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.

Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients.

AIMS: To investigate the steady-state pharmacokinetics of (R)- and (S)-methadone in a methadone maintenance population. METHODS: Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma alpha1-acid glycoprotein concentrations were quantified by radial immunoassay. RESULTS: (R)-methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)-methadone, while AUCtau_¿u¿ss (167%) was significantly (P < 0. 001) greater. There were no significant (P > 0.2) differences between the methadone enantiomers for AUCtauss, steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%. CONCLUSIONS: Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic-pharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.

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

OBJECTIVE: To determine plasma racemic methadone concentration-effect relationships for subjective and objective responses and whether pharmacokinetic and/or pharmacodynamic factors influence withdrawal severity. METHODS: Eighteen patients enrolled in a public methadone maintenance program, nine of whom experienced significant withdrawal, received constant doses of methadone once daily for at least 2 months. During an interdosing interval, 13 blood samples were collected to measure plasma racemic methadone concentrations (patients); subjective (withdrawal severity, direct opioid effects, and pain threshold) and objective (pupil diameter and respiratory rate) opioid effects were quantified on 11 occasions (all participants). The sigmoid Emax model was used to relate plasma concentrations and effects and to calculate the slope factor (N). The rate of decline in plasma concentration during each hour from the peak to the trough concentration was calculated. RESULTS: There was an inverse relationship between plasma concentrations and withdrawal severity and pupil diameter, as well as a direct relationship with subjective opioid effects and pain threshold. The mean N values were 5.4+/-0.9 for withdrawal severity, 5.1+/-1.1 for subjective opioid effects, 1.2+/-0.1 for pupil diameter, and 2.8+/-0.7 for pain threshold. Withdrawal severity correlated with the maximum rate of decrease in plasma concentration (P < .01). There were no differences between those who reported significant withdrawal and those who did not with respect to mean area under the plasma concentration versus time curve and predose plasma concentration, but maximal rate of decline was greater in the former group (74.5 versus 42.1 ng/mL/h). CONCLUSIONS: In this group of long-term methadone-maintained recipients, opioid responses were strongly correlated with changes in plasma racemic methadone concentrations. For the subjective responses, notably withdrawal, small changes in plasma concentrations translate into relatively large changes in effect; therefore, clinically important withdrawal is a consequence of more rapid decline in methadone concentration.

Biochemical and morphologic characterization of acrylamide peripheral neuropathy.

To determine whether reduced Na+/K+-ATPase activity might be involved in acrylamide (ACR)-induced peripheral axon swelling and degeneration, rubidium (Rb+) transport was measured as an index of enzyme function. x-ray microanalysis was used to quantify elemental Rb uptake and accumulation in internodal myelinated axons, mitochondria, Schwann cells, and myelin of rat tibial nerve cryosections. Results demonstrated impairment of Rb uptake in tibial axons from orally intoxicated (2.8 mM ACR for 34 days), moderately affected rats. In severely affected oral rats (49 days), complete inhibition of Rb transport and frank axon degeneration were evident. However, in moderate-to-severely affected rats exposed to ACR via ip injection (50 mg/kg/day for 11 days), neither structural nor enzymatic changes were present in tibial fibers. These findings in nerve cryosections suggested inhibition of axolemmal Na+ pump activity and degeneration were dependent upon route of ACR administration. This possibility was substantiated by a quantitative longitudinal morphometric study of conventionally fixed tibial nerve. Oral ACR treatment (2.8 mM ACR for 15-49 days) was associated with progressive axon degeneration, which was preceded by atrophy. Axonal swellings were rarely (<1%) observed. In contrast, ip ACR injection (50 mg/kg/day for 5-11 days) produced classic behavioral neurotoxicity but did not alter axon morphology in tibial nerve. Thus, fiber degeneration and decreased Na+ pump activity were consequences of subchronic oral ACR administration. This parallel expression suggests a mechanistic relationship. However, the corresponding general neurotoxicological significance is unclear since, behavioral toxicity induced by ip ACR develops without structural and enzymatic changes in tibial nerve.

Patterns of symptom complaints in methadone maintenance patients.

