Plasma Naltrexone Research Articles

Clinical Implications of the Relationship Between Naltrexone Plasma Levels and the Subjective Effects of Heroin in Humans.

Extended-release naltrexone (NTX) is an opioid antagonist approved for relapse prevention after medical withdrawal. Its therapeutic effect is dependent on the NTX plasma level, and as it decreases, patients may lack protection against relapse and overdose. Therefore, identifying the minimally effective NTX level needed to block opioid-induced subjective effects has important clinical implications. This secondary, individual-level analysis of data collected in a human laboratory study was conducted to evaluate the relationship between NTX levels and subjective effects of an intravenously administered 25-mg challenge dose of heroin in non-treatment-seeking participants with opioid use disorder (N = 12). Subjective ratings of drug liking using a 100-mm visual analog scale (VAS) and NTX levels were measured across 6 weeks after participants received a single injection of either extended-release NTX 192 mg (N = 6) or 384 mg (N = 6). Cubic spline mixed-effects models were used to provide 95% prediction intervals for individual changes in liking scores as a function of NTX levels. Naltrexone levels above 2 ng/mL blocked nearly all VAS ratings of drug liking after intravenous heroin administration. Participants with NTX levels ≥ 2 ng/mL had minimal (≤20 mm) changes from placebo in VAS ratings of drug liking based on 95% prediction intervals. In contrast, NTX levels < 2 ng/mL were associated with greater variability in individual-level subjective responses. In clinical practice, a plasma level range of 1 to 2 ng/mL is considered to be therapeutic in providing heroin blockade. The current findings suggest that a higher level (>2 ng/mL) may be needed to produce a consistent blockade.

Extended-release morphine sulfate and naltrexone hydrochloride (EMBEDA): naltrexone-associated withdrawal and abuse-related effects in patients with chronic pain and recreational opioid users

Objective: To review the effects of naltrexone on withdrawal-related adverse events (AEs) and euphoria-related effects, and the relationship between plasma naltrexone concentrations and withdrawal across EMBEDA (MSN; extended-release morphine sulfate with sequestered naltrexone) studies.Methods: Five studies in pain patients and a safety review summarizing AE reports during the first year following approval of MSN were assessed for withdrawal reports. Three of these studies also assessed Clinical Opiate Withdrawal Scale (COWS) scores. Plasma naltrexone concentrations of MSN-treated individuals were summarized. Abuse potential was assessed in four studies in non-dependent recreational opioid users.Results: Withdrawal AEs occurred in 13/1781 patients across five MSN studies, and 25/182 cases involving withdrawal were reported in the safety review. In three of these studies, 11/964 patients experienced moderate withdrawal (COWS score = 13–24) and 1/964 patients experienced moderately severe withdrawal (score = 28); all were either non-compliant with study drug, had undetectable plasma naltrexone concentrations, or were tapering to placebo. In ≥89% of plasma naltrexone concentration samples from patients who took MSN (n = 166), naltrexone was below the limit of quantification (4.0 pg/mL). In four studies with non-dependent recreational opioid users (n = 118), crushed MSN was associated with significantly lower scores of drug liking, high, and take drug again than crushed morphine sulfate (p ≤ 0.005).Conclusions: When taken intact as directed, naltrexone in MSN does not precipitate withdrawal. However, when MSN is crushed, naltrexone mitigates, but does not eliminate, the euphorigenic effects of crushed morphine sulfate.Trial registration: ClinicalTrials.gov identifier: NCT00420992.Trial registration: ClinicalTrials.gov identifier: NCT00415597.Trial registration: ClinicalTrials.gov identifier: NCT01100437.Trial registration: ClinicalTrials.gov identifier: NCT01179191.Trial registration: ClinicalTrials.gov identifier: NCT00751478.Trial registration: ClinicalTrials.gov identifier: NCT01595867.Trial registration: ClinicalTrials.gov identifier: NCT01380093.

Naltrexone Maintenance Decreases Cannabis Self-Administration and Subjective Effects in Daily Cannabis Smokers.

Given that cannabis use is increasing in the United States, pharmacological treatment options to treat cannabis use disorder are needed. Opioid antagonists modulate cannabinoid effects and may offer a potential approach to reducing cannabis use. In this double-blind, placebo-controlled human laboratory study, we assessed the effects of naltrexone maintenance on the reinforcing, subjective, psychomotor, and cardiovascular effects of active and inactive cannabis. Nontreatment-seeking, daily cannabis smokers were randomized to receive naltrexone (50 mg: n=18 M and 5 F) or placebo (0 mg; n=26 M and 2 F) capsules for 16 days. Before, during, and after medication maintenance, participants completed 10 laboratory sessions over 4-6 weeks, assessing cannabis' behavioral and cardiovascular effects. Medication compliance was verified by observed capsule administration, plasma naltrexone, and urinary riboflavin. Relative to placebo, maintenance on naltrexone significantly reduced both active cannabis self-administration and its positive subjective effects ('good effect'). Participants in the placebo group had 7.6 times (95% CI: 1.1-51.8) the odds of self-administering active cannabis compared with the naltrexone group. This attenuation of reinforcing and positive subjective effects also influenced cannabis use in the natural ecology. Naltrexone had intrinsic effects: decreasing ratings of friendliness, food intake, and systolic blood pressure, and increasing spontaneous reports of stomach upset and headache, yet dropout rates were comparable between groups. In summary, we show for the first time that maintenance on naltrexone decreased cannabis self-administration and ratings of 'good effect' in nontreatment-seeking daily cannabis smokers. Clinical studies in patients motivated to reduce their cannabis use are warranted to evaluate naltrexone's efficacy as a treatment for cannabis use disorder.

