Treatment Of Opioid Dependence Research Articles

A G protein signaling-biased agonist at the μ-opioid receptor reverses morphine tolerance while preventing morphine withdrawal.

It has been demonstrated that opioid agonists that preferentially act at μ-opioid receptors to activate G protein signaling over βarrestin2 recruitment produce antinociception with less respiratory suppression. However, most of the adverse effects associated with opioid therapeutics are realized after extended dosing. Therefore, we tested the onset of tolerance and dependence, and assessed for neurochemical changes associated with prolonged treatment with the biased agonist SR-17018. When chronically administered to mice, SR-17018 does not lead to hot plateantinociceptive tolerance, receptor desensitization in periaqueductal gray, nor a super-sensitization of adenylyl cyclase in the striatum, which are hallmarks of opioid neuronal adaptations that are seen with morphine. Interestingly, substitution with SR-17018 in morphine-tolerant mice restores morphine potency and efficacy, whereas the onset of opioid withdrawal is prevented. This is in contrast to buprenorphine, which can suppress withdrawal, but produces and maintains morphine antinociceptive tolerance. Biased agonists of this nature may therefore be useful for the treatment of opioid dependence while restoring opioid antinociceptive sensitivity.

Sleep reductions associated with illicit opioid use and clinic-hour changes during opioid agonist treatment for opioid dependence: Measurement by electronic diary and actigraphy

Sleep problems are commonly reported during opioid agonist treatment (OAT) for opioid use disorders. Inpatient studies have found both sleep disturbances and improved sleep during OAT. Illicit opioids can also disrupt sleep, but it is unclear how they affect sleep in outpatients receiving OAT. Therefore, we used electronic diary entries and actigraphy to measure sleep duration and timing in opioid-dependent participants (n = 37) treated with methadone (n = 15) or buprenorphine (n = 22). For 16 weeks, participants were assigned to attend our clinic under different operating hours in a crossover design: Early hours (07:00–09:00) vs. Late hours (12:00–13:00) for 4 weeks each in randomized order, followed for all participants by our Standard clinic hours (07:00–11:30) for 8 weeks. Throughout, participants made daily electronic diary self-reports of their sleep upon waking; they also wore a wrist actigraph for 6 nights in each of the three clinic-hour conditions. Drug use was assessed by thrice-weekly urinalysis. In linear mixed models controlling for other sleep-relevant factors, sleep duration and timing differed by drug use and by clinic hours. Compared to when non-using, participants slept less, went to bed later, and woke later when using illicit opioids and/or both illicit opioids and cocaine. Participants slept less and woke earlier when assigned to the Early hours. These findings highlight the role OAT clinic schedules can play in structuring the sleep/wake cycles of OAT patients and clarify some of the circumstances under which OAT patients experience sleep disruption in daily life.

New slow-release buprenorphine formulations for optimization of opioid substitution

Opioid maintenance treatment with methadone or buprenorphine is an established first-line treatment for opioid dependence. In addition to the novel weekly and monthly subcutaneously injectable buprenorphine depot CAM 2038 (Buvidal®), which is already available in Germany, two other long-acting buprenorphine formulations may be introduced in the near future: the monthly depot formulation RBP-6000 (Sublocade™) and a6-month buprenorphine depot implant (Probuphine™). Basic pharmacological and clinical data of these three medications are given and possible clinical applications are discussed.

Prisons: ignore them at our peril.

People with HIV and HCV are concentrated within criminal justice settings globally, primarily related to criminalization of drug use. This review examines updated prevention and treatment strategies for HIV and HCV within prison with a focus on people who inject drugs and the challenges associated with the provision of these services within prisons and other closed settings and transition to the community. The prevalence of HIV and HCV are several-fold higher in the criminal justice system than within the broader community particularly in regions with high prevalence of injecting drug use, such as Asia, Eastern Europe and North America and where drug use is criminalized. Strategies to optimize management for these infections include routine screening linked to treatment within these settings and medication-assisted treatments for opioid dependence and access to syringe services programs. We build upon the 2016 WHO Consolidated Guidelines through the lens of the key populations of prisoners. Linkage to treatment postrelease, has been universally dismal, but is improved when linked to medication-assisted therapies like methadone, buprenorphine and overdose management. In many prisons, particularly in low-income and middle-income settings, provision of even basic healthcare including mental healthcare and basic HIV prevention tools remain suboptimal. In order to address HIV and HCV prevention and treatment within criminal justice settings, substantial improvement in the delivery of basic healthcare is needed in many prisons worldwide together with effective screening, treatment and linkage of treatment and prevention services to medication-assisted therapies within prison and linkage to care after release.

