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Recent advances in the opioid mu receptor based pharmacotherapy for rheumatoid arthritis
Abstract
Introduction
Opioids are used for severe forms of acute and cancer pain. Over the last years, their potential use in patients with noncancer pain such as those with rheumatoid arthritis (RA) has been postulated. A recent population-based comparative study showed that chronic opioid use was 12% vs. 4% among RA and non-RA patients, respectively. Another study showed an increase from 7.4% to 16.9% (2002 to 2015). In general, there has been an increasing tendency to use opioids in recent years.
Areas covered
The authors have performed an extensive literature search using PubMed for articles including noncancer pain and the use of the mu opioid receptor (MOR) agonists in patients with RA.
Expert opinion
Data is not sufficient to support opioid use for the treatment of chronic pain in patients with RA. Data is scarce and inconclusive. Rheumatologists should think and ponder the question: Why is this patient in pain? Differential diagnosis should include a disease flare, degenerative changes of the musculoskeletal system, and fibromyalgia. And while there are new strategies for opioid administration currently being researched, unfortunately, they are far from being applied to human subjects in the everyday clinical setting, and are still being evaluated at an experimental level.
CNS
Central nervous system; DORs: delta opioid receptor agonists; GI: Gastrointestinal; GPCRs: G protein-coupled receptors; IL: Interleukin; JAK: Janus kinase; KORs: kappa opioid receptor agonists; MCPs: Metacarpophalangeal joints; MORs: Mu opioid receptor agonists; MTPs: Metatarsophalangeal joints; NSAIDs: Non-steroidal anti-inflammatory drugsOA: Osteoarthritis; ORs: Opioid receptors; PD: Pharmacodynamic; PIPs: Proximal interphalangeal joints; PK: Pharmacokinetic; PNS: Peripheral nervous system; RA: Rheumatoid arthritis; RGS: Regulator of G protein signaling; SSRIs: Selective serotonin reuptake inhibitors; TNF: Tumor necrosis factor
... RA is a systemic autoimmune disease characterized by chronic inflammation and progressive deterioration of the joints, causing significant pain and stiffness (1). Because of this, the initial priority for many RA patients is the search for adequate analgesia (2), Se with up to 90.4% of these patients visiting a healthcare professional with severe pain (3). ...
... It has been found that 97% of patients with early RA present pain, and up to 40% have disability 10 years after diagnosis (4), with 11.9% of patients having clinically significant pain despite meeting remission criteria (3). Albeit, new therapies and sophisticated treatments for RA exist, there are a limited number of pain management options, with a substantial proportion of patients reporting an inadequate analgesic response (1,2). This review focuses on the current pain management strategies in patients with RA reported in the literature, as well as the proposal of a pain management algorithm based on current evidence. ...
... RA is the most common autoimmune inflammatory arthropathy, with a prevalence of 0.5 to 1% in the adult population worldwide, increasing its incidence with age, with a peak at 50 to 60 years, declining in the eighth decade of life (1,2,4,5). The Global Burden of Disease (GBD) 2017 reports 20 million prevalent cases and 1.2 million incident cases worldwide, with North America, Western Europe and the Caribbean being the regions with the highest prevalence. ...
Rheumatoid Arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and progressive deterioration of the joints, which generates pain and stiffness. The origin of this pain is multifactorial, with inflammation, secondary osteoarthritis, as well as central and peripheral sensitization playing important roles in the development. Up to 90.4% of RA patients visit a health professional for severe pain, and despite new therapies and sophisticated treatments, there are a limited number of options for analgesic management. We conducted a narrative review using the Medline and Pubmed search engines for articles in English and Spanish between 2000 and 2021, with the keywords "pain," "rheumatoid arthritis," "non-steroidal anti-inflammatory drugs" (NSAIDs), "opioids," "glucocorticoids," "disease modifying antirheumatic drugs" (DMARDs), "neuromodulators," "antidepressants," and "cannabinoids." The articles describing epidemiology, pathophysiological considerations and current treatments were selected after a screening process carried out by the authors. It was found that DMARDs are the fundamental basis of treatment, since the main mechanism of pain in this entity is inflammation. Nonetheless, a significant number of patients continue to have pain despite optimal treatment. The available evidence for pain management in RA is scarce, however, medications such as NSAIDs, topical capsaicin, weak opioids, and treatments such as joint infiltrations or surgical management, play an important role in its management. We believe more research efforts are needed to optimize analgesic treatment recommendations, however, based on the current existing evidence, we propose a stepwise algorithm in order to properly approach these cases.
Key PointsRA is a systemic autoimmune disease characterized by chronic inflammation, in which the main symptom is pain.Pain in RA is multifactorial, with inflammation, secondary osteoarthritis, as well as central and peripheral sensitization playing determining roles.DMARDs are the mainstay of RA treatment, although many patients continue to experience pain despite optimal management.Medications such as glucocorticoids, NSAIDs, topical capsaicin, and weak opioids are key elements when achieving analgesia in RA.Other pharmacological groups such as neuromodulators, antidepressants, muscle relaxants and cannabinoids currently do not have enough evidence to be recommended.
... Persistent inflammatory responses may result in synovial hyperplasia, joint deformity, and disability. Clinically, nonsteroidal anti-inflammatory drugs (NSAIDs), Janus kinase inhibitors, and disease-modifying anti-rheumatic drugs are used to improve the symptoms [131]. The pathogenesis of RA is complicated. ...
Bone and cartilage disorders are the leading causes of musculoskeletal disability. There is no absolute cure for all bone and cartilage disorders. The exploration of natural compounds for the potential therapeutic use against bone and cartilage disorders is proving promising. Among these natural chemicals, naringin, a flavanone glycoside, is a potential candidate due to its multifaceted pharmacological activities in bone and cartilage tissues. Emerging studies indicate that naringin may promote osteogenic differentiation, inhibit osteoclast formation, and exhibit protective effects against osteoporosis in vivo and in vitro. Many signaling pathways, such as BMP-2, Wnt/β-catenin, and VEGF/VEGFR, participate in the biological actions of naringin in mediating the pathological development of osteoporosis. In addition, the anti-inflammatory, anti-oxidative stress, and anti-apoptosis abilities of naringin also demonstrate its beneficial effects against bone and cartilage disorders, including intervertebral disc degeneration, osteoarthritis, rheumatoid arthritis, bone and cartilage tumors, and tibial dyschondroplasia. Naringin exhibits protective effects against bone and cartilage disorders. However, more efforts are still needed due to, at least in part, the uncertainty of drug targets. Further biological and pharmacological evaluations of naringin and its applications in bone tissue engineering, particularly its therapeutic effects against osteoporosis, might result in developing potential drug candidates.
... Nowadays where novel targeted therapies have emerged, and a multitude of other drugs have been tried [51], GCs still play a pivotal role in the treatment of RA in combination with a correct treatment strategy [52]. Moreover, one should expect that after the introduction of targeted therapies the use of GCs would decrease, but this is not the case [53]. ...
Introduction:
Glucocorticoids are steroid hormones broadly used for the treatment of several inflammatory and autoimmune diseases among other numerous indications, including rheumatoid arthritis.
Areas covered:
For the purposes of this article, the authors have performed an extensive review of the literature to present the latest studies on glucocorticoid use in rheumatoid arthritis. They also provide the reader with their expert perspectives on future developments.
Expert opinion:
The authors do not anticipate that glucocorticoids with be replaced in the near future by newer drugs. As such, rheumatologists should be fully aware of the possible side-effects and educate appropriately their patients to recognize and report them. Newer formulations, such as the liposomal/nanoparticle-based treatments, will result in less pronounced adverse effects, but the input of clinical experience along with the current recommendations for the glucocorticoid use will benefit both clinicians and patients with rheumatoid arthritis.
Rheumatoid Arthritis (RA) is an autoimmune disease that is characterised by progressive joint disorder with significant pain and stiffness, which lead to functional disability and systemic complications if left untreated. The direct (health care costs) and indirect (productivity loss) socioeconomic costs of the disease are of major significance.
