David J. R. Foster

Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: Comparison of those who do and do not experience withdrawal and concentration-effect relationships

To determine plasma racemic methadone concentration‐effect relationships for subjective and objective responses and whether pharmacokinetic and/or pharmacodynamic factors influence withdrawal severity.

Pharmacokinetics, Efficacy, and Tolerability of Fentanyl Following Intranasal Versus Intravenous Administration in Adults Undergoing Third-Molar Extraction : A Randomized, Double-Blind, Double-Dummy, Two-Way, Crossover Study

OBJECTIVE The aim of this study was to compare the pharmacokinetic profile, as well as the efficacy and tolerability, of i.n. and i.v. administration of fentanyl in acute, episodic pain in patients undergoing third-molar extraction. METHODS In this randomized, double-blind, double-dummy, 2-way, crossover study, patients were randomized to receive 1 of 4 doses (75, 100, 150, or 200 microg) by both the i.n. and i.v. routes in random order, after each of 2 separate molar extractions (interval, >or=1 week). Venous blood samples were obtained for quantification of plasma fentanyl concentrations before and at 1, 3, 5, 7, 9, 12, 15, 25, 40, 60, 90, 120, and 180 minutes after administration. Pain scores (on an 11-point numeric rating scale) were recorded before and at 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, and 240 minutes. Patients indicated the times at which they perceived meaningful pain relief (onset of action) and at which analgesia ended (duration of effect), after which they were able to use rescue medication (time to rescue medication use). RESULTS A total of 24 patients were enrolled (in all, 47 extractions) (46% male; mean age, 24.1 years; 94% white, 6% Asian). Mean T(max) values were 12.8 and 6.0 minutes (P<0.001), times to onset of analgesia were 7 and 2 minutes (P<0.001), and durations of effect were 56 and 59 minutes after i.n. and i.v. administration (P=NS), respectively. Differences in the onsets and durations of analgesia after i.n. and i.v. administration of single doses were not significantly different, and neither was the difference in overall analgesia, with pain scores returning to near-predose values at statistically similar times after dosing. Duration of effect was directly related to i.n. fentanyl dose, with significantly less use of rescue medication after i.n. than after i.v. administration (P<0.005). The i.n. and i.v. formulations were both well tolerated, with similar numbers of nasally related adverse events recorded for both routes of administration. CONCLUSIONS Onsets and durations of analgesia were not significantly different between single doses of i.n. and i.v. fentanyl in these adults undergoing third-molar extraction. Both i.n. and i.v. administration were generally well tolerated.

Pharmacokinetics and Pharmacodynamics of Intranasal Versus Intravenous Fentanyl in Patients with Pain after Oral Surgery

Background: Fentanyl, a short-acting synthetic opioid, has a pharmacokinetic profile suited to fast relief of brief episodic pain. Objective: To characterize the pharmacokinetic-pharmacodynamic correlation of intranasal and intravenous fentanyl in opioid-naïve patients undergoing third molar extraction. Methods: A double-blind, double-dummy, crossover design study was conducted, with patients randomized to receive 1 of 4 fentanyl doses (75,100, 150, or 200 μg) by both the intravenous and intranasal routes. Venous fentanyl concentrations were determined for up to 180 minutes and pain scores were recorded up to 240 minutes postdose. Duration of effect and time to rescue medication were also recorded. Results: The pharmacokinetics of intravenous fentanyl reflected a 2-compartment model with a clearance of approximately 1.5 L/min. There was moderate (<50%) between-subject variability (BSV; %CV [coefficient of variation]) in the systemic kinetics of fentanyl. Bioavailability of intranasal fentanyl was 89%, following first-order absorption, with a lag of approximately 5 minutes and a half-life of approximately 6.5 minutes. Interpatient absorption variability was approximately 30% BSV for all absorption parameters. Intranasal versus intravenous administration led to a delayed mean fentanyl time to maximum concentration (13 vs 6 min) and lower maximum concentration (1.2 vs 2.0 ng/mL). Analgesic effect lagged behind the venous fentanyl concentration, with a half-life of approximately 2.5 minutes as described by a fractional sigmoid maximum drug effect dynamic model. The concentration-analgesia relationship was steep, with a 50% effective concentration of 0.46 ng/mL (Hill coefficient 3.5). Intranasal onset and offset of analgesia were slightly delayed, principally due to the delay and lag in systemic absorption, with slightly lower peak analgesic effect, compared with intravenous fentanyl. Duration of effect was directly related to intranasal fentanyl dose, with pain scores returning to predose values at approximately 120 minutes (75μg) to approximately 240 minutes (200 μg) after a single dose. Conclusions: Intranasal fentanyl showed kinetic and dynamic properties that are desirable for the management of acute, episodic (breakthrough) pain.

