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Postoperative pain (POP) is a challenging clinical phenomenon that affects the majority of surgical patients and demands effective management to mitigate adverse outcomes such as persistent pain. The primary goal of POP management is to alleviate suffering and facilitate a seamless return to normal function for the patient. Despite compelling evidence of its drawbacks, opioid analgesia remains the basis of POP treatment. Novel therapeutic approaches rely on multimodal analgesia, integrating different pharmacological strategies to optimize efficacy while minimizing adverse effects. The recognition of the imperative role of the endocannabinoid system in pain regulation has prompted the investigation of cannabinoid compounds as a new therapeutic avenue. Cannabinoids may serve as adjuvants, enhancing the analgesic effects of other drugs and potentially replacing or at least reducing the dependence on other long-term analgesics in pain management. This narrative review succinctly summarizes pertinent information on the molecular mechanisms, clinical therapeutic benefits, and considerations associated with the plausible use of various cannabinoid compounds in treating POP. According to the available evidence, cannabinoid compounds modulate specific molecular mechanisms intimately involved in POP. However, only two of the eleven clinical trials that evaluated the efficacy of different cannabinoid interventions showed positive results. [ABSTRACT FROM AUTHOR]

Chronic neuropathic pain (NP) is an increasingly prevalent disease and leading cause of disability which is challenging to treat. Several distinct classes of drugs are currently used for the treatment of chronic NP, but each drug targets only narrow components of the underlying pathophysiological mechanisms, bears limited efficacy, and comes with dose-limiting side effects. Multimodal therapies have been increasingly proposed as potential therapeutic approaches to target the multiple mechanisms underlying nociceptive transmission and modulation. However, while preclinical studies with combination therapies showed promise to improve efficacy over monotherapy, clinical trial data on their efficacy in specific populations are lacking and increased risk for adverse effects should be carefully considered. Drug-drug co-crystallization has emerged as an innovative pharmacological approach which can combine two or more different active pharmaceutical ingredients in a single crystal, optimizing pharmacokinetic and physicochemical characteristics of the native molecules, thus potentially capitalizing on the synergistic efficacy between classes of drugs while simplifying adherence and minimizing the risk of side effects by reducing the doses. In this work, we review the current pharmacological options for the treatment of chronic NP, focusing on combination therapies and their ongoing developing programs and highlighting the potential of co-crystals as novel approaches to chronic NP management. [ABSTRACT FROM AUTHOR]

Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of currently available opioids, together with the current 'opioid crisis', warrant consideration on new opioid analgesic discovery strategies. Targeting peripheral opioid receptors as effective means of treating pain and avoiding the centrally mediated side effects represents a research area of substantial and continuous attention. Among clinically used analgesics, opioids from the class of morphinans (i.e., morphine and structurally related analogues) are of utmost clinical importance as analgesic drugs activating the mu-opioid receptor. In this review, we focus on peripheralization strategies applied to N-methylmorphinans to limit their ability to cross the blood–brain barrier, thus minimizing central exposure and the associated undesired side effects. Chemical modifications to the morphinan scaffold to increase hydrophilicity of known and new opioids, and nanocarrier-based approaches to selectively deliver opioids, such as morphine, to the peripheral tissue are discussed. The preclinical and clinical research activities have allowed for the characterization of a variety of compounds that show low central nervous system penetration, and therefore an improved side effect profile, yet maintaining the desired opioid-related antinociceptive activity. Such peripheral opioid analgesics may represent alternatives to presently available drugs for an efficient and safer pain therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Pharmacokinetic (PK) studies measure the time for a dose of a drug to reach therapeutic levels in a patient's blood or tissues. This data provides a simple and precise method to compare the response to drugs made by different manufactures or the same drug provided in different delivery formats; for example, oral tablets, intravenous infusions, or subcutaneous (SC) injections. The present study provides the first review of PK data for buprenorphine, an opioid analgesic, in animals dosed with the drug in a lipid or polymer carrier. The PK data from studies using the polymer carrier system illustrate greater variability, an outcome probably related to the different manufacturing conditions of the supplying vendors. The lipid product was produced by a single vendor. 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. [ABSTRACT FROM AUTHOR]