The therapeutic efficacy and safety of active ingredients are limited in several dosage forms, especially for those where the skin is the prime application area. Injectable has the potential of high efficacy and bioavailability but needle phobia, painful delivery, inflammatory response, and non-compliance make them less usable. Microneedle (MN) delivery overcomes almost all the limitations by offering painless self-administration, is highly effective, economical, avoids waste generation, and has high patient compliance. The MN technique is unique and novel for delivering all therapeutic moieties, vaccines, and micro and macromolecular drugs. The MN delivery is based on the mechanism of poke and patch, coat and patch, poke and release, poke and flow. The several types of MN utilized are solid, coated, hollow, dissolving, and hydrogel-forming microneedles. The materials fabricating MNs are mainly non-degradable (metals, PVP, PVA, etc.) and degradable (natural, PLGA, PAMA, etc.). MN delivery finds significant application in diagnosing several diseases by collecting blood samples and biological fluids with minimal pain. Moreover, the tremendous significance of the MN technique is observed in vaccines, hormones, proteins, peptides, psoriasis, ocular diseases, rheumatoid arthritis, malaria, gene delivery, and cosmetics. The delivery of several kinds of injections in cancer therapy is also harrowing. MN delivery worked excellently by delivering immunotherapeutic, immune checkpoint suppressors, photothermal therapy, and photodynamic therapy and thus valuable for targeting cancer with high success and minimal toxicity.
This chapter focuses on pharmacokinetics and pharmacodynamics of analgesics and the appropriate use of oral, intranasal, transmucosal, transdermal, subcutaneous, intravenous, or subcutaneous and intrathecal analgesics and co‐analgesics in strict relation with their indications and contraindications of their use, and when and how to switch toward interventional or non‐pharmacologic pain management to avoid these complications. In the case of a pharmacologic approach for the treatment of pain, specific basic principles should be respected in all cases. First, always select the best possible treatment that best fits the patient and the possible mechanism causing the pain. Second, always make a selection of the adequate mode of administration for a specific drug. Third, always use a clear treatment algorithm such as the World Health Organization pain ladder for cancer pain including the fourth step of invasive pain treatment. Finally, always use a fixed‐rate dosing regimen with escape medication.
Introduction
Pain control is one of the most important aspects of rheumatoid arthritis (RA) management from the patient’s perspective. Newer generations of RA treatment including tumor necrosis factor inhibitor (TNFi) have the potential to alleviate pain and thus reduce opioid utilization. However, patterns of opioid utilization before and after TNFi initiation have not been well characterized. This study aims to examine multiple measures of change in opioid utilization after the initiation of TNFi.
Methods
Patients aged ≥ 18 years with RA and 24 months continuous enrollment between January 2007 and December 2015 who newly initiated a TNFi in IQVIA™ Health Plan Claims Data were included in our study. Opioid utilization at baseline and during follow-up were identified and compared.
Results
Of 2330 patients with RA that were included in the study, 38.8% of patients used opioids in both baseline and follow-up periods. From pre-index to post-index, the proportion of patients receiving any opioid decreased from 54.0 to 51.0%. In addition, the proportion of those who received ≥ 50 mg median daily MED decreased from 12.6 to 10.6% during pre-post periods.
Conclusions
This real-world study of commercially insured patients with RA suggests that opioid use among these patients is prevalent. There was a small decrease in overall opioid utilization after TNFi initiation.
Despite the significant progress in Rheumatoid Arthritis (RA) therapeutics, there are several reports in the literature claiming that the size of unmet needs in RA is large. In the era before biologics, there was indeed a significant number of patients who did not achieve low disease activity (LDA) or disease remission due to limited therapeutic choices in the doctors’ armamentarium. Treatment wise, great progress has been achieved over the last decades with the discovery and introduction in therapeutics of new molecules, such as the biological (b) disease-modifying anti-rheumatic drugs (DMARDs), and the targeted synthetic (ts) DMARDs. Today, with such a plethora of conventional synthetic (cs) DMARDs, tsDMARDs, and bDMARDs, why are we unable to successfully treat RA patients? What is wrong? However, a new drug for RA does not mean it is necessary to switch to a new treatment. It is very easy to change and switch therapies when the patient complains about pain and stiffness. In this setting, it is obligatory to rule out other comorbidities and disorders that may be the cause of the pain first. Thus, clinicians must have a deep knowledge of the drug therapy and be able to adjust the treatment when needed. A minute clinical examination must be carried out on every visit with close monitoring of the patient. A treat-to-target (T2T) approach and the application of the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) recommendations and strategies should minimize the unmet needs.
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the synovial membrane, leading to joint damage and bone destruction. Conventional radiography (CR) of the hands and wrists has been, for many years, the primary imaging modality used to diagnose and monitor RA. On the other hand, many investigators in clinical trials and observational studies used CR of the hands and wrists to demonstrate drug effectiveness and structural damage progression. The purpose of this review is to discuss the evaluation and interpretation of the hands and wrists by CR in RA patients and the radiographic changes occurring in a specific joint. Thus, the literature was reviewed until January 2019 for studies regarding RA radiological evaluation of the hands and wrists, as well as radiological progression using CR. The assessment of joint pathology in RA patients should begin with CR which is the best imaging modality to evaluate any subtle changes occurring at the bone level. Once high-quality radiographs are obtained in appropriate views/projections, then an accurate evaluation can often be made without any further imaging studies. Therefore, CR is a valuable tool for RA screening. It is an easy-to-perform technique and gives important information assisting in differentiating between RA from other arthritides. In contrary CR does not provide good information when early RA changes start to appear, such as synovial inflammation or other soft-tissue structural changes. Nevertheless, it still remains the most commonly used imaging tool in rheumatology and has a number of advantages: it is easily available in most rheumatologists and readily accessible in most patients. It is inexpensive and relatively safe. It provides immediate information and can be interpreted easily by the requested rheumatologist. Finally, the data are reproducible and can be used for serial evaluation and follow-up.
Objective
We aimed to assess the safety of opioids in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials.
Methods
A comprehensive literature search was undertaken in the MEDLINE, Cochrane Central Register of Controlled Trials (Ovid CENTRAL), and Scopus electronic databases. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with opioids in patients with OA were eligible for inclusion. Two authors appraised titles, abstracts and full-text papers for suitability and then assessed the studies for random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective outcomes reporting. The primary outcomes of interest were gastrointestinal (GI) disorders, cardiac disorders, vascular disorders, nervous system disorders, skin and subcutaneous tissue disorders, renal and urinary disorders, respiratory, thoracic and mediastinal disorders, as well as overall severe and serious AEs and drug-related AEs. Secondary outcomes were withdrawals due to AEs (i.e. the number of participants who stopped the treatment due to an AE) and total number of AEs (i.e. the number of patients who experienced any AE at least once).
Results
Database searches identified 2189 records, from which, after exclusions, 17 papers were included in the meta-analysis. More disorders of the lower GI tract (constipation, fecaloma) were reported with both immediate-release (IR) and extended-release (ER) formulations of opioids versus placebo: IR opioids (relative risk [RR] 5.20, 95% confidence interval [CI] 3.42–7.89); ER opioids (RR 4.22, 95% CI 3.44–5.17). The risk of upper GI AEs increased fourfold with ER opioids compared with placebo (RR 4.03, 95% CI 0.87–18.62), and the risk of nausea, vomiting or loss of appetite increased four- to fivefold with both formulations: IR opioids (RR 3.39, 95% CI 2.22–5.18); ER opioids (RR 4.03, 95% CI 3.37–4.83). An increased risk of dermatologic AEs (rash and pruritis; IR opioids: RR 3.60, 95% CI 1.74–7.43; ER opioids: RR 7.87, 95% CI 5.20–11.89) and central nervous system disorders (dizziness, headache, fatigue, somnolence, insomnia; IR opioids: RR 2.76, 95% CI 1.90–4.02; ER opioids: RR 2.76, 95% CI 2.19–3.47) was found with all opioid formulations versus placebo.
Conclusions
Our results confirm that there are considerable safety and tolerability issues surrounding the use of opioids in OA, and support the recommendation of international and national guidelines to use opioids in OA after other analgesic options, and for short time periods.