The relationship between mood state and plasma methadone concentration in maintenance patients

Although methadone maintenance is designed to stabilize opioid-dependent patients, some experience significant withdrawal in the latter part of the 24-hour interdosing interval. This study was designed to determine the mood changes that maybe associated with such withdrawal. Eighteen methadone patients, nine of whom experienced significant withdrawal, were tested over a single interdosing interval. During this time, 13 blood samples were collected to measure plasma racemic methadone concentrations, and the Profile of Mood States (POMS) was administered on 11 of these occasions. The POMS was also administered on 11 occasions over 24 hours to 10 drug-free healthy controls. In comparison with controls, methadone patients showed increased anger, depression, tension, confusion, and fatigue, as well as decreased vigor. For all scales, maximal differences from controls occurred at times of trough methadone concentration and minimal differences around the time of peak concentration. Changes in mood over the interdosing interval were more exaggerated in the nine patients who experienced significant withdrawal compared with those who did not. The composite Total Mood Disturbance (TMD) scores were calculated for each subject at each time point. The sigmoid Emax model was used to relate plasma concentrations to these data and to calculate the slope factor (N). This model could be fitted for 14 of the 18 patients with a mean ± SEM slope factor of 2.2 ± 0.5. TMD score was also shown to be inversely related to the rate of decline in methadone concentration from peak to trough. These results show that significant mood changes occur in response to changes in methadone concentration, and these are more pronounced in those who experience withdrawal. The concentration-effect relationships suggest that relatively small changes in plasma concentration will result in significant mood change. Differences in the degree of mood change between those who do and do not experience significant withdrawal may be explained by variation in the rate of decline in plasma concentration from peak to trough.

Pharmacokinetic‐Pharmacodynamic Modeling of Morphine and Oxycodone Concentrations and Analgesic Effect in a Multimodal Experimental Pain Model

Analgesia from most opioids is mediated by μ receptors located mainly in the central nervous system. Previous studies have shown a different pharmacological profile of oxycodone in respect to visceral analgesia. This study investigated if morphine and oxycodone have different pharmacokinetic/pharmacodynamic profiles, in particular with respect to delay between opioid blood concentration and analgesia. Twenty‐four healthy subjects had oral morphine (30 mg), oxycodone (15 mg), or placebo. Mechanical, thermal, and electrical pain tests were performed in the skin and viscera. Blood samples and pain measurements were taken at baseline and after 15, 30, 60, 90, and 120 minutes. Pharmacokinetic/pharmacodynamic profiles were modeled using a 2‐stage, nonlinear, mixed‐effects approach with an effect compartment to represent the concentration‐analgesia delay. Morphine kinetics was best described by a 2‐compartment model, whereas oxycodone kinetics was best described with a 1‐compartment model. Generally the analgesic effects of morphine were best related to plasma concentration by introducing a delay via an effect compartment. However, for oxycodone, this was only the case for analgesia in the somatic pain measures, whereas the plasma concentration correlated better to the course of the analgesia with no delay in the visceral pain measures. Oxycodone and morphine showed different pharmacodynamic/pharmacokinetic relationships for the visceral analgesia, whereas relationships were alike for somatic analgesia.

