Multimodal assessment of sleep in men and women during treatment for opioid use disorder.

BACKGROUND: Sleep disturbance is common in patients with opioid use disorder (OUD) receiving medication for addiction treatment. Differences between patients on the two primary agonist medications-methadone and buprenorphine-are not well understood. METHODS: In patients receiving either methadone or buprenorphine treatment for OUD, we examined sleep continuity and architecture using ambulatory monitoring to gather both an objective measure (daily sleep EEG; M = 5.76 days, SD = 1.46) and a subjective measure (daily sleep diary; M = 54.10 days, SD = 25.10) of sleep. RESULTS: Patients treated with buprenorphine versus methadone did not differ on any measure of sleep continuity or architecture. Women had longer EEG-derived total sleep time than men (d = -0.68, 95 % CI -1.32 to -0.09), along with lower %N2 (d = 0.94, 95 % CI 0.34-1.64) and greater %N3 (d = -0.94, 95 % CI -1.61 to -0.32). Self-reported sleep differed from EEG-derived estimates: wake after sleep onset was greater by EEG than by diary (d = 2.58, 95 % CI 1.74-3.63), and total sleep time and sleep efficiency were lower by EEG than by diary (d for sleep time = 2.93, 95 % CI 2.06-4.14; d for efficiency = 1.69, 95 % CI 0.98-2.49). CONCLUSIONS: Patients treated with buprenorphine or methadone did not substantively differ in ambulatory measures of sleep. With both medications, there was a discrepancy between objective and subjective sleep measures. Further confirmatory evidence would inform the development of sleep-related recommendations for OUD patients undergoing agonist treatment.

Assessment of a carbon dioxide laser for the measurement of thermal nociceptive thresholds following intramuscular administration of analgesic drugs in pain-free female cats.

OBJECTIVE: To assess the potential of a thermal carbon dioxide (CO2) laser to explore antinociception in pain-free cats. STUDY DESIGN: Experimental, prospective, blinded, randomized study. ANIMALS: Sixty healthy adult female cats with a (mean±standard deviation) weight of 3.3±0.6 kg. METHODS: Cats were systematically allocated to one of six treatments: saline 0.2 mL per cat; morphine 0.5 mg kg(-1); buprenorphine 20 µg kg(-1); medetomidine 2 µg kg(-1); tramadol 2 mg kg(-1), and ketoprofen 2 mg kg(-1). Latency to respond to thermal stimulation was assessed at baseline and at intervals of 15-30, 30-45, 45-60, 60-75, 90-105 and 120-135 minutes. Thermal thresholds were assessed using time to respond behaviourally to stimulation with a 500 mW CO2 laser. Within-treatment differences in response latency were assessed using Friedman's test. Differences amongst treatments were assessed using independent Kruskal-Wallis tests. Where significant effects were identified, pairwise comparisons were conducted to elucidate the direction of the effect. RESULTS: Cats treated with morphine (χ2=12.90, df=6, p=0.045) and tramadol (χ2=20.28, df=6, p=0.002) showed significant increases in latency to respond. However, subsequent pairwise comparisons indicated that differences in latencies at specific time-points were significant (p<0.05) only for tramadol at 60-75 and 90-105 minutes after administration (21.9 and 43.6 seconds, respectively) in comparison with baseline (11.0 seconds). No significant pairwise comparisons were found within the morphine treatment. Injections of saline, ketoprofen, medetomidine or buprenorphine showed no significant effect on latency to respond. CONCLUSIONS AND CLINICAL RELEVANCE: The CO2 laser technique may have utility in the assessment of thermal nociceptive thresholds in pain-free cats after analgesic administration and may provide a simpler alternative to existing systems. Further exploration is required to examine its sensitivity and comparative utility.

A novel approach to pharmaco-EEG for investigating analgesics: assessment of spectral indices in single-sweep evoked brain potentials.

