Concomitant use of pre-emptive analgesia with local and general anesthesia in rat uterine pain surgical model.

Preemptive analgesia is used for postoperative pain management, providing pain relief with few adverse effects. In this study, the effect of a preemptive regime on rat behavior and c-fos expression in the spinal cord of the uterine surgical pain model was evaluated. It was a lab-based experimental study in which 60 female Sprague-Dawley rats; eight to 10 weeks old, weighing 150-300 gm were used. The rats were divided into two main groups: (i) superficial pain group (SG) (with skin incision only), (ii) deep pain group (with skin and uterine incisions). Each group was further divided into three subgroups based on the type of preemptive analgesia administered i.e., "tramadol, buprenorphine, and saline subgroups." Pain behavior was evaluated using the "Rat Grimace Scale" (RGS) at 2, 4, 6, 9 and 24 h post-surgery. Additionally, c-fos immunohistochemistry was performed on sections from spinal dorsal horn (T12-L2), and its expression was evaluated using optical density and mean cell count 2 hours postoperatively. Significant reduction in the RGS was noted in both the superficial and deep pain groups within the tramadol and buprenorphine subgroups when compared to the saline subgroup (p ≤ .05). There was a significant decrease in c-fos expression both in terms of number of c-fos positive cells and the optical density across the superficial laminae and lamina X of the spinal dorsal horn in both SD and DG (p ≤ .05). In contrast, the saline group exhibited c-fos expression primarily in laminae I-II and III-IV for both superficial and deep pain groups and lamina X in the deep pain group only (p ≤ .05). Hence, a preemptive regimen results in significant suppression of both superficial and deep components of pain transmission. These findings provide compelling evidence of the analgesic efficacy of preemptive treatment in alleviating pain response associated with uterine surgery.

Effect of transversus abdominis plane block with or without buprenorphine after inguinal hernia surgery on postoperative pain.

INTRODUCTION: Transversus abdominis plane (TAP) has been mentioned as having bene-ficial effects on chronic pain after hernioplasty. This study assessed the effects of TAP block on acute and persistent postoperative pain after inguinal hernia surgery, with or without buprenorphine. MATERIAL AND METHODS: 64 patients were allocated to group R ( n = 32) and received 20 mL of 0.25% ropivacaine for TAP block; group RB ( n = 32) received 20 mL of 0.25% ropivacaine containing 300 µg of buprenorphine for TAP block. The primary outcome was the analgesic and antihyperalgesic effect of buprenorphine. The duration of analgesia, analgesic consumption, postoperative pain scores at rest and sitting up to 48 hours, and the effect on wound hyperalgesia were evaluated. Secondary outcomes included the incidence of side effects and complications. RESULTS: The median (IQR) duration of analgesia in group R was 386.5 (37.25) minutes vs. 868 (41.3) minutes in the RB group. Median pain scores on sitting were found to be significantly better in group RB than in group R at 6, 12, and 24 hours ( P < 0.001). The wound hyperalgesia index showed a significant difference between groups ( P < 0.001). The incidence of persistent postoperative pain was 6.25% in the R group, as compared to 0% in the RB group. Otherwise, the patients did not have any further complications associated with the block. CONCLUSIONS: The results demonstrated that TAP block with buprenorphine reduced acute postoperative pain severity, but we did not find a difference between groups in persistent pain.

Efficacy and Safety of Buprenorphine in a Single-Shot Peripheral Nerve Block: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The purpose of this study was to evaluate the safety and efficacy of buprenorphine compared with placebo in prolonging the duration of analgesia in single-injection peripheral nerve block. The systematic review and meta-analysis were conducted following the PRISMA statement and Review Manager was used for meta-analysis. Outcomes were calculated using the mean difference (MD) with 95% confidence interval (CI) for continuous data. For dichotomous outcomes, effect sizes were estimated by calculating pooled risk ratio (RR) with 95% CI. Statistical heterogeneity was estimated by the I2 statistic. Compared with placebo, buprenorphine prolonged the duration of analgesia by an average of 8 hours (MD, 8.01; 95% CI, 6.79 to 9.24; P < .00001). The cumulative pain scores within 24 hours (MD, -0.8; 95% CI, -1.21 to -0.40; P < .0001) and the 24-hour opioid consumption (MD, -5.56; 95% CI, -10.60 to -0.52; P = .03) after surgery was lower with buprenorphine group. Conversely, buprenorphine increased the incidence of postoperative nausea and vomiting (PONV) (RR, 1.67; 95% CI, 1.16 to 2.39; P = .006). Buprenorphine is effective in prolonging analgesia, decreasing pain scores and opioid consumption, however, it increases the risk of PONV.