Effect of food on the pharmacokinetics of oxycodone and naltrexone from ALO-02, an extended release formulation of oxycodone with sequestered naltrexone.

ALO-02 is being developed as an abuse-deterrent formulation of extended-release oxycodone hydrochloride with naltrexone hydrochloride sequestered in the core of pellets contained in capsules. The primary objective of this study was to assess the effects of administration of ALO-02 capsule whole under fed conditions or sprinkling the pellets from ALO-02 capsule on applesauce under fasting conditions on the pharmacokinetics (PK) of oxycodone, naltrexone and 6-ß-naltrexol compared with ALO-02 capsule administered whole under fasting conditions. The plasma naltrexone and 6-ß-naltrexol concentrations were used to assess the sequestration of naltrexone in the ALO-02 formulation. The secondary objective was to evaluate the safety and tolerability of single 40 mg doses of ALO-02 in healthy volunteers. This was an IRB-approved, open-label, single-dose, randomized, 3-period crossover study in 24 healthy adult volunteers, aged 18-55 years. Each subject was assigned to receive single 40 mg doses of ALO-02 administered whole (intact capsule) under fasting conditions, administered whole under fed conditions (high-fat breakfast ∼ 950 calories), or sprinkling the contents of the ALO-02 capsule (pellets) over applesauce and swallowing the dose without chewing under fasting conditions. Each treatment was separated by a 7-day washout interval. Plasma samples were analyzed just before dosing through 48 hours postdose for oxycodone, and through 120 hours postdose for naltrexone and its major metabolite, 6-ß-naltrexol. Pharmacokinetic parameters included maximum plasma concentration [Cmax ], area under the plasma concentration-time profile from time 0 to infinity [AUCinf ] and to the last quantifiable concentration [AUClast ], time to Cmax [Tmax ], and terminal half life [t1/2 ]. Adverse events, vital signs, and laboratory parameters were monitored for safety assessment. The t1/2 and Tmax values for oxycodone were similar for all 3 treatments. There was a lack of effect of food (whole capsule, fed vs. fasted) or of sprinkling on applesauce (pellets vs. whole capsule, fasted) on oxycodone bioavailability. The Test/Reference ratios of adjusted geometric means for oxycodone AUCinf , AUClast , and Cmax were 99.2%, 100%, and 107%, respectively, for the effect of food; and 101%, 101%, and 97.5%, respectively, for the effect of sprinkling on applesauce. The 90% confidence intervals contained entirely within the bioequivalence limits of 80% to 125% for each comparison. Naltrexone remained sequestered during each treatment, based on the sporadic and low measurable plasma concentrations of naltrexone and 6-ß-naltrexol. Single doses of ALO-02 40 mg were well tolerated, and adverse events were mild, with no apparent difference in frequency for all 3 treatments. Results indicate that ALO-02 can be administered without regard to food. Also, the contents of ALO-02 can be sprinkled over applesauce and consumed without chewing as an alternative treatment option by subjects with difficulty swallowing. Naltrexone remained sequestered in the ALO-02 formulation under all 3 treatments.

(121) Extended-release morphine sulfate and naltrexone hydrochloride: naltrexone associated effects in chronic pain patients and recreational opioid users

This review examined the effects of naltrexone on withdrawal-related adverse events (AEs) and euphoria-related effects, and the relationship between plasma naltrexone concentrations and withdrawal across studies with EMBEDA® (extended-release morphine sulfate with sequestered naltrexone intended to deter abuse). Five IRB-approved studies in pain patients and a safety review summarizing AE reports during the first year following EMBEDA’s approval were assessed for withdrawal reports. Plasma naltrexone concentrations of individuals treated with EMBEDA were summarized.

