Ashraf Yassen

Naloxone treatment in opioid addiction: the risks and benefits

Naloxone is a non-selective, short-acting opioid receptor antagonist that has a long clinical history of successful use and is presently considered a safe drug over a wide dose range (up to 10 mg). In opioid-dependent patients, naloxone is used in the treatment of opioid-overdose-induced respiratory depression, in (ultra)rapid detoxification and in combination with buprenorphine for maintenance therapy (to prevent intravenous abuse). Risks related to naloxone use in opioid-dependent patients are: i) the induction of an acute withdrawal syndrome (the occurrence of vomiting and aspiration is potentially life threatening); ii) the effect of naloxone may wear off prematurely when used for treatment of opioid-induced respiratory depression; and iii) in patients treated for severe pain with an opioid, high-dose naloxone and/or rapidly infused naloxone may cause catecholamine release and consequently pulmonary edema and cardiac arrhythmias. These risks warrant the cautious use of naloxone and adequate monitoring of the cardiorespiratory status of the patient after naloxone administration where indicated.

Naloxone Reversal of Buprenorphine-induced Respiratory Depression

Background:The objective of this investigation was to examine the ability of the opioid antagonist naloxone to reverse respiratory depression produced by the &mgr;-opioid analgesic, buprenorphine, in healthy volunteers. The studies were designed in light of the claims that buprenorphine is relatively resistant to the effects of naloxone. Methods:In a first attempt, the effect of an intravenous bolus dose of 0.8 mg naloxone was assessed on 0.2 mg buprenorphine–induced respiratory depression. Next, the effect of increasing naloxone doses (0.5–7 mg, given over 30 min) on 0.2 mg buprenorphine–induced respiratory depression was tested. Subsequently, continuous naloxone infusions were applied to reverse respiratory depression from 0.2 and 0.4 mg buprenorphine. All doses are per 70 kg. Respiration was measured against a background of constant increased end-tidal carbon dioxide concentration. Results:An intravenous naloxone dose of 0.8 mg had no effect on respiratory depression from buprenorphine. Increasing doses of naloxone given over 30 min produced full reversal of buprenorphine effect in the dose range of 2–4 mg naloxone. Further increasing the naloxone dose (doses of 5 mg or greater) caused a decline in reversal activity. Naloxone bolus doses of 2–3 mg, followed by a continuous infusion of 4 mg/h, caused full reversal within 40–60 min of both 0.2 and 0.4 mg buprenorphine–induced respiratory depression. Conclusions:Reversal of buprenorphine effect is possible but depends on the buprenorphine dose and the correct naloxone dose window. Because respiratory depression from buprenorphine may outlast the effects of naloxone boluses or short infusions, a continuous infusion of naloxone may be required to maintain reversal of respiratory depression.

Mechanism-based pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of buprenorphine in healthy volunteers.

Background:The objective of this investigation was to characterize the pharmacokinetic–pharmacodynamic relation of buprenorphine’s antinociceptive effect in healthy volunteers. Methods:Data on the time course of the antinociceptive effect after intravenous administration of 0.05–0.6 mg/70 kg buprenorphine in healthy volunteers was analyzed in conjunction with plasma concentrations by nonlinear mixed-effects analysis. Results:A three-compartment pharmacokinetic model best described the concentration time course. Four structurally different pharmacokinetic–pharmacodynamic models were evaluated for their appropriateness to describe the time course of buprenorphine’s antinociceptive effect: (1) Emax model with an effect compartment model, (2) “power” model with an effect compartment model, (3) receptor association–dissociation model with a linear transduction function, and (4) combined biophase equilibration/receptor association–dissociation model with a linear transduction function. The latter pharmacokinetic–pharmacodynamic model described the time course of effect best and was used to explain time dependencies in buprenorphine’s pharmacodynamics. The model converged, yielding precise estimation of the parameters characterizing hysteresis and the relation between relative receptor occupancy and antinociceptive effect. The rate constant describing biophase equilibration (keo) was 0.00447 min−1 (95% confidence interval, 0.00299–0.00595 min−1). The receptor dissociation rate constant (koff) was 0.0785 min−1 (95% confidence interval, 0.0352–0.122 min−1), and kon was 0.0631 ml · ng−1 · min−1 (95% confidence interval, 0.0390–0.0872 ml · ng−1 · min−1). Conclusion:This is consistent with observations in rats, suggesting that the rate-limiting step in the onset and offset of the antinociceptive effect is biophase distribution rather than slow receptor association–dissociation. In the dose range studied, no saturation of receptor occupancy occurred explaining the lack of a ceiling effect for antinociception.

Morphine-6-glucuronide (M6G) for postoperative pain relief.

Morphine‐6‐glucuronide (M6G) is morphines active metabolite acting at the μ‐opioid receptor. Recent experimental human studies and 5 of 6 randomized clinical trials indicate that M6G causes adequate and long lasting pain relief comparable to morphine. There are various observations that M6G is associated with a reduction in the severity of side effects normally associated with opioid use, such as reduced postoperative nausea and vomiting (PONV) and reduced respiratory depression. The present drug profile provides a review of the pharmacological properties of M6G, the clinical evidence relating to its efficacy and safety, and discusses its future role in the treatment of postoperative pain.