Buprenorphine has a concentration-dependent cytotoxic effect on equine chondrocytes in vitro.

OBJECTIVE: To investigate the cytotoxic effects of 2 different concentrations of buprenorphine and compare them with bupivacaine and morphine on healthy equine chondrocytes in vitro. SAMPLE: Primary cultured equine articular chondrocytes from 3 healthy adult horses. PROCEDURES: Chondrocytes were exposed for 0 and 2 hours to the following treatments: media (CON; negative control); bupivacaine at 2.2 mg/mL (BUPI; positive control); morphine at 2.85 mg/mL (MOR); buprenorphine at 0.12 mg/mL (HBUPRE); or buprenorphine at 0.05 mg/mL (LBUPRE). Chondrocyte viability was assessed using live/dead staining, water-soluble tetrazolium salt-8 (WST-8) cytotoxic assay, LDH assay, and flow cytometry. All continuous variables were evaluated with a mixed ANOVA with treatment, time, and their interactions as the fixed effects and each horse as the random effect. RESULTS: Buprenorphine showed a concentration-dependent chondrotoxic effect. The viability of chondrocytes was significantly decreased with exposure to HBUPRE and BUPI compared to CON, MOR, and LBUPRE. CLINICAL RELEVANCE: Negligible chondrotoxic effects were observed in healthy cultured equine chondrocytes exposed to 0.05 mg/mL of buprenorphine, whereas higher concentrations (0.12 mg/mL) showed a marked cytotoxic effect. Based on these results, low concentrations of buprenorphine appear to be safe for intra-articular administration. Further evaluation of this dose in vivo is needed before recommending its clinical use.

Investigation of the Effects of Opioids on Microglial Nitrite and Nitric Oxide Synthase (iNOS) Production and Phagocytosis during Inflammation.

AIM: This study aimed to investigate how opioids affect phagocytosis and microglial nitrite and nitric oxide synthase (iNOS) production during inflammation. BACKGROUND: Opioids are a group of chemicals that are naturally found in the opium poppy plant and exert a variety of effects on the brain, including pain alleviation in some cases. They are commonly used in surgery and perioperative analgesia. However, research on the impact of opioids on microglial inflammatory factor production and phagocytosis is limited. OBJECTIVES: This study was designed to investigate the effects of opioids on inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) generation. Moreover, the influence of opioids on the engulfment of C8-B4 microglial cells after stimulation with LPS was also examined. METHODS: C8-B4 mouse microglial cells were exposed to various concentrations of opioids after stimulation with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Nitrite production was assayed. The iNOS and Cox-2 were determined by Western blotting, and fluorescent immunostaining was performed to assess the percentage of microglia that engulfed fluorescent microspheres in total microglia cultivating with opioids after being activated by LPS. RESULTS: After LPS and IFN-γ stimulation, microglia produced lower amounts of nitric oxide (NO) production with buprenorphine, salvinorin A, and naloxone (P<0.05). When combined with naloxone, no significant differences were found than buprenorphine. It was observed that buprenorphine and salvinorin A could suppress iNOS expression activated by LPS and IFN-γ. Phagocytosis was greatly increased after LPS stimulation, and a significant increase was observed after adding salvinorin A. CONCLUSION: Buprenorphine and salvinorin A were found to reduce NO production and iNOS induction in microglial cells activated by LPS and IFN-γ. Salvinorin A promoted the phagocytosis of microglia cells treated by LPS.