Since the advent of infliximab for the treatment of rheumatoid arthritis (RA), new genetically-engineered molecules have appeared. This review aims to present the current data and body of evidence for golimumab (GLM). Safety, efficacy, tolerability and immunogenicity are all being investigated, not only through phase III trials (GO-BEFORE, GO-FORWARD, GO-AFTER, GO-MORE, GO-FURTHER, GO-NICE), but also through studies of real-world data. It seems that GLM in the subcutaneous form is an efficacious molecule with a good safety profile at the standard dosage scheme, but a 100 mg subcutaneous dose is associated with a higher risk of opportunistic infections, lymphoma and demyelination. Furthermore, when compared to other tumor necrosis factor-α molecules, it is non-inferior, and, at some points, such as when it comes to immunogenicity and persistence of the drug, it has a better profile. In summary, GLM is an effective, well-tolerated option for the treatment of RA, for both the clinician and patients who are seeking a convenient dosage scheme.
Objective
This study aimed to investigate the efficacy, safety and survival of TNF-α inhibitors in patients with rheumatoid arthritis (RA).
Methods
A total of 178 patients over 18 years, were treated with anti-TNF-α inhibitors. Seventy four were treated with infliximab, 75 with adalimumab and 29 with etanercept. Each patient was followed-up for a period of 8 years.
Results
Anti-TNFα therapy resulted in rapid clinical improvement. The rate of good/moderate response according to EULAR response criteria for the index DAS-28-CRP in the first 6 months was 82% for infliximab, 89,6% for adalimumab and 95,6% for etanercept. The rate of withdrawal in eight years was 80% for patients on infliximab, 61,4% for patients on adalimumab and 47,6% for patients on etanercept. The main reasons for discontinuation were allergic reactions for infliximab (rate of discontinuation 25,7%) and inefficacy for adalimumab and etanercept (17,5% and 23,8%, respectively). Systemic allergic reactions and infections were significantly more frequent in infliximab group (p < 0,05 and p < 0,001, respectively). However, there was no significant difference among the three drugs concerning serious infections. According to Kaplan Meier survival analysis a significantly faster withdrawal for infliximab patients was depicted comparing to adalimumab (p = 0,003) and etanercept (p = 0,019), while adalimumab and etanercept were not statistically different (p = 0,089).
Conclusions
TNF-α inhibitors establish an effective therapeutic option in RA showing an acceptable safety profile. Infections and allergic reactions appear more often with infliximab, while serious infections did not differ among them. RA patients treated with infliximab are more likely to discontinue treatment earlier comparing to the other alternatives.
Opioids are the most effective drugs for the treatment of severe pain, but they also cause addiction and overdose deaths, which have led to a worldwide opioid crisis. Therefore, the development of safer opioids is urgently needed. In this article, we provide a critical overview of emerging opioid-based strategies aimed at effective pain relief and improved side effect profiles. These approaches comprise biased agonism, the targeting of (i) opioid receptors in peripheral inflamed tissue (by reducing agonist access to the brain, the use of nanocarriers, or low pH-sensitive agonists); (ii) heteromers or multiple receptors (by monovalent, bivalent, and multifunctional ligands); (iii) receptor splice variants; and (iv) endogenous opioid peptides (by preventing their degradation or enhancing their production by gene transfer). Substantial advancements are underscored by pharmaceutical development of new opioids such as peripheral κ-receptor agonists, and by treatments augmenting the action of endogenous opioids, which have entered clinical trials. Additionally, there are several promising novel opioids comprehensively examined in preclinical studies, but also strategies such as biased agonism, which might require careful rethinking.
Objective
The opioid epidemic is a major public health concern. However, little is known about opioid use among rheumatoid arthritis (RA) patients. We undertook this study to examine trends in chronic opioid use in RA patients in 2002–2015 and to identify clinical predictors.
Methods
RA patients were identified from the Corrona registry. Opioid use was ascertained from surveys obtained at clinical visits as often as every 3 months. Chronic opioid use was defined as any opioid use reported during ≥2 consecutive study visits. Annual prevalence of chronic opioid use was calculated using data from 33,739 RA patients with information on opioid use from ≥2 visits. Among the 26,288 individuals who were not taking opioids at baseline, Cox proportional hazards models identified associations between patient characteristics and incident chronic opioid use. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated.
Results
Chronic opioid use increased from 7.4% in 2002 to 16.9% in 2015. Severe pain (HR 2.53 [95% CI 2.19–2.92]) and antidepressant use (HR 1.79 [95% CI 1.64–1.92]) were associated with an increased risk of chronic opioid use. High disease activity (HR 1.55 [95% CI 1.30–1.84]) and a high level of disability (HR 1.45 [95% CI 1.27–1.65]) were also associated with chronic opioid use, whereas Asian ethnicity (HR 0.49 [95% CI 0.36–0.68]) was associated with a decreased risk of chronic opioid use.
Conclusion
Among RA patients, chronic opioid use doubled from 2002 to 2015. Pain and antidepressant use were the strongest predictors of chronic opioid use. To curb the rise in chronic opioid use, strategies for stringent control of RA disease activity and management of pain and depression should be research priorities.
COX2-selective and nonselective (ns) nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for chronic pain management. There are marked differences in the risk of adverse gastrointestinal (GI) and cardiovascular (CV) events among different NSAIDs. In 2017, publication of two randomized controlled trials and an individual patient-data meta-analysis provided robust data on the relative GI and CV tolerability profiles of currently available NSAIDs. The PRECISION study showed similar CV-event rates with celecoxib vs naproxen and ibuprofen, but GI tolerability was better for celecoxib. In the CONCERN study of high-GI-risk patients, celecoxib was associated with fewer adverse GI-tract events than naproxen. The meta-analysis showed no significant difference between celecoxib and ns-NSAIDs in the rate of acute myocardial infarction, and celecoxib was the only COX2-selective NSAID with a lower risk of adverse CV and GI events vs ns-NSAIDs. These data add to the body of knowledge about the relative tolerability of different NSAIDs and were used to propose an updated treatment algorithm. The decision about whether to use an NSAID and which one should be based on a patient’s risk of developing adverse GI and CV events. Lower- and upper-GI-tract events need to be considered. Celecoxib has a better lower-GI-tract tolerability profile than ns-NSAIDs plus a proton-pump inhibitor. In addition, the latest data suggest that long-term use of celecoxib 200 mg/day may be appropriate for patients at increased CV risk.
Purpose of Review
Cancer-associated pain is a serious and feared consequence of advanced disease, particularly in the emergency room setting, when the treating physician, and a full history of the condition is often unavailable. Opioids remain the mainstay of cancer pain treatment, and with this come the side effects and complications of opioid use, which are attenuated in the cancer pain patient who already may have anxiety and depression exacerbating their pain symptoms. This article seeks to provide an update on the current knowledge and concepts in cancer pain management with an attempt to provide practical education for use in the emergency room.
Recent Findings
Pain presents in various ways, manifesting as either nociceptive or neuropathic types. Classification systems such as the DN4 questionnaire and the Zubrod scoring system have been established in an attempt to provide guidelines for the evaluation and treatment of cancer-associated pain and provide a quick and efficient way to evaluate pain in the ER setting and to guide treatment.
Summary
There are many options for pain control in the cancer patient, consisting of intravenous, oral, or topical medications in order to address the full spectrum of pain, and selection of the appropriate treatment should address as much of the nociceptive and neuropathic pain components as possible, often requiring combination therapy.
Background:
Pain accompanies rheumatoid arthritis and other chronic inflammatory conditions and is difficult to manage. Although opioids provide potent analgesia, chronic opioid use can cause tolerance and addiction. Recent studies have demonstrated functional interactions between chemokine and opioid receptor signaling pathways. Reported heterodimerization of chemokine and opioid receptors led our group to develop bivalent compounds that bind both types of receptors, with the goal of targeting opioids to sites of inflammation. MCC22 is a novel bivalent compound containing a CCR5 antagonist and mu opioid receptor (MOR) agonist pharmacophores linked through a 22-atom spacer. We evaluated the efficacy of MCC22 in the K/B.g7 T-cell receptor transgenic mouse model of spontaneous inflammatory arthritis.
Methods:
MCC22 or morphine was administered intraperitoneally at varying doses to arthritic K/B.g7 mice or nonarthritic control mice. Mechanical pain hypersensitivity was measured each day before and after drug administration, using the electronic von Frey test. The potency of MCC22 relative to that of morphine was calculated. Functional readouts of pain included grip strength and nesting behavior. A separate dosing regimen was used to determine whether the drugs induced pharmacologic tolerance.
