine and/or methadone in the past 6 months. Sharing syringes was not common. A quarter reported public injecting.
Conclusions
Unstable housing and homelessness are related to (former) injecting drug use, and stable housing is related to never-injecting drug use. Our study suggests that the number of ‘new’ IDUs is low. However, public injecting among IDUs is not uncommon and is associated with unstable housing. This emphasizes the potential of housing projects as a component of harm reduction measures. Therefore, prevention of (risks associated with) injecting drug use and supported housing programmes for problematic hard-drug users deserve the continuous attention of policymakers and professionals in low-threshold addiction care.
doi:10.1186/1477-7517-11-6
PMCID: PMC3926265  PMID: 24524263
Injecting drug use; Non-injecting drug use; Housing; Homelessness; Opiate use; Health; Low-threshold care
18.  NAOMI: The trials and tribulations of implementing a heroin assisted treatment study in North America 
Background
Opioid addiction is a chronic, relapsing disease and remains a major public health challenge. Despite important expansions of access to conventional treatments, there are still significant proportions of affected individuals who remain outside the reach of the current treatment system and who contribute disproportionately to health care and criminal justice costs as well as to public disorder associated with drug addiction.
The NAOMI study is a Phase III randomized clinical trial comparing injectable heroin maintenance to oral methadone. The study has ethics board approval at its Montréal and Vancouver sites, as well as from the University of Toronto, the New York Academy of Medicine and Johns Hopkins University.
The main objective of the NAOMI Study is to determine whether the closely supervised provision of injectable, pharmaceutical-grade opioid agonist is more effective than methadone alone in recruiting, retaining, and benefiting chronic, opioid-dependent, injection drug users who are resistant to current standard treatment options.
Methods
The case study submitted chronicles the challenges of getting a heroin assisted treatment trial up and running in North America. It describes: a brief background on opioid addiction; current standard therapies for opioid addiction; why there is/was a need for a heroin assisted treatment trial; a description of heroin assisted treatment; the beginnings of creating the NAOMI study in North America; what is the NAOMI study; the science and politics of the NAOMI study; getting NAOMI started in Canada; various requirements and restrictions in getting the study up and running; recruitment into the study; working with the media; a status report on the study; and a brief conclusion from the authors' perspectives.
Results and conclusion
As this is a case study, there are no specific results or main findings listed. The case study focuses on: the background of the study; what it took to get the study started in Canada; the unique requirements and conditions of getting a site, and the study, approved; working with the media; recruitment into the study; a brief status report on the study; and a brief conclusion from the authors' perspectives.
Trail Registration
ClinicalTrials.gov registration number: NCT00175357
doi:10.1186/1477-7517-6-2
PMCID: PMC2639576  PMID: 19159475
19.  Case report: quantification of methadone-induced respiratory depression using toxicokinetic/toxicodynamic relationships 
Critical Care  2007;11(1):R5.
Introduction
Methadone, the most widely delivered maintenance therapy for heroin addicts, may be responsible for life-threatening poisonings with respiratory depression. The toxicokinetics and the toxicokinetic/toxicodynamic (TK/TD) relationships of methadone enantiomers have been poorly investigated in acute poisonings. The aim of this study was to describe the relationships between methadone-related respiratory effects and their corresponding concentrations.
Methods
We report a 44-year-old methadone-maintained patient who ingested a 240-mg dose of methadone. He was found comatose with pinpoint pupils and respiratory depression. He was successfully treated with intravenous naloxone infusion over the course of 31 hours at a rate adapted to maintain normal consciousness and respiratory rate. We performed a TK/TD analysis of the naloxone infusion rate needed to maintain his respiratory rate at more than 12 breaths per minute (as toxicodynamics parameter) versus plasma R,S- and R-methadone concentrations (as toxicokinetics parameter), determined using an enantioselective high-performance liquid chromatography assay.