Buprenorphine reverses neurocognitive impairment in EcoHIV infected mice: A potential therapy for HIV-NCI.

Thirty-eight million people worldwide are living with HIV, PWH, a major public health problem. Antiretroviral therapy (ART) revolutionized HIV treatment and significantly increased the lifespan of PWH. However, approximately 15-50% of PWH develop HIV associated neurocognitive disorders (HIV-NCI), a spectrum of cognitive deficits, that negatively impact quality of life. Many PWH also have opioid use disorder (OUD), and studies in animal models of HIV infection as well as in PWH suggest that OUD can contribute to HIV-NCI. The synthetic opioid agonist, buprenorphine, treats OUD but its effects on HIV-NCI are unclear. We reported that human mature inflammatory monocytes express the opioid receptors MOR and KOR, and that buprenorphine reduces important steps in monocyte transmigration. Monocytes also serve as HIV reservoirs despite effective ART, enter the brain, and contribute to HIV brain disease. Using EcoHIV infected mice, an established model of HIV infection and HIV-NCI, we previously showed that pretreatment of mice prior to EcoHIV infection reduces mouse monocyte entry into the brain and prevents NCI. Here we show that buprenorphine treatment of EcoHIV infected mice with already established chronic NCI completely reverses the disease. Disease reversal was associated with a significant reduction in brain inflammatory monocytes and reversal of dendritic injury in the cortex and hippocampus. These results suggest that HIV-NCI persistence may require a continuing influx of inflammatory monocytes into the brain. Thus, we recommend buprenorphine as a potential therapy for mitigation of HIV brain disease in PWH with or without OUD.

Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation.

Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.

Demystifying Buprenorphine with Current Evidence-Based Practice in Acute and Chronic Pain Management.

Buprenorphine has been widely used in opioid medication assisted treatment (MAT) in the past decade. However, due to misinterpretation of its intrinsic mu opioid receptor activity extrapolated from preclinical and animal data, buprenorphine's clinical application in pain management has been greatly limited. Buprenorphine acts as a full mu agonist with fewer side effects compared to traditional opioids and can be effectively used in the treatment of acute and chronic pain. A strong body of evidence demonstrates that buprenorphine is an effective analgesic agent in both adult and pediatric surgical patients. In addition, buprenorphine has been successfully used in treating chronic pain, particularly in cancer pain and neuropathic pain. In this Journal course, buprenorphine's receptor pharmacology and pharmacokinetics are reviewed. Specifically, misinterpretation of its intrinsic mu receptor activity, and both analgesic ceiling effect and efficacy are clarified. Differences between suboxone and buprenorphine, and specific applications are explained. Pain management options and guidelines for surgical patients on buprenorphine are discussed, as well.

Comparative Study of Efficacy of Buprenorphine and Fentanyl on Attenuation of Hemodynamic Changes to Laryngoscopy and Intubation: A Prospective, Randomized Double-Blind Study.

BACKGROUND: Hemodynamic changes are the most common predicted response after laryngoscopy and intubation during general anesthesia. We compared the efficacy of buprenorphine with fentanyl to attenuate this stress response. METHODS: One hundred and thirty patients of either sex between the age group of 18-70 years, admitted for the routine surgical procedure under general anesthesia were enrolled in this double blind, randomized, clinical study. Patients were randomly assigned into two equal groups (60 patients in each group): group F received fentanyl 2 µg/kg, and group B received buprenorphine 2.5 µg/kg; both via intravenous route. Each group received a total volume of 10 mL by adding normal saline to the total drug volume, given over 60 seconds, 5 minutes before intubation. Thereafter patients were induced using routine balanced anesthesia technique, and the hemodynamic parameters were observed at baseline (0 minute), 1, 3, and 5 minutes after the administration of the study drug and again at 1, 3, 5, 7, and 10 minutes after intubation. Continuous variables were presented as mean with an 80% confidence interval, and a t-test was applied for comparing the difference of means between two groups after we checked the normality condition. Chi-square test was applied to test the independence of attributes of categorical variables. Repeated measures two-way analysis of variance was performed to compare the outcome variables between the two groups. RESULTS: In both groups, mean arterial blood pressure (MAP) and heart rate (HR) were statistically insignificant up to 5 minutes after study drug, thereafter mean HR and MAP at 1, 3, 5, 7, and 10 minutes after intubation, were statistically significant between the two groups, and P value was less than 0.05. CONCLUSIONS: The dose of 2.5 µg/kg buprenorphine is an effective alternative to fentanyl 2 µg/kg for attenuating the hemodynamic response accompanying laryngoscopy and tracheal intubation without causing any hemodynamic adverse effect.

