Pharmacokinetic Interaction between Naloxone and Naltrexone Following Intranasal Administration to Healthy Subjects.

Naloxone (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one HCl), a µ-opioid receptor antagonist, is administered intranasally to reverse an opioid overdose but its short half-life may necessitate subsequent doses. The addition of naltrexone [17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one], another µ-receptor antagonist, which has a reported half-life of 3 1/2 hours, may extend the available time to receive medical treatment. In a phase 1 pharmacokinetic study, healthy adults were administered naloxone and naltrexone intranasally, separately and in combination. When administered with naloxone, the C max value of naltrexone decreased 62% and the area under the concentration-time curve from time zero to infinity (AUC0-inf) decreased 38% compared with when it was given separately; lower concentrations of naltrexone were observed as early as 5 minutes postdose. In contrast, the C max and AUC0-inf values of naloxone decreased only 18% and 16%, respectively, when given with naltrexone. This apparent interaction was investigated further to determine if naloxone and naltrexone shared a transporter. Neither compound was a substrate for organic cation transporter (OCT) 1, OCT2, OCT3, OCTN1, or OCTN2. There was no evidence of the involvement of a transmembrane transporter when they were tested separately or in combination at concentrations of 10 and 500 µM using Madin-Darby canine kidney II cell monolayers at pH 7.4. The efflux ratios of naloxone and naltrexone increased to six or greater when the apical solution was pH 5.5, the approximate pH of the nasal cavity; there was no apparent interaction when the two were coincubated. The importance of understanding how opioid antagonists are absorbed by the nasal epithelium is magnified by the rise in overdose deaths attributed to long-lived synthetic opioids and the realization that better strategies are needed to treat opioid overdoses.

Comparison of the Pharmacokinetic Properties of Naloxone Following the Use of FDA-Approved Intranasal and Intramuscular Devices Versus a Common Improvised Nasal Naloxone Device.

For more than a decade, first responders and the general public have been able to treat suspected opioid overdoses using an improvised nasal naloxone device (INND) constructed from a prefilled syringe containing 2 mg of naloxone (1 mg/mL) attached to a mucosal atomization device. In recent years, the U.S. Food and Drug Administration (FDA)-approved Ezvio, an autoinjector that delivers 2 mg by intramuscular injection and Narcan nasal spray (2- and 4-mg strengths; 0.1 mL/dose) for the emergency treatment of a known or suspected opioid overdose. The present study was conducted to compare the pharmacokinetics of naloxone using the FDA-approved devices (each administered once) and either 1 or 2 administrations using the INND. When naloxone was administered twice using the improvised device, the doses were separated by 2 minutes. The highest maximum plasma concentration was achieved using the 4-mg FDA-approved spray. The highest exposures at 5 minutes postdose, based on AUC values, were after administration with the autoinjector and the 4-mg FDA-approved spray; at 10, 15, and 20 minutes postdose, the latter yielded the greatest exposure. Even after 2 administrations, the INND failed to achieve naloxone plasma levels comparable to the FDA-approved devices at any time. The ease of use and higher plasma concentrations achieved using the 4-mg FDA-approved spray, compared with the INND, should be considered when deciding which naloxone device to use.

Enhanced Intranasal Absorption of Naltrexone by Dodecyl Maltopyranoside: Implications for the Treatment of Opioid Overdose.

Based on its high affinity for µ opiate receptors and reported half-life after oral administration, the pharmacokinetic properties of intranasal naltrexone were examined to evaluate its potential to treat opioid overdose. This study was prompted by the marked rise in overdose deaths linked to synthetic opioids like fentanyl, which may require more potent, longer-lived opiate antagonists than naloxone. Both the maximum plasma concentration (Cmax ) and the time (Tmax ) to reach Cmax for intranasal naltrexone (4 mg) were comparable to values reported for a Food and Drug Administration-approved 4-mg dose of intranasal naloxone. The addition of the absorption enhancer dodecyl maltoside (Intravail) increased Cmax by ∼3-fold and reduced the Tmax from 0.5 to 0.17 hours. Despite these very rapid increases in plasma concentrations of naltrexone, its short half-life following intranasal administration (∼2.2 hours) could limit its usefulness as a rescue medication, particularly against longer-lived synthetic opioids. Nonetheless, the ability to rapidly attain high plasma concentrations of naltrexone may be useful in other indications, including an as-needed dosing strategy to treat alcohol use disorder.