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory-Depressant Effect of Buprenorphine and Fentanyl in Rats

The purpose of this investigation was to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model to predict the time course of respiratory depression following administration of opioids in rats. The proposed model is based on receptor theory and aims at the separate characterization of biophase distribution and receptor association/dissociation kinetics as determinants of hysteresis between plasma concentration and effect. Individual concentration time courses of buprenorphine and fentanyl were determined in conjunction with continuous monitoring of respiratory depression. Buprenorphine and fentanyl were administered intravenously in various doses. For buprenorphine hysteresis was best described by a combined biophase distribution-receptor association/dissociation model with a linear transducer function. The values of the parameter estimates of the rate constants for biophase distribution (keo), receptor association (kon), and dissociation (koff) were 0.0348 min–1 [95% confidence interval (CI), 0.0193–0.0503 min–1], 0.57 ml/ng/min (95% CI, 0.38–0.76 ml/ng/min), and 0.0903 min–1 (95% CI, 0.035–0.196 min–1), respectively. The values of the equilibrium dissociation constant and intrinsic activity were 0.16 ng/ml and 0.48 (95% CI, 0.45–0.51), respectively. The value of the Kd is close to reported estimates of receptor affinity in vitro confirming the validity of the mechanism-based PK/PD model. For fentanyl, unrealistically high estimates of the rate constants for receptor association and dissociation were obtained, indicating that hysteresis is caused solely by biophase distribution kinetics. This is consistent with fentanyls fast receptor association/dissociation kinetics in vitro. As a result, the mechanism-based PK/PD model of fentanyl could be reduced to a biophase distribution model with fractional sigmoid Emax pharmacodynamic model.

Pharmacokinetic–Pharmacodynamic Modeling of the Effectiveness and Safety of Buprenorphine and Fentanyl in Rats

ObjectiveRespiratory depression is a serious and potentially life-threatening side-effect of opioid therapy. The objective of this investigation was to characterize the relationship between buprenorphine or fentanyl exposure and the effectiveness and safety outcome in rats.MethodsData on the time course of the antinociceptive and respiratory depressant effect were analyzed on the basis of population logistic regression PK–PD models using non-linear mixed effects modeling software (NONMEM). The pharmacokinetics of buprenorphine and fentanyl were described by a three- and two-compartment model, respectively. A logistic regression model (linear logit model) was used to characterize the relationship between drug exposure and the binary effectiveness and safety outcome.ResultsFor buprenorphine, the odds ratios (OR) were 28.5 (95% CI, 6.9–50.1) and 2.10 (95% CI, 0.71–3.49) for the antinociceptive and respiratory depressant effect, respectively. For fentanyl these odds ratios were 3.03 (95% CI, 1.87–4.21) and 2.54 (95% CI, 1.26–3.82), respectively.ConclusionThe calculated safety index (ORantinociception/ORrespiratory depression) for fentanyl of 1.20 suggests that fentanyl has a low safety margin, implicating that fentanyl needs to be titrated with caution. For buprenorphine the safety index is 13.54 suggesting that buprenorphine is a relatively safe opioid.

Animal-to-Human Extrapolation of the Pharmacokinetic and Pharmacodynamic Properties of Buprenorphine

ObjectivesThis investigation describes the interspecies scaling of the pharmacokinetics and pharmacodynamics of buprenorphine.MethodsData on the time course of the antinociceptive and respiratory depressant effects of buprenorphine in rats and in humans were simultaneously analysed on the basis of a mechanism-based pharmacokinetic-pharmacodynamic model.ResultsAn allometric three-compartment pharmacokinetic model described the time course of the concentration in plasma. The value of the allometric coefficient for clearance was 35.2mL/min (relative standard error [RSE] = 5.6%) and the value of the allometric exponent was 0.76 (RSE 5.61%). A combined biophase distribution-receptor association/dissociation model with a linear transduction function described hysteresis between plasma concentration and effect. The values of the drug-specific pharmacodynamic parameters were identical in rats and in humans. For the respiratory depressant effect, the values of the second-order rate constant of receptor association (kon) and the first-order rate constant of receptor dissociation (koff) were 0.23 mL/ng/min (RSE = 15.8%) and 0.014 min−1 (RSE = 27.7%), respectively, and the value of the equilibrium dissociation constant (Kdiss) was 0.13 nmol/L. The value of the intrinsic activity α was 0.52 (RSE = 3.4%). For the antinociceptive effect, the values of the kon and koff were 0.015 mL/ng/min (RSE = 18.3%) and 0.053 min−1 (RSE = 23.1%), respectively. The value of the Kdiss was 7.5 nmol/L. An allometric equation described the scaling of the system-specific parameter, the first-order distribution rate constant (keo). The value of the allometric coefficient for the ke0 was 0.0303 min−1 (RSE = 11.3%) and the value of the exponent was −0.28 (RSE = 9.6%).ConclusionsThe different values of the drug-specific pharmacodynamic parameters are consistent with the different opioid μ receptor subtypes involved in the antinociceptive and respiratory depressant effects.

