Co-located Heroin Assisted Treatment within primary care: A preliminary analysis of the implications for healthcare access, cost, and treatment delivery in the UK.

BACKGROUND: The UK is experiencing its highest rate of drug related deaths in 25 years. Poor and inconsistent access to healthcare negatively impacts health outcomes for people who use drugs. Innovation in models of care which promote access and availability of physical treatment is fundamental. Heroin Assisted Treatment (HAT) is a treatment modality targeted at the most marginalised people who use drugs, at high risk of mortality and morbidity. The first service-provider initiated HAT service in the UK ran between October 2019 and November 2022 in Middlesbrough, England. The service was co-located within a specialist primary care facility offering acute healthcare treatment alongside injectable diamorphine. METHODS: Analysis of anonymised health records for healthcare costs (not including drug treatment) took place using descriptive statistics prior and during engagement with HAT, at both three (n=15) and six (n=12) months. Primary outcome measures were incidents of wound care, skin and soft tissue infections (SSTIs), overdose (OD) events, unplanned overnight stays in hospital, treatment engagement (general and within hospital care settings) and ambulance incidents. Secondary outcome measures were costs associated with these events. RESULTS: A shift in healthcare access for participants during HAT engagement was observed. HAT service attendance appeared to support health promoting preventative care, and reduce reactive reliance on emergency healthcare systems. At three and six months, engagement for preventative wound care and treatment for SSTIs increased at the practice. Unplanned emergency healthcare interactions for ODs, overnight hospital stays, serious SSTIs, and ambulance incidents reduced, and there was an increase in treatment engagement (i.e. a reduction in appointments which were not engaged with). There was a decrease in treatment engagement in hospital settings. Changes in healthcare utilisation during HAT translated to a reduction in healthcare costs of 58% within six months compared to the same timeframe from the period directly prior to commencing HAT. CONCLUSION: This exploratory study highlights the potential for innovative harm reduction interventions such as HAT, co-located with primary care services, to improve healthcare access and engagement for a high-risk population. Increased uptake of primary healthcare services translated to reductions in emergency healthcare use and associated costs. Although costs of HAT provision are substantial, the notable cost-savings in health care should be an important consideration in service implementation planning.

Exploring the Perceived Risks and Benefits of Heroin Use among Young People (18-24 Years) in Mauritius: Economic Insights from an Exploratory Qualitative Study.

The decreasing age of young people injecting illicit drugs is an under-reported challenge for the prevention of HIV transmission worldwide. Young people aged 15-24 years represent 1 in 5 persons living with HIV in Mauritius where the epidemic is driven by injecting drug use and risky sexual behaviours. We recruited 22 heroin users aged 18-24 and 5 service providers working in harm reduction (HR) for the present study. Qualitative data were collected through unstructured interviews. We adopted an economic framework and an inductive approach to the analysis, which implied revising codes and themes. The risks heroin users described as consumers of illicit drugs and as clients of HR services could not be analyzed in isolation. Polydrug use emerged as a recurrent coping mechanism resulting from the changing dynamics within the heroin market. The risks faced by women went beyond addiction and infection with HIV. How participants viewed the risks and benefits linked to using heroin was greatly influenced by gaps in knowledge that left room for uncertainty and reinforcing mechanisms such as peer influence. The study shows that qualitative research can produce in-depth socio-behavioural insights required to produce more effective services for young people.

Incidence and treatment costs of severe bacterial infections among people who inject heroin: A cohort study in South London, England.

BACKGROUND: People who inject drugs often get bacterial infections. Few longitudinal studies have reported the incidence and treatment costs of these infections. METHODS: For a cohort of 2335 people who inject heroin entering treatment for drug dependence between 2006 and 2017 in London, England, we reported the rates of hospitalisation or death with primary causes of cutaneous abscess, cellulitis, phlebitis, septicaemia, osteomyelitis, septic arthritis, endocarditis, or necrotising fasciitis. We compared these rates to the general population. We also used NHS reference costs to calculate the cost of admissions. RESULTS: During a median of 8.0 years of follow-up, 24 % of patients (570/2335) had a severe bacterial infection, most commonly presenting with cutaneous abscesses or cellulitis. Bacterial infections accounted for 13 % of all hospital admissions. The rate was 73 per 1000 person-years (95 % CI 69-77); 50 times the general population, and the rate remained high throughout follow-up. The rate of severe bacterial infections for women was 1.50 (95 % CI 1.32-1.69) times the rate for men. The mean cost per admission was £4980, and we estimate that the annual cost of hospital treatment for people who inject heroin in London is £4.5 million. CONCLUSIONS: People who inject heroin have extreme and long-term risk of severe bacterial infections.