AIMS: To compare results from analysis of averaged and single-sweep evoked brain potentials (EPs) by visual inspection and spectral analysis in order to identify an objective measure for the analgesic effect of buprenorphine and fentanyl. METHODS: Twenty-two healthy males were included in a randomized study to assess the changes in EPs after 110 sweeps of painful electrical stimulation to the median nerve following treatment with buprenorphine, fentanyl or placebo patches. Bone pressure, cutaneous heat and electrical pain ratings were assessed. EPs and pain assessments were obtained before drug administration, 24, 48, 72 and 144 h after beginning of treatment. Features from EPs were extracted by three different approaches: (i) visual inspection of amplitude and latency of the main peaks in the average EPs, (ii) spectral distribution of the average EPs and (iii) spectral distribution of the EPs from single-sweeps. RESULTS: Visual inspection revealed no difference between active treatments and placebo (all P > 0.05). Spectral distribution of the averaged potentials showed a decrease in the beta (12-32 Hz) band for fentanyl (P = 0.036), which however did not correlate with pain ratings. Spectral distribution in the single-sweep EPs revealed significant increases in the theta, alpha and beta bands for buprenorphine (all P < 0.05) as well as theta band increase for fentanyl (P = 0.05). For buprenorphine, beta band activity correlated with bone pressure and cutaneous heat pain (both P = 0.04, r = 0.90). CONCLUSION: In conclusion single-sweep spectral band analysis increases the information on the response of the brain to opioids and may be used to identify the response to analgesics.

Fetal assessment before and after dosing with buprenorphine or methadone.

AIM: To determine pre- and post-dosing effects of prenatal methadone compared to buprenorphine on fetal wellbeing. DESIGN: A secondary analysis of data derived from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial. SETTING: Six United States sites and one European site that provided comprehensive opioid-dependence treatment to pregnant women. PARTICIPANTS: Eighty-one of the 131 opioid-dependent pregnant women completing the MOTHER clinical trial, assessed between 31 and 33 weeks of gestation. MEASUREMENTS: Two fetal assessments were conducted, once before and once after study medication dosing. Measures included mean fetal heart rate (FHR), number of FHR accelerations, FHR reactivity in the fetal non-stress test (NST) and biophysical profile (BPP) score. FINDINGS: Significant group differences were found for number of FHR accelerations, non-reactive NST and BPP scores (all Ps < 0.05). There were no significant group differences before time of dosing. Significant decreases (all Ps < 0.05) occurred from pre- to post-dose assessment for mean FHR, FHR accelerations, reactive NST and fetal movement. The decrease in accelerations and reactive NST were significant only for fetuses in the methadone group, and this resulted in a significantly lower likelihood of a reactive NST compared to fetuses in the buprenorphine group. CONCLUSION: Buprenorphine compared with methadone appears to result in less suppression of mean fetal heart rate, fetal heart rate reactivity and the biophysical profile score after medication dosing and these findings provide support for the relative safety of buprenorphine when fetal indices are considered as part of the complete risk-benefit ratio.

Assessment of locomotion in chlorine exposed mice by computer vision and neural networks.

Assessment of locomotion following exposure of animals to noxious or painful stimuli can offer significant insights into underlying mechanisms of injury and the effectiveness of various treatments. We developed a novel method to track the movement of mice in two dimensions using computer vision and neural network algorithms. By using this system we demonstrated that mice exposed to chlorine (Cl(2)) gas developed impaired locomotion and increased immobility for up to 9 h postexposure. Postexposure administration of buprenorphine, a common analgesic agent, increased locomotion and decreased immobility times in Cl(2)- but not air-exposed mice, most likely by decreasing Cl(2)-induced pain. This method can be adapted to assess the effectiveness of various therapies following exposure to a variety of chemical and behavioral noxious stimuli.

Distribution of vestibulospinal contacts on the dendrites of ipsilateral splenius motoneurons: an anatomical substrate for push-pull interactions during vestibulocollic reflexes.

Excitatory and inhibitory synapses may control neuronal output through a push-pull mechanism--that is, increases in excitation are coupled to simultaneous decreases in inhibition or vice versa. This pattern of activity is characteristic of excitatory and inhibitory vestibulospinal axons that mediate vestibulocollic reflexes. Previously, we showed that medial vestibulospinal tract (MVST) neurons in the rostral descending vestibular nucleus (DVN), an excitatory pathway, primarily innervate the medial dendrites of contralateral splenius motoneurons. In the present study, we tested the hypothesis that the counterparts of the push-pull mechanism, the ipsilateral inhibitory MVST synapses, are distributed on the dendritic tree such that the interactions with excitatory MVST synapses are enhanced. We combined anterograde tracing and intracellular staining in adult felines and show that most contacts (approximately 70%) between inhibitory MVST neurons in the rostral DVN and ipsilateral splenius motoneurons are also located on medial dendrites. There was a weak bias towards proximal dendrites. Using computational methods, we further show that the organization of excitatory and inhibitory MVST synapses on splenius motoneurons increases their likelihood for interaction. We found that if either excitatory or inhibitory MVST synapses were uniformly distributed throughout the dendritic tree, the proportion of inhibitory contacts in close proximity to excitatory contacts decreased. Thus, the compartmentalized distribution of excitatory and inhibitory MVST synapses on splenius motoneurons may be specifically designed to enhance their interactions during vestibulocollic reflexes. This suggests that the push-pull modulation of motoneuron output is based, in part, on the spatial arrangement of synapses on the dendritic tree.

