How To Repair Brain Sleep Recptors Form Long Term Suboxone Use

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Anesthesiology. Author manuscript; bachelor in PMC 2022 Oct 1.

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PMCID: PMC3197808

NIHMSID: NIHMS319694

Buprenorphine Disrupts Sleep and Decreases Adenosine Levels in Sleep-Regulating Brain Regions of Sprague Dawley Rat

Elizabeth A. Gauthier, B.Due south., Medical Student, Sarah E. Guzick, B.S., Graduate Student, Chad G. Brummett, M.D., Assistant Professor, Helen A. Baghdoyan, Ph.D., Professor, and Ralph Lydic, Ph.D., Professor

Abstract

Background

Buprenorphine, a partial μ opioid receptor agonist and κ opioid receptor antagonist, is an effective analgesic. The effects of buprenorphine on slumber have not been well characterized. This report tested the hypothesis that an antinociceptive dose of buprenorphine decreases sleep and decreases adenosine levels in regions of the basal forebrain and pontine brain stalk that regulate sleep.

Methods

Male Sprague Dawley rats were implanted with intravenous catheters and electrodes for recording states of wakefulness and sleep. Buprenorphine (1 mg/kg) was administered systemically via an indwelling catheter and sleep/wake states were recorded for 24 h. In additional rats buprenorphine was delivered by microdialysis to the pontine reticular formation and substantia innominata of the basal forebrain while simultaneously measuring adenosine.

Results

An antinociceptive dose of buprenorphine caused a significant increment in wakefulness (25.ii%) and a decrease in both nonrapid heart motion sleep (−22.1%) and rapid eye movement sleep (−iii.1%). Buprenorphine as well increased electroencephalographic delta power during nonrapid eye movement sleep. Coadministration of the sedative/hypnotic eszopiclone diminished the buprenorphine-induced decrease in sleep. Dialysis delivery of buprenorphine significantly decreased adenosine levels in the pontine reticular formation (−xiv.6%) and substantia innominata (−36.7%). Intravenous administration of buprenorphine significantly decreased (−20%) adenosine in the substantia innominata.

Conclusions

Buprenorphine significantly increased fourth dimension spent awake, decreased nonrapid eye motility sleep, and increased latency to slumber onset. These disruptions in sleep architecture were mitigated by coadministration of the nonbenzodiazepine sedative/hypnotic eszopiclone. The buprenorphine-induced decrease in adenosine levels in basal forebrain and pontine reticular formation is consistent with the estimation that decreasing adenosine in sleep-regulating brain regions is i machinery by which opioids disrupt sleep.

Introduction

Opioids are used effectively in the treatment of chronic and acute pain, and the extensive use of opioids encourages efforts to develop counter-measures to combat unwanted side furnishings.^1,2 Opioids disrupt sleep^3-7 and slumber disruption tin can contribute to hyperalgesia,^8-xvi impaired allowed function,¹⁷ and postoperative cerebral impairment.^{eighteen,nineteen}

Adenosine is an endogenous neuromodulator that significantly enhances sleep²⁰ and diminishes nociception.²¹ Slumber is increased by increasing adenosine in the pontine reticular formation (PnO)^22-24 and in the substantia innominata (SI) area of the basal forebrain.^20,25 Adenosine levels in the PnO and SI are decreased by the μ opioid receptor agonists morphine and fentanyl.²⁶

Buprenorphine, a partial μ opioid receptor agonist and κ opioid receptor antagonist, is an constructive analgesic just no prior studies have quantified the effects of buprenorphine on sleep compages^7,27,28 or on adenosine levels in the PnO and SI. This study was designed to test the hypothesis that buprenorphine decreases sleep and adenosine levels in PnO and SI, brain regions known to modulate slumber and nociception.

Materials and Methods

Animals

Adult, male Crl:CD ^* (SD) (Sprague Dawley) rats (n = 26) purchased from Charles River Laboratories (Wilmington, MA) were used for all studies. Rats weighing 250 to 350 grand were used considering brains from rats in this weight range are known to fit the rat stereotaxic atlas.²⁹ Male rats were chosen to facilitate comparison of the present results to previous data obtained from males.^26,xxx-32 Rats were housed in a 12:12-h light/dark bike (lights on from 8:00 to 20:00) with access to food and water advert libitum. Procedures were reviewed and approved by the University of Michigan Committee on the Employ and Care of Animals. Every stage of this written report adhered to the Guide for the Intendance and Use of Laboratory Animals: 8th Edition, National University of Sciences Press, Washington DC, 2022. ^*

Surgical Procedures

Rats were anesthetized with three% isoflurane (Hospira, Inc., Lake Woods, IL). The jugular vein was exposed and a catheter (12 cm of Micro-Renathane tubing (MRE–040), Braintree Scientific, Braintree, MA) was inserted in the management of the heart. The other finish of the catheter was tunneled subcutaneously and implanted between the scapulas. A back-mounted flange guide cannula (8I 1000BM10, Plastics One, Roanoke, VA) and dummy cannula (8IC313DCCACC, Plastics 1) were secured with the catheter in the midscapular position. This procedure provided subsequent venous access.

Implantation of the jugular vein catheter was immediately followed by implantation of electrodes for recording slumber. Rats were moved to a Kopf Model 962 small animate being stereotaxic instrument fitted with a Model 906 rat anesthesia mask (David Kopf Instruments, Tujunga, CA) and anesthesia was maintained with 2.0 % isoflurane. 3 electrodes (8IE36320SPCE, Plastics Ane) for recording cortical electroencephalogram were placed 2.0 mm posterior and one.3 mm lateral to bregma, 2.0 mm posterior and ane.5 mm lateral to bregma, and one.0 mm anterior and 1.5 lateral to bregma.²⁹ Two electrodes (4 cm of AG 7/40T Medwire, Mt. Vernon, NY) for electromyogram recordings were placed in the dorsal cervix muscle, and a tertiary electrode was placed under the skin of the neck musculus every bit a reference. The nonimplanted ends of the electroencephalogram and electromyogram electrodes were soldered to electrical contact pins (E363/0, Plastics One) that were plugged into a plastic pedestal (8K00022980IF, Plastics Ane). Three stainless steel anchor screws (MPX-0080-02P-C, Small Parts Inc., Miami Lakes, FL) were placed in the skull to secure the electrodes. Dental acrylic was used to construct a head cap roofing the electrodes and to anchor the electric connector and electrodes to the skull. Rats were and so removed from the stereotaxic frame and monitored during recovery from anesthesia. Once ambulatory, animals were returned to their home cages.

Behavioral Conditioning for Slumber Recordings

Following 1 week for surgical recovery, rats were conditioned for an additional week to ten days to sleeping in a Raturn (Bioanalytical Systems, W Lafayette, IN) recording sleeping room. During conditioning the implanted electrodes were attached by a cable (363–441/vi 80CM 6TCM, Plastics One) to amplifiers and a computer for digital recording of electroencephalogram and electromyogram signals. Rats had costless admission to food and water while in the recording chambers.