Relative Bioavailability Study of an Abuse-Deterrent Formulation of Extended-Release Oxycodone with Sequestered Naltrexone (ALO-02) Versus Immediate-Release Oxycodone Tablets in Healthy Volunteers

Background: ALO-02, an opioid formulation intended to deter abuse, comprising capsules filled with pellets of extended-release oxycodone hydrochloride, an opioid, surrounding sequestered naltrexone hydrochloride, an opioid antagonist. This study compared oxycodone pharmacokinetics following ALO-02 (oxycodone/naltrexone 40 mg/4.8 mg) versus immediate-release oxycodone (IRO) tablets (20 mg). Methods: This was an institutional review board–approved, open-label, single-dose, randomized, two-way crossover study in 14 healthy fasted adults (aged 18 to 55 years). Plasma concentrations of oxycodone, naltrexone, and 6-β-naltrexol were determined. Maximum plasma concentration (Cmax), area under the plasma concentrationtime profile from time 0 to infinity (AUCinf) and to the last quantifiable concentration (AUClast), time to Cmax (Tmax), and terminal half-life (t1/2) were determined. Adverse events (AEs) were recorded throughout the study. Results: Median oxycodone Tmax was prolonged (12 versus 1 hours) and mean t1/2 was longer (7.2 versus 4.6 hours) for ALO-02 versus IRO. ALO-02/IRO ratio (90% confidence interval [CI]) of adjusted geometric means for dose-normalized AUCinf was 107.2% (96.7%, 118.8%), with CI contained within equivalence limits of 80%–125%. Dose-normalized ALO-02/IRO Cmax ratio (90% CI) was 33.0% (28.8%, 37.9%). Following ALO-02 administration, plasma naltrexone concentrations were below the limit of quantification (BLQ; 4.00 pg/mL), and 6-β-naltrexol concentrations were BLQ (4.00 pg/mL) in >50% of participants or generally low (<50.0 pg/mL). Most AEs were mild, with nausea and dizziness being most frequent. Conclusion: Pharmacokinetic comparisons indicate equivalent oxycodone bioavailability under fasted conditions. The lower Cmax and longer Tmax and t1/2 observed for ALO-02 versus IRO are consistent with the extended-release profile of ALO-02 formulation. Low naltrexone and 6-β-naltrexol concentrations indicated successful sequestration of naltrexone in ALO-02.

Phase I study of injectable, depot naltrexone for the relapse prevention treatment of opioid dependence

We tested long-acting injectable depot naltrexone for its tolerability, pharmacokinetics, and safety in Phase I. The Phase I trial enrolled 36 healthy participants in two panels (A, B). In Panel A, 24 subjects were randomly assigned to the high-dosage group (400 mg naltrexone, n=6; placebo, n=6) or low-dosage group (200 mg naltrexone, n=6; placebo, n=6). In Panel B, 12 subjects were randomized to take six doses of monthly injectable naltrexone (400 mg) or placebo. After a single injection of naltrexone 200 and 400 mg, means (SD) of naltrexone plasma concentrations were .57 (.28) ng/ml and 1.5 (.8) ng/ml 30 days post-injection. There was no effect of accumulation after multiple dosing. Eleven of 30 subjects (36.67%) who were administered injectable depot naltrexone reported a total of 12 adverse events (AEs). Seven of these 11 AEs were coded as possibly related with study medication. All treatment-related AEs were mild in severity. No serious treatment-related AEs occurred. This long-acting formulation of injectable depot naltrexone is well tolerated, results in constant plasma concentration of naltrexone for at least 1 month. The tolerability and safety of long-acting injectable depot naltrexone are good.

Diclofenac Enables Unprecedented Week-Long Microneedle-Enhanced Delivery of a Skin Impermeable Medication in Humans

Microneedles applied to the skin create micropores, allowing transdermal drug delivery of skin-impermeable compounds. The first human study with this technique demonstrated delivery of naltrexone (an opioid antagonist) for two to three days. Rapid micropore closure, however, blunts the delivery window. Application of diclofenac (an anti-inflammatory) allows seven days of naltrexone delivery in animals. The purpose of the current work was to demonstrate delivery of naltrexone for seven days following one microneedle treatment in humans. Human subjects were treated with microneedles, diclofenac (or placebo), and naltrexone. Impedance measurements were used as a surrogate marker to measure micropore formation, and plasma naltrexone concentrations were measured for seven days post-microneedle application. Impedance dropped significantly from baseline to post-microneedle treatment, confirming micropore formation. Naltrexone was detected for seven days in Group 1 (diclofenac + naltrexone, n = 6), vs. 72 h in Group 2 (placebo + naltrexone, n = 2). At study completion, a significant difference in impedance was observed between intact and microneedle-treated skin in Group 1 (confirming the presence of micropores). This is the first study demonstrating week-long drug delivery after one microneedle application, which would increase patient compliance and allow delivery of therapies for chronic diseases.