Behaviour-based assessment of the duration of laparotomy-induced abdominal pain and the analgesic effects of carprofen and buprenorphine in rats.

Prevention of unnecessary pain in laboratory animals requires reliable and practically useful tools for assessing pain severity and analgesic efficacy. We have used a behaviour-based pain scoring system to determine the duration of pain resulting from laparotomy, and the duration of analgesia afforded by orally administered (p.o.) buprenorphine and subcutaneously administered (s.c.) carprofen or buprenorphine in rats. One hour before laparotomy Fisher 344 rats received either saline as a control (0.2 ml/100 g s.c.), carprofen (5 mg/kg s.c.) or buprenorphine (0.05 mg/kg s.c. or 0.4 mg/kg p.o.). The rats were housed singly for 10-min periods of behaviour recording, beginning 30 min after completing surgery. Recording was repeated at three time points every 2 h. The behaviour of controls was distinct from that of the analgesic-treated animals throughout recording; however, the major signs of pain (back-arching, staggering and writhing) were prominent during only the first 270 min in the saline group. This was followed by a period of more subtle differences between the saline- and drug-treated groups. It was concluded that the most acutely painful effects of surgery in this model lasted for between 270 and 390 min, and that this was alleviated throughout its duration by subcutaneously administered carprofen or buprenorphine, and also buprenorphine administered orally. The study demonstrates a clinically relevant and practically useful approach to assessing the duration of post-surgical abdominal pain and analgesic effects in rats.

Practical considerations for the clinical use of buprenorphine.

Buprenorphine is a new and attractive medication option for many opioid-addicted adults and their physicians. Before initiating buprenorphine treatment, providers must be aware of such critical factors as how the medication works, its efficacy and safety profile, how it is used in opioid withdrawal as well as maintenance treatment, and how patients can best be selected, educated about buprenorphine, and monitored throughout treatment. This article reviews these important issues as well as requirements for physician and staff training and needs for additional research on this unique medication.

Assessment of the postoperative discomfort of intra-auricularly hypophysectomized rats.

Rats subjected to hypophysectomy make up one of the largest groups of experimental animals in Europe, since there is a legal demand for batch testing of industrially produced growth hormones. To describe the clinical performance of rats having undergone hypophysectomy, animals were examined postoperatively by monitoring behaviour, body temperature and food intake. Behavioural changes were observed in rats that had only been anaesthetized, as well as in sham-operated rats, while no behavioural deviations could be shown in hypophysectomized rats. On the first day after surgery all rats had declining body temperature and food intake; and this change was not reversed by treatment with carprofen, buprenorphine or oxytetracycline. The mortality rate in rats treated with buprenorphine was increased, as was the mortality rate in rats hypophysectomized when weighing more than 100 g. As there seemed to be no differences whether methohexital or a combination of fentanyl, fluanison and midazolam was used, the latter anaesthesia is recommended due to its analgesic potential. For post-surgical analgesic treatment, carprofen is recommended rather than buprenorphine. At best, the use of hypophysectomized rats should be replaced in industrial batch testing by an existing in vitro method.

Assessment of opioid partial agonist activity with a three-choice hydromorphone dose-discrimination procedure.

The discriminative stimulus and subjective effects of opioid mixed agonist-antagonists were assessed in volunteer nondependent heroin users trained in a three-choice drug discrimination procedure to discriminate among the effects of i.m. administration of 2 ml of saline, 1 mg of hydromorphone, and 4 mg of hydromorphone (a morphine-like mu agonist). Other subjective, behavioral, and physiological measures were concurrently collected. The discrimination was readily learned by six of the eight subjects. After training, generalization curves were determined for the following i.m. drug conditions: hydromorphone (0.375-4.0 mg), pentazocine (7.5-60 mg), butorphanol (0.75-6 mg), nalbuphine (3-24 mg), and buprenorphine (0.075-0.6 mg). All five of the test drugs were discriminated significantly or showed trends toward being discriminated as hydromorphone 1 mg-like at one or more dose levels. Hydromorphone showed an inverted U-shaped dose-effect function on the hydromorphone 1 mg-like discrimination. Subjective effect measures produced clearer differentiation among the test drugs than did drug discrimination performance. The present results differ from those of a previous study that observed a close relationship between the results of the discrimination measure and subjective effect measures. The previous study used similar methods and test drugs but different training drugs (e.g., 3 mg of hydromorphone versus 6 mg of butorphanol versus saline). It appears that both the sensitivity of drug discrimination performance to between-drug differences and the relationship between discriminative and subjective effects depends upon the specific discrimination that is trained (e.g., two-choice or three-choice). The present high dose-low dose-saline discrimination procedure appears useful for assessing partial agonist activity. The present data are consistent with partial agonist activity for pentazocine, butorphanol, nalbuphine, and buprenorphine.