Nociceptive testing

An initial series of experiments was conducted to confirm that the 1 mg/kg dose of buprenorphine produced anti-nociception every bit reported previously.³³ Procedures for thermal nociceptive testing accept been described in detail.^34,35 Briefly, rats were conditioned to being placed in the Plexiglas bedroom of a Hargreaves Manus Withdrawal unit (Model 336T, IITC Life Science, Woodland Hills, CA) i hour each twenty-four hour period for the week prior to data drove. The Model 400 (IITC Life Science) heated drinking glass stand and base of operations was prepare to xxx°C for the terminal 10 minutes of each conditioning session and both hind paws of the rat were exposed to the estrus stimulus.³⁶ Five baseline measurements were taken afterward the habituation time. As presently as baseline measurements were recorded, saline or buprenorphine hydrochloride (Sigma-Aldrich, Saint Louis, MO; 1 mg/kg) were administered via the jugular vein catheter. Injection volume was 1 ml. Measures of mitt withdrawal latency (PWL) were taken at ten, 20, xxx, threescore, 90, and 120 min after saline or buprenorphine administration. A cutting-off time of 15 s was set to prevent tissue damage of the hind paw.

Drug Administration and Recordings of Sleep/Wake States

A second series of experiments was designed to quantify the effect of intravenously administered buprenorphine on states of sleep and wakefulness. Buprenorphine was dissolved in sterile saline (pH 5.eight ± 0.2) and administered intravenously in a ane-ml volume at a dose of 1 mg/kg. Saline injection provided a negative command condition.

Recordings of sleep and wakefulness began at 08:00 at the initiation of the light phase of the light/dark cycle. Rats are nocturnal and light onset corresponds to the rat subjective night. In lodge to make up one's mind whether buprenorphine caused sleep disruption, as do other opioids,^26,37 this written report was designed to deliver buprenorphine at low-cal onset. Rats were placed in the recording sleeping room and the electromyogram and electroencephalogram electrodes were attached via hinge cable to the amplifiers and computer. All injections were administered during a iv-min interval. The data acquisition software was started when drug or vehicle assistants began. The electroencephalogram signals were filtered between 0.3 and xxx Hz and amplified. Each rat (northward = 7) received one injection of buprenorphine and one injection of saline separated past at to the lowest degree ane week. The rats were so immune to slumber and wake spontaneously for the remainder of the 24-h recording. At the end of the recording interval, rats were returned to the vivarium. Every 10 southward of the 24-h recording was scored as wakefulness, nonrapid center movement (NREM) slumber, or rapid eye movement (REM) sleep. All sleep recordings were besides scored past a second individual who was blinded to the injection condition. There was a 93% understanding between the two sleep scorers.

A third series of experiments was designed to coadminister the nonbenzodiazepine sedative/hypnotic eszopiclone (Toronto Research Chemicals, Toronto, Canada) with buprenorphine in order to quantify the issue on sleep and wakefulness. Eszopiclone is a benzodiazepine receptor agonist with a non-benzodiazepine structure, marketed as Lunesta™ Eszopiclone is the (Southward)-isomer of the cyclopyrrolone zopiclone and is indicated for the treatment of indisposition.³⁸ As discussed in detail elsewhere,²⁶ a major complaint of patients who experience pain is poor sleep. Clinically used doses of opioids significantly disrupt sleep³⁷ and disordered sleep exacerbates pain.^26,39,xl These information raise the question of whether enhancement of slumber by a sedative/hypnotic would have a beneficial upshot of diminishing opioid-induced slumber disruption. If so, this would encourage hereafter studies aiming to determine if combining opioid and sedative/hypnotic therapy could diminish pain. Eszopiclone was dissolved in sterile saline and 1% dimethyl sulfoxide (pH half-dozen.0 ± 0.2) and administered intravenously (iii mg/kg). Buprenorphine (one mg/kg) was so delivered via the same intravenous cannula. For these studies, rats (n = four) received an injection of eszopiclone followed immediately by an injection of saline or buprenorphine.

Measurement of Brain Adenosine Levels during Microdialysis Delivery of Buprenorphine

A 4th set of experiments sought to identify brain regions through which buprenorphine decreased sleep. Normal cholinergic neurotransmission is essential for maintaining wakefulness and opioids disrupt cholinergic neurotransmission in the SI region of the basal forebrain.³⁰ Adenosine is known to promote sleep and previous studies have shown that adenosine levels in the PnO are decreased by fentanyl and by morphine.²⁶ Both fentanyl and morphine crusade sleep disruption. Therefore, the present experiments also used in vivo microdialysis and high performance liquid chromatography to measure out adenosine levels in the PnO and SI during dialysis delivery of buprenorphine.

Buprenorphine (100 μM) was prepared the morning of each experiment. The drug was dissolved in Ringer's solution (pH 5.eight – half dozen.2) comprised of 146 nM NaCl, 4.0 mM KCl, 2.4 mM CaCl_ii, and x μM erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; Sigma-Aldrich) which is an adenosine deaminase inhibitor. Each rat was placed in an consecration sleeping accommodation and anesthetized with 4% isoflurane (Hospira, Inc.) in 100% oxygen. After five min, the rat was moved out of the chamber into a stereotaxic frame and fitted with a rat anesthesia mask, equally described above. Isoflurane concentration was reduced to 2.v%. A midline scalp incision was so made to expose lambda and bregma. A Dremel tool (Racine, WI) was used to make a pocket-sized craniotomy through which a dialysis probe could be placed in the encephalon. A rat brain atlas²⁹ was used to position a CMA-11 microdialysis probe (Cuprophane membrane: 1 mm long, 0.24 mm in diameter, 6-kDa cutting off; CMA Microdialysis, North Chelmsford, MA) in the PnO or in the SI. Stereotaxic coordinates for the PnO were 8.4 mm posterior to bregma, 1.0 mm lateral to the midline, and 9.2 mm below bregma. The coordinates for the SI were ane.half dozen mm posterior to bregma, 2.5 mm lateral to the midline, and eight.vii mm below bregma. Delivered isoflurane concentration was held at 1.v% and was measured continuously throughout the duration of the experiment. A h2o blanket and recirculating estrus pump (Gaymar Industries, Orchard Park, NY) were used to maintain body temperature at 37 degrees C throughout information collection and recovery.