Differentiating new cannabis use from residual urinary cannabinoid excretion in chronic, daily cannabis users.

AIMS: To develop and validate empirically a mathematical model for identifying new cannabis use in chronic, daily cannabis smokers. DESIGN: Models were based on urinary creatinine-normalized (CN) cannabinoid excretion in chronic cannabis smokers. SETTING: For model development, participants resided on a secure research unit for 30 days. For model validation, participants were abstinent with daily observed urine specimens for 28 days. PARTICIPANTS: A total of 48 (model development) and 67 (model validation) daily cannabis smokers were recruited. MEASUREMENTS: All voided urine was collected and analyzed for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) by gas chromatography-mass spectrometry (GCMS; limit of quantification 2.5 ng/ml) and creatinine (mg/ml). Urine THCCOOH was normalized to creatinine, yielding ng/mg CN-THCCOOH concentrations. Urine concentration ratios were determined from 123,513 specimen pairs collected 2-30 days apart. FINDINGS: A mono-exponential model (with two parameters, initial urine specimen CN-THCCOOH concentration and time between specimens), based on the Marquardt-Levenberg algorithm, provided a reasonable data fit. Prediction intervals with varying probability levels (80, 90, 95, 99%) provide upper ratio limits for each urine specimen pair. Ratios above these limits suggest cannabis re-use. Disproportionate numbers of ratios were higher than expected for some participants, prompting development of two additional rules that avoid misidentification of re-use in participants with unusual CN-THCCOOH excretion patterns. CONCLUSIONS: For the first time, a validated model is available to aid in the differentiation of new cannabis use from residual creatinine-normalized 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (CN-THCCOOH) excretion in chronic, daily cannabis users. These models are valuable for clinicians, toxicologists and drug treatment staff and work-place, military and criminal justice drug-testing programs.

Urinary elimination of 11-nor-9-carboxy-delta9-tetrahydrocannnabinol in cannabis users during continuously monitored abstinence.

The time course of 11-nor-9-carboxy-Delta9-tetrahydrocannnabinol (THCCOOH) elimination in urine was characterized in 60 cannabis users during 24 h monitored abstinence on a closed research unit for up to 30 days. Six thousand, one hundred fifty-eight individual urine specimens were screened by immunoassay with values > or = 50 ng/mL classified as positive. Urine specimens were confirmed for THCCOOH by gas chromatography-mass spectrometry following base hydrolysis and liquid-liquid or solid-phase extraction. In 60%, the maximum creatinine normalized concentration occurred in the first urine specimen; in 40%, peaks occurred as long as 2.9 days after admission. Data were divided into three groups, 0-50, 51-150, and > 150 ng/mg, based on the creatinine corrected initial THCCOOH concentration. There were statistically significant correlations between groups and number of days until first negative and last positive urine specimens; mean number of days were 0.6 and 4.3, 3.2 and 9.7, and 4.7 and 15.4 days, respectively, for the three groups. These data provide guidelines for interpreting urine cannabinoid test results and suggest appropriate detection windows for differentiating new cannabis use from residual drug excretion.

Pharmacokinetics of buprenorphine: a comparison of sublingual tablet versus liquid after chronic dosing.

Although buprenorphine is approved for use in the outpatient treatment of opioid addiction in 2 tablet formulations, a monoproduct containing buprenorphine only (Subutex) and a buprenorphine/naloxone combination product (Suboxone), much of the clinical data that support the approval by the U.S. Food and Drug Administration were generated by using a sublingual liquid. To interpret the literature in prescribing parameters for tablet buprenorphine, this study was designed to determine steady state buprenorphine plasma levels for the 2 formulations and to assess the relative bioavailability of each. A randomized, double-blind, crossover study with dose increases was conducted during a 12-week period at an outpatient treatment clinic. Of the 184 subjects initially randomized to treatment, 133 (72.3%) were evaluated for the steady-state trough plasma concentration, 16 (8.7%) for relative bioavailability, and 31 (16.8%) for dose proportionality. At steady state, differences in the trough plasma concentrations of buprenorphine between the 2 formulations were found across all the dose levels. Average plasma concentration (Cavg) of the tablet at twice the milligram dose of the liquid was twice that of the liquid; intersubject variability was greater for the tablet. At double the dose of tablet, there is no difference in steady state plasma concentrations. The bioavailability seems equivalent for the 2 formulations across all the dose levels.