Results
Initial plasma R,S-methadone concentration was 1,204 ng/ml. Decrease in plasma R- and S-methadone concentrations was linear and demonstrated a first-order pharmacokinetics (maximal observed concentrations 566 and 637 ng/ml, half-lives 16.1 and 13.2 hours, respectively). TK/TD correlation between naloxone infusion rate and R,S- and R-methadone concentrations fitted well a sigmoidal Emax model (concentration associated with a half-maximum effect [EC50] 334 and 173 ng/ml, Hill coefficient 10.0 and 7.8, respectively). In our chronically treated patient, EC50 values were in the range of previously reported values regarding methadone analgesic effects, suggesting that plasma methadone concentrations to prevent withdrawal are lower than those associated with methadone analgesic effects.
Conclusion
After the ingestion of a toxic dose of a racemic mixture, plasma R- and S-enantiomer concentrations decreased in parallel. Despite large inter-individual variability in methadone toxicokinetics and toxicodynamics, TK/TD relationships would be helpful for providing quantitative data regarding the respiratory response to methadone in poisonings. However, further confirmatory TK/TD data are needed.
doi:10.1186/cc5150
PMCID: PMC2151854  PMID: 17224045
20.  Escalation Patterns of Varying Periods of Heroin Access 
The prevalence of opioid abuse and dependence has been on the rise in just the past few years. Animal studies indicate that extended access to heroin produces escalation of intake over time, whereas stable intake is observed under limited-access conditions. Escalation of drug intake has been suggested to model the transition from controlled drug use to compulsive drug seeking and taking. Here, we directly compared the pattern of heroin intake in animals with varying periods of heroin access. Food intake was also monitored over the course of escalation. Rats were allowed to lever press on a fixed-ratio 1 schedule of reinforcement to receive intravenous infusions of heroin for 1, 6, 12, or 23 h per day for 14 sessions. The results showed that heroin intake in the 12 and 23 h groups markedly increased over time, whereas heroin intake in the 1 h group was stable. The 6 h group showed a significant but modest escalation of intake. Total heroin intake was similar in the 12 and 23 h groups, but the rate of heroin self-administration was two-fold higher in the 12 h group compared with the 23 h group. Food intake decreased over sessions only in the 12 h group. The 12 and 23 h groups showed marked physical signs of naloxone-precipitated withdrawal. These findings suggest that 12 h heroin access per day may be the optimal access time for producing escalation of heroin intake. The advantages of this model and the potential relevance for studying drug addiction are discussed.
doi:10.1016/j.pbb.2011.03.004
PMCID: PMC3081940  PMID: 21406200
Heroin self-administration; opioid dependence; drug addiction; escalation; naloxone-precipitated withdrawal
21.  Enhancing motivation within a rapid opioid substitution treatment feasibility RCT: a nested qualitative study 
Background
Opioid substitution treatment (OST) has multiple benefits for heroin injectors and is an evidence-based major component of international treatment. The current qualitative study sought to explore participants’ attitudes to and reasons for participating in a feasibility randomised trial in primary care offering ‘same day’ OST (methadone) for injecting heroin users compared to usual care.
Methods
Twenty injecting heroin users (8 intervention and 12 controls; 16 males and 4 females) were interviewed; purposive sampling was used to select a maximum variation sample from those who agreed; and analysis used thematic methods.
Results
Motivation to join the trial included the need to secure treatment set against some ambivalence due to previous negative experiences of trying to obtain OST. Positive effects of securing methadone via the trial, included self-reported improvements in health and self-care; reduction in crime, stress and drug use. Completing the baseline questionnaires at recruitment appeared to enhance motivation for treatment for all participants. For some control participants, this motivation seemed to increase a sense of self-efficacy and cognitive dissonance generated was resolved by seeking treatment from their GP. Self-determination theory suggests that behaviour change may have been initiated during the recruitment appointment, resulting in an increased determination to seek treatment amongst control participants.
Conclusions
Taking part in the ‘script in a day’ trial enabled participants in the intervention arm to gain same-day access to methadone and reduce their drug use. For those in the control arm, completing the baseline questionnaires at recruitment appeared to create cognitive dissonance between their current health state and own aspirations, so increasing motivation for treatment. Over 50% obtained and were still in receipt of OST (methadone or buprenorphine) at the 3 month follow-up. We suggest that a regular ‘health evaluation’ for injecting heroin users not in treatment, paired with low-barrier access to treatment, may be a way of exploring this and encouraging more into obtaining OST more quickly and at the best time for them. This intervention should be delivered without pressure for change.