The dialysis probe was perfused with Ringer's at a abiding period rate of 2 μl/min using a CMA/400 pump. Dialysis intervals of 15 min produced 30-μl samples which were injected into an high performance liquid chromatography arrangement coupled to a UV-Vis detector (wavelength of 254 nm). This organization made it possible to express measured adenosine levels as nM. The digitized chromatographs were quantified against a standard curve using ChromGraph software (Bioanalytical Systems). Adenosine levels were allowed to stabilize for two h before beginning information collection. A control sample was collected every 15 min for one h during dialysis with Ringer'southward. At the cease of the fourth control sample, a liquid switch was activated to brainstorm dialysis with Ringer'south containing buprenorphine (100 μM). As noted elsewhere^26,41,42 the characteristics of the dialysis membrane are such that only about 5% of the 100 μM buprenorphine was delivered to the brain. Later on the final dialysis sample was collected, the probe was removed from the brain and the scalp incision was closed. The commitment of isoflurane was and so discontinued and the animal was removed from the stereotaxic frame. The rats were returned to their cages and were monitored until they were ambulatory.

Histological Localization of Dialysis Sites

Four to v days after the microdialysis experiment each rat was deeply anesthetized and decapitated. Brains were removed, cut into 40-μm thick coronal sections with a cryostat (Leica Microsystems, Nussloch, Germany), and slide-mounted serially. Slides with brain sections containing the SI and PnO were fixed in paraformaldehyde vapor (80 degrees C) and stained with cresyl violet. All sections were then digitized using a Nikon Super Coolscan 4000 scanner (Tokyo, Japan). Coronal sections were compared to plates in a rat brain atlas²⁹ and the dialysis sites were localized to either the PnO or the SI.

Statistical Analysis

Statistical programs used for information assay included Prism 5 (Graph Pad Software, Inc., La Jolla, CA) and SAS v9.2 (SAS Institute Inc., Cary, NC). All information were tested to insure they met the assumptions of the underlying statistical model. PWL was converted to Percent Maximum Possible Event (% MPE) using the post-obit equation: % MPE = (PWL experimental – PWL baseline)/(fifteen s – PWL baseline) × 100. Repeated measures, two-way analysis of variance (ANOVA) was used to analyze results for changes over time and changes due to drug, and Bonferonni post-hoc tests were used to detect differences at specific fourth dimension points.

Every ten s of the 24-h recordings of sleep and wakefulness was scored as wakefulness, NREM sleep, or REM sleep. Dependent measures included percent of time spent in each country, latency to onset of the first episode of NREM sleep and REM sleep, number of episodes, average episode duration, and number of transitions between states. To avoid the problem of inflated degrees of freedom resulting from the large number of ten-s epochs analyzed, the sleep-wake data were averaged for each rat. Dependent measures of slumber and wakefulness were analyzed past repeated measures 2-way ANOVA and paired t-tests using Bonferonni correction.

Equally described in detail elsewhere^24,43,44 fast Fourier transform of the electroencephalogram was performed in order to determine whether the electroencephalogram was contradistinct past buprenorphine. Electroencephalographic power was analyzed by repeated measures two-way ANOVA and post-hoc tests for comparing at every 0.5 Hz frequency band (Wake and REM sleep 5.0 to 10.0 Hz; NREM sleep 0.5 to five.0 Hz).

For each experiment, adenosine measures during dialysis with Ringer'southward (control) were compared to adenosine levels during dialysis delivery of buprenorphine. This pattern allowed each experiment to contribute i mean adenosine value derived from four control (Ringer's) samples and i hateful adenosine value derived from iv measures obtained during administration of buprenorphine. These values were then averaged across multiple experiments and analyzed individually for PnO and SI brain regions using paired t-tests. A probability value of P ≤ 0.05 was considered to be statistically significant.

Results

Buprenorphine was Antinociceptive

Figure i depicts % MPE for mitt withdrawal latency as a function of time after intravenous administration of saline and buprenorphine. ANOVA revealed that buprenorphine caused significant (P = 0.0072) antinociception. Bonferroni post-hoc comparisons indicated that buprenorphine significantly (P < 0.05) increased % MPE at 20, xxx, sixty, and 120 min after injection. This antinociceptive dose of buprenorphine was used for subsequent studies of sleep and wakefulness.

Buprenorphine increased latency of manus withdrawal (PWL) away from a thermal stimulus. Ordinate shows PWL expressed as pct maximum possible effect (% MPE). Abscissa shows time-class of % MPE relative to injection at time zero. Asterisks (*) indicate a significant increase in % MPE later on intravenous administration of buprenorphine (1 mg/kg) compared to saline (vehicle control).

Buprenorphine Altered the Temporal Organization of Sleep and Wakefulness

Figure ii illustrates the temporal distribution of wakefulness, NREM sleep, and REM sleep for 24 h following intravenous assistants of saline (command) and buprenorphine. Figure iii summarizes grouping data for the low-cal phase (1^st 12 h after injection) showing buprenorphine-induced changes in the temporal arrangement of sleep and wakefulness. ANOVA indicated a significant (P < 0.01) result of buprenorphine on percent of time spent in states of wakefulness, NREM sleep, and REM slumber, likewise as a significant (P < 0.0001) drug-by-country interaction (fig. 3A). Paired t-tests with Bonferonni correction showed that buprenorphine significantly (P < 0.05) increased the percent of time spent in waking (25.2%) and significantly decreased the amount of time spent in NREM slumber (−22.i%) and REM slumber (−3.ane%). Buprenorphine significantly delayed the onset of NREM sleep and REM slumber (fig. 3C).

Representative 24-h plots from one rat illustrating the buprenorphine-induced disruption of sleep architecture. Ordinate plots the temporal distribution of wakefulness (wake), nonrapid center movement sleep (NREM), and rapid middle movement sleep (REM) for 24 h after intravenous assistants of saline (A) and 1 mg/kg buprenorphine (B). The injections and recordings of sleep and wakefulness began at 08:00 (time 0 on ordinate) at the initiation of the light phase (white horizontal rectangle) of a 12:12 h low-cal/dark cycle. During the 12-h light stage (abcissa 0 to 12) frame A illustrates extended blocks of NREM sleep typically displayed by these nocturnal animals. In dissimilarity, frame B shows that during this same interval buprenorphine decreased NREM sleep and REM sleep.

Buprenorphine altered the temporal organisation of sleep and wakefulness and eszopiclone countered buprenorphine-induced slumber disruption. The left column summarizes the effect of buprenorphine relative to saline (control) on five dependent measures averaged for seven rats recorded during the light portion (rat sleep stage) of the light/dark cycle. The right column summarizes the temporal changes in sleep and wakefulness later co-administration of buprenorphine and eszopiclone (n = 4). Eszopiclone counteracted most of the sleep disruption caused by buprenorphine. Asterisks (*) betoken meaning differences compared to saline across states of wakefulness (Wake), nonrapid center movement sleep (NREM), and rapid eye movement sleep (REM).