Buprenorphine dose self-selection: effects of an alternative reinforcer, behavioral economic analysis of demand, and examination of subjective drug effects.

Buprenorphine (BUP)-maintained patients were first exposed to various BUP doses and then chose between BUP doses and money. In the choice phase, they had 10 units exchangeable for units of BUP (constant at 3 mg/unit) or money (varied from $0.30 to $20/unit). They chose BUP exclusively (30 mg) when the money alternative was low. As available money increased, they selected lower daily BUP doses (down to 3 mg). An economic analysis indicated demand for BUP was inelastic; changes in drug intake were proportionally lower than changes in price. Subjective reports of agonist and withdrawal effects increased > 200% when high and low BUP doses, respectively, were given during the exposure phase. In the choice phase, subjective drug effects were constant regardless of the BUP dose selected. Thus, BUP dose selection varies with the magnitude of alternative reinforcers, and subjective drug effects depend on whether doses are self- or experimenter-selected.

Assessment of orocaecal transit time in cats by the breath hydrogen method: the effects of sedation and a comparison of definitions.

Oro-caecal transit times (OCTTs) were assessed in 10 healthy adult cats by the lactulose breath hydrogen method with either no sedation (group A), or after the intramuscular administration of three sedative regimens: a combination of acetylpromazine at 0.1 mg kg-1 with buprenorphine at 10 micrograms kg-1 (group B), ketamine at 5 mg kg-1 with midazolam at 0.1 mg kg-1 (group C), or medetomidine at 50 micrograms kg-1 (group D). For each test, the OCTT was defined by four methods: a visual assessment, the first maintained 4 ppm increase in hydrogen production, and the first maintained 0.5 ml hr-1 increase in hydrogen production assessed by two cumulative sum methods. Depending on the definition, the median OCTTs of the cats were between 113 and 131.5 minutes in group A, 86.5 and 97.5 minutes in group B, 218 and 235.5 minutes in group C and 86.5 and 97.5 minutes in group D. By two of the definitions, the median OCTTs in group C were significantly longer than in group A (P < or = 0.037) and approached significance by the other two definitions. The use of sedatives significantly increased the inter-individual variability of the OCTTs, particularly in groups C and D. There were significant differences between the median OCTTs defined by the four different methods, but all the methods were very highly and significantly correlated (rs < or = 0.9503, P < 0.0001).

The effects of chronic morphine on the generalization of buprenorphine stimulus control: an assessment of kappa antagonist activity.

Rats trained to discriminate the mixed mu agonist/kappa antagonist buprenorphine from its vehicle generalize buprenorphine control to morphine. Buprenorphine, however, does not generalize to MR2266. The generalization to morphine suggests that buprenorphine's mu agonist properties mediated in part its discriminative control. The failure to generalize to MR2266, a compound reported to block kappa-mediated effects, however, suggests that its kappa antagonist activity was not involved in its discriminative effects. The ability of buprenorphine's mu (but not kappa) activity to establish stimulus control may be a function of the overshadowing of the kappa properties of buprenorphine by its concurrent mu activity. To test this possibility, in the present experiment rats were chronically exposed to morphine prior to buprenorphine discrimination training. This procedure has been reported to result in tolerance to buprenorphine's mu agonist effects and a more pronounced display of its kappa antagonist properties. The rats were then tested for the generalization of buprenorphine control to morphine, MR2266, and pentobarbital. As expected, buprenorphine failed to generalize to the nonopioid pentobarbital. Although subjects were tolerant to morphine (as evidenced by reductions in morphine-induced behavioral effects and a rightward shift in the doses of morphine substituting for buprenorphine), buprenorphine still failed to generalize to MR2266. The failure of buprenorphine to generalize to MR2266 under conditions that should have allowed for the development of stimulus control by buprenorphine's kappa antagonist activity was discussed in terms of the general inability of kappa antagonist activity to support discrimination learning.

Drug discrimination assessment of agonist-antagonist opioids in humans: a three-choice saline-hydromorphone-butorphanol procedure.