Clinical trial registration
This trial is registered with International Standard Randomised Controlled Trial Number Register: SCript In a Day for injecting drug users: feasibility trial: ISRCTN16846554.
doi:10.1186/1747-597X-9-44
PMCID: PMC4240819  PMID: 25407020
Opioid substitution treatment; Motivational interviewing; Cognitive dissonance; Self-determination theory; Qualitative interviews
22.  Patients in long-term maintenance therapy for drug use in Italy: analysis of some parameters of social integration and serological status for infectious diseases in a cohort of 1091 patients 
BMC Public Health  2006;6:216.
Background
Heroin addiction often severely disrupts normal social functioning. The aims of this multi-centre study of heroin users in long-term replacement treatment were: i) to provide information on aspects of social condition such as employment, educational background, living status, partner status and any history of drug addiction for partners, comparing these data with that of the general population; ii) to assess the prevalence of hepatitis, syphilis and HIV, because serological status could be a reflection of the social conditions of patients undergoing replacement treatment for drug addiction; iii) to analyse possible relationships between social conditions and serological status.
Methods
A cross-sectional study was carried out in sixteen National Health Service Drug Addiction Units in northern Italy. The data were collected from February 1, 2002 to August 31, 2002. Recruitment eligibility was: maintenance treatment with methadone or buprenorphine, treatment for the previous six months, and at least 18 years of age. In the centres involved in the study no specific criteria or regulations were established concerning the duration of replacement therapy. Participants underwent a face-to-face interview.
Results
The conditions of 1091 drug treatment patients were evaluated. The mean duration of drug use was 14.5 years. Duration was shorter in females, in subjects with a higher educational background, and in stable relationships. Most (68%) had completed middle school (11–14 years of age). Seventy-nine percent were employed and 16% were unemployed. Fifty percent lived with their parents, 34% with a partner and 14% alone. Males lived more frequently with their parents (55%), and females more frequently with a partner (60%). Sixty-seven percent of male patients with a stable relationship had a partner who had never used heroin. HCV prevalence was 72%, HBV antibodies were detected in 42% of patients, while 30% had been vaccinated; 12.5% of subjects were HIV positive and 1.5% were positive for TPHA.
Conclusion
A significant percentage of heroin users in treatment for opiate addiction in the cohort study have characteristics which indicate reasonable integration within broader society. We posit that the combination of effective treatment and a setting of economic prosperity may enhance the social integration of patients with a history of heroin use.
doi:10.1186/1471-2458-6-216
PMCID: PMC1570141  PMID: 16928267
23.  When higher doses in opioid replacement treatment are still inadequate – association to multidimensional illness severity: a cohort study 
Background
Opioid replacement treatment (ORT) with methadone is regarded as gold standard in the treatment of opioid addiction. Treatment doses of 60 mg methadone per day and above are associated with better treatment retention and reduction in the use of heroin and cocaine. However, an absolute dose level cannot function as parameter for adequate dosing. This study aims to determine dose adequacy in a sample of patients on stable methadone treatment, and to relate dose adequacy to disease severity.
Methods
This study was designed as open prospective cohort study over 12 months, with baseline data reported here. Patients on stable substitution treatment with methadone (Eptadone®) were consecutively included. Medical and socio-demographic data were gathered and the instruments Opiate Dosage Adequacy Scale (ODAS), European Addiction Severity Index (EuropASI) and the Derogatis Interview for Sexual Functioning – Self Report (DISF-SR) were applied.
Results
Five hundred and sixteen subjects, who received on average 60.3 (±30.4) mg methadone per day, were included. According to ODAS, 40.6% suffered from an inadequate dosing, and 59.4% had an adequate dose. Patients with an adequate dose received on average 57.8 (±27.5) mg methadone per day, whilst patients with an inadequate dose received on average 70.6 (±33.0) mg per day. The frequencies of patients with methadone doses of less than 60 mg per were 45.4% in the inadequate and 60.6% in the adequate group. The inadequate group suffered from a statistically significant higher burden of addiction related problems in all EuropASI domains. Sexual functioning did not differ by adequacy group, but women suffered from more pronounced sexual dysfunction as compared to men.