Results:
MCC22 provided ~ 3000-fold more potent analgesia than morphine in this model. Daily treatment with MCC22 also led to a cumulative analgesic effect, reducing the daily baseline pain level. MCC22 produced no observable analgesic effect in nonarthritic control mice. Importantly, repeated administration of MCC22 did not induce pharmacologic tolerance, whereas a similar regimen of morphine did. Both grip strength and nesting behaviors improved among arthritic mice treated with MCC22. Ankle thickness and arthritis scores were not affected by MCC22. The analgesic effect of MCC22 was abolished in K/B.g7 mice genetically lacking CCR5, demonstrating the receptor specificity of the antagonist pharmacophore.
Conclusions:
MCC22 is a novel bivalent ligand that targets CCR5 and MOR. Our findings demonstrate that MCC22 provides highly potent analgesia and improved functional outcomes in a model of inflammatory arthritis, without inducing typical opioid tolerance. These findings suggest that MCC22 or similar compounds could be used to treat the pain associated with inflammatory arthritis and related conditions, while minimizing the risks typically associated with chronic opioid use.
Recently, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), a newly designed μ-opioid receptor (MOR) agonist with a low pKa, has been shown to produce injury-restricted analgesia in models of inflammatory and postoperative pain, without exhibiting typical opioid side effects. Here, we investigated MOR binding of NFEPP in brain and dorsal root ganglia (DRG), pH in injured tissues, and the analgesic efficacy of NFEPP compared to fentanyl in a chronic constriction injury (CCI) model of neuropathic pain, and in the acetic acid-induced abdominal writhing assay in rats. Binding experiments revealed significantly lower affinity of NFEPP compared to fentanyl at pH 7.4. In vivo, pH significantly dropped both at injured nerves following CCI and in the abdominal cavity after acetic acid administration. Intravenous NFEPP as well as fentanyl dose-dependently diminished neuropathy-induced mechanical and heat hypersensitivity, and acetic acid-induced abdominal constrictions. In both models, NFEPP-induced analgesia was fully reversed by naloxone methiodide, a peripherally-restricted opioid receptor antagonist, injected at the nerve injury site or into the abdominal cavity. Our results indicate that NFEPP exerts peripheral opioid receptor-mediated analgesia exclusively in damaged tissue in models of neuropathic and abdominal pain.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Novel pain killers without adverse effects are urgently needed. Opioids induce central and intestinal side effects such as respiratory depression, sedation, addiction, and constipation. We have recently shown that a newly designed agonist with a reduced acid dissociation constant (pKa) abolished pain by selectively activating peripheral μ-opioid receptors (MOR) in inflamed (acidic) tissues without eliciting side effects. Here, we extended this concept in that pKa reduction to 7.22 was achieved by placing a fluorine atom at the ethylidene bridge in the parental molecule fentanyl. The new compound (FF3) showed pH-sensitive MOR affinity, [35S]-GTPγS binding, and G protein dissociation by fluorescence resonance energy transfer. It produced injury-restricted analgesia in rat models of inflammatory, postoperative, abdominal, and neuropathic pain. At high dosages, FF3 induced sedation, motor disturbance, reward, constipation, and respiratory depression. These results support our hypothesis that a ligand's pKa should be close to the pH of injured tissue to obtain analgesia without side effects.
IntroductionHere we examine the relationship between achieving different levels of disease activity with tofacitinib (an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis), long-term structural progression, and patient-reported physical function.Methods
This was a post hoc analysis of two 24-month, phase III randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder (IR) patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily as either monotherapy or with background MTX. The modified total Sharp score (mTSS) and Health Assessment Questionnaire-Disability Index (HAQ-DI) were analyzed at month 24 according to disease activity at month 6 defined by the Clinical Disease Activity Index (CDAI) or the Disease Activity Score in 28 joints, C-reactive protein (DAS28CRP).ResultsMean changes from baseline in mTSS at month 24 were less in patients with CDAI remission at month 6 than in those with CDAI moderate/high disease activity (MDA/HDA) at month 6. A DAS28CRP of < 1.9 most closely approximated CDAI remission (≤ 2.8). Tofacitinib appeared to inhibit joint damage in the presence of persistent inflammation compared with MTX. More patients receiving tofacitinib or MTX with CDAI remission or low disease activity (LDA) at month 6 reported normative HAQ-DI scores (< 0.5) at month 24 than did those with CDAI MDA/HDA.Conclusion
Regardless of treatment, in both MTX-naïve and MTX-IR patients, remission or LDA at month 6 was associated with successful long-term outcomes: inhibition of structural progression and normative HAQ-DI scores. Long-term outcomes were similar when patients achieved CDAI remission or a DAS28CRP of < 1.9, confirming that this is an appropriate cut-off for remission with DAS28CRP. Tofacitinib potentially inhibits joint damage even with persistent inflammation.FundingPfizer Inc.Trial registrationClinicaltrials.gov identifiers: NCT01039688 and NCT00847613.
Background:
Most clinical opioids act through μ-opioid receptors. They effectively relieve pain but are limited by side effects, such as constipation, respiratory depression, dependence, and addiction. Many efforts have been made toward developing potent analgesics that lack side effects. Three-iodobenzoyl-6β-naltrexamide (IBNtxA) is a novel class of opioid active against thermal, inflammatory, and neuropathic pain, without respiratory depression, physical dependence, and reward behavior. The μ-opioid receptor (OPRM1) gene undergoes extensive alternative precursor messenger ribonucleic acid splicing, generating multiple splice variants that are conserved from rodents to humans. One type of variant is the exon 11 (E11)-associated truncated variant containing 6 transmembrane domains (6TM variant). There are 5 6TM variants in the mouse OPRM1 gene, including mMOR-1G, mMOR-1M, mMOR-1N, mMOR-1K, and mMOR-1L. Gene-targeting mouse models selectively removing 6TM variants in E11 knockout (KO) mice eliminated IBNtxA analgesia without affecting morphine analgesia. Conversely, morphine analgesia is lost in an exon 1 (E1) KO mouse that lacks all 7 transmembrane (7TM) variants but retains 6TM variant expression, while IBNtxA analgesia remains intact. Elimination of both E1 and E11 in an E1/E11 double KO mice abolishes both morphine and IBNtxA analgesia. Reconstituting expression of the 6TM variant mMOR-1G in E1/E11 KO mice through lentiviral expression rescued IBNtxA but not morphine analgesia. The aim of this study was to investigate the effect of lentiviral expression of the other 6TM variants in E1/E11 KO mice on IBNtxA analgesia.
Methods:
Lentiviruses expressing 6TM variants were packaged in HEK293T cells, concentrated by ultracentrifugation, and intrathecally administered 3 times. Opioid analgesia was determined using a radiant-heat tail-flick assay. Expression of lentiviral 6TM variant messenger ribonucleic acids was examined by polymerase chain reaction (PCR) or quantitative PCR.
Results:
All the 6TM variants restored IBNtxA analgesia in the E1/E11 KO mouse, while morphine remained inactive. Expression of lentiviral 6TM variants was confirmed by PCR or quantitative PCR. IBNtxA median effective dose values determined from cumulative dose-response studies in the rescued mice were indistinguishable from wild-type animals. IBNtxA analgesia was maintained for up to 33 weeks in the rescue mice and was readily antagonized by the opioid antagonist levallorphan.
Conclusions:
Our study demonstrated the pharmacological relevance of mouse 6TM variants in IBNtxA analgesia and established that a common functional core of the receptors corresponding to the transmembrane domains encoded by exons 2 and 3 is sufficient for activity. Thus, 6TM variants offer potential therapeutic targets for a distinct class of analgesics that are effective against broad-spectrum pain models without many side effects associated with traditional opioids.