At that place was a significant (P < 0.0001) drug main-outcome and land-by-drug interaction (p < 0.0001) for the number of sleep/wake episodes (fig. 3E). Buprenorphine decreased the number of episodes of wakefulness (−88.ii%), NREM slumber (−89.five%), and REM slumber (−xc.8%). Effigy 3G shows that buprenorphine significantly (P < 0.0001) contradistinct the elapsing of slumber/wake episodes. Average duration of wakefulness was significantly increased (529.half-dozen%) and the duration of sleep epochs was decreased for both NREM slumber (−30.8%) and REM sleep (−87.5%). Figure 3I shows that buprenorphine too significantly (P < 0.0001) decreased the number of transitions (−89.eight%) betwixt states.

Effigy 4 plots the percent state for each drug condition during the 12-h dark phase (rat subjective day) of the light/dark wheel that followed the 12-h light phase depicted by figure 3. Within the night stage, when rats are commonly awake and active, the fourth dimension spent awake was significantly (P = 0.012) decreased by buprenorphine. The buprenorphine condition within the dark stage revealed significantly (P = 0.0019) more NREM slumber and a nonsignificant decrease in REM sleep compared to the saline status.

The percent of time during the 12-h night stage that rats (n = 7) spent in states of wakefulness (Wake), nonrapid eye motility sleep (NREM), and rapid eye move slumber (REM). These recordings were obtained during hours 12 through 24 after administration of either saline (control) or buprenorphine. Asterisks (*) betoken significant differences compared to saline. These results illustrate that following the buprenorphine-induced inhibition of slumber during the lite phase (fig. 3A) there was a meaning rebound increase in NREM sleep and REM slumber during the nighttime phase, when these rats would normally be awake.

The effect of buprenorphine on states of sleep and wakefulness tin can also be visualized by comparison the light stage (fig. 3A) and dark phase (fig. 4) results. NREM sleep after buprenorphine increased significantly (P = 0.0003) from an average of v.5% in the lite phase (fig. 3A) to 27.4% in the dark stage (fig. 4). There was also a meaning (P = 0.003) rebound increase in REM sleep from an average of 0.33% afterwards buprenorphine during the light phase (fig. 3A) to nearly 4% after buprenorphine during the dark phase (fig. four).

Eszopiclone Decreased the Sleep Disruption Acquired by Buprenorphine

The 5 illustrations in the right column of figure 3 summarize the results of experiments designed to determine whether the sedative/hypnotic eszopiclone countered the buprenorphine-induced inhibition of sleep. Eszopiclone when coadministered with buprenorphine prevented the significant increase in wakefulness (fig. 3B) caused past buprenorphine lone (fig. 3A). Similarly, the significant buprenorphine-induced decrease in NREM sleep and REM sleep (fig. 3A) was prevented by coadministration of eszopiclone (fig. 3B). Eszopiclone blocked the pregnant increase in latency to slumber onset (figs. 3C vs. 3D). Eszopiclone partially reversed the buprenorphine-induced decrease in both the number of wakefulness and NREM sleep episodes (fig. 3E vs. 3F). The 530% increase in average elapsing of waking episodes acquired by buprenorphine (fig. 3G) was reduced to a 171% increase by coadministration of eszopiclone (fig. 3H). Eszopiclone blocked the significant subtract in number of state transitions caused by buprenorphine (fig. 3I vs. 3J).

Buprenorphine Increased Electroencephalogram Delta Ability during NREM Slumber

Figures 5A-C illustrate electroencephalogram ability recorded across states of sleep and wakefulness later on intravenous administration of buprenorphine to awake, freely moving rats. Buprenorphine did non alter electroencephalogram power during wakefulness or REM sleep (figs. 5A & C), just did increase electroencephalogram power in the delta frequency range during NREM sleep (fig. 5B). ANOVA revealed a meaning (P = 0.007) buprenorphine main-outcome on electroencephalogram frequency bands ranging from 0.v to 5.0 Hz in 0.5 Hz increments (fig. 5B). The fast Fourier transform analyses were conducted for electroencephalogram measures obtained during the 12-h light flow (i.e., rat'southward subjective night) that immediately followed buprenorphine administration. As figures 2 and ​ 3 show, buprenorphine depressed NREM sleep for 6 to 8 h. Measurement of the increase in electroencephalogram delta power was conducted for upward to 12-h after buprenorphine administration. A future report will exist needed to determine whether, and for how long beyond 12-h, electroencephalogram delta power is increased past buprenorphine.

Electroencephalographic power (ordinate) plotted equally a function of frequency (abscissa) averaged for 5 rats across states of sleep and wakefulness. During wakefulness (A) and rapid eye motility (REM) slumber (C) buprenorphine did not change electroencephalographic power. In dissimilarity, during NREM slumber that occurred after buprenorphine administration (B) there was a meaning increase in electroencephalogram delta power (black horizontal bar above 2.0 to 3.0 Hz).

Buprenorphine Decreased Adenosine Levels in PnO and SI

Histological analyses confirmed that all microdialysis sites were localized to the PnO or to the SI (fig. 6A). Figure 6B shows the results of i representative experiment. Adenosine levels in the SI are plotted as a office of time during dialysis with Ringer'due south (121-180 min afterwards probe placement) followed by dialysis delivery of buprenorphine (181-240 min after probe placement). Figures 6C and D confirm chromatographic identification of adenosine Figure 6C illustrates chromatograms produced by five known concentrations of adenosine. Figure 6D shows chromatograms reflecting encephalon adenosine (dialyzed Ringer's), a negative control (nondialyzed Ringer's), a positive control (encephalon adenosine sampled during dialysis delivery of the adenosine deaminase inhibitor EHNA), and an adenosine standard.

Microdialysis delivery of buprenorphine decreased adenosine levels in the basal forebrain and pontine reticular formation. Cresyl-violet stained coronal sections bear witness representative dialysis sites in (A) the pontine reticular formation, oral part (PnO) and in the substantia innominata (SI) region of the basal forebrain. Arrows indicate the location of each microdialysis membrane. B. Time form of a representative experiment showing adenosine levels in the SI before (Ringer's) and during dialysis delivery of buprenorphine. Each bar represents one sample (30 μl) acquired during fifteen min of dialysis. Frames C and D illustrate procedures used to confirm adenosine measurement. Frame C prove chromatograms produced by ultraviolet measurement during the detection of adenosine concentrations ranging from 0 to 200 nM. Each microdialysis experiment began past creating a 5-bespeak standard curve. The standard bend was used to convert ultraviolet absorbance values to concentration (nM) of brain adenosine for each microdialysis sample. D. Chromatograms resulting from iv different measurement conditions. The black trace illustrates the chromatogram produced when the instrument was injected with Ringer'southward that did non pass through the microdialysis probe (negative control). The light-green trace shows a chromatogram reflecting encephalon adenosine measured during encephalon microdialysis with Ringer's solution. The blue trace is a chromatogram produced by measurement of a 100 nM adenosine standard. The red trace represents a brain sample obtained during dialysis with Ringer's + ane mM erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor that increased adenosine (positive command). The central point is that all chromatograms showed the same elution time for adenosine. Thus, the magnitude of the standards (C) and the elution times (D) ostend the presence of adenosine in the encephalon samples.