Chronic pain is a major source of morbidity for which there are limited effective treatments. Palmitoylethanolamide (PEA), a naturally occurring fatty acid amide, has demonstrated utility in the treatment of neuropathic and inflammatory pain. Emerging reports have supported a possible role for its use in the treatment of chronic pain, although this remains controversial. We undertook a systematic review and meta-analysis to examine the efficacy of PEA as an analgesic agent for chronic pain. A systematic literature search was performed, using the databases MEDLINE and Web of Science, to identify double-blind randomized controlled trials comparing PEA to placebo or active comparators in the treatment of chronic pain. All articles were independently screened by two reviewers. The primary outcome was pain intensity scores, for which a meta-analysis was undertaken using a random effects statistical model. Secondary outcomes including quality of life, functional status, and side effects are represented in a narrative synthesis. Our literature search identified 253 unique articles, of which 11 were ultimately included in the narrative synthesis and meta-analysis. Collectively, these articles described a combined sample size of 774 patients. PEA was found to reduce pain scores relative to comparators in a pooled estimate, with a standard mean difference of 1.68 (95% CI 1.05 to 2.31, p = 0.00001). Several studies reported additional benefits of PEA for quality of life and functional status, and no major side effects were attributed to PEA in any study. The results of this systematic review and meta-analysis suggest that PEA is an effective and well-tolerated treatment for chronic pain. Further study is warranted to determine the optimal dosing and administration parameters of PEA for analgesic effects in the context of chronic pain. [ABSTRACT FROM AUTHOR]

Opioid-induced hyperalgesia (OIH) is a paradoxical effect of opioids that is not consensually recognized in clinical settings. We conducted a revision of clinical and preclinical studies and discuss them side by side to provide an updated and renewed view on OIH. We critically analyze data on the human manifestations of OIH in the context of chronic and post-operative pain. We also discuss how, in the context of cancer pain, though there are no direct evidence of OIH, several inherent conditions to the tumor and chemotherapy provide a substrate for the development of OIH. The review of the clinical data, namely in what concerns the strategies to counter OIH, emphasizes how much OIH rely mechanistically on the existence of µ-opioid receptor (MOR) signaling through opposite, inhibitory/antinociceptive and excitatory/pronociceptive, pathways. The rationale for the maladaptive excitatory signaling of opioids is provided by the emerging growing information on the functional role of alternative splicing and heteromerization of MOR. The crossroads between opioids and neuroinflammation also play a major role in OIH. The latest pre-clinical data in this field brings new insights to new and promising therapeutic targets to address OIH. In conclusion, although OIH remains insufficiently recognized in clinical practice, the appropriate diagnosis can turn it into a treatable pain disorder. Therefore, in times of scarce alternatives to opioids to treat pain, mainly unmanageable chronic pain, increased knowledge and recognition of OIH, likely represent the first steps towards safer and efficient use of opioids as analgesics. [ABSTRACT FROM AUTHOR]

Background and Objectives: Characterising the features of methodologies, clinical attributes and intervention protocols, of studies is valuable to advise directions for research and practice. This article reports the findings of a secondary analysis of the features from studies screened as part of a large systematic review of TENS (the meta-TENS study). Materials and Methods: A descriptive analysis was performed on information associated with methodology, sample populations and intervention protocols from 381 randomised controlled trials (24,532 participants) evaluating TENS delivered at a strong comfortable intensity at the painful site in adults with pain, irrespective of diagnosis. Results: Studies were conducted in 43 countries commonly using parallel group design (n = 334) and one comparator group (n = 231). Mean ± standard deviation (SD) study sample size (64.05 ± 58.29 participants) and TENS group size (27.67 ± 21.90 participants) were small, with only 13 of 381 studies having 100 participants or more in the TENS group. Most TENS interventions were 'high frequency' (>10 pps, n = 276) and using 100 Hz (109/353 reports that stated a pulse frequency value). Of 476 comparator groups, 54.2% were active treatments (i.e., analgesic medication(s), exercise, manual therapies and electrophysical agents). Of 202 placebo comparator groups, 155 used a TENS device that did not deliver currents. At least 216 of 383 study groups were able to access other treatments whilst receiving TENS. Only 136 out of 381 reports included a statement about adverse events. Conclusions: Clinical studies on TENS are dominated by small parallel group evaluations of high frequency TENS that are often contaminated by concurrent treatment(s). Study reports tended focus on physiological and clinical implications rather than the veracity of methodology and findings. Previously published criteria for designing and reporting TENS studies were neglected and this should be corrected in future research using insights gleaned from this analysis. [ABSTRACT FROM AUTHOR]

