A Sad State of Affairs: Psychostimulant Addiction Treatment Leaves Much to be Desired

The authors of a new paper, published ahead of a special issue of Neuropharmacology, give the reader a good look at the current state of psychostimulant substance use disorder treatment - and the results are disappointing. Starting with behavioral treatments and ending with a review of medications, the clear fact remains that there is no single treatment that outperforms most others.

Meta-analyses of behavioral interventions for the treatment of cocaine use disorder have shown modest benefits; while one review found, "there is currently no evidence for a differential treatment effect of any psychosocial treatment in the management of" cocaine or amphetamine use disorders. CBT and Contingency Management (CM) remain the mainstay of psychostimulant treatment, and the authors cite data suggesting a combination of CM plus Community Reinforcement Approach might produce the best outcomes.

In terms of pharmacological treatments, researched medications include antagonist therapy, agonist therapy, medications to treat withdrawal symptoms and medications to treat co-occurring psychiatric symptoms or disorders; and the authors of the present paper devote the bulk of their attention to weighing the evidence of such options.

Naltrexone, they note, has shown some promise in laboratory studies, as it has been shown to weaken amphetamine- and cocaine-related effects in some subjects in both human and animal trials. Because it also seems to weaken the subjective euphoric effects of methylphenidate (Ritalin), one area of promise could be in the combination of naltrexone and methylphenidate to limit the abuse potential of an agonist-like treatment.

Disulfiram (aka Antabuse) has also shown some promise in the lab, but mainly in the treatment of cocaine-use disorders. It was shown to increase the brain ratio of dopamine to norepinephrine and to prevent stress-induced cocaine reinstatement. In pilot studies, disulfiram was shown to be effective in reducing cocaine use in patients with cocaine use disorders (CUD), and among buprenorphine-maintained polydrug users. However, in a more recent study, disulfiram showed less promise reducing cocaine use among methadone-maintained patients. The authors of the review point to evidence that disulfiram may only be effective among CUD patients with specific genotypes - and may be more effective among men than women.

Agonist-like treatments are also reviewed by the authors, and appear to offer some of the more exciting, and possibly effective, interventions for psychostimulant addiction. D-amphetamine has been shown to improve treatment retention and reduce illicit cocaine use in early trials; while a later study showed a reduction in withdrawal and craving, but a failure to reduce methamphetamine use. Not mentioned in the review, but a small study we wrote about in 2012 appeared to show promising results in the combination of mixed amphetamine salts (Adderall) and topiramate (Topamax)

For its part, sustained-release methamphetamine has been tested as a maintenance agent for CUD, and appeared to significantly reduce cocaine-positive urine samples and cocaine craving. The familiar medication, methylphenidate, has been shown to be non-superior to placebo in some studies for meth/amphetamine use and cocaine use, but appears to warrant further research at improved dosages. The other agonist-like medication discussed, modafanil, seems to be an interesting candidate for maintenance treatment. Known to be a cognitive enhancer, modafanil may be useful in addressing the impairments in a range of cognitive functions that can result from psychostimulant addiction; but studies have thus far produced more "equivocal" results in most trials as treatments for cocaine or for methamphetamine - even when combined with D-amphetamine. Post-hoc analysis of the available data does, however, suggest efficacy in the less severe cases of addiction.

Additionally, researchers in Latin America have argued in favor oral coca for the treatment of cocaine use disorder. Their "Handbook on Oral Cocaine as Agonist Therapy for Cocaine Dependence" is an intriguing read, and the authors of the review posit that political, cultural and commercial barriers - not scientific ones - are likely to blame for the "lack of follow-up on this line of research".

A host of other medications have been tried and tested for psychostimulant use disorders, with little success. Vaccines, on the other hand, are now gaining momentum in the field and are being used in multiple studies at various phases. A vaccine that that produces antibodies to prevent cocaine from crossing the blood-brain barrier has performed well in Phase I and Phase II trials. A methamphetamine vaccine is still in preclinical development, but initial results have shown good levels of antibodies in animal models and a Phase I  trial is scheduled to begin in 2015.

Considering the vast global toll which is the result of psychostimulant addiction, treatment for these disorders is as desperately needed as ever. If there is one thing that this review makes clear, it's the fact that we still have a long way to go before we can say that we have effective treatment options for the consumer. A question for readers of this blog: what are the techniques and interventions that you have found to be helpful stimulant use disorders? Is there a particular line of research that you feel would be important to investigate further? Do you see the utility of agonist-like medications? Your thoughts are always appreciated.