Methylphenidate and cocaine: a placebo-controlled drug interaction study.

Up to thirty percent of cocaine addicted individuals may meet diagnostic criteria for Attention-Deficit/Hyperactivity Disorder (ADHD). Methylphenidate (MPH) is a highly effective and commonly used treatment for ADHD but, like cocaine, is a cardiovascular and central nervous system stimulant with the potential to cause toxicity at high doses. The present study was undertaken to investigate the likelihood of a toxic reaction in individuals who use cocaine while concurrently taking MPH. Seven non-treatment seeking cocaine-dependent individuals completed this placebo-controlled, crossover study with two factors: Medication (placebo, 60 mg MPH, 90 mg MPH) and Infusion (saline, 20 mg cocaine, 40 mg cocaine). Physiological measures included vital signs, adverse events, and electrocardiogram. Subjective response was measured with visual analog scale (VAS) ratings of craving and drug effect. Cocaine pharmacokinetic parameters were calculated for each participant at each drug combination, using a non-compartmental model. MPH was well tolerated, did not have a clinically significant impact on cocaine's physiological effects, and decreased some of the positive subjective effects of cocaine. MPH did not significantly alter the pharmacokinetics of cocaine. The study results suggest that MPH at the doses studied can likely be used safely in an outpatient setting with active cocaine users.

Intravenous cocaine and QT variability.

BACKGROUND: Dynamic instability in cardiac repolarization may contribute to drug-induced arrhythmogenesis. We hypothesized that intravenous cocaine would significantly destabilize repolarization as measured by QT variability. METHODS AND RESULTS: Twenty-nine cocaine-experienced volunteers not seeking treatment for cocaine addiction received randomized, sequential intravenous infusions of placebo or cocaine (20 and 40 mg). Five-minute epochs of digitized ECG were recorded 10 minutes before, during, and at intervals following the infusions. QT variability was measured using a semiautomated method and expressed as the log ratio of normalized QT variance to normalized heart rate variance (QTVI). Seventeen subjects received a repeat course of cocaine infusions 1 week later. Placebo infusion resulted in a small but significant increase in QTVI, while cocaine caused a highly significant, dose-dependent increase in QTVI that peaked at 10 minutes and dissipated by 45 minutes following infusion (P < 0.0001). The increase in QTVI was reproducible at 1 week (P = 0.8). CONCLUSIONS: Cocaine injection results in a significant dose-dependent increase in QT variability as indexed by QTVI. This destabilizing effect on repolarization may increase vulnerability to reentrant arrhythmias and may partially explain an increased risk of sudden cardiac death associated with cocaine use.

Pharmacokinetics and pharmacodynamics of multiple sublingual buprenorphine tablets in dose-escalation trials.

In this investigation, the pharmacokinetic and pharmacodynamic properties were determined of multiple doses of sublingual tablets containing either buprenorphine alone or buprenorphine and naloxone. Subjects were experienced opiate users who received escalating doses (4-24 mg) of buprenorphine either alone or in combination with naloxone. Peak concentration (Cmax) and area under the concentration-time curves (AUCs) increased for both buprenorphine and naloxone with escalating doses. Significant differences were found across the range of doses administered for dose-adjusted Cmax for both tablet formulations and for the dose-adjusted AUCs for the buprenorphine-naloxone tablets. For both formulations, the maximal buprenorphine-induced decreases in respiratory rate and pupil diameter did not vary significantly across doses. Several of the subjective effects of buprenorphine did not increase as the dose of buprenorphine administered was increased. These findings are consistent with the ceiling effect associated with the partial agonist actions of buprenorphine. They also indicate a lack of dose proportionality for buprenorphine sublingual tablets, at least during the times at which levels of this agent are highest.