Microinduction to Buprenorphine from Methadone for Chronic Pain: Outpatient Protocol with Case Examples.

The negative sequelae of full mu agonist chronic opioid analgesic therapy (COAT) are numerous and well documented. One safer alternative to COAT use in chronic, non-cancer pain (CNCP) is a transition to buprenorphine. However, transitioning patients from methadone COAT regimens can be challenging due to the pharmacodynamics of buprenorphine, as well as to the limited commercial formulations of buprenorphine available, and their restrictive instructions for use. Presented here are clinical cases transitioned to buprenorphine from methadone via a novel microinduction protocol during enrollment in an outpatient, group, integrative, multidisciplinary program. The protocol was successful to promote satisfactory and sustained COAT cessation for patients with CNCP and is arguably safer than current conventional practices.

Research progress on the potential novel analgesic BU08028.

Pain is a common symptom accompanying several clinical conditions and causes serious distress to patients. Addressing pain management is an important aspect of disease treatment, including cancer therapy. Opioid analgesics used to manage pain in human and veterinary medicine have been associated with substance dependence and other adverse effects, thereby limiting their application. Thus, the development of opioid analgesics with good safety profiles with minimal adverse effects and no addictive effects, is presently the focus of pain research. As a new potential analgesic, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028) has fewer adverse effects than other analgesics and is expected to be a safer alternative. In this review, we discuss the development of the opioid analog BU08028 and summarize its analgesic effects and biological characteristics, including efficiency, safety, and tolerance. Furthermore, we elaborate on studies showing the bifunctional effect of BU08028, which targets both mu opioid peptide and nociceptin-orphanin FQ peptide receptors, as well as the unique advantages of using BU08028 over single-target opioid agonists. Previous studies have suggested that BU08028 can not only weaken the reward and abuse effects of opioids and other drugs, but also enhance the anti-nociceptive effect of the mu opioid peptide receptors, making it a potent analgesic. Besides, we describe studies suggesting that BU08028 inhibits the effects of alcohol, making it a candidate drug for the management of alcohol addiction. Our review suggests that BU08028 is a potential novel medicine for managing pain and addiction.

Sustained release buprenorphine effectively attenuates postoperative hypersensitivity in an incisional pain model in neonatal rats (Rattus norvegicus).

Despite the need for safe and effective postoperative analgesia in neonates, research regarding pain management in neonatal rodents is relatively limited. Here, we investigate whether sustained release buprenorphine (Bup SR) effectively attenuates thermal hypersensitivity in a neonatal rat model of incisional pain. Male and female postnatal day 3 Sprague Dawley rat pups (n = 34) were randomly assigned to one of four treatment groups: 1) saline (control), 0.1 mL, once subcutaneously (SC); 2) buprenorphine HCl (Bup HCl), 0.05 mg/kg, once SC; 3) low dose Bup SR (low-SR), 0.5 mg/kg, once SC; 4) high dose Bup SR (high-SR), 1 mg/kg, once SC. Pups were anesthetized with sevoflurane and a 0.5-cm long skin incision was made over the left lateral thigh. The underlying muscle was dissected and closed using surgical glue. Thermal hypersensitivity testing was performed at 24 h prior to surgery and subsequently at 1, 4, 8, 24, and 48 h post-surgery using an infrared diode laser. Thermal hypersensitivity was attenuated at 1 h post-surgery in the Bup HCl group, while it was attenuated through the entire postoperative period in both low-SR and high-SR groups. This data suggests that a single dose of low-SR (0.5 mg/kg) or high-SR (1 mg/kg) effectively attenuates thermal hypersensitivity for at least 8 h in neonatal rat pups.