Morphine Sulfate and Naltrexone Hydrochloride Extended-Release Capsules: Naltrexone Release, Pharmacodynamics, and Tolerability

Background: Morphine sulfate and naltrexone hydrochloride extended-release capsules (EMBEDA, King Pharmaceuticals, Inc., Bristol, TN), indicated for management of chronic, moderate-to-severe pain, contain pellets of extended-release morphine sulfate with a sequestered naltrexone core (MS-sNT). Taken as directed, morphine provides analgesia while naltrexone remains sequestered; if tampered with by crushing, naltrexone is released to mitigate morphine-induced euphoric effects. While it is necessary to establish that formulations intended to reduce attractiveness for abuse are successful in doing so, it is also necessary to demonstrate that product therapeutic integrity is maintained for patients. Objectives: Data were reviewed from 3 studies to determine: 1) the quantity of naltrexone released when MS-sNT pellets are crushed (MS-sNTC) for at least 2 minutes with mortar and pestle); 2) the extent to which the naltrexone released upon crushing mitigated morphine-induced subjective effects; and 3) whether sequestered naltrexone precipitates opioid withdrawal when MSsNT is taken as directed. Methods: The naltrexone bioavailability study compared naltrexone release from MS-sNTC with that from whole intact MS-sNT capsules (MS-sNTW) and an equal naltrexone solution (NS) dose. Equivalent bioavailability was established if 90% confidence intervals (CIs) for geometric mean ratios (maximum plasma naltrexone concentration [Cmax] and area under the concentration-time curve extrapolated to infinity [AUC∞]) fell between 80% and 125%. The oral pharmacodynamic study assessed drug liking and euphoria and pharmacokinetic properties of MS-sNTC and MS-sNTW compared with morphine sulfate solution (MSS) and placebo. The 12-month, open-label (OL) safety study evaluated safety of MS-sNT administered orally as directed in patients with chronic, moderate-to-severe pain. Safety assessments included withdrawal symptoms based on the Clinical Opiate Withdrawal Scale (COWS). Results: Naltrexone from MS-sNTC met criteria for equivalent bioavailability to NS. Although morphine relative bioavailability was similar for MS-sNTC and MSS, mean peak (Emax) visual analog scale (VAS) scores for drug liking and Cole/Addiction Research Center Inventory Stimulation-Euphoria were significantly reduced for MS-sNTC vs MSS (P &lt; 0.001). In these 2 studies, a total of 6 participants had one measurement of plasma naltrexone after MS-sNTW that was above the lower limit of quantification. In the OL safety study, 72/93 participants (77%) had no quantifiable naltrexone concentrations. There was neither evidence of naltrexone accumulation for any participant nor any significant correlation with MSsNT dose, age, or sex. Of 4 participants with the highest naltrexone concentrations, none had COWS scores consistent with moderate opioid withdrawal symptoms. Only 5 participants had COWS scores consistent with moderate opioid withdrawal; all 5 had not taken MS-sNT as directed. Limitations: Study populations may not be fully representative of patients receiving opioid therapy for the management of chronic, moderate-to-severe pain and of opioid abusers. Conclusions: When MS-sNT capsules are crushed, all of the sequestered naltrexone (relative to oral NS) is released and immediately available to mitigate morphine-induced effects. When MSsNT was crushed, the naltrexone released abated drug liking and euphoria relative to that from an equal dose of immediate-release morphine from MSS administration in a majority of participants. Naltrexone concentrations were low over a period of 12 months without evidence of accumulation, and there were no observable opioid withdrawal symptoms when MS-sNT was taken as directed. Key words: Chronic pain, drug liking, euphoria, extended-release opioids, morphine, naltrexone, opioid withdrawal, pharmacodynamics, pharmacokinetics

Diclofenac Enables Prolonged Delivery of Naltrexone Through Microneedle-Treated Skin

The purpose of this study was to determine if non-specific COX inhibition could extend pore lifetime in hairless guinea pigs following microneedle treatment. Hairless guinea pigs were treated with microneedle arrays ± daily application of Solaraze® gel (3% diclofenac sodium (non-specific COX inhibitor) and 2.5% hyaluronic acid); transepidermal water loss was utilized to evaluate pore lifetime. To examine the permeation of naltrexone, additional guinea pigs were treated with microneedles ± daily Solaraze® gel followed by application of a 16% transdermal naltrexone patch; pharmacokinetic analysis of plasma naltrexone levels was performed. Histological analysis was employed to visualize morphological changes following microneedle and Solaraze® treatment. Animals treated with microneedles + Solaraze® displayed extended pore lifetime (determined by transepidermal water loss measurements) for up to 7 days. Enhanced naltrexone permeation was also observed for an extended amount of time in animals treated with microneedles + Solaraze®. No morphological changes resulting from microneedle treatment or COX inhibition were noted. Non-specific COX inhibition is an effective means of extending pore lifetime following microneedle treatment in hairless guinea pigs. This may have clinical implications for extending transdermal patch wear time and therefore increasing patient compliance with therapy.