Modafinil influences the pharmacokinetics of intravenous cocaine in healthy cocaine-dependent volunteers.

OBJECTIVE: To determine if modafinil, a putative treatment for cocaine dependence, influences the pharmacokinetics of intravenous cocaine in otherwise healthy cocaine-dependent volunteers. METHODS: Cocaine 20 or 40 mg was administered intravenously on consecutive days over 1 minute at baseline and after modafinil administration at each of two dosages of 400 and 800 mg/day for 7 days. RESULTS: Twelve subjects completed the clinical protocol. Compared with baseline, the cocaine peak plasma concentration was decreased after both the 20 and 40 mg cocaine infusions, but the reduction was only statistically significant after the 40 mg cocaine infusion (p < 0.01 after modafinil 400 mg/day; p < 0.05 after modafinil 800 mg/day). The area under the cocaine plasma concentration-time curve from 0 to 180 minutes (AUC180) was significantly decreased by modafinil administration (p < 0.01 and p < 0.001 for modafinil 400 and 800 mg/day, respectively, for the cocaine 20mg dose; p < 0.001 for the cocaine 40 mg dose at both modafinil levels). There were no significant changes in total AUC, clearance or elimination half-life of cocaine. CONCLUSION: This study did not find evidence for a harmful pharmacokinetic interaction between modafinil and cocaine. In contrast, long-term administration of modafinil significantly decreased systemic exposure to cocaine during the first 180 minutes following intravenous cocaine administration.

Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone.

BACKGROUND: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone has been proposed, but its efficacy and safety have not been well studied. METHODS: We conducted a multicenter, randomized, placebo-controlled trial involving 326 opiate-addicted persons who were assigned to office-based treatment with sublingual tablets consisting of buprenorphine (16 mg) in combination with naloxone (4 mg), buprenorphine alone (16 mg), or placebo given daily for four weeks. The primary outcome measures were the percentage of urine samples negative for opiates and the subjects' self-reported craving for opiates. Safety data were obtained on 461 opiate-addicted persons who participated in an open-label study of buprenorphine and naloxone (at daily doses of up to 24 mg and 6 mg, respectively) and another 11 persons who received this combination only during the trial. RESULTS: The double-blind trial was terminated early because buprenorphine and naloxone in combination and buprenorphine alone were found to have greater efficacy than placebo. The proportion of urine samples that were negative for opiates was greater in the combined-treatment and buprenorphine groups (17.8 percent and 20.7 percent, respectively) than in the placebo group (5.8 percent, P<0.001 for both comparisons); the active-treatment groups also reported less opiate craving (P<0.001 for both comparisons with placebo). Rates of adverse events were similar in the active-treatment and placebo groups. During the open-label phase, the percentage of urine samples negative for opiates ranged from 35.2 percent to 67.4 percent. Results from the open-label follow-up study indicated that the combined treatment was safe and well tolerated. CONCLUSIONS: Buprenorphine and naloxone in combination and buprenorphine alone are safe and reduce the use of opiates and the craving for opiates among opiate-addicted persons who receive these medications in an office-based setting.

Pharmacokinetics of the combination tablet of buprenorphine and naloxone.

The sublingual combination tablet formulation of buprenorphine and naloxone at a fixed dose ratio of 4:1 has been shown to be as effective as the tablet formulation containing only buprenorphine in treating opiate addiction. The addition of naloxone does not affect the efficacy of buprenorphine for two reasons: (1) naloxone is poorly absorbed sublingually relative to buprenorphine and (2) the half-life for buprenorphine is much longer than for naloxone (32 vs. 1 h for naloxone). The sublingual absorption of buprenorphine is rapid and the peak plasma concentration occurs 1 h after dosing. The plasma levels for naloxone are much lower and decline much more rapidly than those for buprenorphine. Increasing dose results in increasing plasma levels of buprenorphine, although this increase is not directly dose-proportional. There is a large inter-subject variability in plasma buprenorphine levels. Due to the large individual variability in opiate dependence level and the large variability in the pharmacokinetics (PK) of buprenorphine, the effective dose or effective plasma concentration is also quite variable. Doses must be titrated to a clinically effective level for individual patients.