Circumstances of death of opioid users being treated with naltrexone.

Naltrexone is an opioid antagonist used as a maintenance drug for the treatment of opioid dependence and in opioid withdrawal regimens. The current study aimed to: (1) determine the clinical characteristics and circumstances of death of people undergoing naltrexone treatment for opioid dependence; and (2) determine the blood toxicology of cases including naltrexone concentrations, the presence of other drugs and a comparison of morphine concentrations in the presence and absence of naltrexone. Retrospective study of all deaths among people undergoing naltrexone treatment for opioid dependence retrieved from the National Coronial Information System, 2000-17. Australia-wide. Seventy-four cases, with a mean age of 32.5years; 81.1% male. Information was collected on demographics, manner of death, naltrexone treatment history, toxicology and major organ pathology. Death was attributed to opioid toxicity in 86.5% of cases: accidental (79.7%), deliberate (6.8%). In 55.4% of all cases the decedent was maintained on oral naltrexone and 32.4% had a recent naltrexone implant. In five cases the decedent was undergoing opioid detoxification. Among those screened for naltrexone, naltrexone was present in the blood or urine of 52.5% (15.8% of oral maintenance cases, 85.7% of implant cases). Fourteen cases were known to have died from opioid toxicity with naltrexone present in their blood or urine. The median blood naltrexone concentrations were within the reported therapeutic range. The primary cause of death among people undergoing naltrexone treatment for opioid dependence in Australia from 2000 to 2017 was opioid toxicity, the majority of cases having been maintained on oral naltrexone. Cases in which naltrexone was not detected indicate the importance of treatment compliance. Deaths due to opioid toxicity where naltrexone was present indicates the possibility of overdose while naltrexone medication is maintained.

Effects of ascending buprenorphine doses on measures of experimental pain: A pilot study

BackgroundBuprenorphine is widely used in the treatment of opioid use disorder and pain management. Little is known about the analgesic effects of high-dose sublingual buprenorphine, particularly in doses of >8 mg. The aim of this study was to examine the effect of ascending doses of buprenorphine upon acute pain measures in patients stabilized on buprenorphine as treatment for opioid dependence. MethodsThe pilot study (n = 7) was a randomised, controlled, double-blind, double-dummy, within-subject crossover study examining cold-pressor threshold and tolerance testing under different buprenorphine dose conditions. Each participant attended three sessions to test the analgesic effect of buprenorphine in their usual dose (100%), 150% and 200% of their usual daily dose. ResultsNo significant effects of increased dose were seen on experimental pain measures. Expected physiological effects on pupil size and pulse were observed with increasing dose. No effect of buprenorphine condition was seen on subjective ratings of drug strength, or self-reported sedation, though lower ratings drug liking were seen with 150% and 200% conditions, and lower ratings of ‘bad effects’ and intoxication were reported with the 200% buprenorphine dose condition. No safety concerns with the 150 and 200% buprenorphine dose condition were observed. DiscussionThis pilot study suggests that a ceiling effect on analgesia may be observed in people maintained on buprenorphine, though larger studies may confirm this finding.Clinical Trial Number: ACTRN12614001038684.

Editorial introductions

Editorial introductions

Meeting the challenges of opioid dependence in China: experience of opioid agonist treatment.

This article reviews the role of methadone maintenance treatment (MMT) clinics in minimizing the harms caused by opioid dependence, as well as China's current challenges in this area. In addition, we aim to discuss the treatment strategies for opioid dependence within the international community in the current global situation of serious abuse of opioids. Like other countries facing the opioid crisis, China is actively working on revising policy, improving the addiction treatment system and promotion of MMT clinics to cope with the risks of opioid abuse. As they provide one of the most effective opioid agonist treatments for opioid dependence, MMT clinics play an extremely important role in this campaign. The MMT programme in China has had a significant beneficial effect on reduction of opioid use and the prevalence rate of HIV/AIDS. The efficacy of MMT for patients with opioid dependence in China is confirmed by the present review. However, several important challenges still need to be resolved. China's treatment experience also provides a reference for other countries facing the danger of opioid dependence.