Challenges to antagonist blockade during sustained‐release naltrexone treatment

Naltrexone is a competitive opioid antagonist that effectively blocks the action of heroin and other opioid agonists. Sustained-release naltrexone formulations are now available that provide long-acting opioid blockade. This study investigates the use of heroin and other opioids among opioid-dependent patients receiving treatment with long-acting naltrexone implants, their subjective experience of drug 'high' after opioid use, and factors associated with opioid use. Participants (n = 60) were opioid-dependent patients receiving treatment with naltrexone implants. Outcome data on substance use, drug 'high', depression and criminal activity were collected over a 6-month period. Blood samples were taken to monitor naltrexone plasma levels, and hair samples to verify self-reported opioid use. More than half [n = 34 or 56%; 95% confidence interval (CI) 44-68%)] the patients challenged the blockade with illicit opioids during the 6-month treatment period; 44% (n = 26; 95% CI 32-56%) were abstinent from opioids. Mean opioid use was reduced from 18 [standard deviation (SD)13] days during the month preceding treatment to 6 days (SD 11) after 6 months. Of the respondents questioned on opioid 'high' (n = 31), nine patients (30%; 95% CI 16-47%) reported partial drug 'high' following illicit opioid use, and three (12%; 95% CI 3-26%) reported full 'high'. Opioid use was associated with use of non-opioid drugs and criminal behaviour. Challenging naltrexone blockade with heroin on at least one occasion is common among sustained-release naltrexone patients, but only a minority of patients use opioids regularly. Challenges represent a warning sign for poor outcomes and often occur in the context of polydrug use and social adjustment problems.

Relative oral bioavailability of morphine and naltrexone derived from crushed morphine sulfate and naltrexone hydrochloride extended-release capsules versus intact product and versus naltrexone solution: A single-dose, randomized-sequence, open-label, three-way crossover trial in healthy volunteers

Background: Morphine sulfate/sequestered naltrexone hydrochloride (HCl) (MS-sNT) extended-release fixed-dose combination capsules, approved by the US Food and Drug Administration (FDA) in August 2009 for chronic moderate to severe pain, contain extended-release morphine pellets with a sequestered core of the opioid antagonist naltrexone. MS-sNT was designed so that if the product is tampered with by crushing, the naltrexone becomes bioavailable to mitigate morphine-induced subjective effects, rendering the product less attractive for tampering. Objectives: The primary aim of this study was to compare the oral bioavailability of naltrexone and its metabolite 6-β-naltrexol, derived from crushed pellets from MS-sNT capsules, to naltrexone solution. This study also assessed the relative bioavailability of morphine from crushed pellets from MS-sNT capsules and that from the whole, intact product. Methods: This single-dose, randomized-sequence, open-label, 3-period, 3-treatment crossover trial was conducted in healthy volunteers. Adults admitted to the study center underwent a 10-hour overnight fast before study drug administration. Each subject received all 3 of the following treatments, 1 per session, separated by a 14-day washout: tampered pellets (crushed for ≥2 minutes with a mortar and pestle) from a 60-mg MS-sNT capsule (60 mg morphine/2.4 mg naltrexone); 60-mg whole, intact MS-sNT capsule; and oral naltrexone HCl (2.4 mg) solution. Plasma concentrations of naltrexone and 6-β-naltrexol were measured 0 to 168 hours after administration. Morphine pharmaco-kinetics of crushed and whole pellets were determined 0 to 72 hours after administration. The analysis of relative bioavailability was based on conventional FDA criteria for assuming bioequivalence; that is, 90% CIs for ratios of geometric means (natural logarithm [In]-transformed C max and AUC) fell within the range of 80% to 125%. Subjects underwent physical examinations, clinical laboratory tests, and ECG at screening and study discharge and were monitored for adverse events (AEs) throughout the study. Results: Of the 24 subjects enrolled in the study, 23 completed it. Most subjects were white (79%) and male (63%); the mean (SD) age was 39.3 (11.2) years and the mean weight was 77.6 (13.5) kg (range, 55.0102.5 kg). Plasma C max and AUC 0-t of naltrexone after the administration of crushed pellets of MS-sNT (579 pg/mL and 1811 h · pg/mL, respectively) and naltrexone solution (584 pg/mL and 1954 h · pg/mL) were not significantly different; 90% CIs were 83.8% to 116% and 83.3% to 102%, meeting the regulatory requirements for assuming bioequivalence in this study population. Plasma naltrexone concentration was below the lower limit of quantitation (4.0 pg/mL) in 23 of 24 subjects (96%) after whole MS-sNT administration. Morphine AUC 0-t was not significantly different whether MS-sNT was crushed (163 h · ng/mL) or administered whole (174 h · ng/mL), but C max was numerically higher (24.5 vs 7.7 ng/mL) and T max was numerically shorter (2.00 vs 7.03 hours) with MS-sNT crushed versus whole. The most commonly reported AEs were nausea (8/23 [35%], 10/24 [42%], and 3/23 [13%] subjects in the crushed, whole, and naltrexone groups, respectively) and emesis (6 [26%], 7 [29%], and 2 [9%]). Conclusions: In this single-dose study, when pellets from MS-sNT were crushed, naltrexone appeared to be completely released and available to mitigate morphine-induced effects. When MS-sNT was administered whole, morphine was released in an extended-release fashion while naltrexone remained sequestered.