AIM: Not all maintenance patients respond to methadone in the same manner, and many complain of withdrawal symptoms during the 24-hour inter-dosing interval (i.e. the dose does not 'hold'). The persistence of these complaints are a source of concern as they may signal unsanctioned drug use and poor treatment outcome. This study examined the prevalence and profile of symptom complaints in methadone maintenance patients who report that their methadone dose does not 'hold'. DESIGN: In the first phase, a cross-sectional survey of 114 methadone patients examined a range of symptoms including direct opioid effects and withdrawal. Phase 2 involved a comparison of the temporal pattern of symptom complaints between patients who reported the oral dose not 'holding' and those who did not. SETTING: Participants in this study were enrolled in the South Australian Public Methadone Maintenance Program. MEASUREMENTS: In Phase 1, a checklist of 21 commonly reported symptom complaints associated with methadone maintenance treatment was administered. In Phase 2, this checklist was modified to include only those symptoms that changed in the 24-hour inter-dosing interval. The checklist was administered eight times over this period. Further data were collected using the Morphine Benzedrine Group Scale of the Addiction Research Centre Inventory, a measure of positive opioid effect. FINDINGS: In Phase 1, it was found that approximately one-third of the sample reported that the methadone dose was consistently inadequate in preventing withdrawal symptoms for the entire inter-dosing interval. They could not be differentiated by demographic, health, other drug use or treatment characteristics. In Phase 2, despite having a higher oral methadone dose, patients reporting that their daily dose did not 'hold' experienced a smaller degree of opioid effect, and a greater intensity of opioid withdrawal, during the 24-hour period. CONCLUSION: These data demonstrate that there is a change in pharmacodynamic response over the 24-hour period for all methadone patients, but the degree of change is greater in a subgroup of patients. Charting symptom presentation throughout the inter-dosing interval can aid in identifying those patients who are experiencing difficulties with their treatment regime.

Evaluation of three fixation techniques for repair of mandibular fractures in dogs.

Bilateral midbody hemimandibular osteotomies were performed between premolars 3 and 4 in 18 adult dogs. Hemimandibles were repaired by use of monocortically applied bone plates (n = 6), an interdental fixator composed of an Erich arch bar and acrylic (n = 6), or a type I external skeletal fixator (n = 6). At the immediate postoperative evaluation, hemimandibles stabilized with interdental fixators had an osteotomy gap distance (mean +/- SEM, 1.6 +/- 0.2 mm) that was significantly (P < 0.05) greater than for hemimandibles stabilized with external skeletal fixators (1.2 +/- 0.3 mm). Osteotomy gap distance of hemimandibles stabilized with external skeletal fixators (1.5 +/- 0.2 mm) was significantly (P < 0.05) greater at weeks 4 (1.1 +/- 0.2 mm) and 8 (0.8 +/- 0.3 mm) after surgery than the osteotomy gap distance of hemimandibles stabilized by application of bone plates. By week 16, significant differences in osteotomy gap distance were not detected between groups. Immediately after surgery, mandibular alignment measurements were not significantly different for dogs with bone plates (0.3 +/- 0.1 mm), interdental fixators (0.3 +/- 0.1 mm), and external skeletal fixators (0.9 +/- 0.5 mm). Mandibular alignment scores were not significantly different between treatment groups during the remaining postoperative period. Occlusal measurements were not significantly different between evaluations performed before surgery and 16 weeks after surgery, regardless of treatment group. Radiographic evidence of healing in hemimandibles stabilized with external skeletal fixators was significantly (P < 0.05) less at 4 and 8 weeks, compared with hemimandibles stabilized with bone plates and interdental fixators; however, radiographic evidence of bone healing was not significantly different between fixation groups at 16 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of short- and long-term administration of phenobarbital on endogenous ACTH concentration and results of ACTH stimulation tests in dogs.

The effects of short-term phenobarbital administration were evaluated in 6 adult mixed-breed dogs that received phenobarbital (5 mg/kg of body weight, PO, q 12 h) for 8 consecutive weeks. Six additional dogs served as untreated controls. At 2-week intervals, endogenous adrenocorticotropic hormone (ACTH) concentration and cortisol concentration before and 2 hours after administration of porcine aqueous ACTH (2.2 IU/kg, IM) were measured. By means of one-way ANOVA, we were not able to detect a significant (P > or = 0.05) difference in endogenous ACTH concentration and cortisol concentration before and after exogenous ACTH administration within groups over time or between groups at any time. To evaluate effects of long-term phenobarbital administration, sera and plasma were collected from 5 epileptic dogs that had received phenobarbital for > 2 years and had serum phenobarbital concentrations > 20 micrograms/dl. Endogenous ACTH concentration and cortisol concentration, before and after administration of ACTH, were within established reference ranges for all 5 dogs. Together, these results suggest that phenobarbital administration alone does not affect endogenous ACTH concentration or response to exogenous ACTH administration in dogs, and that these may be valid screening tests for hyperadrenocorticism in most dogs receiving phenobarbital.

