No abstract available

No abstract available

Postsurgical pain is commonly associated with dental and oral surgery, and the use of analgesics has been investigated in the management of postoperative pain. This systematic review summarizes available evidence on analgesics used to manage dental implant surgery postoperative pain, to identify best therapeutic protocols and knowledge gap. A comprehensive search was conducted including MEDLINE/Pubmed, EMBASE, SCOPUS, clinicaltrials.gov, and the Cochrane Database of Systematic Reviews through May 2020. Only randomized controlled trials were included. PRISMA guidelines were followed, and risk of bias was appraised using Cochrane RoB2 tool. Eleven trials (762 patients overall) were included. Some aspects limited the feasibility of a meaningful meta-analysis; thus, a narrative synthesis was conducted. Risk of bias was low in four studies and high in two studies, while five studies raised some concerns due to the randomization process. Analgesic use seemed to be associated with improved postoperative outcomes (pain, patient's satisfaction, and need for rescue medication) when compared to placebo. Overall, this review suggests that the administration of analgesics may provide some advantages in the management of postoperative outcomes after dental implant placement, while indications about the best analgesics cannot be provided.

Biologic drugs are novel therapeutic agents with demonstrated effectiveness in the management of a variety of chronic inflammatory disorders. Unmet needs in the treatment of chronic pain have led physicians to utilize a similar approach to patients suffering from conditions not characterized by systemic inflammation such as osteoarthritis (OA). The aim of this review is to discuss the current knowledge on the use of commonly used biologic agents [i.e., anti-tumor necrosis factor alpha (anti-TNF alpha) and anti-nerve growth factor (anti-NGF)] for the management of OA.

Long-acting injectable (LAI) opioid formulations mitigate the harm profiles and management challenges associated with providing effective analgesia for animals. A single dose of a long-acting opioid analgesic can provide up to 72 h of clinically relevant pain management. Yet, few of these new drugs have been translated to products for veterinary clinics. Regulatory pathways allow accelerated drug approvals for generic and biosimilar drugs. These pathways depend on rigorous evidence for drug safety and pharmacokinetic evidence demonstrating bioequivalence between the new and the legacy drug. This report reviews the animal PK data associated with lipid and polymer-bound buprenorphine LAI formulations. Buprenorphine is a widely used veterinary opioid analgesic. Because of its safety profile and regulatory status, buprenorphine is more accessible than morphine, methadone, and fentanyl. This review of PK studies coupled with the well-established safety profile of buprenorphine suggests that the accelerated approval pathways may be available for this new family of LAI veterinary pharmaceuticals.

Adequate pain management is one of the biggest challenges of the modern healthcare system. Physician perception of patient subjective pain, which is crucial to pain management, is susceptible to a host of potential biases. Here we explore the timing of physicians' work as a previously unrecognized source of systematic bias in pain management. We hypothesized that during night shifts, sleep deprivation, fatigue, and stress would reduce physicians' empathy for others' pain, leading to underprescription of analgesics for patient pain relief. In study 1, 67 resident physicians, either following a night shift or not, performed empathy for pain assessment tasks and simulated patient scenarios in laboratory conditions. As predicted, following a night shift, physicians showed reduced empathy for pain. In study 2, we explored this phenomenon in medical decisions in the field. We analyzed three emergency department datasets from Israel and the United States that included discharge notes of patients arriving with pain complaints during 2013 to 2020 (n = 13,482). Across all datasets, physicians were less likely to prescribe an analgesic during night shifts (compared to daytime shifts) and prescribed fewer analgesics than generally recommended by the World Health Organization. This effect remained significant after adjusting for patient, physician, type of complaint, and emergency department characteristics. Underprescription for pain during night shifts was particularly prominent for opioids. We conclude that night shift work is an important and previously unrecognized source of bias in pain management, likely stemming from impaired perception of pain. We consider the implications for hospitals and other organizations employing night shifts.