In the states

The Coalition of Medication‐Assisted Treatment Providers and Advocates of New York State (COMPA) issued support and further encouragement to New York legislators last week for the passage of a package of bills to combat the opioid addiction epidemic by increasing access to medication‐assisted treatment (MAT). “We applaud the Senate and Assembly passing A2904 Quart/S4808 Harckham, which eliminates prior authorizations for all MAT medications for commercial insurance policies,” said Allegra Schorr, president of COMPA. “This will increase access to treatment and reduce barriers for delivering care.” She added, “We urge the passage of A7246 Rosenthal/S5935 Harckham, which provides critical access to all medications to vulnerable Medicaid populations during this opioid crisis. Moreover, in order to ensure that all New Yorkers can access care, we urge the state to implement the policy outlined in A833 Rosenthal/S2161 Bailey that would establish a patient‐centered MAT program for incarcerated individuals in jails and prisons, and COMPA supports A972A Rosenthal/S4643A Harckham, which would prohibit copays during the course of treatment at an opioid treatment program.” COMPA is a nonprofit membership organization dedicated to treating addiction through the use of pharmacotherapy as a part of a comprehensive biopsychosocial approach to treatment. COMPA's program members include both opioid treatment programs and office‐based opioid treatment providers. COMPA is the New York state member program of the American Association for the Treatment of Opioid Dependence.

Briefly Noted

Carmen Beatrice Pearman Arlt died last December after a long illness. News of her death started circulating throughout the field only last month, however. Arlt, a longtime Indiana resident, was born in 1955. She organized one of the oldest chapters of the National Alliance for Medication Assisted Recovery (NAMA Recovery), the Methadone Advocacy Group (MAG) of Indiana. NAMA Recovery Director Joycelyn Woods recalled last week that Arlt, in the early 1990s, sent an index card to NAMA Recovery with dimes taped to it and a short message saying she could not afford the $10 membership fee. “Like all letters we receive from patients, she received a letter back saying that we would rather have her advocacy than money,” said Woods. One of the things MAG of Indiana did was clean the street around the methadone clinic. “While they were out picking up garbage and sweeping the street, the reverend from the church across the street came out to warn them about those addicts over there. Carmen explained that they were those addicts,” said Woods. “From this encounter, patients were given space in the church to set up 12‐Step groups and to have meetings. The following year, there was a big drug conference in Indiana, and the chapter acted as the color guard for the governor when he entered the arena. I remember Carmen sending a picture of them all dressed in white shirts, navy bowties for women and regular ties for men and navy pants.” Arlt received the Nyswander/Dole Award from the American Association for the Treatment of Opioid Dependence in 2001 for organizing the state provider organization — at the time, Indiana had no opioid treatment program representation and clinics saw one another more as competitors than associates working for a common cause, said Woods. More recently, in addition to being president of NAMA Recovery, Arlt developed the program for women and children at Porter‐Starke Services in Valparaiso. She was continuing her education to get a Ph.D. in social work when she became ill. “NAMA Recovery will miss Ms. Pearman‐Arlt's dedication and compassion to patients and the field,” said Woods..