Simple Summary: This review discusses treatment approaches for providing pain relief to oncological patients affected by pain caused by nerve damage due to the tumor, also known as neuropathic cancer pain. Although being encountered often and causing a relevant burden to these patients, neuropathic cancer pain remains still difficult to diagnose and treat. Strong evidence about the best drugs to be used remain limited, as do therapeutic choices. Neuropathic pain can be defined as pain related to abnormal somatosensory processing in either the peripheral or central nervous system. In this review article, with neuropathic cancer pain (NCP), we refer to pain due to nervous tissue lesions caused by the tumor or its metastases. Nervous tissue damage is the cause of cancer pain in approximately 40% of those experiencing cancer pain. Recognizing a neuropathic pathophysiology in these cases may be difficult and requires specific criteria that are not homogenously applied in clinical practice. The management of this type of pain can be challenging, requiring the use of specific non-opioid adjuvant drugs. The majority of the criteria for NCP diagnosis and management have been based mainly on results from the noncancer population, risking the failure of addressing the specific needs of this population of patients. In this review, we summarize current management options available for NCP and provide some insights on new promising treatments. [ABSTRACT FROM AUTHOR]

For the first time, the high-performance liquid chromatography–diode array detector (HPLC–DAD) approach was operated for the simultaneous assessment of methyl nicotinate (MN), methyl salicylate (MS), ethyl salicylate (ES) and 2-hydroxyethyl salicylate (HES) in one pharmaceutical formulation. The limits of detection of MN, HES, MS and ES were found to be 0.0144, 0.0455, 0.0087 and 0.0061 μg/mL. The recovery percentages and relative standard deviations ranged from 93.48 to 102.12% and 0.301 to 6.341% for all active ingredients. Accordingly, the previously described data demonstrate the sensitivity, accuracy and precision of the developed method. Therefore, the investigated approach was effectively applied for the simultaneous assessment of MN, HES, MS and ES in DEEP HEAT Spray. [ABSTRACT FROM AUTHOR]

Background Pain and discomfort are main concerns at the commencement of orthodontic treatment. It may have negative impact on compliance or even discourage patients from being treated. Orthodontic pain can be alleviated by paracetamol or use of chewing gum. However, studies comparing their effectiveness are scarce. Objectives To compare the effectiveness of paracetamol versus chewing gum for pain alleviation and to investigate the frequency of bracket loss during the first day of fixed orthodontic treatment. Trail design Prospective randomized multicentre clinical trial. Methods Sixty patients (28 boys and 32 girls), between 12 and 18 years of age were randomly allocated either to take paracetamol (31 patients) or to use chewing gum (29 patients). After one arch bonding and insertion of the initial archwire, the patients rated the sensation of pain on a visual analogue scale with the jaw at rest and when biting after 6 hours (T1), at bedtime (T2), and the next morning (T3). Paracetamol (1000 mg) was taken 1 hour and chewing gum was used 10 minutes prior to pain rating at T2 and T3. A simple method of randomization was used in this study, and blinding of subjects and the operators to the type of intervention was not possible because of the nature of the treatments. Results There was no detectable difference in pain sensation between the groups at T1. At T2 and T3 the chewing gum group displayed higher mean values than the paracetamol group but when adjusting for age, gender, and mode of pain registration, there was no significant difference between the groups. There was no bracket loss in the chewing gum group, whereas two patients in the paracetamol group lost two brackets. Conclusions The effect of chewing gum and paracetamol for initial orthodontic pain relief seems equivalent. Short term use of chewing gum is not a risk factor for bracket loss. Trial registration This study was not registered. [ABSTRACT FROM AUTHOR]