Given the increase in narcotic addiction and diversion, understanding how patients use their opioid prescriptions and store or dispose of any remainders is important. We set out to determine the frequency in which patients had leftover opioid quantities from prescriptions received in the emergency department (ED). In addition, we sought to describe patients' reasons for taking or not taking all of their prescribed medications and their strategies to manage and/or dispose of any excess or leftovers.

Classical opioid analgesics, including morphine, mediate all of their desired and undesired effects by specific activation of the μ-opioid receptor (μ receptor). The use of morphine for treating chronic pain, however, is limited by the development of constipation, respiratory depression, tolerance and dependence. Analgesic effects can also be mediated through other members of the opioid receptor family such as the κ-opioid receptor (κ receptor), δ-opioid receptor (δ receptor) and the nociceptin/orphanin FQ peptide receptor (NOP receptor). Currently, a new generation of opioid analgesics is being developed that can simultaneously bind with high affinity to multiple opioid receptors. With this new action profile, it is hoped that additional analgesic effects and fewer side effects can be achieved. Recent research is mainly focused on the development of bifunctional μ/NOP receptor agonists, which has already led to novel lead structures such as the spiroindole-based cebranopadol and a compound class with a piperidin-4-yl-1,3-dihydroindol-2-one backbone (SR16835/AT-202 and SR14150/AT-200). In addition, the ornivol BU08028 is an analogue of the clinically well-established buprenorphine. Moreover, the morphinan-based nalfurafine exerts its effect with a dominant κ receptor-component and is therefore utilized in the treatment of pruritus. The very potent dihydroetorphine is a true multi-receptor opioid ligand in that it binds to μ, κ and δ receptors. The main focus of this review is to assess the paradigm of opioid ligands targeting multiple receptors with a single chemical entity. We reflect on this rationale by discussing the biological actions of particular multi-opioid receptor ligands, but not on their medicinal chemistry and design.

TWIK-related K(+) channel-2 (TREK-2) and TWIK-related spinal cord K(+) (TRESK) channel are members of two-pore domain K(+) channel family. They are well expressed and help to set the resting membrane potential in sensory neurons. Modulation of TREK-2 and TRESK channels are involved in the pathogenesis of pain, and specifi c activators of TREK-2 and TRESK may be benefi cial for the treatment of pain symptoms. However, the effect of commonly used analgesics on TREK-2 and TRESK channels are not known. Here, we investigated the effect of analgesics on TREK-2 and TRESK channels. The effects of analgesics were examined in HEK cells transfected with TREK-2 or TRESK. Amitriptyline, citalopram, escitalopram, and fluoxetine significantly inhibited TREK-2 and TRESK currents in HEK cells (p<0.05, n=10). Acetaminophen, ibuprofen, nabumetone, and bupropion inhibited TRESK, but had no effect on TREK-2. These results show that all analgesics tested in this study inhibit TRESK activity. Further study is needed to identify the mechanisms by which the analgesics modulate TREK-2 and TRESK differently.

Non-opioid analgesics are widely used for pain relief in palliative medicine. However, there is a lack of evidence-based recommendations addressing the efficacy, tolerability, and safety of non-opioids in this field. A comprehensive systematic review and meta-analysis on current evidence can provide a basis for sound recommendations in clinical practice. A database search for controlled trials on the use of non-opioids in adult palliative patients was performed in Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, and EMBASE from inception to 18 February 2018. Endpoints were pain intensity, opioid-sparing effects, safety, and quality of life. Studies with similar patients, interventions, and outcomes were included in the meta-analyses. Our systematic search was able to only identify studies dealing with cancer pain. Of 5991 retrieved studies, 43 could be included (n = 2925 patients). There was no convincing evidence for satisfactory pain relief by acetaminophen alone or in combination with strong opioids. We found substantial evidence of moderate quality for a satisfactory pain relief in cancer by non-steroidal anti-inflammatory drugs (NSAIDs), flupirtine, and dipyrone compared with placebo or other analgesics. There was no evidence for a superiority of one specific non-opioid. There was moderate quality of evidence for a similar pain reduction by NSAIDs in the usual dosage range compared with up to 15 mg of morphine or opioids of equianalgesic potency. The combination of NSAID and step III opioids showed a beneficial effect, without a decreased tolerability. There is scarce evidence concerning the combination of NSAIDs with weak opioids. There are no randomized-controlled studies on the use of non-opioids in a wide range of end-stage diseases except for cancer. Non-steroidal anti-inflammatory drugs, flupirtine, and dipyrone can be recommended for the treatment of cancer pain either alone or in combination with strong opioids. The use of acetaminophen in the palliative setting cannot be recommended. Studies are not available for long-term use. There is a lack of evidence regarding pain treatment by non-opioids in specific cancer entities.