Briefly Noted

In an oft‐repeated myth, perpetuated by STAT this week in an article about a move to eliminate the waiver requirement for buprenorphine prescribing, the American Association for the Treatment of Opioid Dependence (AATOD) is frequently assumed to have tried to oppose DATA 2000, the law that enabled buprenorphine to be prescribed to treat opioid use disorder. This was the first real competitor to opioid treatment programs (OTPs), which constitute the membership of AATOD. We asked AATOD to respond, because STAT simply stated it as a fact, and because we covered much of the regulation process and did not observe this to be a fact at all. “And in the early 2000s, when buprenorphine was first approved, some treatment advocates, including AATOD and other methadone providers, lobbied to keep buprenorphine tightly restricted. Initially, physicians waivered to prescribe the drug could only treat 30 patients — a cap later relaxed to 100, then 275,” according to STAT. However, it was the federal government that was concerned about diversion and pill mills — specifically, the Substance Abuse and Mental Health Services Administration (SAMHSA). “We did not oppose DATA 2000,” AATOD President Mark Parrino told us last week. “This was a popular myth at the time and continues to this day.” Parrino continued: “When DATA 2000 was being marked up, we had two specific questions. The first question was about eight hours being enough training for medical practitioners, who had no previous experience, in treating opioid use disorder. There was no answer to that aside from not inconveniencing physicians with any more training. The second question was concerning the language ‘capacity to refer’ the patients to counseling. Our argument was that this language was meaningless, since there was no guidance on how the practitioner would follow through on this.” As far as AATOD can tell (and us too), very little counseling is either made available on‐site or through a referral. SAMHSA doesn't require any recordkeeping on this, so nobody knows. “The other part of the myth of AATOD's position is that we were protecting the interests of OTPs as the only providers of opioid disorder treatment,” said Parrino. “This is also not true, and no evidence exists to have supported this issue.” For the otherwise excellent STAT story, go to https://www.statnews.com/2019/04/30/loosen‐restrictions‐on‐prescribing‐buprenorphine‐addiction‐treatment/.

Names in the News

The American Association for the Treatment of Opioid Dependence (AATOD) will be presenting the 2019 Richard Lane/Robert Holden Patient Advocacy Award to Zachary Talbott at the organization's conference in October. Talbott was selected by his peers for the award. Nominations were announced last month (see ADAW, April 15, https://onlinelibrary.wiley.com/doi/10.1002/adaw.32331). Talbott has opened and directed new opioid treatment programs, and had “compassionate advocacy of people with opioid use disorder,” as well as “fierce dedication to our patient population,” according to AATOD's May 1 letter to Talbott announcing the award offer, a copy of which was obtained by ADAW. Congratulations!

Rapastinel as a non‐opioid treatment for opioid dependence

An increasing number of opioid overdose deaths have resulted from the rising availability of both prescription and nonprescription opioids. Pharmacotherapies, such as buprenorphine and methadone, are used to treat those dependent on opioids. However, these commonly used pharmacotherapies are opioid partial agonists and agonists, so the patient remains in an opioid‐dependent state throughout treatment. Treatment requires long‐term tapering with buprenorphine or methadone, during which withdrawal symptoms can occur. These limitations show a clear need for a non‐opioid pharmacotherapy. Drugs that target the NMDA receptor have been proposed as alternatives to opioid‐targeted pharmacotherapies. The NMDA receptor is involved in the maintenance of opioid dependence and its blockade may reverse the neuroadaptive changes induced by opioid dependence. Regulation of the NMDA receptor could accelerate treatment of opioid dependency (Glass, 2011). Ketamine, an NMDA antagonist, has potential as a treatment, but has associated side effects and potential for abuse. Rapastinel is a novel drug marketed as an antidepressant, and it acts as a partial agonist of the NMDA receptor complex. The negative side effects reported with ketamine have not been reported with rapastinel (Moskal et al., 2016). Since rapastinel acts as a partial agonist and has no reported side effects, it may be a more tolerable treatment option for those dependent on opioids. Male and female adolescent (between 28 and 30 days old) Sprague‐Dawley rats were injected with morphine in increasing doses twice a day for five days (5 mg/kg/day–25 mg/kg/day) to induce opioid dependency. On day six, rats were injected with naloxone (1 mg/kg) and withdrawal signs were quantified. Rats were then given either ketamine injections (1 mg/kg) twice daily (n=12), rapastinel injections (5 mg/kg) every other day (n=14), or saline injections (n=24). On day nine, rats were again administered naloxone (1 mg/kg), and withdrawal signs were quantified to measure efficacy of ketamine and rapastinel. Rapastinel treated rats exhibited significantly fewer withdrawal signs than those treated with ketamine, which did not differ from controls. These results show that rapastinel significantly enhances recovery from opioid dependence.Support or Funding InformationFunding provided by ASPET, Duke University SURPH program, and Duke University Department of Pharmacology and Cancer BiologyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Comparing the Effects of Methadone, Buprenorphine, and Opium Tincture Maintenance Therapy on Sexual Function.