Effigy 7A summarizes a last set of experiments that quantified adenosine levels in SI and PnO as a office of route of buprenorphine administration. Microdialysis delivery of buprenorphine significantly (P = 0.03) decreased adenosine levels in PnO (−14.viii%) and significantly (P = 0.0004) decreased adenosine levels in the SI region of the basal forebrain (−36.7%). Figure 7B plots adenosine levels in the SI before and after intravenous administration of buprenorphine to isoflurane-anesthetized rat. Buprenorphine significantly (P < 0.0001) decreased (−xx.iii%) adenosine levels in the SI.

Cardinal and systemic delivery of buprenorphine decreased encephalon adenosine levels. (A) Microdialysis commitment of buprenorphine to the pontine reticular formation, oral part (PnO) (n=five rats) or to the substantia innominata (SI) (due north=5 rats) decreased adenosine levels in the PnO or SI, respectively. (B) When administered systemically (n=5), buprenorphine also decreased adenosine levels in the SI. Asterisks (*) in A indicate a pregnant decrease in adenosine levels during microdialysis delivery of buprenorphine compared to Ringer's (control). Asterisk (*) in B indicates a significant subtract in adenosine levels in the substantia innominata (SI) acquired by intravenous delivery of buprenorphine. Thus, SI adenosine levels were decreased by microdialysis delivery of buprenorphine to the SI and by intravenous buprenorphine (B).

Discussion

Buprenorphine can exist efficacious in the treatment of opioid and heroin addiction,^45-47 and at that place is increasing interest in the apply of buprenorphine for pain management.^27,28 The analgesic effects of buprenorphine are mediated, in role, via agonist actions at the μ opioid receptor.⁴⁸ This is the first study presenting electrographic data that demonstrate significant sleep disturbance (fig. 3) acquired by an antinociceptive dose of buprenorphine (fig. ane). The present finding that an antinociceptive dose of buprenorphine disrupts sleep is discussed relative to the relationship betwixt sleep and nociception, the potential for developing counter-measures for opioid-induced sleep disruption, and the underlying mechanisms.

Buprenorphine Disrupted Sleep

Some data suggest that buprenorphine is superior to traditional opioids for the handling of hurting due to its reported analgesic and antihyperalgesic effects with fewer side effects (low incidence of respiratory depression and less constipation).²⁸ Buprenorphine shares some similar pharmacodynamic properties with traditional opioids, and patient-study data betoken benefits from buprenorphine therapy. Freye et al. ²⁷ found that self-report slumber quality rated as "proficient" or "very good" increased from 14% to 74% when patients were transitioned from high-dose oral morphine to transdermal buprenorphine. Transdermal buprenorphine has been compared to placebo for power to decrease pain and promote sleep, and patients randomized to receive buprenorphine report less pain and improved sleep.⁴⁹ Specifically, subjects who received buprenorphine reported less trouble falling comatose, decreased requirement for sleeping medication, and decreased awakening at night caused by hurting. Another report establish a nonsignificant trend of improved sleep favoring transdermal buprenorphine over extended release tramadol tablets for the treatment of osteoarthritis.⁵⁰ A known limitation of such studies is that self-assessment of slumber quality may non show faithful cyclopedia with objective, electrographic measures of sleep.⁵¹

At that place is a growing appreciation for the interrelationship between sleep and hurting.³⁹ Sleep deprivation in healthy normals lowers pain perception thresholds.⁵² The chronic effects of μ-opioid receptor agonists on sleep in pain patients are not completely understood.³⁹ Opioids crusade slumber disturbance^4,37,53 and the present results demonstrate that buprenorphine increases wakefulness and disrupts the temporal system of slumber (figs. two-​ 4). Sleep, like breathing, is an endogenously generated biological rhythm. Just as rhythmic switching from inspiration to expiration is essential for gas exchange, the ability of slumber to produce reports of rest and recovery requires a normal temporal organization. Buprenorphine caused a subtract in the number (fig. 3E) and an increment in the elapsing (fig. 3G) of wakefulness episodes. The decreased number of state transitions (fig. 3I) reflects the buprenorphine-induced disruption of slumber continuity. Figure 4 summarizes the percentage of fourth dimension spent in states of sleep and wakefulness during the 12-h night stage when rats are normally agile. These night phase recordings were continuous with the figure three information during the 12-h light phase. Thus, the figure 4 data show that for 12 to 24 h subsequently assistants of buprenorphine there was a rebound increase in sleep at a time when nocturnal rodents are commonly about agile. The potential clinical relevance of buprenorphine-induced disruption of sleep continuity derives from the fact that repeated sleep disruption negatively impacts neurocognitive function as severely every bit does total sleep impecuniousness.⁵⁴

Opioid-induced sleep disruption has the potential to negatively affect patient intendance because sleep deprivation is known to lower hurting threshold.^15,16,52 This report did non address the affect of hurting or the treatment of hurting on sleep disturbance. Some believe that medications from the agonist/antagonist class, such every bit buprenorphine, may be less associated with the adverse furnishings of traditional μ-agonists; all the same, the present information indicate that the sleep-disrupting furnishings of buprenorphine are similar to those of other opioids.^26,30,37,53 The present results encourage studies designed to objectively quantify the effects of buprenorphine on sleep in humans.

The U.S. Food and Drug Assistants canonical buprenorphine for the handling of opioid addiction. Suboxone (buprenorphine/naloxone sublingual tablet, Reckitt Benckiser Pharmaceuticals Inc., Richmond, VA), Subutex (buprenorphine sublingual tablet, Reckitt Benckiser Pharmaceuticals Inc.), and transdermal buprenorphine (not available in the U.s.) are increasingly used to care for pain. The present finding of buprenorphine-induced sleep disruption also is relevant to evidence indicating that sleep disturbance can lead to a higher potential for addiction relapse.^55-57

Electroencephalogram delta waves (0.five to 4 Hz) are 1 of three rhythmic waveforms characteristic of NREM sleep.⁵⁸ Delta waves provide an index of sleep intensity^59,60 and electroencephalogram power in the delta frequency increases during recovery sleep that follows sleep deprivation.^61,62 The finding that buprenorphine caused an increment in electroencephalogram delta power during NREM sleep (fig. 5B) is consequent with subjective reports that buprenorphine improves sleep^7,27 and with evidence that opioids increase delta ability in humans.⁶³ A search of the Medline database from 2001 to 2022 revealed no polysomnographic data characterizing the effect of buprenorphine on human sleep.