Despite a more than tenfold increase in opioid consumption in the past decades, many cancer patients still suffer pain. The current understanding of this situation is poorly understood. It is still possible that in some countries pain is still undertreated, but it is also possible that we do not appreciate opioid induced toxicity and other phenomena an/or our opioid prescribing needs to be refreshed. At the moment the only evidence based tool to deal with opioid toxicity is switching to another opioid. Other methods are also described, but are far less well evidenced. However, the effects after switching are short-lived and sometimes a number of switches are needed. In this article we discuss the rationale behind and the possibility of combining different opioids with each other. Opioids are all different and opioid receptors are heterogenous. There are data to suggest that widening the activity spectrum of opioids may be the way forward in order to decrease adverse effects and maintain analgesia. At the moment there are only some data on the interaction of fentanyl and morphine, morphine and oxycodone, and buprenorphine and morphine. These data suggest that we should investigate these problems vigorously and, instead of switching from one opioid to another, we may, in future, adopt the concept of a semi-switch, where the dose of the first opioid is decreased and a second opioid is added. [ABSTRACT FROM AUTHOR]

Morphine is a well-known μ-opioid receptor (MOR) agonist and an efficient analgesic, but its long-term use inevitably leads to drug addiction and tolerance. Here, we show that specific inhibition of β-arrestin2 with its siRNA lentivirus microinjected in mice periaqueductal gray matter (PAG) significantly improved both acute and chronic morphine analgesia and delayed the tolerance in the hotplate test. The specific effect of β-arrestin2 was proven by overexpression or knockdown of its homology β-arrestin1 in PAG, which showed no significant effects on morphine analgesia. These findings suggest that specific siRNA targeting β-arrestin2 may constitute a new approach to morphine therapy and other MOR agonist-mediated analgesia and tolerance. [ABSTRACT FROM AUTHOR]

Opioids are widely used as therapeutic agents against moderate to severe acute and chronic pain. Still, these classes of analgesic drugs have many potential limitations as they induce analgesic tolerance, addiction and numerous behavioural adverse effects that often result in patient non-compliance. As opium and opioids have been traditionally used as painkillers, the exact mechanisms of their adverse reactions over repeated use are multifactorial and not fully understood. Older adults suffer from cancer and non-cancer chronic pain more than younger adults, due to the physiological changes related to ageing and their reduced metabolic capabilities and thus show an increased number of adverse reactions to opioid drugs. All clinically used opioids are μ-opioid receptor agonists, and the major adverse effects are directly or potentially connected to this receptor. Multifunctional opioid ligands or peripherally restricted opioids may elicit fewer adverse effects, as shown in preclinical studies, but these results need reproducibility from further extensive clinical trials. The current review aims to overview various mechanisms involved in the adverse effects induced by opioids, to provide a better understanding of the underlying pathophysiology and, ultimately, to help develop an effective therapeutic strategy to better manage pain. [ABSTRACT FROM AUTHOR]