BackgroundOpioid use disorder is a major concern to public health, and opioid maintenance treatment on methadone or buprenorphine is a widely used approach. On the other hand, in recent years, there has been more regards for the use of opium tincture for detoxification and maintenance treatment of opioid dependence in certain parts of the world. The purpose of our research was to compare sexual impairments of methadone maintenance treatment (MMT), buprenorphine maintenance treatment (BMT), and opium tincture maintenance treatment (OMT) in patients.MethodsThe study sample consisted of opium-addicted men candidates for maintenance treatment in an addiction quitting clinic in Tehran, Iran, from November 2017 to February 2018. Participants (n = 84) were randomly assigned to three groups (of the equal number), receiving either methadone tablet, buprenorphine sublingual tablet, and opium tincture. The average score for sexual function was evaluated using the Arizona Sexual Experiences Scale (ASEX) at the beginning and after 3 months after treatment.FindingsAlthough there was no significant different in ASEX scores between the groups at the beginning and end of the study (P > 0.05), but the difference was significant in each group in comparing by themselves.ConclusionThese results showed that sexual dysfunction became better after opioid substitution therapies, and no differences were observed on sexual dysfunction between the three groups.

Engineered endomorphin-2 gene: A novel therapy for improving morphine reinstatement in CPP model of rats by using deficient adenovirus as the vector

Optimal therapeutics to deal with high relapse rates when discontinued is urgent for opioid dependence treatments. Endogenous endomorphin-2 (EM2) level in the central nervous system (CNS) down-regulates obviously after sustained morphine exposure, which suggested that to up-regulate the EM2 level could be a novel method for reinstatement. But the clinical applications of EM2 through conventional administration are limited owing to its short half-life. In our study, we engineered an EM2 gene to achieve the sustained release of EM-2 in CNS by utilizing a signal peptide of mouse growth factor for out-secreting EM2 and a deficient adenovirus as the vector. By intrathecally injecting engineering EM2 gene, a sustained increase of EM2 concentration in the cerebral spinal fluid (CSF) was observed along with a reduction of CPP scores. Also, the activation of astrocytes was suppressed in the hippocampus. In summary, this study provides evidence and reference for using intraspinal gene therapy with a combination of mouse growth factor and EM2 to treat morphine reinstatement.

In Case You Haven't Heard…

Last week, Paul Bowman, regional supervisor for the Boston Family Housing Office and a medication‐assisted treatment (MAT) advocate, spoke at a meeting of the state's MAT Commission. Bowman, who is NAMA (patient advocacy for methadone, mainly) representative for the state, received the American Association for the Treatment of Opioid Dependence's peer award at last year's AATOD conference. At the MAT commission meeting last week, he made specific recommendations regarding opioid treatment programs (OTPs) in the state, where regulations are not patient‐friendly. These included: extend take‐home to 28 days to keep with the federal standards, change MassHealth regulations to be the same as those of the Department of Public Health, get rid of prior authorizations for buprenorphine, stop Blue Cross from charging patients copays, remove tetrahydrocannabinol (THC) from the current OTP drug screen panel, make it possible for OTPs to provide mobile service to patients on weekends, and license more OTPs in the western part of the state to reduce the current eight‐week wait for methadone treatment. The commission agreed to rewrite state regulations to keep them closer to the federal regulation, and to get MassHealth to fix regulations to align with those of the Department of Public Health. “Blue Cross stated that they will meet with Massachusetts NAMA to find out why patients are still paying copays when these have been completely removed for all patients with substance use disorder,” Bowman told us. A legislator promised to move a proposal to remove THC testing from all patients in treatment at OTPs and OBOTs. Finally, the Department of Public Health said it is working to fix mobile services for patients, and is planning to open several new OTPs, as well as considering the 120‐day rule that would allow patients to start methadone without counseling. Talk about a good day's work! Thanks, Paul, for being there, and for reporting in.