Impact of Buprenorphine on Learning and Memory Ability, Oxidative Status and Inflammation in the Hippocampus of Rats.

BACKGROUND: Buprenorphine (BUP), a "synthetic derivative of the opioid alkaloid thebaine", may be associated with cellular damage in the central nervous system. AIMS: This study was designed to investigate the effects of low and high doses of BUP on oxidative and inflammatory indices in the hippocampus and learning and memory behavior in an animal model. OBJECTIVE: The association between BUP administration and oxidative and inflammatory damage and also learning and memory impairment is not clear. METHODS: For this reason, twenty-four male Wistar rats were randomly allocated into one control and two BUP-treated groups (0.3 and 1 mg/kg, SC), (n=8, for each group). After 4 weeks, learning and memory abilities were assessed by using Y-maze test. Then, oxidative stress indices including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were assessed in the serum and hippocampus of each animal by using spectrophotometer. Inflammatory parameters such as tumor necrotic factor-α (TNF-α), interleukin- 6 (IL-6), and interleukin-1ß (IL-1ß) were also measured in the serum and hippocampus of rats by using ELISA. RESULTS: The present findings indicated that the memory and learning time was lengthened in BUP (1mg/kg)-treated rats versus control animals (p<0.05). Additionally, it was observed that BUP (1 mg/kg) significantly increased the serum and hippocampal levels of MDA and TNF-α and also decreased GSH levels versus the control group (p< 0.05). CONCLUSION: The results of the present study revealed that BUP may cause learning and memory dysfunction by inducing oxidative stress and inflammation in the hippocampus.

Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block.

Buprenorphine is a µ-opioid receptor (MOR) partial agonist used to manage pain and addiction. QTC prolongation that crosses the 10 msec threshold of regulatory concern was observed at a supratherapeutic dose in two thorough QT studies for the transdermal buprenorphine product BUTRANS®. Because QTC prolongation can be associated with Torsades de Pointes (TdP), a rare but potentially fatal ventricular arrhythmia, these results have led to further investigation of the electrophysiological effects of buprenorphine. Drug-induced QTC prolongation and TdP are most commonly caused by acute inhibition of hERG current (IhERG) that contribute to the repolarizing phase of the ventricular action potentials (APs). Concomitant inhibition of inward late Na+ (INaL) and/or L-type Ca2+ (ICaL) current can offer some protection against proarrhythmia. Therefore, we characterized the effects of buprenorphine and its major metabolite norbuprenorphine on cardiac hERG, Ca2+, and Na+ ion channels, as well as cardiac APs. For comparison, methadone, a MOR agonist associated with QTC prolongation and high TdP risk, and naltrexone and naloxone, two opioid receptor antagonists, were also studied. Whole cell recordings were performed at 37°C on cells stably expressing hERG, CaV1.2, and NaV1.5 proteins. Microelectrode array (MEA) recordings were made on human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The results showed that buprenorphine, norbuprenorphine, naltrexone, and naloxone had no effect on IhERG, ICaL, INaL, and peak Na+ current (INaP) at clinically relevant concentrations. In contrast, methadone inhibited IhERG, ICaL, and INaL. Experiments on iPSC-CMs showed a lack of effect for buprenorphine, norbuprenorphine, naltrexone, and naloxone, and delayed repolarization for methadone at clinically relevant concentrations. The mechanism of QTC prolongation is opioid moiety-specific. This remains undefined for buprenorphine, while for methadone it involves direct hERG channel block. There is no evidence that buprenorphine use is associated with TdP. Whether this lack of TdP risk can be generalized to other drugs with QTC prolongation not mediated by acute hERG channel block warrants further study.

Thienorphine induces antinociception without dependence through activation of κ- and δ-, and partial activation of µ- opioid receptor.