Chronic pain negatively impacts the quality of life in a variety of patient populations. The current therapeutic repertoire is inadequate in managing patient pain and warrants the development of new therapeutics. Adenosine and its four cognate receptors (A1 , A2A , A2B and A3 ) have important roles in physiological and pathophysiological states, including chronic pain. Preclinical and clinical studies have revealed that while adenosine and agonists of the A1 and A2A receptors have antinociceptive properties, their therapeutic utility is limited by adverse cardiovascular side effects. In contrast, our understanding of the A3 receptor is only in its infancy, but exciting preclinical observations of A3 receptor antinociception, which have been bolstered by clinical trials of A3 receptor agonists in other disease states, suggest pain relief without cardiovascular side effects and with sufficient tolerability. Our goal herein is to briefly discuss adenosine and its receptors in the context of pathological pain and to consider the current data regarding A3 receptor-mediated antinociception. We will highlight recent findings regarding the impact of the A3 receptor on pain pathways and examine the current state of selective A3 receptor agonists used for these studies. The adenosine-to-A3 receptor pathway represents an important endogenous system that can be targeted to provide safe, effective pain relief from chronic pain.

The risk of opioid-related aberrant behavior (OAB) in Korean cancer patients has not been previously evaluated. The purpose of this study is to investigate the Opioid Risk Tool (ORT) in Korean cancer patients receiving opioid treatment.

Intravenous opioids are administered for the management of visceral pain after laparoscopic surgery. Whether oxycodone has advantages over other opioids in the treatment of visceral pain is not yet clear.

Serious concern has arisen about the cardiovascular safety of selective cyclo-oxygenase-2 (COX-2) inhibitors. However, recent studies have shown that the cardiovascular risks of regular use of traditional analgesics also deserve attention. We investigated the use of traditional analgesics for their prediction of major coronary events during 16 years of follow-up.

Biased agonism has been proposed as a means to separate desirable and adverse drug responses downstream of G protein-coupled receptor (GPCR) targets. Herein, we describe structural features of a series of mu-opioid-receptor (MOR)-selective agonists that preferentially activate receptors to couple to G proteins or to recruit βarrestin proteins. By comparing relative bias for MOR-mediated signaling in each pathway, we demonstrate a strong correlation between the respiratory suppression/antinociception therapeutic window in a series of compounds spanning a wide range of signaling bias. We find that βarrestin-biased compounds, such as fentanyl, are more likely to induce respiratory suppression at weak analgesic doses, while G protein signaling bias broadens the therapeutic window, allowing for antinociception in the absence of respiratory suppression.