Many Patients with Alcohol Use Disorders Not Offered Medications

An exhaustive and brand new meta-analysis and systematic review, published today in the Journal of the American Medical Association, paints a disappointing picture of medication access for those with alcohol use disorders (AUD) in the US. The authors included 123 studies, involving nearly 23,000 participants, and determined that while acamprosate and naltrexone have been shown to be effective treatments, fewer than 10% of those who might benefit are ever prescribed an AUD medication.

Here's the Abstract, via JAMA:

IMPORTANCE Alcohol use disorders cause substantial morbidity and early mortality yet

remain greatly undertreated. Medications are considerably underused.

OBJECTIVE To conduct a systematic review and meta-analysis of the benefits and harms of

medications (US FDA-approved and others) for adults with alcohol use disorders.

DATA SOURCES PubMed, Cochrane Library, PsycINFO, CINAHL, EMBASE, FDA website, and

clinical trials registries (January 1, 1970, to March 1, 2014).

STUDY SELECTION Two reviewers selected randomized clinical trials (RCTs) with at least 12

weeks’ duration that reported eligible outcomes and head-to-head prospective cohort

studies reporting health outcomes or harms.

DATA EXTRACTION AND SYNTHESIS We conducted meta-analyses using random-effects

models and calculated numbers needed to treat for benefit (NNTs) or harm (NNHs).

MAIN OUTCOMES AND MEASURES Alcohol consumption, motor vehicle crashes, injuries,

quality of life, function, mortality, and harms.

RESULTS We included 122 RCTs and 1 cohort study (total 22 803 participants). Most assessed

acamprosate (27 studies, n = 7519), naltrexone (53 studies, n = 9140), or both. The NNT to

prevent return to any drinking for acamprosate was 12 (95% CI, 8 to 26; risk difference [RD],

−0.09; 95% CI, −0.14 to −0.04) and was 20 (95% CI, 11 to 500; RD, −0.05; 95% CI, −0.10 to

−0.002) for oral naltrexone (50 mg/d). The NNT to prevent return to heavy drinking was 12

(95% CI, 8 to 26; RD −0.09; 95% CI, −0.13 to −0.04) for oral naltrexone (50 mg/d).

Meta-analyses of trials comparing acamprosate to naltrexone found no statistically significant

difference between them for return to any drinking (RD, 0.02; 95% CI, −0.03 to 0.08) or

heavy drinking (RD, 0.01; 95% CI, −0.05 to 0.06). For injectable naltrexone, meta-analyses

found no association with return to any drinking (RD, −0.04; 95% CI, −0.10 to 0.03) or heavy

drinking (RD, −0.01; 95% CI, −0.14 to 0.13) but found an association with reduction in heavy

drinking days (weighted mean difference [WMD], −4.6%; 95% CI, −8.5% to −0.56%). Among

medications used off-label, moderate evidence supports an association with improvement in

some consumption outcomes for nalmefene (heavy drinking days per month: WMD, −2.0;

95% CI, −3.0 to −1.0; drinks per drinking day: WMD, −1.02; 95% CI, −1.77 to −0.28) and

topiramate (% heavy drinking days: WMD, −9.0%; 95% CI, −15.3% to −2.7%; drinks per

drinking day: WMD, −1.0; 95% CI, −1.6 to −0.48). For naltrexone and nalmefene, NNHs for

withdrawal from trials due to adverse events were 48 (95% CI, 30 to 112) and 12 (95% CI, 7 to

50), respectively; risk was not significantly increased for acamprosate or topiramate.

CONCLUSIONS AND RELEVANCE Both acamprosate and oral naltrexone were associated with

reduction in return to drinking. When directly compared with one another, no significant

differences were found between acamprosate and naltrexone for controlling alcohol

consumption. Factors such as dosing frequency, potential adverse events, and availability of

treatments may guide medication choice.

Would love to know what readers think about the results of this large study. What are the main drivers of this gap, and why aren't more patients requesting these medications? What needs to be done to improve access?

Cochrane Releases New Reviews on MAT

The highly-respected Cochrane Library, known for its meticulous reviews of the current state of medical knowledge, has updated and released two reviews on medication-assisted treatment recently. The first, "Maintenance agonist treatments for opiate-dependent women", aims to " assess the effectiveness of any maintenance treatment alone or in combination with psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions for child health status, neonatal mortality, retaining pregnant women in treatment and reducing the use of substances." The second, "Pharmacological interventions for drug-using offenders" aims to " assess the effectiveness of pharmacological interventions for drug-using offenders in reducing criminal activity and/or drug use." In both cases, the authors note the effectiveness of opioid medications in assisting patients to achieve desired outcomes (although the effect on criminal activity in the second study was significant, but less pronounced). However, they cautioned against generalizing the findings as the body of evidence of both topics is still too small.