AMA’s Incoming President to Deliver Distinguished Psychiatrist Lecture

AMA’s Incoming President to Deliver Distinguished Psychiatrist Lecture

Patient Dropout from Opioid Substitution Treatment

Opioid Substitution Treatment (OST) is an established treatment for opioid dependence. In New Zealand, OST programs are regulated by the Ministry of Health (2014) and Methadone and Buprenorphine/Naloxone (Suboxone) are the primary medications. Retention on OST is a key indicator for stabilisation of patients with opioid dependence. The purpose of the present research was to study dropout rates and identify factors associated with the dropout of patients from OST at the Community Alcohol and Drug Service (CADS), Hamilton, from 1st January 2013 to 30th April 2014. A retrospective clinical audit of patients on OST was conducted. There were 150 patients on OST in Hamilton under the CADS team during the period of study. Nine patients dropped out during the study period. Sixty-four patients were randomly selected from the remaining 141 patients who remained on treatment as a comparison group and for the study sample to be approximately half of the overall population of 150 patients. File review was conducted and potential predictors of dropout were identified. Thirty-five independent variables were selected and dropout was the dependent variable. The statistical programme SPSS22 was used to analyse the data. Fisher’s exact test was used and four variables were identified as being associated with dropout: history of intravenous drug use; (Fisher’s exact p = 0.05); history of lifetime imprisonment (Fisher’s exact p =0.05); other medications prescribed, (Fisher’s exact p = 0.04); and opioid type prescribed during the study, i.e. methadone or Suboxone. Patients on Suboxone dropped out more than those on methadone, (Fisher’s exact p = 0.00). The overall dropout rate was 6%, which was less than the rates of 15-85% found in previous studies. The limitations of the study were that it was retrospective and the number of dropouts was small. Furthermore, only patient factors associated with dropout were included in the study and service factors were not included.

Research suggests possible role of e‐cigs for smoking cessation in OUD patients

Smoking cessation is considered a particularly vexing challenge for patients with opioid use disorders (OUDs), in part because of ways in which nicotine can interact with opioid agonist therapies. In order to add to the base of knowledge on whether electronic cigarette use could be considered a viable strategy for smoking cessation in this population, researchers at the Yale School of Medicine have released data on the prevalence of e‐cigarette use among patients seeking agonist treatment for opioid dependence.

Nonmedical prescription psychiatric drug use and the darknet: A cryptomarket analysis

BackgroundNonmedical prescription psychiatric drug use (NMPDU) is an increasing global health problem, with recent concern focusing on darknet cryptomarkets as sources of procurement. There is a shortage of evidence regarding comparative worldwide NMPDU trends, due in part to data collection difficulties. This problem is particularly marked for non-opioid drugs, particularly those psychiatric drugs which act on the central nervous system (CNS) and have high misuse potential and are associated with high levels of dependency and fatal overdose. This paper therefore has two goals: 1) to report on the kinds of psychiatric prescription drugs available on cryptomarkets, and 2) to use this data to uncover temporal and geographical trends in sales of these products, potentially informing policy regarding NMPDU more generally. MethodDigital trace data collected from 31 cryptomarkets in operation between September 2013 and July 2016 was analysed by country of origin descriptively and for trends in the sales for 7 psychiatric drug groupings, based on their main indication or intended use in psychiatric practice. ResultsSedatives (such as diazepam and alprazolam) and CNS stimulants (mainly Adderall, modafinil and methylphenidate) had the greatest share of sales, but usage and trends varied by location. The UK has high and rising levels of sedative sales, whilst the USA has the greatest stimulant sales and increasing sedative rates. Sales of drugs used in the treatment of opioid dependency are also substantial in the USA. The picture is less clear in mainland Europe with high sales levels reported in unexpected Central and Northern European countries. There is evidence of a move towards the more potent sedative alprazolam – already implicated as a source of problematic NMPDU in the USA – in Australia and the UK. Sales of drugs such as antidepressants, antipsychotics, mood stabilisers and antidementia drugs – all drugs with limited abuse potential – were negligible, indicating minimal levels of online cryptomarket procurement for self-medicating mental health problems. ConclusionPredominantly, psychiatric drugs with potent sedative, stimulant or euphoriant effects are sold on cryptomarkets and this varies by country. With some caveats regarding the limitations of cryptomarket digital trace data taken into account, the study of trends of these products sold online over time may offer a novel and increasingly important window onto wider drug purchasing habits.