Heroin choice depends on income level and economy type.

RATIONALE: In a previous study, investigating choice between heroin and a non-drug alternative in animals and reductions in income (i.e., choices/day) caused the percentage of income spent on heroin to progressively decrease. In contrast, another study found that humans with opioid use disorder spent the majority of their income on heroin even though they had little income. Comparison of these two studies suggests that the seemingly conflicting results could be explained by differences in the underlying economy types of the choice alternatives. OBJECTIVE: The present experiment tested the hypothesis that the effect of income changes on choice between heroin and a non-drug alternative depends on economy type. METHODS: Rats chose between heroin and saccharin under three income levels. For the Closed group, the choice session was the only opportunity to obtain these reinforcers. For the Heroin Open group and the Saccharin Open group, choice sessions were followed by 3-h periods of unlimited access to heroin or saccharin, respectively. RESULTS: As income decreased, the Closed and Heroin Open groups, but not the Saccharin Open group, spent an increasingly greater percentage of income on saccharin than on heroin. The Saccharin Open group, compared to the other groups, spent a greater percentage of income on heroin as income decreased. CONCLUSIONS: Results confirm that the effects of income and economy type can interact and this may explain the apparently discrepant results of earlier studies. More generally, findings suggest that situations where heroin choice has little consequence for consumption of non-drug alternatives may promote heroin use.

A further assessment of a role for Toll-like receptor 4 in the reinforcing and reinstating effects of opioids.

The Toll-like receptor 4 (TLR4) antagonists, (+)-naloxone and (+)-naltrexone, have been reported to decrease self-administration of opioids in rats and to reduce other preclinical indicators of abuse potential. However, under the self-administration conditions studied, the effects of TLR4 antagonists were not reinforcer selective, questioning the involvement of those receptors and their mediated inflammatory response specifically in opioid abuse. The objectives of the current study were to further characterize the reinforcer specificity of TLR4 antagonism in opioid self-administration and to explore its effects in a preclinical model of craving/relapse. The TLR4 antagonist (+)-naltrexone decreased responding in rats trained to self-administer the µ-opioid receptor agonist remifentanil, but with a potency that was not significantly different from that observed in another group of subjects in which responding was maintained by food reinforcement. Responding reinstated by heroin injection was decreased by (+)-naltrexone; however, a similar reduction was not reproduced with the administration of another TLR4 antagonist, lipopolysaccharide from Rhodobacter sphaeroides, administered into the NAcc shell. Thus, TLR4 antagonists lacked reinforcer selectivity in reducing opioid self-administration and were not uniformly effective in a model of craving/relapse, suggesting limitations on the development of (+)-naltrexone or TLR4 antagonists as treatments for opioid abuse.

Solving the Opioid Epidemic in Ohio.

On May 31, 2017, Ohio Attorney General Mike DeWine took a step in fighting Ohio's opioid epidemic, bringing the first of many lawsuits against five top pharmaceutical companies. However, under Federal and State law, there is an exception called the Learned Intermediary Doctrine, which can absolve drug manufacturers of liability from any misconduct that might be found and transfer that liability to a treating physician. This exception is the way many drug manufacturers were able to avoid being held responsible in the past. This Note proposes that with the current pending lawsuit in the State of Ohio, an exception to the Learned Intermediary Doctrine should be introduced. This Note begins with a discussion of opioids and how these drugs have become such an aggressive problem in a very short amount of time in Ohio. Part II talks about the role the government can play and the drug manufacturers have played and continue to play in the availability of opioids. It discusses the effect these pharmaceutical companies have had on this problem and in increasing this problem. Part II also discusses why this is a problem and why this problem matters. Further, it talks about the steps that have already been taken by the Ohio Legislature to combat the opioid problems. Finally, it delves into a discussion of what this current lawsuit means for fighting and decreasing the opioid problem and how it will directly affect the heroin epidemic in Ohio.

Heroin-assisted treatment: has a controversial treatment come of age?†.