Thienorphine hydrochloride is a new anti-relapse drug for opioid abusers that is currently in phase II clinical trial. In the present study, the antinociception, dependence, and signal transduction induced by thienorphine were examined. Thienorphine showed a potent antinociception effect in acetic acid-induced writhing test and formalin test. In the hot plate test and tail-flick test, thienorphine presented the typical partial opioid agonist character with a ceiling dose-response curve in addition to a bell-shaped curve. The hot plate test revealed that thienorphine induced approximately 50% of antinociception in µ receptor knockout (µ-KO) mice compared to wild-type controls (P < 0.05). The κ, δ selective antagonist nor-binaltorphimine (nor-BNI), and naltrindole decreased approximately 50-60% of theinorphine antinociception in µ-KO mice, respectively. The ORL1 receptor-selective antagonist J113397 did not affect theinorphine antinociception in µ-KO mice. Chronic treatment with thienorphine (1.5 mg/kg) induced some tolerance that was lower compared to buprenorphine or morphine addition. In contrast to buprenorphine or morphine, thienorphine did not lead to psychological dependence by conditioned place preference (CPP). The maximum inhibition of thienorphine on protein kinase A (PKA) activity was about 36%, 100%, 100%, and 12% in CHO-µ/κ/δ/ORL1-PKAcatEGFP cells, respectively. Similar results were observed in cyclic adenosine monophosphate (cAMP) accumulation inhibited by thienorphine in cells. Thienorphine significantly increased pERK1/2 in CHO-κ/δ-PKAcatEGFP cells. These results indicated that thienorphine induced analgesia through activation of κ- and δ-, partial activation of µ- opioid receptor without a bias between G-protein- and ß-arrestin-mediated pathways. Thienorphine might be used for antinociception with minimal adverse effects.

A narrative review of buprenorphine in adult cancer pain.

INTRODUCTION: Adult cancer pain is a disease state battled on a global scale. Proper pain management is essential to prevent health complications and promote patient well-being. Due to the opioid misuse crisis in the United States, providers are looking for alternatives to traditional opioids used for adult cancer pain. Buprenorphine has a unique pharmacologic profile, allowing it to be delivered in noninvasive ways; thus, it offers an alternative to traditional options. Randomized controlled trials have shown improved pain scores with transdermal buprenorphine, and they showed reductions in pain scores and increased improvement in quality of life scores versus other opioids. Sublingual buprenorphine has more limited, but promising data for reducing cancer pain. AREAS COVERED: We provide a narrative review of pathophysiological pathways of pain in cancer, how they are treated, and the unique properties of buprenorphine. Guidelines addressing pain management during cancer treatment are assessed to identify buprenorphine's place in therapy. Recent literature reporting efficacy and safety of buprenorphine use in pain management during cancer treatment will be presented. EXPERT OPINION: Current literature shows strong data for transdermal buprenorphine and promising data for sublingual buprenorphine. With this evidence, buprenorphine could have a more expanded role in managing adult cancer pain.

Sustained-release buprenorphine induces acute opioid tolerance in the mouse.

Sustained-release buprenorphine is widely used in mice with the intention of providing long-lasting analgesia. Statements about duration of therapeutic efficacy are based on persistence of serum buprenorphine levels over a minimum threshold, but behavioral data demonstrating sustained efficacy is not established. Additionally, chronic opioid exposure can induce tolerance and/or hyperalgesia; mice receiving sustained-release buprenorphine have not been evaluated for these effects. This study assessed clinical efficacy and duration of sustained-release buprenorphine in inflammatory, post-operative, and cancer pain; and screened for centrally-mediated opioid-induced hyperalgesia as well as opioid tolerance. At 1-2 mg/kg sustained-release buprenorphine, statistically significant analgesic efficacy occurred only at time points up to 2 h. These animals showed no changes in von Frey thresholds on the contralateral side, i.e. no centrally-mediated opioid hyperalgesia. To establish whether acute onset opioid tolerance resulted from a single sustained-release buprenorphine administration, we used the tail flick assay, exposing mice to sustained-release buprenorphine or saline on Day 1 and buprenorphine on Day 2. We measured duration and efficacy of 1 mg/kg buprenorphine after 1 mg/kg sustained-release buprenorphine, and also quantified a dose-response curve of buprenorphine (0.1-3 mg/kg) after 2 mg/kg sustained-release buprenorphine. Compared to control animals, mice previously exposed to sustained-release buprenorphine showed diminished analgesic response to buprenorphine; the resultant dose-response curve showed decreased efficacy. Pretreatment with naloxone, an opioid receptor antagonist, blocked sustained-release buprenorphine analgesic action. The short duration of antinociception following administration of sustained-release buprenorphine in mice is caused by the rapid development of tolerance.