Subjective Effects and Safety of Whole and Tampered Morphine Sulfate and Naltrexone Hydrochloride (ALO-01) Extended-Release Capsules versus Morphine Solution and Placebo in Experienced Non-Dependent Opioid Users

Background and Objective: Given the dual public health challenges of under-treated pain and opioid abuse, there is a need to reduce attractiveness of opioid analgesics to drug abusers. ALO-01 (morphine sulfate and naltrexone hydrochloride) extended-release capsules, indicated for treatment of chronic, moderate to severe pain, contain polymer-coated pellets of morphine, each with a core of sequestered naltrexone intended for release only upon tampering (crushing). The purpose of this study was to assess the pharmacodynamic effects (including drug-liking and euphoria) of whole and crushed ALO-01 versus morphine sulfate solution (MSS) and placebo. Methods: This was a randomized, double-blind, placebo-controlled, triple-dummy, four-way crossover study carried out at a clinical research centre. Participants were experienced non-dependent opioid users. Subjects were given either two ALO-01 60 mg capsules, crushed pellets from two ALO-01 60 mg capsules, MSS 120 mg or placebo; there was a 14- to 21-day washout between treatments. The primary endpoints were drug-liking visual analogue scale score, scores on items from the Addiction Research Center Inventory (ARCI) and Cole/ARCI scales characterizing abuse potential and euphoria, and pupil diameter as measured by pupillometry. Results: Morphine plasma concentrations were similar after ALO-01 crushed and MSS, with a median time to reach maximum plasma concentration (tmax) of 1.1 and 1.2 hours, respectively; the plasma naltrexone median tmax was 1.1 hours after ALO-01 crushed. By comparison, the median tmax for morphine with ALO-01 whole was 8.1 hours. The maximum effect (Emax) of MSS was significantly greater than placebo on pupillometry and the subjective measures (all p < 0.001). ALO-01 whole and crushed produced lower Emax values and flatter effect-time profiles for subjective measures and caused less pupillary constriction than MSS. Conclusions: The results of this study demonstrated that ALO-01, whether taken orally whole as intended or tampered with by crushing and taken orally, had reduced desirability compared with MSS.

ALO-01 (Morphine Sulfate and Naltrexone Hydrochloride) Extended-Release Capsules in the Treatment of Chronic Pain of Osteoarthritis of the Hip or Knee: Pharmacokinetics, Efficacy, and Safety

ALO-01 (EMBEDA [morphine sulfate and naltrexone hydrochloride] extended-release capsules [King Pharmaceuticals, Inc, Bridgewater, NJ]), indicated for chronic moderate-to-severe pain, is designed to release naltrexone upon tampering (eg, by crushing), reducing morphine-induced subjective effects. This multicenter, randomized, double-blind, crossover study assessed pharmacokinetics, efficacy, and safety of ALO-01 and compared them with extended-release morphine sulfate (ERMS, KADIAN [morphine sulfate extended-release] capsules [Actavis US, Morristown, NJ]) in adults (N = 113) with osteoarthritis pain. Study periods included washout until pain flare (intensity > or =5, 0 to 10; 0 = no pain, 10 = worst pain); dose titration with ERMS (20 to 160mg BID); and randomization to 2 (crossover) 14-day treatment periods with ERMS or ALO-01, separated by 7 days of open-label ERMS. Assessments included pharmacokinetics (morphine, naltrexone), pain scores (0 to 10), Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index; Patient Global Assessment of Medication (1 to 5; poor to excellent). Mean score at pain flare was 7.1. Morphine exposure from both formulations at steady state was similar. Plasma naltrexone concentrations were below limit-of-quantification for most patients and, when present, did not impact pain scores. During treatment, mean pain intensity (day 14: ERMS, 2.4; ALO-01, 2.3, P = .31), WOMAC change-from-baseline (mean pain, physical function, composite scores), and adverse event frequency were similar. ALO-01 and ERMS provided similar relief of osteoarthritis pain. We present data demonstrating that ALO-01 has steady-state morphine exposure, efficacy, and safety similar to marketed ERMS capsules. Results highlight the potential for morphine in ALO-01 to manage moderate-to-severe osteoarthritis pain, while the sequestered naltrexone does not interfere with efficacy.

Route of administration affects the ability of naltrexone to reduce amphetamine-potentiated brain stimulation reward in rats