Here are the abstracts, via Wiley:

Maintenance agonist treatments for opiate-dependent pregnant women

Abstract

Background

The prevalence of opiate use among pregnant women can range from 1% to 2% to as high as 21%. Heroin crosses the placenta and pregnant, opiate-dependent women experience a six-fold increase in maternal obstetric complications such as low birth weight, toxaemia, third trimester bleeding, malpresentation, puerperal morbidity, fetal distress and meconium aspiration. Neonatal complications include narcotic withdrawal, postnatal growth deficiency, microcephaly, neuro-behavioural problems, increased neonatal mortality and a 74-fold increase in sudden infant death syndrome.

Objectives

To assess the effectiveness of any maintenance treatment alone or in combination with psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions for child health status, neonatal mortality, retaining pregnant women in treatment and reducing the use of substances.

Search methods

We searched the Cochrane Drugs and Alcohol Group Trials Register (September 2013), PubMed (1966 to September 2013), CINAHL (1982 to September 2013), reference lists of relevant papers, sources of ongoing trials, conference proceedings and national focal points for drug research. We contacted authors of included studies and experts in the field.

Selection criteria

Randomised controlled trials assessing the efficacy of any maintenance pharmacological treatment for opiate-dependent pregnant women.

Data collection and analysis

We used the standard methodological procedures expected by The Cochrane Collaboration.

Main results

We found four trials with 271 pregnant women. Three compared methadone with buprenorphine and one methadone with oral slow-release morphine. Three out of four studies had adequate allocation concealment and were double-blind. The major flaw in the included studies was attrition bias: three out of four had a high drop-out rate (30% to 40%) and this was unbalanced between groups.

Methadone versus buprenorphine: the drop-out rate from treatment was lower in the methadone group (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.41 to 1.01, three studies, 223 participants). There was no statistically significant difference in the use of primary substance between methadone and buprenorphine (RR 1.81, 95% CI 0.70 to 4.69, two studies, 151 participants). For both, we judged the quality of evidence as low. Birth weight was higher in the buprenorphine group in the two trials that could be pooled (mean difference (MD) -365.45 g (95% CI -673.84 to -57.07), two studies, 150 participants). The third study reported that there was no statistically significant difference. For APGAR score neither of the studies which compared methadone with buprenorphine found a significant difference. For both, we judged the quality of evidence as low. Many measures were used in the studies to assess neonatal abstinence syndrome. The number of newborns treated for neonatal abstinence syndrome, which is the most critical outcome, did not differ significantly between groups. We judged the quality of evidence as very low.

Methadone versus slow-release morphine: there was no drop-out in either treatment group. Oral slow-release morphine seemed superior to methadone for abstinence from heroin use during pregnancy (RR 2.40, 95% CI 1.00 to 5.77, one study, 48 participants). We judged the quality of evidence as moderate.

Only one study which compared methadone with buprenorphine reported side effects. For the mother there was no statistically significant difference; for the newborns in the buprenorphine group there were significantly fewer serious side effects.

In the comparison between methadone and slow-release morphine no side effects were reported for the mother, whereas one child in the methadone group had central apnoea and one child in the morphine group had obstructive apnoea.

Authors' conclusions

We did not find sufficient significant differences between methadone and buprenorphine or slow-release morphine to allow us to conclude that one treatment is superior to another for all relevant outcomes. While methadone seems superior in terms of retaining patients in treatment, buprenorphine seems to lead to less severe neonatal abstinence syndrome. Additionally, even though a multi-centre, international trial with 175 pregnant women has recently been completed and its results published and included in this review, the body of evidence is still too small to draw firm conclusions about the equivalence of the treatments compared. There is still a need for randomised controlled trials of adequate sample size comparing different maintenance treatments.

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006318.pub3/abstract

 

Pharmacological interventions for drug-using offenders

Abstract

Background

The review represents one in a family of four reviews focusing on a range of different interventions for drug-using offenders. This specific review considers pharmacological interventions aimed at reducing drug use and/or criminal activity for illicit drug-using offenders.

Objectives

To assess the effectiveness of pharmacological interventions for drug-using offenders in reducing criminal activity and/or drug use.