This editorial considers the findings of the systematic review of heroin-assisted treatment, with six different studies from six different countries, published in this issue. The meta-analysis focuses on supervised injected heroin and reports significant crime reduction and an overall cost-effectiveness of treatment. Despite this body of evidence, policy makers remain reluctant to develop this treatment further. The question remains, what else is required to convince policy makers of the value of such treatment for severe and refractory heroin dependence?

The whole is just the sum of its parts: limited polydrug use among the "big three" expensive drugs in the United States.

Data from surveys of arrestees and the household population in the U.S. suggest there is only modest overlap among demand for the big three expensive illegal drugs (cocaine/crack, heroin, and methamphetamine). In particular, the number of chronic users of these substances (defined as consuming on four or more days in the previous month) is only about 10% below a naïve estimate obtained by simply summing the numbers of chronic users for each of the three substances, while ignoring polydrug use entirely. This finding does not gainsay that polydrug use is common or important. One would estimate greater overlap if one adopted a more expansive definition of polydrug use (e.g., has the individual ever used another substance at any time in their life) or a more expansive list of substances (e.g., allowing marijuana or alcohol to count as one of the substances makes polydrug use seem much more common). However, it does suggest that when focusing on the illegal drug markets that generate the most crime, violence, and overdose death in the U.S., one can usefully think of three more or less separate markets populated at any given time by largely distinct populations of drug users.

Cost-effectiveness of injectable opioid treatment v. oral methadone for chronic heroin addiction.

BACKGROUND: Despite evidence of the effectiveness of injectable opioid treatment compared with oral methadone for chronic heroin addiction, the additional cost of injectable treatment is considerable, and cost-effectiveness uncertain. AIMS: To compare the cost-effectiveness of supervised injectable heroin and injectable methadone with optimised oral methadone for chronic refractory heroin addiction. METHOD: Multisite, open-label, randomised controlled trial. Outcomes were assessed in terms of quality-adjusted life-years (QALYs). Economic perspective included health, social services and criminal justice resources. RESULTS: Intervention costs over 26 weeks were significantly higher for injectable heroin (mean £8995 v. £4674 injectable methadone and £2596 oral methadone; P<0.0001). Costs overall were highest for oral methadone (mean £15 805 v. £13 410 injectable methadone and £10 945 injectable heroin; P = n.s.) due to higher costs of criminal activity. In cost-effectiveness analysis, oral methadone was dominated by injectable heroin and injectable methadone (more expensive and less effective). At willingness to pay of £30 000 per QALY, there is a higher probability of injectable methadone being more cost-effective (80%) than injectable heroin. CONCLUSIONS: Injectable opioid treatments are more cost-effective than optimised oral methadone for chronic refractory heroin addiction. The choice between supervised injectable heroin and injectable methadone is less clear. There is currently evidence to suggest superior effectiveness of injectable heroin but at a cost that policy makers may find unacceptable. Future research should consider the use of decision analytic techniques to model expected costs and benefits of the treatments over the longer term.

Finite mixture varying coefficient models for analyzing longitudinal heterogenous data.

This paper aims to develop a mixture model to study heterogeneous longitudinal data on the treatment effect of heroin use from a California Civil Addict Program. Each component of the mixture is characterized by a varying coefficient mixed effect model. We use the Bayesian P-splines approach to approximate the varying coefficient functions. We develop Markov chain Monte Carlo algorithms to estimate the smooth functions, unknown parameters, and latent variables in the model. We use modified deviance information criterion to determine the number of components in the mixture. A simulation study demonstrates that the modified deviance information criterion selects the correct number of components and the estimation of unknown quantities is accurate. We apply the proposed model to the heroin treatment study. Furthermore, we identify heterogeneous longitudinal patterns.

Injection of buprenorphine and buprenorphine/naloxone tablets in Malaysia.

