Impact of Pharmacological Treatments for Opioid Use Disorder on Mortality.

The use of pharmacological treatments for opioid use disorders, including methadone, buprenorphine and naltrexone has been associated with a reduction in mortality compared with illicit opioid use. However, these treatments can also contribute significantly to the risk of death. The opioid agonists methadone and buprenorphine achieve clinical efficacy in patients with an opioid use disorder through suppressing craving and diminishing the effectiveness of illicit opioid doses, while the antagonist naltrexone blocks the action of opioids. Pharmacological differences between opioid pharmacotherapies then create different temporal patterns of protection and mortality risk, different risks of relapse to illicit opioid use, and variations in direct and indirect toxicity, which are revealed in clinical and epidemiological studies. Induction onto methadone and the cessation of oral naltrexone treatment are associated with an elevated risk of opioid poisoning, which is not apparent in patients treated with buprenorphine or sustained-release naltrexone. Beyond drug-related mortality, these pharmacotherapies can impact a participant's risk of death. Buprenorphine may also have some advantages over methadone in patients with depressive disorders or cardiovascular abnormalities. Naltrexone, which is also commonly prescribed to manage problem alcohol use, may reduce deaths in chronic co-alcohol users. Understanding these pharmacologically driven patterns then guides the judicious choice of drug and dosing schedule and the proactive risk management that is crucial to minimising the risk of death in treatment.

Overdose following initiation of naltrexone and buprenorphine medication treatment for opioid use disorder in a United States commercially insured cohort.

BACKGROUND AND AIMS: Despite the growing opioid overdose crisis, medication treatment for opioid use disorder remains uncommon. The comparative effectiveness of buprenorphine and naltrexone treatment in reducing overdose and the comparative risks of discontinuing treatment in the real world, remain uncertain. Our aim was to examine the effectiveness of medications for opioid use disorder in preventing opioid-related overdose. DESIGN: Retrospective cohort study SETTING: United States. PATIENTS: 46,846 commercially insured individuals diagnosed with opioid use disorder and initiating medication treatment between 2010 and 2016. MEASUREMENTS: Opioid-related overdose identified by International Classification of Diseases, Ninth and Tenth Revisions. FINDINGS: In our sample, 1386 individuals were prescribed extended-release injectable naltrexone (median filled prescriptions = 9 months), 7782 were prescribed oral naltrexone (5 months), and 40,441 were prescribed buprenorphine (19 months) at least once during follow-up. Individuals receiving buprenorphine therapy were at significantly reduced risk of opioid-related overdose compared to no treatment (adjusted hazard ratio (HR) = 0.40, 95% CI 0.35-0.46), while a significant association was not observed in extended-release injectable (HR = 0.74, 95% CI 0.42-1.31) or oral (HR = 0.93, 95% CI 0.71-1.22) naltrexone. We found no association with opioid overdose within four weeks of discontinuation of any medication. CONCLUSION: Among commercially-insured patients who initiate medications for opioid use disorder, buprenorphine, but not naltrexone, was associated with lower risk of overdose during active treatment compared to post-discontinuation. More research is needed to understand the benefits and risks unique to each treatment option to better tailor therapies to patients with opioid use disorder.

Safety assessment of combination therapies in the treatment of obesity: focus on naltrexone/bupropion extended release and phentermine-topiramate extended release.

INTRODUCTION: Few studies on combination therapies for the treatment of obesity had been conducted until recently, when two fixed-dose combinations, bupropion-naltrexone ER fixed-dose combination and phentermine-topiramate ER titrated-dose combinations were evaluated in clinical studies that ultimately led to FDA approval. Areas covered: In this review, we discuss safety concerns about both combinations, the rationale and history of combination therapies for obesity (including phentermine plus fenfluramine), and possible future new combinations. Expert opinion: Combination therapies are a promising new area in obesity treatment, similar to what occurs with diabetes and hypertension. Safety assessment is highly important due to the high number of potential users on a chronic basis.

Assessment of pharmacodynamic effects following oral administration of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules compared with crushed morphine sulfate controlled-release tablets and placebo in nondependent recreational opioid users.