Eszopiclone was an Effective Counter-Measure out that Prevented Sleep Disruption by Buprenorphine

Buprenorphine significantly disrupted the temporal arrangement of sleep (fig. 3, left column). Nearly aspects of sleep disturbance were prevented by cotreatment with the nonbenzodiazepine hypnotic eszopiclone (fig. 3, right column). Sedative/hypnotics are a standard treatment for insomnia, simply their furnishings in the treatment of pain- and opioid-induced sleep disturbance are still poorly understood. The utilise of sedative/hypnotics may not be a mainstay of addiction therapy, but the nowadays results (fig. iii, right cavalcade) indicate their potential to prevent buprenorphine-induced sleep disturbance. Eszopiclone as an adjunctive agent coadministered with the antidepressant fluoxetine resulted in a faster onset and greater magnitude of the desired antidepressant result.⁶⁴ An heady expanse open to future written report is to determine whether hypnotics can be used as an effective counter-measure for opioid-induced sleep disruption.

Limitations, Potential Clinical Relevance, and Conclusions

The present report was designed to quantify the furnishings of burprenorphine on sleep and adenosine levels. The results are limited to documenting that burprenorphine, similar to morphine and fentanyl, disrupted sleep and decreased adenosine levels in slumber-related brain regions. The results do not imply that the furnishings of burprenorphine were mediated but by μ opioid receptors. Burprenorphine may accept disrupted sleep and decreased adenosine, in part, by acting as a κ antagonist.

The analgesic²¹ and sleep-promoting⁶⁵ furnishings of adenosine are well known and suggest adenosine equally a molecule of potential clinical relevance for anesthesiology. There is adept agreement between preclinical and clinical data that opioids disrupt sleep³⁷, a finding confirmed past administering opioids to pain free humans.⁵³ The restorative effects of slumber require normal temporal arrangement of sleep. Unfortunately, morphine and fentanyl wearisome the electroencephalogram during wakefulness, increase lighter phase 2 NREM slumber, subtract stage 3 and iv NREM sleep, and decrease or eliminate REM sleep. Disruption of normal sleep impairs allowed function, exacerbates hurting³⁹, and, peculiarly in older patients, can be a precipitating factor for postoperative delirium.⁶⁶

In determination, the results show for the commencement time that buprenorphine disrupted normal sleep architecture and decreased adenosine levels in sleep regulating regions of the basal forebrain and pontine reticular formation (figs. 6 and ​ 7). The buprenorphine results are consequent with the discovery that fentanyl and morphine decrease adenosine levels in basal forebrain and pontine reticular formation.²⁶ The present study extends the earlier findings by providing mechanistic insights into a encephalon site and a molecule past which buprenorphine disrupts slumber. Novel insights were obtained by holding site of adenosine measurement abiding within the substantia innominata region of the basal forebrain while varying route of buprenorphine delivery. The results prove that both microdialysis delivery to the substantia innominata and systemic administration of buprenorphine acquired a significant decrease in adenosine in the substantia innominata. As demonstrated elsewhere^30,44 when effects caused by drug delivery to a specific brain region replicate the furnishings acquired past systemic delivery, information technology is logical to infer that the actions of systemically administered drugs are mediated, in part, past that brain region and by the neurotransmitter molecule being measured. Thus, the neurochemical results, combined with the sleep disrupting effect of buprenorphine, back up the interpretation that one mechanism through which buprenorphine disrupts sleep is by decreasing adenosine levels in the substantia innominata region of the basal forebrain.

Acknowledgments

For expert aid the authors thank Sha Jiang, B.South.m Research Associate, Mary A. Norat, B.S., Senior Research Associate, and Sarah 50. Watson, B.S., Senior Research Acquaintance, from the Department of Anesthesiology, and Kathy Welch, M.A., M.P.H., Statistician Staff Specialist, Eye for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan.

Support: Supported by grants HL40881 (RL), HL65272 (RL), and MH45361 (HAB) from the National Institutes of Wellness, UL1RR024986 (CMB) from the National Center for Research Resources, Bethesda, Maryland, and by the Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan

Footnotes

Attribution: Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan

Meetings at which work was presented: Abstracts presented at the American Society of Pain Meeting, Baltimore, Maryland, May 6, 2022.

^*http://www.nap.edu/catalog.php?record_id=12910. Terminal accessed May 31, 2022.

References

1. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic noncancer pain: A meta-assay of effectiveness and side effects. CMAJ. 2006;174:1589–94. [PMC gratuitous commodity] [PubMed] [Google Scholar]

2. Noble M. Long-term opioid therapy for chronic noncancer hurting: A systematic review and meta-analysis of efficacy and safety. J Hurting Symptom Manag. 2008;35:214–28. [PubMed] [Google Scholar]

3. Cronin A, Keifer JC, Baghdoyan HA, Lydic R. Opioid inhibition of rapid eye motility sleep by a specific mu receptor agonist. Br J Anaesth. 1995;74:188–92. [PubMed] [Google Scholar]

4. Dimsdale JE, Norman D, DeJardin D, Wallace MS. The upshot of opioids on sleep architecture. J Clin Sleep Med. 2007;iii:33–6. [PubMed] [Google Scholar]

five. Keifer JC, Baghdoyan HA, Lydic R. Sleep disruption and increased apneas afterward pontine microinjection of morphine. Anesthesiology. 1992;77:973–82. [PubMed] [Google Scholar]

half-dozen. Shaw IR, Lavigne G, Mayer P, Choiniére K. Acute intravenous administration of morphine perturbs sleep compages in good for you pain-free young adults: A preliminary written report. Sleep. 2005;28:677–82. [PubMed] [Google Scholar]

7. Sittl R. Analgesic efficacy and tolerability of transdermal buprenorphine in patients wtih inadequately controlled chronic pain related to cancer and other disorders: A multicenter, randomized, double-blind, placebo-controlled trial. Clin Ther. 2003;25:150–68. [PubMed] [Google Scholar]

8. Baghdoyan HA. Hyperalgesia induced past REM sleep loss: A phenomenon in search of a mechanism. Slumber. 2006;29:137–nine. [PubMed] [Google Scholar]

nine. Haack Yard, Mullington JM. Sustained sleep restriction reduces emotional and physical well-being. Pain. 2005;119:56–64. [PubMed] [Google Scholar]

10. Kundermann B, Krieg JC, Schreiber W, Lautenbacher S. The effect of sleep deprivation on pain. Hurting Res Manag. 2004;nine:25–32. [PubMed] [Google Scholar]

eleven. Menefee LA, Cohen MJ, Anderson WR, Doghramji M, Frank ED, Lee H. Sleep disturbance and nonmalignant chronic pain: A comprehensive review of the literature. Hurting Med. 2000;1:156–72. [PubMed] [Google Scholar]

12. Naughton F, Ashworth P, Skevington SM. Does sleep quality predict pain-related disability in chronic hurting patients? The mediating roles of depression and hurting severity. Pain. 2007;127:243–52. [PubMed] [Google Scholar]