BACKGROUND: Buprenorphine maintenance is efficacious for treating opioid dependence, but problems with diversion and misuse of buprenorphine (BUP) may limit its acceptability and dissemination. The buprenorphine/naloxone combination tablet (BNX) was developed to reduce potential problems with diversion and abuse. This paper provides data regarding the characteristics of BUP injection drug users in Malaysia and preliminary data regarding the impact of withdrawing BUP and introducing BNX. BUP was introduced in 2002 and subsequently withdrawn from the Malaysian market in 2006. BNX was introduced in 2007. METHODS: A two wave survey of BUP IDUs was conducted shortly prior to BUP withdrawal from the Malaysian market (n=276) and six months after BNX was introduced (n=204). Six focus groups with BUP and/or BNX IDUs were also conducted shortly before the second wave. RESULTS: In addition to current BUP or BNX IDU, 96% of first wave participants and 97% second wave participants reported lifetime heroin IDU preceding the onset of their BUP/BNX IDU. Additionally, 58% of first and 64% of second wave survey participants reported current heroin IDU. Benzodiazepine abuse, often injected with BUP, was reported in both the surveys. Focus group participants reported that BNX was not as desirable as BUP, nonetheless, the results of the second wave survey suggest a continuing widespread BNX IDU, at least in Kuala Lumpur. CONCLUSIONS: In Malaysia, BUP and BNX IDU occur among heroin IDUs. The introduction of BNX and withdrawal of BUP may have helped to reduce, but did not eliminate the problems with diversion and abuse.

Heroin-assisted treatment in the Netherlands: History, findings, and international context.

This monograph describes the history, findings and international context of heroin-assisted treatment (HAT) in the Netherlands. The monograph consists of (1) a short introduction and seven paragraphs describing the following aspects of HAT in the Netherlands: (2) history of HAT studies and implementation of routine HAT in the Netherlands; (3) main findings on efficacy, safety and cost-effectiveness from the two randomized controlled HAT trials in the Netherlands; (4) new findings from a large cohort study on the effectiveness of HAT in routine clinical practice in the Netherlands; (5) unique data on the patient's perspective of HAT; (6) data on the pharmacological and pharmaceutical basis for HAT in the Netherlands; (7) description of the registration process; and (8) account of the international context of HAT. Together, these data show that HAT can now be considered a safe and proven-effective intervention for the treatment of chronic, treatment-resistant heroin dependent patients.

Intravenous and intranasal heroin-dependent treatment-seekers: characteristics and treatment outcome.

AIMS: This study compared the characteristics of intravenous (i.v.) and intranasal (i.n.) heroin users seeking methadone treatment, and their response to treatment. PARTICIPANTS: A total of 319 heroin-dependent adults. DESIGN: Participants were assigned randomly to receive interim methadone treatment or to a waiting list control on a 3 : 2 basis. Analyses were conducted by dividing participants into two groups based on their route of heroin ingestion: i.v. or i.n. SETTING: A methadone clinic in Baltimore City, Maryland. INTERVENTION: Interim methadone treatment consisted of providing an adequate and stable dose of methadone, but no psychosocial services, to heroin-dependent adults for up to 120 days while they awaited an opening for comprehensive methadone treatment. MEASURES: Addiction Severity Index, Texas Christian University AIDS Risk Assessment, a questionnaire on treatment entry and a urine drug test were collected at baseline and at entry into a comprehensive treatment program, or at 120 days after baseline assessment, whichever came first. FINDINGS: At baseline, over 60% of participants were i.n. users and had been for an average of over 12 years; i.v. users, compared to i.n. users, were more likely to have ever used cocaine, to have used cocaine in the past 30 days, to have more medical complications and to report more income generated from criminal behavior. Both i.v. and i.n. users reduced their self-reported days of heroin use, cocaine use and days of criminal activity in response to interim methadone treatment. CONCLUSIONS: Despite differences in baseline characteristics, i.n. and i.v. heroin-dependent individuals did not differ in their response to interim methadone treatment.

[Treatment of chronic hepatitis C within a heroine-assisted treatment program]. / Therapie der chronischen Hepatitis C im Rahmen einer heroingestützten Behandlung.

HISTORY AND FINDINGS: A 37-year-old man with a 19-years history of injection drug use (IDU) who had acquired a chronic hepatitis C virus (HCV-) infection 9 years ago, entered the German clinical study on heroine assisted treatment ("Modellprojekt zur heroingestützten Behandlung Opiatabhängiger"). Before study onset he received buprenorphine maintainance treatment, while at the same time engaging in illicit IDU (heroine, cocaine). He lived in a caravan and was on social welfare. INVESTIGATIONS: PCR revealed a genotype 2 and an HCV-viral load of 310,000 IU/ml. Liver biopsy showed a moderate chronic active hepatitis and a mild portal fibrosis without signs of liver cirrhosis. DIAGNOSIS, TREATMENT AND COURSE: Within the heroine-assisted treatment program the patient injected heroine under medical supervision several times a day and attended the standardized psychosocial program that comprised an intensive education on HCV-infection. Within a period of ten months of physical and social stabilization he managed to stop illicit drug use, found stable housing and started to work. We then initiated treatment of HCV-infection. Subcutaneous pegylated interferon alpha-2a, peroral ribavirin and intravenous heroine were administered as directly observed therapy. Based on the close mashed care of the heroine assisted treatment setting, side effects were well controllable and reversible after the end of antiviral therapy. A sustained response was obtained. CONCLUSION: After careful indication, heroine-assisted treatment with particularly intensive medical and psychological care can offer appropriate conditions for a save and successful treatment of hepatitis C as well as for a sustained result.