To assess the discriminative stimulus properties of mixed agonist-antagonist opioids in humans, postaddict volunteers were trained in a three-choice drug discrimination procedure to discriminate among the effects of saline (4 ml i.m.), hydromorphone (3 mg i.m.) and butorphanol (6 mg i.m.). Subjects earned monetary reinforcement by correctly identifying the training drugs by letter code. Other subjective, behavioral and physiological measures were concurrently collected. After training, generalization curves for hydromorphone, butorphanol, pentazocine, nalbuphine and buprenorphine were determined. In generalization testing, both hydromorphone and butorphanol produced dose-related increases in hydromorphone-appropriate and butorphanol-appropriate responses, respectively, and other characteristic subjective effect measures. Nalbuphine produced dose-related increases in discrimination as butorphanol and in those subjective effect measures increased by butorphanol. Buprenorphine produced dose-related increases in discrimination as hydromorphone and in those subjective effect measures increased by hydromorphone. Pentazocine was not consistently discriminated as either butorphanol or hydromorphone. These results differ from those of previous discrimination studies using similar methods but different training drugs. Compared to a previous study in which pentazocine served as the kappa-like training drug, the use as a training drug of the more pharmacologically specific kappa-like drug butorphanol permitted greater differentiation among test drugs and yielded discrimination results more consistent with other pharmacological evidence (buprenorphine being mu-like and nalbuphine being kappa-like). There was a close relationship between results of the discrimination measures and the subjective effect measures.

Buprenorphine as a stimulus in drug discrimination learning: an assessment of mu and kappa receptor activity.

Using the conditioned taste aversion baseline of drug discrimination learning, different groups of animals were trained to discriminate either buprenorphine or morphine from distilled water. Specifically, animals were injected with buprenorphine or morphine prior to a saccharin-LiCl pairing and the drug vehicle prior to saccharin alone. By the fifth conditioning trial, animals differentially consumed saccharin on the basis of administration of the drug or its vehicle. In subsequent generalization tests, buprenorphine stimulus control generalized completely to the mu agonist morphine in four of the five subjects tested, while morphine stimulus control completely generalized to buprenorphine in two of five subjects and partially generalized in the remaining three. Buprenorphine failed to generalize to the relatively selective kappa antagonist MR2266 and the broad-based antagonist diprenorphine. Morphine also failed to generalize to MR2266, but did generalize to diprenorphine. That morphine and buprenorphine displayed some degree of cross-generalization suggests that these compounds share some stimulus property, presumably their agonist activity at the mu receptor, and that the mu activity of these compounds was used in the establishment of the discrimination, a conclusion supported by the fact that compounds with mu antagonist activity (e.g., naloxone, MR2266) blocked both buprenorphine and morphine stimulus control. That buprenorphine failed to generalize to compounds with kappa antagonist activity suggests that animals trained to discriminate buprenorphine from its vehicle do not use the kappa antagonist activity of the drug in the establishment of the discrimination. The basis for the differential ability of various receptor subtypes to mediate the discriminative properties of compounds with mixed receptor activity was discussed.

Assessment of buprenorphine in a drug discrimination procedure in humans.

These studies indicate that buprenorphine shares stimulus effects with other opioid drugs and that in overall profile of effects buprenorphine is more similar to hydromorphone than are the other opioid mixed agonist-antagonists tested-pentazocine, butorphanol, and nalbuphine. This characterization is supported by the behavioral drug discrimination results and by the subjective effect self-report results. In the drug discrimination assessments buprenorphine showed a pattern of generalization that was different from that of the other opioid-mixed agonist-antagonists. It did not generalize completely to either pentazocine or butorphanol, but it did generalize to hydromorphone in two studies and partially in a third. Both nalbuphine and pentazocine showed at least partial generalization to butorphanol, but buprenorphine did not. Butorphanol showed little generalization to hydromorphone except in the two-choice hydromorphone vs. saline discrimination in which all the tested mixed agonist-antagonists generalized to hydromorphone. The subjective effect self-report data also revealed a pattern of response to buprenorphine that was different from that to the other mixed agonist-antagonists. In particular, buprenorphine's profile of acute subjective effects was similar to that of hydromorphone. There were dose-related increases on various scales reflecting positive subjective effects, with little evidence of the dysphoric effects that are characteristic of high doses of the other mixed agonist-antagonists. These data are compatible with the view that buprenorphine is a partial agonist at the mu-receptor. Although they do not demonstrate the ceiling on magnitude of pharmacological effects that would be characteristic of a partial agonist, they do demonstrate that buprenorphine's profile of activity--both stimulus effects and subjective effects--is similar to that of the pure mu-agonist hydromorphone.