OBJECTIVES: To compare the pharmacodynamic effects, including self-reports of "drug liking" and "high," of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules (MSN), crushed morphine sulfate controlled-release (CR) tablets, and placebo in an abuse potential study. DESIGN: Randomized, double-blind, placebo-controlled, three-way crossover study. SETTING: Single-center. SUBJECTS: Nondependent recreational opioid users. INTERVENTIONS: Orally administered crushed MSN (120-mg morphine sulfate and 4.8-mg naltrexone hydrochloride), crushed 120-mg morphine sulfate CR, and placebo. OUTCOME MEASURES: Subjective ratings (100-point visual analog scales) of positive drug effects (drug liking, high, good effects, take drug again, and overall drug liking), any effects, and negative effects (bad effects, feel sick, nausea, sleepy, and dizzy), along with pupillometry, pharmacokinetic (PK), and safety assessments. RESULTS: Crushed morphine sulfate CR significantly increased ratings of all positive subjective measures relative to placebo (P < 0.0001). Crushed MSN significantly decreased all positive subjective ratings compared with morphine sulfate CR (P ≤ 0.005), but significantly increased ratings compared with placebo (P < 0.03). Peak pupil diameter was significantly larger for MSN than morphine sulfate (P < 0.0001). PK analysis of morphine plasma concentrations indicated that Cmax was significantly lower and tmax significantly longer for crushed MSN compared with crushed morphine sulfate CR. Plasma concentrations of naltrexone and 6-ß-naltrexol were present following crushed MSN. CONCLUSIONS: This study demonstrated that when crushed and administered orally to nondependent recreational opioid users, MSN was associated with significantly lower scores on all positive subjective measures including drug liking and high, and significantly less pupil constriction compared with crushed morphine sulfate CR.

Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone.

RATIONALE: Prescription opioid abuse has risen dramatically in the United States as clinicians have increased opioid prescribing for alleviation of both acute and chronic pain. Opioid analgesics with decreased risk for abuse are needed. OBJECTIVE: Preclinical and clinical studies have shown that opioids combined with ultra-low-dose naltrexone (NTX) may have increased analgesic potency and have suggested reduced abuse or dependence liability. This study addressed whether addition of ultra-low-dose naltrexone might decrease the abuse liability of oxycodone (OXY) in humans. MATERIALS AND METHODS: This double-blind, placebo-controlled study systematically examined the subjective and physiological effects of combining oral OXY and ultra-low NTX doses in 14 experienced opioid abusers. Seven acute drug conditions given at least 5 days apart were compared in a within-subject crossover design: placebo, OXY 20 mg, OXY 40 mg, plus each of the active OXY doses combined with 0.0001 and 0.001 mg NTX. RESULTS: The methods were sensitive to detecting opioid effects on abuse liability indices, with significant differences between all OXY conditions and placebo as well as between 20 and 40 mg OXY doses on positive subjective ratings (e.g., "I feel a good drug effect" or "I like the drug"), on observer- and participant-rated opioid agonist effects, and on a drug-versus-money value rating. There were no significant differences or evident trends associated with the addition of either NTX dose on any abuse liability indices. CONCLUSIONS: The addition of ultra-low-dose NTX to OXY did not decrease abuse liability of acutely administered OXY in experienced opioid abusers.

Cost and cost-effectiveness of the COMBINE study in alcohol-dependent patients.

CONTEXT: The COMBINE (Combined Pharmacotherapies and Behavioral Intervention) clinical trial recently evaluated the efficacy of medications, behavioral therapies, and their combinations for the outpatient treatment of alcohol dependence. The costs and cost-effectiveness of these combinations are unknown and of interest to clinicians and policy makers. OBJECTIVE: To evaluate the costs and cost-effectiveness of the COMBINE Study interventions after 16 weeks of treatment. DESIGN: A prospective cost and cost-effectiveness study of a randomized controlled clinical trial. SETTING: Eleven US clinical sites. PARTICIPANTS: One thousand three hundred eighty-three patients having a diagnosis of primary alcohol dependence. INTERVENTIONS: The study included 9 treatment groups; 4 groups received medical management for 16 weeks with naltrexone, 100 mg/d, acamprosate, 3 g/d, or both, and/or placebo; 4 groups received the same therapy as mentioned earlier with combined behavioral intervention; and 1 group received combined behavioral intervention only. MAIN OUTCOMES MEASURES: Incremental cost per percentage point increase in percentage of days abstinent, incremental cost per patient of avoiding heavy drinking, and incremental cost per patient of achieving a good clinical outcome. RESULTS: On the basis of the mean values of cost and effectiveness, 3 interventions are cost-effective options relative to the other interventions for all 3 outcomes: medical management (MM) with placebo ($409 per patient), MM plus naltrexone therapy ($671 per patient), and MM plus combined naltrexone and acamprosate therapy ($1003 per patient). CONCLUSIONS: To our knowledge, this is only the second prospective cost-effectiveness study with a randomized controlled clinical trial design that has been performed for the treatment of alcohol dependence. Focusing only on effectiveness, MM-naltrexone-acamprosate therapy is not significantly better than MM-naltrexone therapy. However, considering cost and cost-effectiveness, MM-naltrexone-acamprosate therapy may be a better choice, depending on whether the cost of the incremental increase in effectiveness is justified by the decision maker.

Barriers to the use of medications to treat alcoholism.

In 1994, naltrexone became the first medication approved by the Food and Drug Administration as an adjunct in alcoholism treatment in almost fifty years. Despite evidence of its efficacy, use of naltrexone is not widespread. Patient and physician focus groups were used to identify reasons naltrexone has not been prescribed more widely. Barriers to its widespread use include a lack of awareness, a lack of evidence of efficacy in practice, side effects, time for patient management, a reluctance to take medications, medication addiction concerns, Alcoholics Anonymous (AA) philosophy, and price. The study indicates that medications to treat alcoholism must overcome numerous barriers before becoming widely accepted.