13. Onen Southward. Effects of rapid eye motility (REM) sleep deprivation on hurting sensitivity in the rat. Brain Res. 2001;900:261–vii. [PubMed] [Google Scholar]

xiv. Roehrs T. Sleep and hurting: Interaction of 2 vital functions. Semin Neurol. 2005;25:106–16. [PubMed] [Google Scholar]

xv. Roehrs T, Hyde One thousand, Blaisdell B, Greenwald M, Roth T. Slumber loss and REM sleep loss are hyperalgesic. Sleep. 2006;29:145–51. [PubMed] [Google Scholar]

sixteen. Smith MT, Edwards RR, McCann UD, Haythornthwaite JA. The effects of sleep deprivation on pain inhibition and spontaneous hurting in women. Slumber. 2007;30:494–505. [PubMed] [Google Scholar]

17. Rogers NL, Szuba MP, Staab JP, Evans DL, Dinges DF. Neuroimmunologic aspects of sleep and sleep loss. Semin Clin Neuropsychiatry. 2001;vi:295–307. [PubMed] [Google Scholar]

18. Clemons M, Regnard C, Appleton T. Alacrity, knowledge and morphine in patients with avant-garde cancer. Cancer Treat Rev. 1996;22:451–68. [PubMed] [Google Scholar]

19. Sjogren P. Psychomotor and cognitive functioning in cancer patients. Acta Anaesthesiol Scand. 1997;41:159–61. [PubMed] [Google Scholar]

20. Porkka-Heiskanen T, Strecker RE, Thakkar M, Bjorkum AA, Greene RW, McCarley RW. Adenosine: A mediator of the slumber-inducing furnishings of prolonged wakefulness. Science. 1997;276:1265–8. [PMC complimentary article] [PubMed] [Google Scholar]

21. Gan TJ, Habib AS. Adenosine equally a non-opioid analgesic in the perioperative setting. Anesth Analg. 2007;105:487–94. [PubMed] [Google Scholar]

22. Coleman CG, Baghdoyan HA, Lydic R. Dialysis delivery of an adenosine A2A agonist into the pontine reticular formation of C57BL/6J mouse increases pontine acetylcholine release and sleep. J Neurochem. 2006;96:1750–9. [PubMed] [Google Scholar]

23. Marks GA, Shaffery JP, Speciale SG, Birabil CG. Enhancement of rapid eye movement slumber in the rat by actions at A1 and A2a adenosine receptor subtypes with a differential sensitivity to atropine. Neuroscience. 2003;116:913–20. [PubMed] [Google Scholar]

24. Van Dort CJ. Adenosine A1 and A2A receptors in mouse prefrontal cortex modulate acetylcholine release and behavioral arousal. J Neurosci. 2009;29:871–81. [PMC free article] [PubMed] [Google Scholar]

25. Kalinchuk AV, Urrila AS, Alanko L, Heiskanen S, Wigren HK, Suomela M, Stenberg D, Porkka-Heiskanen T. Local free energy depletion in the basal forebrain increases sleep. Eur J Neurosci. 2003;17:863–9. [PubMed] [Google Scholar]

26. Nelson AM, Battersby As, Baghdoyan HA, Lydic R. Opioid-induced decreases in rat encephalon adenosine levels are reversed by inhibiting adenosine deaminase. Anesthesiology. 2009;111:1327–33. [PMC free article] [PubMed] [Google Scholar]

27. Freye East, Anderson-Hillemacher A, Ritzdorf I, Levy JV. Opioid rotation from high-dose morphine to transdermal buprenorphine (Transtec) in chronic pain patients. Pain Pract. 2007;7:123–9. [PubMed] [Google Scholar]

28. Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain. 2009;13:219–30. [PubMed] [Google Scholar]

29. Paxinos Grand, Watson C. The Rat Encephalon in Stereotaxic Coordinates. 6th. London: Elsevier; 2007. [Google Scholar]

xxx. Osman NI, Baghdoyan HA, Lydic R. Morphine inhibits acetylcholine release in rat prefrontal cortex when delivered systemically or by microdialysis to basal forebrain. Anesthesiology. 2005;103:779–87. [PubMed] [Google Scholar]

31. Tanase D, Martin WA, Baghdoyan HA, Lydic R. One thousand protein activation in rat ponto-mesencephalic nuclei is enhanced by combined treatment with a mu opioid and an adenosine A₁ receptor agonist. Sleep. 2001;24:52–62. [PubMed] [Google Scholar]

32. Watson CJ, Lydic R, Baghdoyan HA. Sleep and GABA levels in the oral role of rat pontine reticular formation are decreased by local and systemic administration of morphine. Neuroscience. 2007;144:375–86. [PMC gratis article] [PubMed] [Google Scholar]

33. Gades NM, Danneman PJ, Wixson SK, Tolley EA. The magnitude and duration of the analgesic issue of morphine, butorphanol, and buprenorphine in rats and mice. Contemp Top Lab Anim Sci. 2000;39:8–13. [PubMed] [Google Scholar]

34. Wang W, Baghdoyan HA, Lydic R. Leptin replacement restores supraspinal cholinergic antinociception in leptin-scarce obese mice. J Hurting. 2009;ten:836–43. [PMC free article] [PubMed] [Google Scholar]

35. Watson SL, Watson CJ, Baghdoyan HA, Lydic R. Thermal nociception is decreased by hypocretin-ane and an adenosine A(ane) receptor agonist microinjected into the pontine reticular formation of Sprague Dawley rat. J Pain. 2010;11:535–44. [PMC gratuitous article] [PubMed] [Google Scholar]

36. Dirig DM, Salani A, Rathbun ML, Ozaki GT, Yaksh TL. Characterization of variables defining hindpaw withdrawal latency evoked by radiant thermal stimuli. J Neurosci Meth. 1997;76:183–91. [PubMed] [Google Scholar]

37. Lydic R, Baghdoyan HA. In: Neurochemical mechanisms mediating opioid-induced REM sleep disruption, Sleep and Pain. Lavigne G, Sessle BJ, Choinière One thousand, Soja PJ, editors. Seattle, WA: International Association for the Study of Pain (IASP) Press; 2007. pp. 99–122. [Google Scholar]

38. Krystal Advertisement, Walsh JK, Laska E, Caron J, Amato DA, Wessel TC, Roth T. Sustained efficacy of eszopiclone over half-dozen months of nightly treatment: Results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep. 2003;26:793–ix. [PubMed] [Google Scholar]

39. Lavigne G, Sessle BJ, Choiniére M, Soja PJ. Slumber and Hurting. Seattle, WA: International Association for the Study of Pain (IASP) Press; 2007. [Google Scholar]

40. Lavigne GJ. Result of slumber restriction on pain perception: Towards greater attention! Hurting. 2010;148:6–7. [PubMed] [Google Scholar]

41. Watson CJ, Soto-Calderon H, Lydic R, Baghdoyan HA. Pontine reticular germination (PnO) administration of hypocretin-one increases PnO GABA levels and wakefulness. Sleep. 2008;31:453–64. [PMC costless article] [PubMed] [Google Scholar]