Health services utilization for people with HIV infection: comparison of a population targeted for outreach with the U.S. population in care.

BACKGROUND: Many persons with HIV infection do not receive consistent ambulatory medical care and are excluded from studies of patients in medical care. However, these hard-to-reach groups are important to study because they may be in greatest need of services. OBJECTIVE: This study compared the sociodemographic, clinical, and health care utilization characteristics of a multisite sample of HIV-positive persons who were hard to reach with a nationally representative cohort of persons with HIV infection who were receiving care from known HIV providers in the United States and examined whether the independent correlates of low ambulatory utilization differed between the 2 samples. METHODS: We compared sociodemographic, clinical, and health care utilization characteristics in 2 samples of adults with HIV infection: 1286 persons from 16 sites across the United States interviewed in 2001-2002 for the Targeted HIV Outreach and Intervention Initiative (Outreach), a study of underserved persons targeted for supportive outreach services; and 2267 persons from the HIV Costs and Services Utilization Study (HCSUS), a probability sample of persons receiving care who were interviewed in 1998. We conducted logistic regression analyses to identify differences between the 2 samples in sociodemographic and clinical associations with ambulatory medical visits. RESULTS: Compared with the HCSUS sample, the Outreach sample had notably greater proportions of black respondents (59% vs. 32%, P = 0.0001), Hispanics (20% vs. 16%), Spanish-speakers (9% vs. 2%, P = 0.02), those with low socioeconomic status (annual income < Dollars 10,000 75% vs. 45%, P = 0.0001), the unemployed, and persons with homelessness, no insurance, and heroin or cocaine use (58% vs. 47%, P = 0.05). They also were more likely to have fewer than 2 ambulatory visits (26% vs. 16%, P = 0.0001), more likely to have emergency room visits or hospitalizations in the prior 6 months, and less likely to be on antiretroviral treatment (82% vs. 58%, P = 0.0001). Nearly all these differences persisted after stratifying for level of ambulatory utilization (fewer than 2 vs. 2 or more in the last 6 months). In multivariate analysis, several variables showed significantly different associations in the 2 samples (interacted) with low ambulatory care utilization. The variables with significant interactions (P values for interaction shown below) had very different adjusted odds ratios (and 95% confidence intervals) for low ambulatory care utilization: age greater than 50 (Outreach 0.55 [0.35-0.88], HCSUS 1.17 [0.65-2.11)], P = 0.05), Hispanic ethnicity (Outreach 0.81 [0.39-1.69], HCSUS 2.34 [1.56-3.52], P = 0.02), low income (Outreach 0.73 [0.56-0.96], HCSUS 1.35 [1.04-1.75], P = 0.002), and heavy alcohol use (Outreach 1.74 [1.23-2.45], HCSUS 1.00 [0.73-1.37], P = 0.02). Having CD4 count less than 50 was associated with elevated odds of low ambulatory medical visits in the Outreach sample (1.53 [1.00-2.36], P = 0.05). CONCLUSIONS: Compared with HCSUS, the Outreach sample had far greater proportions of traditionally vulnerable groups, and were less likely to be in care if they had low CD4 counts. Furthermore, heavy alcohol use was only associated with low ambulatory utilization in Outreach. Generalizing from in care populations may not be warranted, while addressing heavy alcohol use may be effective at improving utilization of care for hard-to-reach HIV-positive populations.

Innovations in agonist maintenance treatment of opioid-dependent patients.