Opioid receptor antagonism has been shown to attenuate behavioral and neurochemical effects of amphetamine in humans and rodents. The effects of acute (oral or subcutaneous) or extended-release naltrexone (XR-NTX) were tested on the reward-enhancing effects of amphetamine using the intracranial self-stimulation (ICSS) paradigm. Acute exposure to drugs of abuse reduces the locus of rise (LOR) in the ICSS procedure, reflecting enhanced brain stimulation reward (BSR). Rats were treated once a day with naltrexone orally (PO; 5.0 mg/kg) or subcutaneously (SC; 0.5 mg/kg) for four consecutive days and tested with D-amphetamine (0.5 mg/kg, intraperitoneal) in the ICSS paradigm 30 minutes later on days 1 and 4. Separate groups of rats received XR-NTX (50 mg/kg, SC) or placebo microspheres (similar mass to XR-NTX, SC) on day 0 and tested with D-amphetamine in the ICSS paradigm on days 4, 14, 21, 28 and 41 after administration. Naltrexone plasma concentrations were determined for each amphetamine testing session using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). In rats pretreated with naltrexone acutely, amphetamine-potentiated BSR did not differ from vehicle-pretreated rats on either day 1 or day 4 (25-30% decrease in LOR). In XR-NTX-pretreated rats, amphetamine-potentiated BSR was reduced by 64 and 70% on days 4 and 14, respectively, compared to placebo microsphere-treated controls. This effect dissipated by day 21. Naltrexone plasma concentrations were comparable across all treatment groups (14-30 ng/ml) on days 1, 4 and 14. In summary, an extended-release formulation of naltrexone results in significant attenuation of psychostimulant-enhanced BSR that is not observed with acute naltrexone.

Protease inhibitor-induced nausea and vomiting is attenuated by a peripherally acting, opioid-receptor antagonist in a rat model

BackgroundProtease inhibitors such as ritonavir can cause nausea and vomiting which is the most common reason for discontinuation. Rats react to nauseous and emetic stimuli by increasing their oral intake of non-nutritive substances like kaolin, known as pica behavior. In this study, we evaluated the effects of methylnaltrexone, a peripherally acting mu-opioid receptor antagonist that does not affect analgesia, on ritonavir-induced nausea and vomiting in a rat pica model.ResultsWe observed that 24 to 48 hr after administration of oral ritonavir 20 mg/kg, kaolin consumption increased significantly in rats (P < 0.01). This increase was attenuated by pretreatment with an intraperitoneal injection of methylnaltrexone (0.3–3.0 mg/kg) in a dose dependent manner (P < 0.01) and also with naloxone (0.1–0.3 mg/kg) (P < 0.01). The areas under the curve for kaolin intake from time 0 to 120 hr were significantly reduced after administration of the opioid antagonists. Food intake was not significantly affected. Plasma naltrexone levels were measured after methylnaltrexone injection, and no detectable levels were found, indicating that methylnaltrexone was not demethylated in our experimental paradigm.ConclusionThese results suggest that methylnaltrexone may have potential clinical utility in reducing nausea and vomiting in HIV patients who take ritonavir.

(236) Relative bioavailability of plasma naltrexone from crushed ALO-01 (an investigational, abuse-deterrent, extended-release, morphine sulfate formulation with sequestered naltrexone) to a naltrexone oral solution

Nonprescription use of opioids has increased dramatically, resulting in a need for products with reduced abuse potential.1Katz Clin J Pain. 2007; 23: 103-118Crossref PubMed Scopus (131) Google Scholar ALO-01, an investigational, extended-release, abuse-deterrent opioid formulation intended for moderate-to-severe chronic pain, contains polymer-coated extended-release morphine sulfate pellets with a sequestered core of naltrexone, an opioid antagonist. The formulation is designed to release naltrexone upon tampering (crushing/chewing/dissolution) to reduce morphine-induced euphoria. This study compares the oral bioavailability of naltrexone released after crushing ALO-01 pellets with that of an equivalent amount of naltrexone solution. This single-dose, open-label, randomized, 3-period, 3-treatment crossover study included 24 subjects aged 18-55 years who took 1 of 3 oral treatments: crushed ALO-01 pellets (ALO-01C), whole intact ALO-01 (ALO-01W), or naltrexone solution (N) following a 10-hour overnight fast. Subjects received each of the 3 treatments, which were separated by a washout of ≥14 days. Blood for plasma naltrexone determinations was drawn at scheduled times from 0-168 hours postdose. Twenty-three subjects completed the study. Naltrexone absorption rate (median Tmax: 1.0 for both) and mean concentration-time curves from ALO-01C and N were similar. Maximal and systemic exposure of naltrexone released from ALO-01C or N were bioequivalent (90% confidence intervals for Cmax and AUC∞ between 80%-125%). Plasma naltrexone was below the limit of quantification following ALO-01W administration. Most adverse events were mild (87/89) or moderate (2/89), and were gastrointestinal-related. Crushing ALO-01 pellets successfully released the sequestered naltrexone to a level bioequivalent with that of naltrexone oral solution and rendered it available to reduce morphine-induced euphoria. Supported by a grant from Alpharma Pharmaceuticals LLC.