This study evaluates the prophylactic effect of the peripherally-selective mu-opioid receptor agonist, loperamide, administered topically in a liposomal gel formulation on pain, inflammation, and disease progression in the adjuvant-induced model of experimental rheumatoid arthritis in female Lewis rats. In a randomized, blinded and controlled animal trial, AIA rats were divided into six groups consisting of eleven rats per group based on the following treatments: loperamide liposomal gel, free loperamide gel, empty liposomal gel, diclofenac gel (Voltaren®), no treatment, and naive control. Topical formulations were applied daily for a maximum of 17 days—starting from day 0 at the same time as immunization. The time course of the effect of the treatments on antinocieption and inflammation was assessed using a paw pressure analgesiometer and plethysmometer, respectively. Arthritis progression was scored daily using an established scoring protocol. At the end of the study, hind paws were processed for histological analysis. Administration of loperamide liposomal gel daily across the duration of the study produced significant peripheral antinociception as expected; however, increased the severity of inflammation and accelerated arthritis progression. This was indicated by an increase in paw volume, behavioral and observational scoring, and histological analysis compared to the control groups. In particular, histology results showed an increase in pannus formation and synovial inflammation, as well as an upregulation of markers of inflammation and angiogenesis. These findings may have implications for the use of loperamide and other opioids in arthritis and potentially other chronic inflammatory diseases.
Opioid receptors and their ligands produce powerful analgesia that is effective in perioperative period and chronic pain managements accompanied with various side effects including respiratory depression, constipation and addiction etc. Opioids can also interfere with the immune system, not only participating in the function of the immune cells, but also modulating innate and acquired immune responses.
The traditional notion of opioids is immunosuppressive. Recent studies indicate that the role of opioid receptors on immune function is complicated, working through various different mechanisms. Different opioids or opioids administrations show various effects on the immune system: immunosuppressive, immunostimulatory, or dual effect. It is important to elucidate the relationship between opioids and immune function, since immune system plays critical role in various physiological and pathophysiological processes, including the inflammation, tumor growth and metastasis, drug abuse, and so on. This review article tends to have an overview of the recent work and perspectives on opioids and the immune function.
Background
T cell-derived opioids play a key role in the control of inflammatory pain. However, the nature of opioids produced by T cells is still matter of debate in mice. Whereas β-endorphin has been found in T lymphocytes by using antibody-based methods, messenger RNA (mRNA) quantification shows mainly mRNA encoding for enkephalins. The objective of the study is to elucidate the nature of T cell-derived opioids responsible for analgesia and clarify discrepancy of the results at the protein and genetic levels.
Methods
CD4+ T lymphocytes were isolated from wild-type and enkephalin-deficient mice. mRNA encoding for β-endorphin and enkephalin was quantified by RT-qPCR. The binding of commercially available polyclonal anti-endorphin antibodies to lymphocytes from wild-type or enkephalin knockout mice was assessed by cytofluorometry. Opioid-mediated analgesic properties of T lymphocytes from wild-type and enkephalin-deficient mice were compared in a model of inflammation-induced somatic pain by measuring sensitivity to mechanical stimuli using calibrated von Frey filaments.
Results
CD4+ T lymphocytes expressed high level of mRNA encoding for enkephalins but not for β-endorphin in mice. Anti-β-endorphin polyclonal IgG antibodies are specific for β-endorphin but cross-react with enkephalins. Anti-β-endorphin polyclonal antibodies bound to wild-type but not enkephalin-deficient CD4+ T lymphocytes. Endogenous regulation of inflammatory pain by wild-type T lymphocytes was completely abolished when T lymphocytes were deficient in enkephalins. Pain behavior of immune-deficient (i.e., without B and T lymphocytes) mice was superimposable to that of mice transferred with enkephalin-deficient lymphocytes.
Conclusions
Rabbit polyclonal anti-β-endorphin serum IgG bind to CD4+ T lymphocytes because of their cross-reactivity towards enkephalins. Thus, staining of T lymphocytes by anti-β-endorphin polyclonal IgG reported in most of studies in mice is because of their binding to enkephalins. In mice, CD4+ T lymphocytes completely lose their analgesic opioid-mediated activity when lacking enkephalins.
Objective:
Summarize the comparative effectiveness of oral non-steroidal anti-inflammatory drugs (NSAIDs) and opioids in reducing knee osteoarthritis (OA) pain.
Methods:
Two reviewers independently screened reports of randomized controlled trials, published in English between 1982 and 2015, evaluating oral NSAIDs or opioids for knee OA. Included studies were at least eight weeks duration, conducted in Western Europe, the Americas, New Zealand, or Australia, and reported baseline and follow-up pain using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale (0-100, 100-worst). Effectiveness was evaluated as reduction in pain, accounting for study dropout and heterogeneity.
Results:
27 treatment arms (9 celecoxib, 4 non-selective NSAIDs [diclofenac, naproxen, piroxicam], 11 less potent opioids [tramadol], and 3 potent opioids [hydromorphone, oxycodone]) from 17 studies were included. NSAID and opioid studies reported similar baseline demographics and efficacy withdrawal rates; NSAID studies reported lower baseline pain and toxicity withdrawal rates. Accounting for efficacy-related withdrawals, all drug classes were associated with similar pain reductions (NSAIDs: -18; less potent opioids: -18; potent opioids: -19). Meta-regression did not reveal differential effectiveness by drug class but found that study cohorts with a higher proportion of male subjects and worse mean baseline pain had greater pain reduction. Similarly, results of the network meta-analysis did not find a significant difference in WOMAC Pain reduction for the three analgesic classes.
Conclusion:
NSAIDs and opioids offer similar pain relief in OA patients. These data could help clinicians and patients discuss likely benefits of alternative analgesics.
Longitudinal care of a community-based cohort of patients with rheumatoid arthritis (RA) was evaluated retrospectively. Candidate determinants of disability included visual analog scales (VAS) for patient global assessment and pain, comorbidities, and medications. The outcome was the ‘patient-acceptable symptom state’ for disability as defined by the Health Assessment Questionnaire (HAQ) disability index, using a cutoff of <1.04. Two-sample t tests and multivariable logistic regression were used to determine odds ratios (OR) for associations between predictor variables and disability. Out of a total of 99 patients, 28 (28%) patients had HAQ ≥1.04 at their last visit. The greatest odds of not attaining the patient-acceptable symptom state in a multivariable model was associated with corticosteroids (OR: 5.1; p=0.02), antidepressants (OR: 5.3; p=0.02), and female sex (OR: 6.5; p=0.05). In the era of biologic therapy, female sex, corticosteroids, and antidepressants remain profound determinants of disability highlighting the need to understand the underlying mechanisms.
The efficacy and safety of long-term (≥ 6 months) opioid therapy (LtOT) in chronic noncancer pain (CNCP) is under debate. A systematic review with meta-analysis of the efficacy and harms of opioids in open-label extension studies of randomized controlled trials (RCTs) has not been conducted until now.
We screened MEDLINE and clinicaltrials.gov (through to December 2013), as well as reference sections of systematic reviews of long-term RCTs of opioids in CNCP. We included open-label extension trials with a study duration ≥ 26 weeks of RCTs of ≥ 2 weeks duration. Using a random effects model, pooled estimates of event rates for categorical data and standardized mean differences (SMD) for continuous variables were calculated.
We included 11 open-label extension studies with 2445 participants with nociceptive (low back, osteoarthritis) and neuropathic (radicular, polyneuropathy) pain. Median study duration was 26 (range 26-108) weeks. Four studies tested oxycodone, two studies tramadol and buprenorphine; hydromorphone, morphine, oxymorphone and tapentadol were each tested in one study. Of the patients randomized at baseline, 28.5 % (95 % confidence interval, CI, 17.9-39.2 %) finished the open-label period; 53.5 % (95 % CI 38.1-68.2 %) of patients entering the open-label period finished the open-label period. In sum, the total loss was 71.5 % (95 % CI 60.9-83.1 %) of all patients primarily included into the RCT. A total of 4.9 % (95 % CI 2.9-8.2 %) of patients dropped out due lack of efficacy; 16.8 % (95 % CI 11.0-24.8 %) dropped out to due adverse events (AE) in the open-label period and 0.08 % (95 % CI 0.001-0.05 %) of patients died during the open-label period. Only one study systematically assessed aberrant drug behavior of the patients: 5.7 % (95 % CI 3.4-9.6 %) showed aberrant drug behavior in the opinion of the investigators and 2.6 % (95 % CI 1.2-5.8 %) were judged to show aberrant drug behavior by independent expert assessment. There was no significant change (p = 0.50) in pain intensity between the end of the randomized period and the end of open-label phase (SMD 0.19 [- 0.03, 0.41]; six studies with 1360 participants).