A Comparison of Buprenorphine, Sustained release Buprenorphine, and High concentration Buprenorphine in Male New Zealand White Rabbits.

Pain management in rabbits can be difficult because they are adept at hiding pain and can be stressed by handling and restraint for injection. The use of opioid analgesics with prolonged durations of activity could alleviate pain, but associated adverse effects including gastrointestinal ileus, inappetence, and tissue reactions have been reported. In this study, we compared gross tissue reactions at the site of injection, food consumption, and fecal production after single injections of buprenorphine HCl (Bup; n = 7), sustained-release buprenorphine (BupSR; n = 8), and high-concentration buprenorphine (BupHC; n = 7) during the first 3 d after minor survival surgery. We also measured plasma concentrations of the parent drug, buprenorphine, and 3 metabolites (buprenorphine-3-glucuronide (B3G), norbuprenorphine-3ß-glucuronide (N3G), and norbuprenorphine (NB)). Plasma levels of buprenorphine remained above the theoretical minimal analgesic concentration for 4 h for Bup and 42 h for BupHC. For BupSR, plasma levels of buprenorphine remained above the theoretical minimal analgesic concentration for approximately 77 h, starting 15 h after administration. For all 3 formulations, N3G was the most prominent metabolite in the blood. No injection site reactions were visible grossly in any rabbit. Relative to baseline measures and compared with controls (n = 8), food consumption was suppressed on days 1 through 3 in rabbits that received BupSR and on days 2 through 3 in those given BupHC. Feces production on day 3 was reduced to a greater extent in BupSR rabbits than control animals. Two rabbits in the BupHC group exhibited neurologic signs after drug administration. These adverse effects should be considered when choosing a long-lasting buprenorphine formulation to manage pain in rabbits.

Perioperative Management of Patients on Buprenorphine and Methadone: A Narrative Review

The opioid epidemic has emerged as a major health and social problem over the last few decades. An increasing number of patients with opioid use disorder are presenting for perioperative management. These patients are either on buprenorphine or methadone for the maintenance and treatment of opioid addiction or chronic pain. In the settings of acute pain, the optimal management of patients with opioid use disorder is challenging, and recovery can be jeopardized secondary to the unique pharmacology of these agents. The purpose of this narrative review is to summarize the existing studies on the perioperative management of patients who are using buprenorphine and methadone and provide guidance for the management of patients with opioid use disorder during the perioperative period.

Managing long-term high-dose prescription opioids in patients with non-cancer pain: The potential role of sublingual buprenorphine.

BACKGROUND: Opioids are frequently used to manage chronic non-cancer pain despite the lack of evidence of benefit and clear evidence of opioid-related harms. Patients undergoing high-dose opioid therapy are at risk of multiple complications, such as opioid toxicity, including fatal overdose and opioid dependence. OBJECTIVE: This article provides an overview of the pharmacology of buprenorphine and reviews current evidence for the use of high-dose sublingual buprenorphine-naloxone in the pharmacological management of patients at high risk of complications from chronic opioid use. DISCUSSION: Buprenorphine-naloxone is well tolerated by patients with chronic pain, and has the potential to improve pain scores and affective symptoms. This is exemplified in a case study based on these authors' experience in an addiction medicine setting. As the rates of pharmaceutical opioid prescribing and related harms continue to increase in Australia, buprenorphine-naloxone is a viable option to manage high-risk chronic pain patients who are unable to reduce or cease their opioid use.