PURPOSE OF REVIEW: To provide an overview of published studies on agonist maintenance treatment options for opioid-dependent patients. RECENT FINDINGS: The recent publication of controlled trials confirms earlier clinical evidence of the efficacy of diamorphine (heroin) in the treatment of opioid dependence. Findings show not only efficacy with respect to improvement of health, reduction of illicit drug use, reduction of criminality and stabilization of social conditions, but also cost effectiveness in the treatment of chronic treatment-resistant heroin addicts. SUMMARY: Agonist maintenance treatment has become the first-line treatment for chronic opioid dependence. High-quality studies demonstrate the effectiveness of a growing number of different agonist maintenance treatments for opioid dependence such as methadone and buprenorphine. In addition, there is new evidence for the effectiveness of other agonists, mainly slow-release morphine, intravenous and inhalable diamorphine and possibly oral diamorphine. Maintenance treatment with intravenous or inhalable diamorphine should be implemented into the healthcare system to treat a group of severely dependent treatment-resistant patients. Furthermore, the opioid-dependent patients not under treatment need to be engaged in maintenance treatments through other harm reduction measures. Agonist maintenance treatment is very effective in stabilizing the health condition and social situation, while also reducing harm, thereby increasing life expectancy and quality of life.

Cost utility analysis of co-prescribed heroin compared with methadone maintenance treatment in heroin addicts in two randomised trials.

OBJECTIVE: To determine the cost utility of medical co-prescription of heroin compared with methadone maintenance treatment for chronic, treatment resistant heroin addicts. DESIGN: Cost utility analysis of two pooled open label randomised controlled trials. SETTING: Methadone maintenance programmes in six cities in the Netherlands. PARTICIPANTS: 430 heroin addicts. INTERVENTIONS: Inhalable or injectable heroin prescribed over 12 months. Methadone (maximum 150 mg a day) plus heroin (maximum 1000 mg a day) compared with methadone alone (maximum 150 mg a day). Psychosocial treatment was offered throughout. MAIN OUTCOME MEASURES: One year costs estimated from a societal perspective. Quality adjusted life years (QALYs) based on responses to the EuroQol EQ-5D at baseline and during the treatment period. RESULTS: Co-prescription of heroin was associated with 0.058 more QALYs per patient per year (95% confidence interval 0.016 to 0.099) and a mean saving of 12,793 euros (8793 pounds sterling, 16,122 dollars) (1083 to 25,229 euros) per patient per year. The higher programme costs (16 222 euros; lower 95% confidence limit 15,084 euros) were compensated for by lower costs of law enforcement (- 4129 euros; upper 95% confidence limit - 486 euros) and damage to victims of crime (- 25,374 euros; upper 95% confidence limit - 16,625 euros). The results were robust for the use of national EQ-5D tariffs and for the exclusion of the initial implementation costs of heroin treatment. Completion of treatment is essential; having participated in any abstinence treatment in the past is not. CONCLUSIONS: Co-prescription of heroin is cost effective compared with treatment with methadone alone for chronic, treatment resistant heroin addicts.

Self-Administration of cocaine-opioid combinations by rhesus monkeys: evaluation of the role of mu receptor efficacy using labor supply analysis.

Cocaine and heroin often are abused by self-administering the drugs in combination as a "speedball". We evaluated the extent to which intrinsic efficacy at the mu-opioid receptor influences combined cocaine-opioid self-administration and used the behavioral economic model termed "labor supply" to quantitatively evaluate the reinforcing effects of cocaine-opioid combinations. Rhesus monkeys (n = 8) were trained under a progressive-ratio schedule of i.v. cocaine injection in which the response requirement increased during the experimental session and the initial response requirement was varied. Combination of cocaine with heroin enhanced self-administration compared with the drugs individually, with ineffective doses of both drugs maintaining self-administration when combined. These effects also were observed with the high-efficacy mu agonist alfentanil and low-efficacy agonist nalbuphine. Using the labor supply economic model, combinations of heroin, alfentanil, or nalbuphine with relatively low doses of cocaine were found to increase the number of injections per session ("income") and total responses per session ("labor"). Combination of a relatively high dose of cocaine with either heroin or alfentanil, but not nalbuphine, also resulted in only a small reduction in income concomitant with increased labor, suggesting that heroin and alfentanil made cocaine consumption more resistant to increasing response costs, or more "inelastic." Collectively, these findings suggest that speedball self-administration may occur even with relatively low levels of intrinsic efficacy at mu-opioid receptors and that an inelastic relationship between drug consumption and labor may contribute to the persistence of speedball abuse.