The reversible fatty acid amide hydrolase (FAAH) inhibitor OL135 reverses mechanical allodynia in the spinal nerve ligation (SNL) and mild thermal injury (MTI) models in the rat. The purpose of this study was to investigate the role of the cannabinoid and opioid systems in mediating this analgesic effect.Elevated brain concentrations of anandamide (350 pmol g−1 of tissue vs 60 pmol g−1 in vehicle-treated controls) were found in brains of rats given OL135 (20 mg kg−1) i.p. 15 min prior to 20 mg kg−1 i.p. anandamide.Predosing rats with OL135 (2–60 mg kg−1 i.p.) 30 min before administration of an irreversible FAAH inhibitor (URB597: 0.3 mg kg−1 intracardiac) was found to protect brain FAAH from irreversible inactivation. The level of enzyme protection was correlated with the OL135 concentrations in the same brains.OL135 (100 mg kg−1 i.p.) reduced by 50% of the maximum possible efficacy (MPE) mechanical allodynia induced by MTI in FAAH+/+mice (von Frey filament measurement) 30 min after dosing, but was without effect in FAAH−/− mice.OL135 given i.p. resulted in a dose-responsive reversal of mechanical allodynia in both MTI and SNL models in the rat with an ED50 between 6 and 9 mg kg−1. The plasma concentration at the ED50 in both models was 0.7 μM (240 ng ml−1).In the rat SNL model, coadministration of the selective CB2 receptor antagonist SR144528 (5 mg kg−1 i.p.), with 20 mg kg−1 OL135 blocked the OL135-induced reversal of mechanical allodynia, but the selective CB1 antagonist SR141716A (5 mg kg−1 i.p.) was without effect.In the rat MTI model neither SR141716A or SR144528 (both at 5 mg kg−1 i.p.), or a combination of both antagonists coadministered with OL135 (20 mg kg−1) blocked reversal of mechanical allodynia assessed 30 min after dosing.In both the MTI model and SNL models in rats, naloxone (1 mg kg−1, i.p. 30 min after OL135) reversed the analgesia (to 15% of control levels in the MTI model, to zero in the SNL) produced by OL135.British Journal of Pharmacology (2006) 148, 102–113. doi:10.1038/sj.bjp.0706699; published online 27 February 2006 [ABSTRACT FROM AUTHOR]

Although persistent pain is estimated to affect about 20% of the adult population, current treatments have poor results. Polypharmacology, which is the administration of more than one drug targeting on two or more different sites of action, represents a prominent therapeutic approach for the clinical management of persistent pain. Thus, in the drug discovery process the "one-molecule-multiple targets" strategy nowadays is highly recognized. Indeed, multitarget ligands displaying a better antinociceptive activity with fewer side effects, combined with favorable pharmacokinetic and pharmacodynamic characteristics, have already been shown. Multitarget ligands possessing non-opioid/opioid and opioid/opioid mechanisms of action are considered as potential drug candidates for the management of various pain conditions. In particular, dual-target MOPr (mu opioid peptide receptor)/DOPr (delta opioid peptide receptor) ligands exhibit an improved antinociceptive profile associated with a reduced tolerance-inducing capability. The benzomorphan-based compounds LP1 and LP2 belong to this class of dual-target MOPr/DOPr ligands. In the present manuscript, the structure–activity relationships and the pharmacological fingerprint of LP1 and LP2 compounds as suitable drug candidates for persistent pain relief is described. [ABSTRACT FROM AUTHOR]

The treatment of dermal injuries is associated with pain in both adult and pediatric populations. We reviewed traditional treatments for controlling the pain of these lesions, such as infiltrated local anesthetics and topical local anesthetics. The objective of this review was to elucidate the efficacy of topical anesthetics in reducing the pain of dermal injuries, as well as the efficacy of topical anesthetics versus other anesthetics, or versus a placebo. Methodology: a systematic review was carried out by searching Medline (PubMED), Scopus, Cinahl, Cochrane, Lilacs, and ENFISPO for randomized clinical trials on the control of pain in dermal lesions through the use of topical anesthetics, versus a placebo or versus another anesthetic. Results: twelve randomized clinical trials with a total of 952 patients were included. Seven studies analyzed the efficacy of topical anesthetics compared to a placebo, and six of them observed statistically significant differences in favor of the experimental group. Five studies analyzed the efficacy of topical anesthetics compared to other anesthetics or sedatives; three of them observed statistically significant differences in favor of the experimental group, and two found no difference between the anesthetics analyzed. Conclusion: topical anesthesia is a useful method for pain control, is safe compared to other traditional methods, and offers a satisfactory form of pain relief in relation to infiltration anesthesia and compared to placebo. [ABSTRACT FROM AUTHOR]