Stereoselective quantification of methadone and its major oxidative metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, in human urine using high-performance liquid chromatography

A stereoselective HPLC assay was developed for the quantification of the enantiomers of methadone and its major oxidative metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in human urine. The compounds were quantified in a single assay following liquid-liquid extraction and stereoselective HPLC with UV detection. Calibration curve concentrations ranged from 0.125 to 12.5 microM for each enantiomer. Assay performance was assessed using quality control samples, and the inter- and intra-assay bias (<10%) and precision (<15%) were acceptable for all compounds. The assay was successfully used to quantitate the enantiomers of methadone and EDDP in urine samples obtained from subjects receiving methadone maintenance therapy.

ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics

Background: Genetic variability in ABCB1, encoding the P-glycoprotein efflux transporter, has been linked to altered methadone maintenance treatment dose requirements. However, subsequent studies have indicated that additional environmental or genetic factors may confound ABCB1 pharmacogenetics in different methadone maintenance treatment settings. There is evidence that genetic variability in OPRM1, encoding the mu opioid receptor, and ABCB1 may interact to affect morphine response in opposite ways. This study aimed to examine whether a similar gene-gene interaction occurs for methadone in methadone maintenance treatment. Methods: Opioid-dependent subjects (n = 119) maintained on methadone (15–300 mg/day) were genotyped for five single nucleotide polymorphisms of ABCB1 (61A > G; 1199G > A; 1236C > T; 2677G > T; 3435C > T), as well as for the OPRM1 118A > G single nucleotide polymorphism. Subjects’ methadone doses and trough plasma (R)-methadone concentrations (Ctrough) were compared between ABCB1 haplotypes (with and without controlling for OPRM1 genotype), and between OPRM1 genotypes (with and without controlling for ABCB1 haplotype). Results: Among wild-type OPRM1 subjects, an ABCB1 variant haplotype group (subjects with a wild-type and 61A:1199G:1236C:2677T:3435T haplotype combination, or homozygous for the 61A:1199G:1236C:2677T:3435T haplotype) had significantly lower doses (median ± standard deviation 35 ± 5 versus 180 ± 65 mg/day, P < 0.01) and Ctrough (78 ± 22 versus 177 ± 97 ng/mL, P < 0.05) than ABCB1 wild-type subjects. Among subjects with the most common ABCB1 haplotype combination (wild-type with 61A:1199G:1236T:2677T:3435T), the OPRM1 118 A/G genotype was associated with a significantly higher Ctrough than 118 A/A (250 ± 126 versus 108 ± 36 ng/mL, P = 0.016). No ABCB1 haplotype group or OPRM1 genotype was associated with dose or Ctrough without taking into account confounding genetic variability at the other locus. Therefore, two interacting pharmacogenetic determinants of methadone maintenance treatment response were identified, ie, ABCB1, where variants are associated with lower methadone requirements, and OPRM1, where the variant is associated with higher methadone requirements. Conclusion: These opposing pharmacogenetic effects therefore need to be considered in combination when assessing methadone maintenance treatment pharmacogenetics.

Lack of influence of CYP2D6 genotype on the clearance of (R)-, (S)- and racemic-methadone

OBJECTIVE To investigate the influence of CYP2D6 genotype on the oral clearance of (R)-, (S)- and rac-methadone. METHODS In this retrospective study, CYP2D6 genotypes were identified in 56 methadone maintained subjects. Plasma concentrations of (R)-, (S)- and rac-methadone were determined by stereoselective HPLC and sufficient data were available to estimate the apparent oral clearances of (R)-, (S)- and rac-methadone using a population kinetic model in 37 of the genotyped subjects. RESULTS The CYP2D6 allele frequencies were similar to those previously reported in Caucasians, the most common being: CYP2D6*1 (35.2%), CYP2D6*2 (12.0%) and CYP2D6*4 (22.2%). Three unknown SNPs were found in four subjects: 1811G > A (n = 1), 1834C > T (n = 1) and 2720G > C (n = 2). The oral clearances of (R)-, (S)- and rac-methadone varied 5.4-, 6.8- and 6.1-fold, respectively. No significant differences in methadone oral clearance were found between CYP2D6 genotypic PM, IM and EM (p = 0.57, 0.40 and 0.43 for (R)-, (S)- and rac-methadone, respectively). Only 1 subject had duplication of functional CYP2D6 alleles and the oral clearance of the three analytes was not markedly altered. CONCLUSIONS CYP2D6 poor, intermediate and extensive metabolizer genotypes did not appear to impact on the oral clearance of (R)-, (S)- or rac-methadone. In addition, methadone dosage requirements were not influenced by CYP2D6 genotypes in these subjects. However, the impact of duplication of functional CYP2D6 alleles on oral clearance and dosage requirements requires further investigation.