(260) Efficacy and safety evaluation of an extended-release morphine sulfate formulation with sequestered naltrexone for the treatment of osteoarthritis

llicit use of prescription opioids has caused need for products that discourage abuse.1Wright Drug Alcohol Depend. 2006; Google Scholar, 2Kuehn JAMA. 2007; Google Scholar ALO-01 capsules, an abuse-deterrent product under investigation for treatment of chronic moderate-to-severe pain, contain pellets of extended-release morphine sulfate surrounding a core of sequestered naltrexone intended to be released following tampering (crushing/chewing/dissolution). This multicenter, prospective, randomized, double-blind, crossover study compared pharmacokinetics, efficacy, and safety of ALO-01 with KADIAN, a marketed extended-release morphine sulfate product, in adults (N=113) with moderate-to-severe osteoarthritis pain. Outcome measures included pain-intensity ratings, Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index; Patient Global Assessment of Medication (scale 1-5; poor-excellent); and morphine and naltrexone pharmacokinetics. After washout-period to induce pain-flare (intensity ≥5, 0-10 scale; 0=no pain, 10=worst pain), patients were dose-titrated with KADIAN, (20mg-160mg BID) until pain-intensity score ≤3 was reached, then randomized to 2 (crossover) 14-day treatments with KADIAN and ALO-01, each followed by 7-day open-label KADIAN treatment. Most patients were women (68.5%) and white (88.3%); median age was 57.0 years. Mean pain-intensity scores were similar during treatment (Day 14: KADIAN, 2.4; ALO-01, 2.3, p=0.31), as were Brief Pain Inventory scores, and WOMAC mean pain, physical function, and composite change from baseline scores. Most patients (KADIAN, 78.9%; ALO-01, 91.5%) rated medications as good-to-excellent. Morphine exposure at steady-state was similar (95% CI, 0.82-1.07 for KADIAN/ALO-01 AUC0-12). Plasma naltrexone levels were below the limit of quantification for most patients (82.1%) treated with ALO-01; when detected, levels were just above the limit of quantification and had no impact on decrease in pain scores. Most common adverse events during the double-blind phase were constipation (KADIAN, 12.7%; ALO-01, 15.5%), nausea (KADIAN, 8.5%; ALO-01, 9.9%), and somnolence (KADIAN, 8.5%; ALO-01, 9.9%), and were of mild-to-moderate intensity. ALO-01 provided similar pain relief as KADIAN; both medications were rated good-to-excellent. Supported by Alpharma Pharmaceuticals LLC.

Naltrexone Implants – Duration, Tolerability and Clinical Usefulness

Naltrexone blocks opioid effects effectively, but poor compliance limits the clinical usefulness in the treatment of opioid dependence. Long-acting implanted formulations might increase the clinical feasibility. Several implants have been produced, but few clinical reports have been published. This paper describes an open trial with an Australian implant. This implant is claimed to have duration of up to six months with double implants and acceptable levels of side effects. This was explored in the present pilot study with 13 opioid-dependent patients. By single implant of 1.8 g naltrexone the duration judged by naltrexone plasma levels above 1 ng/ml naltrexone was between 2 and 4 months. Double implants maintained such plasma levels for 5–6.5 months. Clinically, the implants appeared promising. Side effects were minimal. During the period with adequate plasma levels of naltrexone, use of opioids was absent and use of other psychoactive drugs reduced. At 1-year follow-up, the patients rated the implants highly positively.

Single‐ and Multiple‐Dose Pharmacokinetics of Long‐acting Injectable Naltrexone

Oral naltrexone is effective in the treatment of alcohol dependence; however, a major limitation of its clinical utility is poor patient adherence to the daily dosing schedule. A biodegradable, long-acting naltrexone microsphere formulation was developed to achieve continuous naltrexone exposure for 1 month in the treatment of alcohol dependence. The single- and multiple-dose safety and pharmacokinetics of a long-acting naltrexone microsphere preparation were evaluated in healthy subjects. One group of subjects (n = 28) received a single dose of oral naltrexone 50 mg followed by a single gluteal intramuscular (IM) injection of long-acting naltrexone 190 or 380 mg or placebo. A different group of subjects (n = 14) received oral naltrexone 50 mg daily for 5 days, followed by IM long-acting naltrexone 380 mg or placebo every 28 days for a total of 4 doses. A 7-day washout period separated oral and IM administrations. Blood samples were collected to determine plasma concentrations of naltrexone and the primary metabolite, 6beta-naltrexol. After a single IM injection of long-acting naltrexone 380 mg, naltrexone plasma concentrations were measurable in all subjects for at least 31 days postdose. The pharmacokinetics were proportional to the dose and multiple dose observations were consistent with single dose observations. Mean apparent elimination half-lives for naltrexone and 6beta-naltrexol ranged from 5 to 7 days. Exposure to 6beta-naltrexol was reduced with IM injection compared with that oral administration. No serious adverse events occurred. This study demonstrated that the long-acting naltrexone formulation was well tolerated, displayed predictable pharmacokinetics, and resulted in no meaningful drug accumulation upon multiple dosing. Intramuscular administration avoids first-pass metabolism and changes the exposure ratio of 6beta-naltrexol to naltrexone compared with oral administration. By providing continuous exposure to naltrexone for several weeks following IM injection, this long-acting naltrexone formulation may offer therapeutic benefit to those patients who experience difficulty adhering to the daily administration schedule necessitated by oral naltrexone therapy.