Only a minority of patients selected for opioid therapy at randomization finished the long-term open-label study. However, sustained effects of pain reduction could be demonstrated in these patients. LtOT can be considered in carefully selected and monitored CNCP patients who experience clinically meaningful pain reduction with at least tolerable AE in short-term opioid therapy. The English full-text version of this article is freely available at SpringerLink (under "Supplementary Material").
Sustained delivery of analgesic agents at target sites remains a critical issue for effective pain management. The use of nanocarriers has been reported to facilitate effective delivery of these agents to target sites while minimizing systemic toxicity. These include the use of biodegradable liposomal or polymeric carriers. Of these, liposomes present as an attractive delivery system due to their flexible physicochemical properties which allow easy manipulation in order to address different delivery considerations. Their favorable toxicity profiles and ease of large scale production also make their clinical use feasible. In this review, we will discuss the concept of using liposomes as a drug delivery carrier, their in vitro characteristics as well as in vivo behavior. Current advances in the targeted liposomal delivery of analgesic agents and their impacts on the field of pain management will be presented.
Introduction:
Centrally acting opioids are well established in the treatment of acute, surgical and cancer pain. However, their use in chronic noncancer pain (CNCP) is controversial because of side effects such as tolerance, somnolence, respiratory depression, confusion, constipation and addiction. Chronic arthritis and other musculoskeletal diseases are among the leading causes of CNCP.
Areas covered:
This manuscript will discuss the role of conventional opioids in chronic arthritis. In addition, future developments and strategies exploiting peripheral effects of opioids on pain and inflammation will be outlined.
Expert opinion:
Aims in drug development include the design of peripherally restricted opioid agonists, selective targeting of endogenous opioids to sites of painful injury and the augmentation of peripheral ligand and receptor synthesis, for example, by gene therapy. Although a large number of peripherally acting opioid compounds have been developed, clinical Phase III studies have not been published so far. Another strategy is to augment the effects of endogenously released opioid peptides by the inhibition of their degrading enzymes. Technology-oriented research is needed to find novel ways of peripheral restriction of opioids. Such analgesics would be desirable for their lack of central side effects and of adverse effects typical of nonsteroidal anti-inflammatory drugs (gastrointestinal ulcers, bleeding, myocardial infarction and stroke).
Opioids are a group of analgesic agents commonly used in clinical practice. There are three classical opioid receptors (DOP, KOP and MOP), while the novel NOP receptor is considered to be a non-opioid branch of the opioid receptor family. Opioids can act at these receptors as agonists, antagonists or partial agonists. Opioid agonists bind to G-protein coupled receptors to cause cellular hyperpolarisation. Most clinically relevant opioid analgesics bind to MOP receptors in the central and peripheral nervous system in an agonist manner to elicit analgesia. Opioids may also be classified according to their mode of synthesis into alkaloids, semi-synthetic and synthetic compounds.
The worldwide use of opiates is increasing yet there is little evidence that in long-term, non-cancer patients, they have an efficacious effect on functional outcomes and quality of life measures. Although it seems paradoxical, chronic opiate use may lead to a pro-nociceptive state. Mechanisms for the development of the hyperalgesic state include activation of the opiate bimodal regulatory systems, dynorphin and spinal cord glia. A potential consequence of chronic opiate usage is the development of narcotic bowel syndrome, which is characterized by chronic or intermittent colicky abdominal pain or discomfort that worsens after the narcotic effects of opiates wear off. It is likely that this is an under-recognized diagnosis. We describe here a case of 26-year old female who had visited our institution multiple times with intractable chronic abdominal pain in the context of normal findings on haematological, biochemical, metabolic, endoscopic and radiological investigations. She had been treated with a multitude of opioid agonists with escalating doses. A diagnosis of narcotic bowel syndrome was made. On elective admission her daily analgesic requirements were 150 µg/hr fentanyl, 100 mg oramorph and 400 mg tramadol (equating to 740 mg oral morphine/24 hr). A detoxification regimen was prescribed which included rapid opiate withdrawal couple with the commencement of methadone, lorazepam, clonidine and duloxetine. She was discharged opiate free, with no abdominal pain, 14 days after admission. Clinicians must be aware of narcotic bowel syndrome, which is often erroneously labelled as a functional gastrointestinal disorder, in patients who have been on long-term opiates.
The concept of ligand bias at G protein-coupled receptors broadens the possibilities for agonist activities and provides the opportunity to develop safer, more selective therapeutics. Morphine pharmacology in beta-arrestin2 knock out mice suggested that a ligand that promotes coupling of the mu-opioid receptor (MOR) to G proteins, but not beta-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine. Here we report the discovery of TRV130 ([(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine), a novel MOR G protein-biased ligand. In cell-based assays, TRV130 elicits robust G protein signaling, with potency and efficacy similar to morphine, but with far less beta-arrestin recruitment and receptor internalization. In mice and rats, TRV130 is potently analgesic while causing less gastrointestinal dysfunction and respiratory suppression than morphine at equianalgesic doses. TRV130 successfully translates genetic evidence of distinct analgesic and adverse MOR signaling pathways into a biased ligand with differentiated pharmacology. These preclinical data suggest that TRV130 may be a safer and more tolerable therapeutic for treating severe pain.
Objective:
This 5-year observational posthoc analysis of the REFLEX study and its open-label extension assessed clinical efficacy, radiographic response, and safety of rituximab (RTX) in patients with rheumatoid arthritis (RA) who had an inadequate response to tumor necrosis factor (TNF) inhibitors.
Methods:
Patients in REFLEX were originally randomized to placebo (PBO) + methotrexate (MTX; PBO-randomized) or RTX + MTX (RTX-randomized). PBO-randomized patients were rescued with RTX as appropriate. Patients responding to initial RTX treatment could receive further RTX courses. For clinical efficacy and safety analyses, PBO-randomized patients were re-baselined prior to first RTX treatment and the data were pooled with RTX-randomized patient data. Efficacy outcomes 24 weeks after each course were calculated relative to first RTX pretreatment baseline. Radiographic outcomes were assessed relative to randomization baseline for both PBO-randomized and RTX-randomized groups.
Results:
A total of 480 patients received ≥ 1 RTX course. At 24 weeks, American College of Rheumatology 20/50/70 responses were 62.0%, 30.8%, and 13.0%, respectively at course 1 (n = 400) and 70.3%, 41.8%, and 22.0% at course 5 (n = 91). European League Against Rheumatism good/moderate responses were 77.2% and 84.4% at courses 1 (n = 390) and 5 (n = 90). Rates of adverse events (AE), serious AE, and infections generally remained stable. Rate of progressive joint damage (PJD; change in mean Total Sharp Score) decreased over time in both PBO-randomized (n = 79) and RTX-randomized (n = 105) groups. Mean change from baseline in PJD over 5 years was greater in PBO-randomized versus RTX-randomized patients (5.51 vs 3.21).
Conclusion:
RTX re-treatment over 5 years is associated with maintained or improved efficacy, continued inhibition of PJD, and a safety profile consistent with that previously reported. A delay in initiating RTX treatment may result in increased PJD.
This article provides an integrative review of the literature on long-term opioid use, its effects on the cardiovascular system, and its implications for nurses.
Introduction: Biosimilars are highly similar molecules to other biological medicines that have already been authorised for use. Etanercept (ETN) was the first anti-tumour necrosis factor inhibitor (TNFi) approved by the Food and Drug Administration for the treatment of moderate to severe rheumatoid arthritis (RA) in November 1998 and in February 2000 by the European Medicines Agency. Twenty years later, the first ETN biosimilar has come of age.
Areas covered: In this review we examined SB-4 as a biosimilar candidate to ETN, focusing on the available data. Current data indicate that SB-4 is a highly similar alternative to ETN in terms of safety, efficacy, tolerability and immunogenicity. SB-4 has already been approved by health authorities in Europe, South Korea, Australia and Canada, as a subcutaneous therapy option for the treatment of patients with RA but also for the full spectrum approved for its bio-originator ETN.