Previous histories of animal experimentation, e.g., Franco (2013) have focused on ethics, the law and the personalities involved, but not on the involvement of anaesthetics or analgesics. Given that these were major subjects of (UK) Parliamentary debates on vivisection in the mid-19th century and viewed as "indisputable refinements in animal experimentation" (Russell and Burch 1959), it seemed that an analysis of their role was overdue. This commentary has, in interweaving the history of animal experimentation in the UK with the evolution of anaesthesia, attempted to: (1) clarify the evidence for Russell and Burch's view; and (2) evaluate anaesthesia's ongoing contribution to experimental refinement. The history that emerges reveals that the withholding or misuse of anaesthetics and, or analgesics from laboratory animals in the UK has had a profound effect on scientists and indirectly on the attitudes of the British public in general, becoming a major driver for the establishment of the anti-vivisection movement and subsequently, the Cruelty to Animals Act (1876)-the world's first legislation for the regulation of animal experimentation. In 1902, the mismanaged anaesthetic of a dog in the Department of Physiology, University College London resulted in numerous events of public disorder initiated by medical students against the police and a political coalition of anti-vivisectionists, trade unionists, socialists, Marxists, liberals and suffragettes. The importance of anaesthesia in animal experiments was sustained over the following 150 years as small mammalian species gradually replaced dogs and cats as the principle subjects for vivisection. In discussing experimental refinement in their 1959 report, "The Principles of Humane Experimental Technique" Russell and Burch described anaesthetics as "… the greatest single advance in humane technique, (which) has at the same time been virtually indispensable for the advance of experimental biology". Since then, the role of anaesthetics and in particular analgesics has become an unavoidable consideration whenever animal experiments are planned and conducted. This has been accompanied by a proliferation of training and educational programmes in laboratory animal anaesthesia.

Several small studies have previously investigated associations between the cytochrome P450 2D6 (CYP2D6) metabolism and response to opioids. We used a large sample of patients to study associations between CYP2D6 phenotypes and estimated CYP2D6 enzymatic activity scores with pain control and adverse reactions related to codeine and tramadol use. We conducted additional analyses to determine whether our results were consistent among men and women.

Management of pain from open wounds is a growing unmet healthcare need. However, the models available to study pain from wounds or to develop analgesics for the patients suffering from them have primarily relied on incisional models. Here, we present the first characterized and validated model of open wound pain.

Aberrant increases in NMDA receptor (NMDAR) signaling contributes to central nervous system sensitization and chronic pain by activating neuronal nitric oxide synthase (nNOS) and generating nitric oxide (NO). Because the scaffolding protein postsynaptic density 95kDA (PSD95) tethers nNOS to NMDARs, the PSD95-nNOS complex represents a therapeutic target. Small molecule inhibitors IC87201 (EC5O: 23.94 μM) and ZL006 (EC50: 12.88 μM) directly inhibited binding of purified PSD95 and nNOS proteins in AlphaScreen without altering binding of PSD95 to ErbB4. Both PSD95-nNOS inhibitors suppressed glutamate-induced cell death with efficacy comparable to MK-801. IC87201 and ZL006 preferentially suppressed phase 2A pain behavior in the formalin test and suppressed allodynia induced by intraplantar complete Freund's adjuvant administration. IC87201 and ZL006 suppressed mechanical and cold allodynia induced by the chemotherapeutic agent paclitaxel (ED50s: 2.47 and 0.93 mg/kg i.p. for IC87201 and ZL006, respectively). Efficacy of PSD95-nNOS disruptors was similar to MK-801. Motor ataxic effects were induced by MK-801 but not by ZL006 or IC87201. Finally, MK-801 produced hyperalgesia in the tail-flick test whereas IC87201 and ZL006 did not alter basal nociceptive thresholds. Our studies establish the utility of using AlphaScreen and purified protein pairs to establish and quantify disruption of protein-protein interactions. Our results demonstrate previously unrecognized antinociceptive efficacy of ZL006 and establish, using two small molecules, a broad application for PSD95-nNOS inhibitors in treating neuropathic and inflammatory pain. Collectively, our results demonstrate that disrupting PSD95-nNOS protein-protein interactions is effective in attenuating pathological pain without producing unwanted side effects (i.e. motor ataxia) associated with NMDAR antagonists.

A previous Delphi survey from the Rational Use of Analgesics (RUA) project involving Italian palliative care specialists revealed some discrepancies between current guidelines and clinical practice with a lack of consensus on items regarding the use of strong opioids in treating cancer pain. Those results represented the basis for a new Delphi study addressing a better approach to pain treatment in patients with cancer.