Conclusion
A high frequency of inadequate dosing was found in this sample of patients on ORT. Higher disease severity should alert for possible need of even higher methadone doses. The tendency to low methadone doses warrants further research in the treatment system. Higher methadone doses are not related to increased sexual dysfunction. Sexual dysfunction, especially in women, should be considered in treatment.
doi:10.1186/1747-597X-9-13
PMCID: PMC3975916  PMID: 24581310
Opiate dependence; Substitution treatment; Dose adequacy; Illness severity; Sexual functioning
24.  Heroin and cocaine co-use in a group of injection drug users in Montréal 
Objective
To describe the pattern of co-use of heroin and cocaine in individuals who were not receiving methadone maintenance treatment.
Design
Structured interviews.
Setting
Community hospital.
Participants
Individuals (n = 1111) selected from a cohort of out-of-treatment injection drug users in Montréal, Que.
Outcome measure
Frequency (injections per day) and quantity (number of days of use) of heroin, cocaine and speedball (the simultaneous administration of heroin and cocaine) use reported in the month preceding the interview.
Results
About 50% of the sample reported using only cocaine intravenously (C group), about 8% reported using only heroin (H group) intravenously and about 15% reported using both heroin and cocaine (HC group) intravenously. Reported cocaine consumption was similar in the HC and C groups. Heroin was used on fewer days by the HC than by the H group, but the number of injections per day was similar. Speedball use, which was quantified independently from heroin and cocaine use, was reported almost exclusively by the HC group, and speedball was used less often than either heroin or cocaine alone. Finally, a similar proportion of individuals in the C and the HC groups consumed alcohol in the 24 hours preceding the interview, but a larger proportion of individuals in the HC group reported the use of marijuana.
Conclusion
In a cohort of injection drug users in Montréal, cocaine was the most prevalent illicit drug. Furthermore, about 70% of the heroin users also injected cocaine, but not in the form of speedball. Thus, the sequential co-use of heroin and cocaine is highly prevalent in Montréal and deserves particular clinical attention.
PMCID: PMC305269  PMID: 14719049
cocaine; heroin; substance abuse, intravenous
25.  A Randomized Investigation of Methadone Doses at or Over 100 mg/day, Combined with Contingency Management* 
Drug and alcohol dependence  2012;130(0):77-84.
BACKGROUND
Methadone maintenance for heroin dependence reduces illicit drug use, crime, HIV risk, and death. Typical dosages have increased over the past few years, based on strong experimental and clinical evidence that dosages under 60 mg/day are inadequate and that dosages closer to 100 mg/day produce better outcomes. However, there is little experimental evidence for the benefits of exceeding 100 mg/day, or for individualizing methadone dosages. We sought to provide such evidence.
METHODS
We combined individualized methadone dosages over 100 mg/day with voucher-based cocaine-targeted contingency management (CM) in 58 heroin- and cocaine-dependent outpatients. Participants were randomly assigned to receive a fixed dose increase from 70 mg/day to 100 mg/day, or to be eligible for further dose increases (up to 190 mg/day, based on withdrawal symptoms, craving, and continued heroin use). All dosing was double-blind. The main outcome measure was simultaneous abstinence from heroin and cocaine.
RESULTS
We stopped the study early due to slow accrual. Cocaine-targeted CM worked as expected to reduce cocaine use. Polydrug use (effect-size h = .30) and heroin craving (effect-size d = .87) were significantly greater in the flexible/high-dose condition than in the fixed-dose condition, with no trend toward lower heroin use in the flexible/high-dose participants.
CONCLUSIONS
Under double-blind conditions, dosages of methadone over 100 mg/day, even when prescribed based on specific signs and symptoms, were not better than 100 mg/day. This counterintuitive finding requires replication, but supports the need for additional controlled studies of high-dose methadone.
doi:10.1016/j.drugalcdep.2012.10.025
PMCID: PMC3595382  PMID: 23195924
methadone maintenance; methadone dose; individualized dosing; flexible dosing; polydrug dependence; contingency management

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