[Alcohol dependence treatment with naltrexone: safety assessment. Observation study group of alcoholic dependence]. / Evaluación de la seguridad del tratamiento con naltrexona en la dependencia del alcohol. Grupo de Estudio Observacional de la Dependencia Alcohólica (GEODA).

OBJECTIVES: The security the naltrexone treatment in alcohol dependence was evaluated by clinic follow-up (tolerance and secondary effects) and analitic follow-up (transaminases and another biological assessment). MATERIAL AND METHODS: This is an one open study, not controlled, prospective and multicentric treatment of the alcoholism of Spain. 42 centres recruited alcoholic patients who were treated with 50 mg of naltrexone with pursuit of 6 months. RESULTS: 234 patient were selected, 173 concluded the study. The more frequent secondary effects were: astenia (16%), nausea (11.6%), sleepiness (8%), and insomnia (7%). The majority of patients tolerated well the treatment with naltrexone. Only 5 (3%) patients were dropped out of the study by intolerance to naltrexone. GOT, GPT, GGT levels decreased during the six months of treatment. CONCLUSIONS: The naltrexone treatment in alcoholic dependent is well tolerated. The secondary effects are infrequent and only in 3% of them the treatment were interrupted.

A risk-benefit assessment of naltrexone in the treatment of alcohol dependence.

There is a great deal of interest in the use of naltrexone as a treatment for alcohol (ethanol) dependence since there is a rapidly expanding body of evidence to support its efficacy and tolerability in this indication. Naltrexone, a long-acting, nonselective opioid receptor antagonist has been shown to reduce alcohol intake when combined with behavioural treatment. Naltrexone may prevent the return to clinically significant drinking by blocking the pleasurable effects or "high' associated with alcohol drinking. Results from controlled studies showed that in alcohol dependent patients taking naltrexone 50 mg/day in combination with behavioural treatment, relapse rates were reduced by 50% compared with placebo treated patients. Historically, several factors have limited the use of effective pharmacological adjuncts in the treatment of alcohol dependence. These include safety considerations in this vulnerable population, and the fact that some treatment programmes discourage alcohol-dependent patients from taking medications. The most common adverse effects reported with the use of naltrexone at a dosage of 50 mg/day include nausea and vomiting. Naltrexone does not appear to be hepatotoxic in dosages recommended in the treatment of alcohol dependence, i.e. 50 mg/day. Thus, naltrexone appears to offer significant therapeutic benefits at a relatively low risk, when used judiciously and with behavioural treatment for alcohol dependent patients.

Assessment of nalmefene glucuronide as a selective gut opioid antagonist.

Opioid use often causes troublesome constipation as a side-effect. Selective antagonism of the intestinal actions of opioids might be useful in the treatment of opioid-induced constipation. We tested the inactive metabolite of nalmefene, nalmefene glucuronide, which showed promise of gut selectivity in rodent models, by administering ascending doses in single-blind, placebo-controlled fashion to five methadone-maintained, opioid-dependent male volunteers. Assessment of whether systemic or gut-selective opioid antagonist effects occurred was measured by vital signs, pupillary diameter, opioid withdrawal symptom scales, and bowel function. Oral nalmefene glucuronide precipitated symptoms and signs consistent with the opioid abstinence syndrome in all five subjects a mean of 9.0 h after dosing. We conclude that nalmefene glucuronide does not appear to exert sufficient gut selectivity to be useful in antagonizing constipation due to exogenous opioid administration without antagonizing systemic opioid effects.

A review of parenteral sustained-release naltrexone systems.

The ideal naltrexone sustained-release delivery system should be easy to inject or implant, not cause adverse tissue reaction, release the drug at a relatively constant rate for at least 30 days, and biodegrade within a short time afterwards. Mechanisms which can be used for sustaining drug release include reducing solubility and surface area, coating, encapsulation and microencapsulation, complexation, binding and hydrophilic gelation. Drug release from such systems is controlled by diffusion through a barrier/film, diffusion from a monolithic device, erosion of the surface, hydrolysis, ion exchange, biodegradation, or a combination of these. Injectable systems would seem to be ultimately preferred because of the ease of administration and handling, while the implantable devices may find first use in man since they are easily removable, should that be necessary. Maintaining particulate-free products and sterilization methods are two problems with all parenteral dosage forms. Production must be particularly well controlled and validated.

Assessment of naltrexone in the treatment of schizophrenia.

Naltrexone, a long acting opiate antagonist, and placebo were administered to eight schizophrenics in doses of 200 mg per day for 1 week in a double-blind, crossover design. No improvement was noted, and no side effects resembling the opiate withdrawal syndrome with naltrexone were found. Naltrexone does not appear to alter schizophrenic symptomatology.