Injecting behaviour and risky needle use amongst methadone maintenance clients.

The injecting behaviour and risky needle use of a sample of 193 methadone maintenance clients was investigated. The majority of the sample (n = 116) reported injecting one or more drugs in the month prior to data collection. Compared with non-injectors, the injectors were slightly younger, had been on the methadone program for a shorter period of time, had lower methadone doses and more severe drug and legal problems. The injecting sub-group was examined in more detail by comparing those subjects whose injecting practices conformed to guidelines on minimizing risk of HIV transmission with those who, in the preceding month, made at least one injection contravening these guidelines and thus placed themselves at risk of contracting HIV. A greater proportion of these risky injectors were unemployed. Importantly, risky injectors had lesser knowledge of means of preventing the spread of HIV than safe injectors. It is concluded that the reduction of HIV transmission could be enhanced by improvements in methadone programs, particularly ensuring adequate dosing and high retention rates. Further, there is a need to improve knowledge with regard to what are safe and what are risky injecting practices and needle/syringe cleaning methods.

Effects of a 44-day administration of phenobarbital on disposition of clorazepate in dogs.

The disposition of clorazepate, a benzodiazepine anticonvulsant, was determined in dogs after administration of a single oral dose of clorazepate (2 mg/kg of body weight) and after oral administration of clorazepate (2 mg/kg, q 12 h) concurrently with phenobarbital (5 mg/kg, q 12 h) for 44 consecutive days. Serum concentrations of nordiazepam, the active metabolite of clorazepate, were measured. After a single oral dose of clorazepate, maximal nordiazepam concentrations ranged from 569.6 to 1,387.9 ng/ml (mean, 880.2 +/- 248.9 ng/ml) and were detected 16.8 to 131.4 minutes (mean, 85.2 +/- 36 minutes) after dosing. After administration of phenobarbital for 44 consecutive days, maximal nordiazepam concentrations were significantly (P < 0.01) lower, ranging from 209.6 to 698.5 ng/ml (mean, 399.3 +/- 155.6 ng/ml) at 68.4 to 145.8 minutes (mean, 93 +/- 25.8 minutes) after dosing. Mean area under the curve (AUC) on day 1 (mean, 3.37 +/- 0.598 ng.min/ml) was significantly (P < 0.001) greater than AUC on day 44 (1.66 +/- 0.308 ng.min/ml). Oral clearance was significantly (P < 0.01) greater on day 44 (12.44 +/- 2.55 ml/min/kg), compared with that on day 1 (6.16 +/- 1.35 ml/min/kg). Values for area under the first moment curve, oral volume of distribution, mean residence time, and elimination half-life were not significantly altered by concurrent administration of phenobarbital. Administration of phenobarbital altered the disposition of clorazepate such that the amount of nordiazepam in circulation during each dose interval was significantly reduced. Adequate control of seizures in epileptic dogs, therefore, may require higher dosages of clorazepate when it is coadministered with phenobarbital.

Comparative dose-response studies of organophosphorus ester-induced delayed neuropathy in rats and hens administered mipafox.

A single injection of mipafox was administered to both Long-Evans hooded rats and White Leghorn hens in dosages which inhibited the activity of brain neurotoxic esterase 30-50%, 60-80%, or greater than 80% four hr after intoxication. All animals were monitored for clinical evidence of organophosphorus induced delayed neuropathy for 21 days, euthanatized, and regions of the nervous system were histologically evaluated. Only hens manifested clinical signs of neuropathy; however, light and electron microscopic lesions were present in the nervous systems of both species. In rats, these lesions were well developed in only the highest dosage group and confined to the rostral level of the fasciculus gracilis in the medulla oblongata. Swollen axons containing a single vacuole filled with flocculent material were the most prominent lesion in rats. Hens manifested more extensive and varied fiber breakdown in multiple spinal cord tracts, with the intensity of degeneration increasing with increasing dosages of mipafox. Both marked Wallerian-like degeneration and swollen axons filled with aggregates of cellular debris were observed in the nervous systems of hens. This study indicates that both rats and hens are susceptible to OPIDN. However, there are qualitative and quantitative differences in both clinical manifestations and histologic appearances between the two species.