Expert opinion: The current body of evidence suggests that all biologic activities have been demonstrated to be equivalent between SB-4 and the originator, including pharmacodynamic and pharmacokinetic activities. In some areas, and more specifically when it comes to immunogenicity, SB-4 showed lower incidents. Therefore, it is fully expected to have same efficacy and safety in all indications.
Objectives:
To estimate the size of unmet needs in the treatment of early Rheumatoid Arthritis (eRA), using all the conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and/or biological DMARDs (bDMARDs) in a long-term observational study.
Materials and methods:
538 patients with eRA were evaluated. The 2010 ACR/EULAR classification criteria were used. All patients were csDMARDs and bDMARDs-naive with disease duration less than one year. They were treated according to EULAR and ACR recommendations for RA. All the csDMARDs and bDMARDs were used. Clinical, laboratory findings with the disease activity score-28 and treatment decisions were all recorded as well as adverse drug reactions, reason of therapy termination, disease complications and comorbidities.
Results:
Methotrexate (58%) and Infliximab (37%) where the first csDMARD and bDMARD choice respectively. During follow-up, 14 patients were lost and 7 developed comorbidities. The final results are referred to 517 patients. Among those, 66% were treated with csDMARDs as monotherapy or in combination therapy with sustained low disease activity (LDA). However, 3.2% from this group neither achieved LDA, nor received bDMARDs, due to comorbidities. On the other hand, 34% were treated with bDMARDs with or without csDMARDs. The majority of them demonstrated sustained LDA. From this group, 17.7% never achieved LDA, despite that they switched and received all bDMARDs. Thus, 20.9% of our patients never achieved LDA.
Conclusions:
Using the current recommendations for RA therapy we successfully treated the majority of our patients. However, we found that the size of gap and the unmet needs for treatment is about 20%.
Opioid receptors (ORs) precisely modulate behavior when activated by native peptide ligands but distort behaviors to produce pathology when activated by non-peptide drugs. A fundamental question is how drugs differ from peptides in their actions on target neurons. Here, we show that drugs differ in the subcellular location at which they activate ORs. We develop a genetically encoded biosensor that directly detects ligand-induced activation of ORs and uncover a real-time map of the spatiotemporal organization of OR activation in living neurons. Peptide agonists produce a characteristic activation pattern initiated in the plasma membrane and propagating to endosomes after receptor internalization. Drugs produce a different activation pattern by additionally driving OR activation in the somatic Golgi apparatus and Golgi elements extending throughout the dendritic arbor. These results establish an approach to probe the cellular basis of neuromodulation and reveal that drugs distort the spatiotemporal landscape of neuronal OR activation.
Chronic constipation is a very common medical problem with relevant impact on the patients' quality of life. Modern definitions recognize constipation as a polysymptomatic disorder, including various aspects of disturbed defecation. Current guidelines recommend a stepwise approach in the management of chronic constipation. Isolated or concomitant evacuation disorders should be identified and may need differential/additional treatment. Baseline measures include lifestyle components and bulking agents. The next step recommends treatment with conventional laxatives. In refractory patients, modern medical therapies, such as the prokinetic prucalopride or the secretagogues linalotide or lubiprostone, may be used effectively. For patients with opioid-induced constipation, the modern concept of peripherally acting µ-opioid antagonists has shown to successfully improve this increasing medical problem and even to potentially increase survival time in terminally ill patients on opioid therapy. Prolonged-released oral naloxone (in fixed combination with oxycodone), oral naloxegol or naldemedine, and subcutaneous methylnaltrexone have all demonstrated good efficacy and tolerability in the treatment of opioid-induced constipation. To adequately apply stepwise treatment algorithms, a simple tool to identify treatment failure may improve patient care.
Introduction: Rheumatoid arthritis (RA) is an autoimmune disease, which has a negative impact on the ability to perform activities daily. Tumour necrosis factor α (TNF) is a cytokine with diverse cellular effects, and a key regulator of the inflammatory response. ABP 501 is a biosimilar to adalimumab, a TNF inhibitor.
Areas covered: In this review, we examined ABP 501, as a biosimilar candidate to adalimumab in the treatment of RA focusing on the available data. Current data indicate that ABP 501 is a highly similar alternative to adalimumab in terms of safety, efficacy, tolerability and immunogenicity. ABP 501 has already been approved by health authorities in Europe and the United States of America, as a subcutaneous (s.c.) therapy option for the treatment of patients with RA, but also for the full spectrum approved for its bio-originator adalimumab.
Expert opinion: Current body of evidence suggests that all biologic activities have been demonstrated to be equivalent between ABP 501 and the originator, including binding rates and affinity to TNF, and also the effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC). Therefore, it is fully expected to have same efficacy and safety in all indications.
Context:
Opioid-induced constipation is a common problem associated with chronic use of opioid analgesics.
Objectives:
To compare available interventions for the treatment of opioid-induced constipation, using principles of network meta-analysis.
Methods:
Electronic databases were searched for randomized controlled clinical trials evaluating drugs used in opioid induced constipation. Number of patients with rescue-free bowel movements (RFBM) was the primary outcome and time for achieving RFBM, adverse events and changes in the analgesic activity of the opioid analgesics were the secondary outcomes. Inverse variance heterogeneity model was used for direct and mixed treatment comparison analysis. Odds ratio for categorical outcomes and weighted mean difference for numerical outcomes were the effect estimates.
Results:
We included a total of 23 studies in the systematic review and 21 in the network meta-analysis. Lubriprostone, prucalopride, naldemedine, naloxegol, alvimopan, subcutaneous and oral methyl naltrexone were observed to perform better than placebo in terms of RFBM. Additionally, subcutaneous methyl naltrexone was significantly better than lubiprostone, naloxegol, oral methyl naltrexone and prucalopride. Lubiprostone and naldemedine were associated with increased risks of adverse events. Sub-cutaneous methyl naltrexone did not significantly affect the analgesia due to background opioid use. Quality of evidence for the comparisons is either low or very low.
Conclusion:
Subcutaneous methyl naltrexone was found to perform better than other interventions for managing opioid-induced constipation.
Objective:
Opioid prescribing recently has come under intense scrutiny. However, longitudinal patterns of prescription opioid receipt in a population-based cohort of patients with chronic pain, such as those with rheumatoid arthritis (RA), have not been well characterized. The aim of this study was to examine both trends over time and variability in individual physician prescribing of short-term and long-term use of opioids.
Methods:
We identified a cohort of RA patients based on 2006-2014 Medicare data and evaluated longitudinal time trends in "regular" use of opioids. A separate analysis conducted in 2014 assessed rheumatologist-specific variability in regular use of opioid prescriptions in patients with RA.
Results:
We identified 97,859 RA patients meeting the eligibility criteria. The mean age of the patients was 67 years, 80% were female, 82% were white, and 12% were African American. The most commonly used opioids were those that combined acetaminophen with hydrocodone or propoxyphene. Regular opioid prescribing increased slowly but peaked in 2010 before propoxyphene was withdrawn from the market. Following the withdrawal of propoxyphene, receipt of hydrocodone and tramadol increased commensurately, and overall opioid use declined only slightly. Factors associated with regular use of opioids included younger age, female sex, African American race, back pain, fibromyalgia, anxiety, and depression. Variability between US rheumatologists (n = 4,024) in prescribing the regular use of opioids for their RA patients was high; in the average rheumatologist's practice, 40% of RA patients used prescription opioids regularly. In almost half of the patients, at least some opioid prescriptions were written by a rheumatologist, and 14% received opioids that were co-prescribed concurrently by more than 1 physician.
Conclusion:
In the US, opioid use in older patients with RA peaked in 2010 and is now declining slightly. Withdrawal of propoxyphene from the US market in 2010 had minimal effect on overall opioid use, because use of propoxyphene was replaced by increased use of other opioids.
A pain killer without side effects
Opioids are very strong and effective pain killers. However, they also have a range of well-known side effects and can cause addiction. Painful conditions such as inflammation or trauma are often associated with localized tissue acidification. Spahn et al. designed a novel opioid receptor agonist that, unlike clinically used opioids, best activates the receptors in such acidified tissues. In rat models of inflammatory pain, the new drug exerted strong pain relief essentially without the side effects of standard opioids.