Search methods

Fourteen electronic bibliographic databases (searched between 2004 and 21 March 2013) and five additional Web resources (searched between 2004 and 11 November 2011) were searched. Experts in the field were contacted for further information.

Selection criteria

Randomised controlled trials assessing the efficacy of any pharmacological interventions for reducing, eliminating or preventing relapse in drug-using offenders were included. Data on the cost and cost-effectiveness of interventions were reported.

Data collection and analysis

We used standard methodological procedures as expected by The Cochrane Collaboration.

Main results

A total of 76 trials across the four reviews were identified. After a process of prescreening had been completed, 17 trials were judged to meet the inclusion criteria for this specific review (six of the 17 trials are awaiting classification for the review). The remaining 11 trials contained a total of 2,678 participants. Nine of the eleven studies used samples with a majority of men. The interventions (buprenorphine, methadone and naltrexone) were compared to non pharmacological treatments (e.g., counselling) and other pharmacological drugs. The methodological trial quality was poorly described, and most studies were rated as 'unclear' by the reviewers. The biggest threats to risk of bias were generated through blinding (performance and detection bias) and incomplete outcome data (attrition bias). When combined, the results suggest that pharmacological interventions do significantly reduce subsequent drug use using biological measures, (three studies, 300 participants, RR 0.71 (95% CI 0.52 to 0.97)), self report dichotomous data (three studies, 317 participants, RR 0.42, (95% CI 0.22 to 0.81)) and continuous measures (one study, MD -59.66 (95% CI -120.60 to 1.28)) . In the subgroups analysis for community setting, (two studies, 99 participants: RR 0.62 (95% CI 0.35 to 1.09)) and for secure establishment setting, (one study, 201 participants: RR 0.76 (95% CI 0.52 to 1.10)), the results are no longer statistically significant. Criminal activity was significantly reduced favouring the dichotomous measures of re arrest, (one study, 62 participants, RR 0.60 (95% CI 0.32 to 1.14)), re-incarceration, (three studies, 142 participants, RR 0.33 (95% CI 0.19 to 0.56)) and continuous measures (one study, 51 participants, MD -74.21 (95% CI -133.53 to -14.89)). Findings on the effects of individual pharmacological interventions on drug use and criminal activity show mixed results. Buprenorphine in comparison to a non pharmacological treatment seemed to favour buprenorphine but not significantly with self report drug use, (one study, 36 participants, RR 0.58 (95% CI 0.25 to 1.35)). Methadone and cognitive behavioural skills in comparison to standard psychiatric services, did show a significant reduction for self report dichotomous drug use (one study, 253 participants, RR 0.43 (95% CI 0.33 to 0.56)) but not for self report continuous data (one study 51 participants) MD -0.52 (95% CI -1.09 to 0.05)), or re incarceration RR 1.23 (95% CI 0.53 to 2.87)). Naltrexone was favoured significantly over routine parole and probation for re incarceration (two studies 114 participants, RR 0.36 (95% CI 0.19 to 0.69)) but no data was available on drug use. Finally, we compared each pharmacological treatment to another. In each case we compared methadone to: buprenorphine, diamorphine and naltrexone. No significant differences were displayed for either treatment for self report dichotomous drug use (one study, 193 participants RR 1.23 (95% CI 0.86 to 1.76)), continuous measures of drug use MD 0.70 (95% CI -5.33 to 6.73) or criminal activity RR 1.25 (95% CI 0.83 to 1.88)) between methadone and buprenorphine. Similiar results were found for comparisons with Diamorphine with no significant differences between the drugs for self report dichotomous drug use for arrest (one study, 825 participants RR 1.25 (95% CI 1.03-1.51)) or Naltrexone for dichotomous measures of re incarceration (one study, 44 participants, RR 1.10 (95% CI 0.37 to 3.26)), and continuous outcome measure of crime MD -0.50 (95% CI -8.04 to 7.04)) or self report drug use MD 4.60 (95% CI -3.54 to 12.74)).

Authors' conclusions

Pharmacological interventions for drug-using offenders do appear to reduce overall subsequent drug use and criminal activity (but to a lesser extent). No statistically significant differences were displayed by treatment setting. Individual differences are displayed between the three pharmacological interventions (buprenorphine, methadone and naltrexone) when compared to a non pharmacological intervention, but not when compared to each other. Caution should be taken when interpreting these findings, as the conclusions are based on a small number of trials, and generalisation of these study findings should be limited mainly to male adult offenders. Additionally, many studies were rated at high risk of bias because trial information was inadequately described.

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010862/abstract