Mechanism-based pharmacokinetic-pharmacodynamic modelling of the reversal of buprenorphine-induced respiratory depression by naloxone : A study in healthy volunteers

Background and objectiveRespiratory depression is a potentially life-threatening adverse effect of opioid therapy. It has been postulated that the difficulty of reversing buprenorphine-induced respiratory depression is caused by slow receptor association-dissociation kinetics at the opioid μ receptor. The aim of this study was to characterise the pharmacodynamic interaction between buprenorphine and naloxone in healthy volunteers.MethodsA competitive pharmacodynamic interaction model was proposed to describe and predict the time course of naloxone-induced reversal of respiratory depression. The model was identified using data from an adaptive naloxone dose-selection trial following intravenous administration of buprenorphine 0.2mg/70kg or 0.4mg/70kg.ResultsThe pharmacokinetics of naloxone and buprenorphine were best described by a two-compartment model and a three-compartment model, respectively. A combined biophase equilibration-receptor association-dissociation pharmacodynamic model described the competitive interaction between buprenorphine and naloxone at the opioid μ receptor. For buprenorphine, the values of the rate constants of receptor association (kon) and dissociation (koff) were 0.203 mL/ng/min and 0.0172 min−1, respectively. The value of the equilibrium dissociation constant (KD) was 0.18 nmol/L. The half-life (t½) of biophase equilibration was 173 minutes. These estimates of the pharmacodynamic parameters are similar to values obtained in the absence of naloxone co-administration. For naloxone, the half-life of biophase distribution was 6.5 minutes.ConclusionsBecause of the slow receptor association-dissociation kinetics of buprenorphine in combination with the fast elimination kinetics of naloxone, naloxone is best administered as a continuous infusion for reversal of buprenorphine-induced respiratory depression.

Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of norbuprenorphine in rats.

The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic (PK-PD) correlation of buprenorphines active metabolite norbuprenorphine for the effect on respiration in rats. Following i.v. administration in rats (dose range 0.32–1.848 mg), the time course of the concentration in plasma was determined in conjunction with the effect in ventilation as determined with a novel whole-body plethysmography technique. The PK of norbuprenorphine was best described by a three-compartment PK model with nonlinear elimination. A saturable biophase distribution model with a power PD model described the PK-PD relationship best. No saturation of the effect at high concentrations was observed, indicating that norbuprenorphine acts as a full agonist with regard to respiratory depression. Moreover, analysis of the hysteresis based on the combined receptor association-dissociation biophase distribution model yielded high values of the rate constants for receptor association and dissociation, indicating that these processes are not rate-limiting. In a separate analysis, the time course of the plasma concentrations of buprenorphine and norbuprenorphine following administration of both the parent drug and the metabolite were simultaneously analyzed based on a six-compartment PK model with nonlinear elimination of norbuprenorphine. This analysis showed that following i.v. administration, 10% of the administered dose of buprenorphine is converted into norbuprenorphine. By simulation it is shown that following i.v. administration of buprenorphine, the concentrations of norbuprenorphine reach values that are well below the values causing an effect on respiration.

Pharmacodynamic analysis of the analgesic effect of capsaicin 8% patch (Qutenza™) in diabetic neuropathic pain patients: detection of distinct response groups

Treatment of chronic pain is associated with high variability in the response to pharmacological interventions. A mathematical pharmacodynamic model was developed to quantify the magnitude and onset/offset times of effect of a single capsaicin 8% patch application in the treatment of painful diabetic peripheral neuropathy in 91 patients. In addition, a mixture model was applied to objectively match patterns in pain-associated behavior. The model identified four distinct subgroups that responded differently to treatment: 3.3% of patients (subgroup 1) showed worsening of pain; 31% (subgroup 2) showed no change; 32% (subgroup 3) showed a quick reduction in pain that reached a nadir in week 3, followed by a slow return towards baseline (16% ± 6% pain reduction in week 12); 34% (subgroup 4) showed a quick reduction in pain that persisted (70% ± 5% reduction in week 12). The estimate of the response-onset rate constant, obtained for subgroups 1, 3, and 4, was 0.76 ± 0.12 week−1 (median ± SE), indicating that every 0.91 weeks the pain score reduces or increases by 50% relative to the score of the previous week (= t½). The response-offset rate constant could be determined for subgroup 3 only and was 0.09 ± 0.04 week−1 (t½ 7.8 weeks). The analysis allowed separation of a heterogeneous neuropathic pain population into four homogenous subgroups with distinct behaviors in response to treatment with capsaicin. It is argued that this model-based approach may have added value in analyzing longitudinal chronic pain data and allows optimization of treatment algorithms for patients suffering from chronic pain conditions.