42. Zhu Z, Bowman HR, Baghdoyan HA, Lydic R. Morphine increases acetylcholine release in the trigeminal nuclear complex. Slumber. 2008;31:1629–37. [PMC free commodity] [PubMed] [Google Scholar]

43. Vanini G, Watson CJ, Lydic R, Baghdoyan HA. γ-aminobutyric acrid-mediated neurotransmission in the pontine reticular formation modulates hypnosis, immobility, and breathing during isoflurane anesthesia. Anesthesiology. 2008;109:978–88. [PMC gratuitous article] [PubMed] [Google Scholar]

44. Hambrecht-Wiedbusch VS, Gauthier EA, Baghdoyan HA, Lydic R. Benzodiazepine receptor agonists cause drug-specific and state-specific alterations in EEG power and acetylcholine release in rat pontine reticular formation. Sleep. 2010;33:909–18. [PMC free article] [PubMed] [Google Scholar]

45. Fudala PJ, Jaffe JH, Dax EM, Johnson RE. Use of buprenorphine in the treatment of opioid addiction. Two. Physiologic and behavioral furnishings of daily and alternate-day administration and abrupt withdrawal. Clin Pharmacol Ther. 1990;47:525–34. [PubMed] [Google Scholar]

46. Orman JS, Keating GM. Buprenorphine/naloxone: A review of its utilise in the treatment of opioid dependence. Drugs. 2009;69:577–607. [PubMed] [Google Scholar]

47. Ponizovsky AM, Margolis A, Heled L, Rosca P, Radomislensky I, Grinshpoon A. Improved quality of life, clinical, and psychosocial outcomes amidst heroin-dependent patients on convalescent buprenorphine maintenance. Subst Use Misuse. 2010;45:288–313. [PubMed] [Google Scholar]

48. Yamamoto T, Shono K, Tanabe S. Buprenorphine activates mu and opioid receptor like-i receptors simultaneously, but the analgesic result is mainly mediated past mu receptor activation in the rat formalin test. J Pharmacol Exp Ther. 2006;318:206–13. [PubMed] [Google Scholar]

49. Gordon A, Callaghan D, Spink D, Coloutier C, Dzongowski P, O'Mahony W, Sinclair D, Rashiq S, Buckley N, Cohen Thousand, Kim JK, Boulanger A, Piraino PS, Eisenhoffer J, Harsanyl Z, Darke Air conditioning, Michalko KJ. Buprenorphine transdermal organisation in adults with chronic depression back pain: A randomized, double-blind, placebo-controlled crossover written report, followed by an open up-label extension phase. Clin Ther. 2010;32:844–60. [PubMed] [Google Scholar]

50. Karlsson M, Berrgren Ac. Efficacy and rubber of low-dose transdermal buprenorphine patches (5, 10, and 20 pg/h) versus prolonged-release tramadol tablets (75, 100, 150, and 200 mg) in patients with chronic osteoarthritis hurting: A 12-week, randomized, open-label, controlled, parallel-group noninferiority study. Clin Ther. 2009;31:503–13. [PubMed] [Google Scholar]

51. Baker FC, Maloney Southward, Driver HS. A comparison of subjective estimates of sleep with objective polysomographic data in good for you men and women. J Psychsom Res. 1999;47:335–41. [PubMed] [Google Scholar]

52. Chhangani BS, Roehrs TA, Harris EJ, Hyde Thou, Drake C, Hudgel DW, Roth T. Pain sensitivity in sleepy hurting-free normals. Sleep. 2009;32:1011–7. [PMC gratis commodity] [PubMed] [Google Scholar]

53. Bonafide CP, Aucutt-Walter Northward, DiVittore N, Rex T, Bixler EO, Cronin AJ. Remifentanil inhibits rapid eye motion sleep simply non the nocturnal melatonin surge in humans. Anesthesiology. 2008;108:627–33. [PubMed] [Google Scholar]

54. Van Dongen HPA, Maislin Thou, Mullington JM, Dinges DF. The cumulative toll of additional wakefulness: Dose-response effects on neurobehavioral office and sleep physiology from chronic sleep restriction and full slumber deprivation. Sleep. 2003;26:117–26. [PubMed] [Google Scholar]

55. Arnedt JT, Conroy DA, Brower KJ. Handling options for slumber disturbances during booze recovery. J Addict Dis. 2007;26:41–54. [PMC free commodity] [PubMed] [Google Scholar]

56. Brower KJ, Perron Exist. Sleep disturbance as a universal risk factor for relapse in addictions to psychoactive substances. Med Hypotheses. 2010;74:928–33. [PMC free article] [PubMed] [Google Scholar]

57. Mahfoud Y, Talih F, Streem D, Budur K. Sleep disorders in substance abusers: How common are they? Psychiatry. 2009;six:38–42. [PMC free article] [PubMed] [Google Scholar]

58. Steriade M, McCarley RW. Brain Control of Wakefulness and Sleep. 2nd. New York: Plenum Press; 2005. [Google Scholar]

59. Friedman L, Bergmann BM, Rechtschaffen A. Effects of sleep deprivation on sleepiness, sleep intensity, and subsequent slumber in the rat. Slumber. 1979;ane:369–91. [PubMed] [Google Scholar]

60. Brunner DP, Dijk DJ, Borbely AA. Repeated partial sleep impecuniousness progressively changes the EEG during sleep and wakefulness. Slumber. 1993;16:100–thirteen. [PubMed] [Google Scholar]

61. Tobler I, Borbely AA. Sleep EEG in the rat as a function of prior activeness. Electroencephalogr Clin Neurophysiol. 1986;64:74–six. [PubMed] [Google Scholar]

62. Feinberg I, Floyd TC, March JD. Effects of sleep loss on delta (0.three-3 Hz) EEG and middle movement density: New observations and hypotheses. Electroencephalogr Clin Neurophysiol. 1987;67:217–21. [PubMed] [Google Scholar]

63. Greenwald MK, Roehrs TA. Mu opioid self-administration vs passive assistants in heroin abusers produces differential EEG activation. Neuropsychopharm. 2005;thirty:212–21. [PubMed] [Google Scholar]

64. Fava Yard, McCall WV, Krystal A, Wessel T, Rubens R, Caron J, Amato D, Roth T. Eszopiclone co-administered with fluoxetine in patients with insomnia circumstantial with major depressive disorder. Biol Psychiatry. 2006;59:1052–60. [PubMed] [Google Scholar]

65. Porkka-Heiskanen T, Alanko L, Kalinchuk A, Stenberg D. Adenosine and sleep. Sleep Med Rev. 2002;six:321–32. [PubMed] [Google Scholar]

66. Rudolph JL, Marcantonio ER. Postoperative delirium: Astute changes with long-term implications. Anesth Analg. 2011;112:1201–11. [PMC complimentary commodity] [PubMed] [Google Scholar]

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197808/

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