Comparison of organophosphate-induced delayed neuropathy between branches of the tibial nerve and the biventer cervicis nerve in chickens.

Delayed neuropathy induced by organophosphorus esters has been reported to be more selective for large diameter myelinated fibers, especially in distal portions of long nerves. This concept was re-evaluated in chickens by quantitatively comparing the effects of the organophosphates tri-ortho-tolyl (TOTP) and phenyl saligenin phosphate (PSP) on two separate nerves, the branch of the tibial nerve that supplies the gastrocnemius muscle, and the small cervical nerve that innervates the biventer cervicis muscle. Histograms illustrating the distribution of myelinated fibers within each nerve showed that the biventer nerve is composed of a population of fibers smaller than those within the tibial nerve branch. However, the number of myelinated fibers measured per mm2 of endoneurium was reduced in both nerves 10 and 15 days after organophosphate administration, providing indirect evidence that fiber diameter is not critical in determining susceptibility to organophosphorus-induced delayed neuropathy (OPIDN). More direct evidence was provided by fiber diameter histograms of both biventer nerves and tibial nerve branches taken from hens that received PSP. In comparison to control values, there was a decrease in all fiber sizes in both nerves, indicating that factors other than axonal size are important in determining nerve fiber susceptibility to OPIDN.

Metal-inducible pathology in the liver, pancreas, and kidney of transgenic mice expressing SV40 early region genes.

Transgenic mice (SV-202) that carry the SV40 early region genes under the control of an inverted metallothionein promoter developed islet cell adenomas, hepatocellular carcinomas, and a generalized peripheral neuropathy. Both the islet cell adenomas and the hepatocellular carcinomas developed from the proliferation of T antigen-positive cells. However, T antigen expression was not seen in either the peripheral or central nervous systems. Stimulation of the metallothionein promoter with heavy metals altered the temporal onset of hepatic expression and broadened the distribution of oncogene expression to include exocrine pancreas and renal tubular epithelium. Although solid tumors were not seen in the exocrine pancreas or kidneys of SV-202 mice, all immunopositive tissues developed histologic changes. These results indicate that metallothionein-directed T antigen expression can induce abnormal cellular growth in a variety of tissues, and the distribution of these tissues can be manipulated with heavy metals.

Peripheral neuropathy associated with functional islet cell adenomas in SV40 transgenic mice.

A line of SV40 transgenic mice (SV-202) developed a generalized peripheral neuropathy, islet cell adenomas of the pancreas, and hepatocellular carcinomas. The neuropathy was not directly associated with T-antigen expression in the nervous system. This study was designed to characterize the morphologic appearance and distribution of the neuropathologic lesions in SV-202 mice, and to relate the temporal development of peripheral nerve lesions to transgene-induced tumorigenesis in pancreatic islet cells. SV-202 mice developed an acute axonal degeneration that preferentially affected large diameter myelinated fibers. The onset of the neuropathy is closely correlated with the development of the hyperinsulinemia and hypoglycemia resulting from the islet cell adenomas.

The intraneural distribution of myelinated fibres in the equine recurrent laryngeal nerve.

The intraneural course of nerve fibres in the equine recurrent laryngeal nerve was investigated by partially ligating the nerve at a proximal site, and 3-8 weeks later, tracing the course and spatial relationships of intact and degenerating fibres along the distal stump. This nerve was chosen because of its great length, the fact that it is a nonbranching motor nerve and because of debate about the course of abductor and adductor nerve fibres in the recurrent laryngeal nerve. Six ponies were used and in each the recurrent nerve was partially ligatured about 20 cm from the larynx, using a fine silk suture. In all there was a clear separation of intact and degenerating fibres just distal to the suture, but they became mixed close to the point of innervation of the laryngeal muscles. The numbers of intact myelinated fibres remained similar along the partially denervated nerve segment. These results suggest that myelinated fibres mix within the recurrent laryngeal nerve and that focal lesions of this nerve should not result in denervation of individual laryngeal muscles.