A Pharmacokinetic and Pharmacodynamic Study of Oral Oxycodone in a Human Experimental Pain Model of Hyperalgesia

Background and ObjectiveOxycodone is not as well characterized, with respect to its pharmacokinetic/ pharmacodynamic properties, as other opioids. Moreover, the pharmacodynamic profile of oxycodone can be affected by changes in the pain system, e.g. hyperalgesia. Therefore, the aim of this study was to investigate the pharmacokinetic/pharmacodynamic profiles of oxycodone in a human experimental pain model of hyperalgesia.MethodsTwenty-four healthy subjects received oral oxycodone (15 mg) or placebo. Pharmacodynamics were assessed utilizing a multimodal, multi-tissue paradigm where pain was assessed from skin (heat), muscle (pressure) and viscera (heat and electricity) before and 30, 60 and 90 minutes after induction of generalized hyperalgesia evoked by perfusion of acid and capsaicin in the oesophagus. Venous blood samples were obtained for quantification of oxycodone plasma concentrations before and 5, 10, 15, 30, 45, 60, 90 and 120 minutes after drug administration.ResultsOxycodone blood concentrations could be described by a one-compartment model but, given the necessarily short timescale of the study, the concentrations were represented by linear interpolation for subsequent pharmacodynamic models. Time-dependent changes in the pain measures in the placebo arm of the study were represented by linear or quadratic functions. The time course of the pain measures in the oxycodone arm was taken to be the time course for the placebo arm plus a concentration-effect relationship that was either zero (no drug effect), linear or a maximum effect (Emax) model.For three of the four pain measures, there was a time-dependent change after administration of placebo (e.g. due to the development of generalized hyperalgesia).ConclusionThere was a measurable effect of oxycodone, compared with placebo, on all pain measures, and a linear concentration-effect relationship without an effect delay was demonstrated. This could indicate an initial peripheral analgesic effect of oxycodone.

Pharmacokinetic/Pharmacodynamic Relationships of Transdermal Buprenorphine and Fentanyl in Experimental Human Pain Models

Pharmacokinetic/pharmacodynamic (PK/PD) modelling can be used to characterize the relationship between dose regimen of opioids, plasma concentration and effect of opioids, which in turn can lead to more rational treatment regimens of pain. The aim of this study was to investigate the concentration-effect relationship for transdermal buprenorphine and fentanyl in experimentally induced pain. Twenty-two healthy volunteers were randomized to receive transdermal patches with fentanyl (25 μg/hr, 72 hr), buprenorphine (20 μg/hr, 144 hr) or placebo. The experimental pain tests were pressure at the tibial bone, cutaneous thermal stimulation, cold pressor test (conditioning stimulus (3 ± 0.3°C cold water), nerve growth factor-induced muscle soreness and intradermal capsaicin-induced hyperalgesia and allodynia. Experiments were carried out at baseline, 24, 48, 72 and 144 hr after application of patches. Time-course of placebo was described first and was afterwards added to the description of the time-courses of buprenorphine and fentanyl. This was either described by zero (no drug effect), linear or E(max) model concentration-effect relationships. Time-dependent changes in pain measures in the placebo arm were described by linear or quadratic functions. The time-course of fentanyl and buprenorphine plasma concentrations was complex but could be represented by cubic spline interpolation in the models. Buprenorphine significantly attenuated bone-associated pain, heat pain, nerve growth factor-induced soreness and cold pressor pain. Fentanyl significantly attenuated cold pressor pain for the administered dose regimens. Although the PK/PD relationship for both drugs could be described with similar models, tissue-differentiated analgesic effects between buprenorphine and fentanyl was shown.