Science , this issue p. 966
Opioid prescriptions have seen an increase across the USA, Canada, Europe, and the UK. In the USA, they have quadrupled from 1999 to 2010. Opioid use among patients with rheumatoid arthritis (RA) over time is not well described. This study examined trends of opioid use in patients with RA. Retrospective prescription data was examined from 2005 to 2014 in a population-based incidence cohort of patients with RA by 1987 ACR criteria and comparable non-RA subjects. Differences in opioid use were examined with Poisson models. A total of 501 patients with RA (71 % female) and 532 non-RA subjects (70 % female) were included in the study. Total and chronic opioid use in 2014 was substantial in both cohorts 40 % RA vs 24 % non-RA and 12 % RA vs. 4 % non-RA, respectively. Opioid use increased by 19 % per year in both cohorts during the study period (95 % confidence interval [CI] 1.15, 1.25). Relative risk (RR) of chronic opiate use for RA patients compared to non-RA subjects was highest in adults aged 50-64 years (RR 2.82; 95 % CI 1.43-6.23). RA disease characteristics, biologic use at index, treated depression/fibromyalgia, education, and smoking status were not significantly associated with chronic opiate use. Over a third of patients with RA use opioids in some form, and in more than a tenth use is chronic. Use has increased in recent years. Patients aged 50-64 with RA use substantially more opioids than their non-RA counterparts.
Chemokine release promotes crosstalk between opioid and chemokine receptors that in part leads to reduced efficacy of morphine in the treatment of chronic pain. Based on the possibility that a MOR-CCR5 heteromer is involved in such crosstalk, we have synthesized bivalent ligands (MCC series) that contain mu opioid agonist and CCR5 antagonist pharmacophores linked through homologous spacers (14-24 atoms). When tested on lipopolysaccharide-inflamed mice, a member of the series (MCC22; 3e) with a 22-atom spacer exhibited profound antinociception (i.t. ED50 = 0.0146 pmol/mouse) that was >2000x greater than morphine. Moreover, MCC22 was ~3500x more potent than a mixture of mu agonist and CCR5 antagonist monovalent ligands. These data strongly suggest that MCC22 acts by bridging the protomers of a MOR-CCR5 heteromer having a TM5,6 interface. Molecular simulation studies are consistent with such bridging. This study supports the MOR-CCR5 heteromer as a novel target for treatment of chronic pain.
In the the past two decades the medical use of prescription opioids (POs), in particular oxycodone, increased up to 14-fold in the U.S. and Canada. The high consumption of these pain relievers also led to non-medical use and abuse of these substances which in turn resulted in a dramatic increase in the number of PO related fatalities and opioid dependent subjects. In the U.S. POs became the second most prevalent type of abused drug (4.5 million abusers; 1.7% of the population) after marijuana (8 million abusers) with currently 1.9 million (0.7% of the population) people dependent on opioid pain relievers. Pain relief was the leading motive for non-medical use in about 40% of the cases, but about half of non-medical PO users reported non-pain relief motives only, like to get high or to relax. Since 2011, there is a decline in the use and misuse of POs and reduction in painkiller overdose deaths in the U.S. probably due to the introduction of a variety of restrictive regulations. In Europe, the medical use of POs is increasing as well, but at a much slower rate than in the U.S. Moreover, in Europe non-medical use of POs and fatal PO incidents are (still) rare. The paper highlights and discusses the differences between Europe versus U.S. and Canada in an attempt to assess the risk of a PO abuse and overdose epidemic in Europe. It is concluded that the risk in Europe seems to be rather limited but vigilance is needed.
Chronic opioid use has been associated with the development of sleep-disordered breathing (SDB) such as central sleep apnea (CSA). Patients receiving chronic opioids may suffer from unrecognized sleep apnea that contributes to opioid-overdose death. Currently, information regarding the perioperative management of patients with chronic opioid-associated CSA is limited. The objectives of this review are to define the clinical manifestations of SDB associated with chronic opioid therapy, especially CSA, and to highlight their prevalence, mechanisms, risk factors, and perioperative management.
We searched Medline (1983-2014), Medline In-Process and other nonindexed citations (July 2014), EMBASE (1983-2014), the Cochrane Database of Systematic Reviews (January 2005-2014), the Cochrane Central Registry of Controlled Trials (July 2014), and PubMed basic search for new materials (1983-2014). Anesthesia and Sleep Medicine meeting abstracts were also searched for relevant articles. We included all prospective, retrospective studies and case reports in which CSA and chronic opioid use was confirmed by polysomnography. CSA was defined as the absence of airflow for ≥10 seconds with the absence of breathing efforts. A Central Apnea Index ≥5 events/h was considered significant.
The search strategy yielded 8 studies which included 560 patients. The overall prevalence of CSA in patients taking chronic opioids was high (24%). The morphine equivalent daily dose (MEDD) was strongly associated with the severity of the SDB, predominantly CSA, with an MEDD of >200 mg being a threshold of particular concern. Concurrent use of benzodiazepines or hypnotics was associated with the severity of CSA in one study. Body mass index was inversely related to the severity of SDB. There were various recommendations regarding the best type of positive airway pressure therapy for the treatment of opioid-associated CSA. Continuous positive airway pressure may be ineffective in eliminating, or may even increase, CSA. Adaptive servoventilation and bilevel positive airway pressure ventilation were effective according to some reports.
The overall prevalence of CSA in patients taking chronic opioids was 24%. The most important risk factors for severity of CSA were an MEDD >200 mg, and low or normal body mass index. Continuous positive airway pressure is often ineffective for treating CSA. Limited data are available on the perioperative management of patients with CSA associated with chronic opioid use. Further prospective studies on the perioperative risks and management of these patients are needed.
Chemokines and opioids are important regulators of immune, inflammatory and neuronal responses in peripheral and central pain pathways. Recent studies have provided insights into the functional interactions between chemokine receptors and opioid receptors, and their role in pain modulation. In this Progress article, we discuss how crosstalk between these two systems might provide a molecular and cellular framework for the development of novel analgesic therapies for the management of acute and/or chronic pain.
Opioid use in chronic pain treatment is complex, as patients may derive both benefit and harm. Identification of individuals currently using opioids in a problematic way is important given the substantial recent increases in prescription rates and consequent increases in morbidity and mortality. The present review provides updated and expanded information regarding rates of problematic opioid use in chronic. Because previous reviews have indicated substantial variability in this literature, several steps were taken to enhance precision and utility. First, problematic use was coded using explicitly defined terms, referring to different patterns of use (ie, misuse, abuse, and addiction). Second, average prevalence rates were calculated and weighted by sample size and study quality. Third, the influence of differences in study methodology was examined. In total, data from 38 studies were included. Rates of problematic use were quite broad, ranging from ,1% to 81% across studies. Across most calculations, rates of misuse averaged between 21% and 29% (range, 95% confidence interval [CI]: 13%-38%). Rates of addiction averaged between 8% and 12% (range, 95% CI: 3%-17%). Abuse was reported in only a single study. Only 1 difference emerged when study methods were examined, where rates of addiction were lower in studies that identified prevalence assessment as a primary, rather than secondary, objective. Although significant variability remains in this literature, this review provides guidance regarding possible average rates of opioid misuse and addiction and also highlights areas in need of further clarification.
In the United States, opioid analgesics have increasingly been prescribed in the treatment of chronic pain, and this trend has accompanied increasing rates of misuse and overdose. Lawmakers have responded with myriad policies to curb the growing epidemic of opioid misuse, and a global alarm has been sounded amongst countries wishing to avoid this path. In the United Kingdom, a similar trend of increasing opioid consumption, albeit at lower levels, has been observed without an increase in reported misuse or drug-related deaths. The comparison between these two countries in opioid prescribing and opioid overdose mortality underscores important features of prescribing, culture, and health systems that may be permissive or protective in the development of a public health crisis. As access to opioid medications increases around the world, it becomes vitally important to understand the forces impacting opioid use and misuse. Trends in benzodiazepine and methadone use in the UK as well as structural elements of the National Health Service may serve to buffer opioidrelated harms in the face of increasing prescriptions. In addition, the availability and price of heroin, as well as the ease of access to opioid agonist treatment in the UK may limit the growth of the illicit market for prescription opioids. The comparison between the US and the UK in opioid consumption and overdose rates should serve as a call to action for UK physicians and policymakers. Basic, proactive steps in the form of surveillance - of overdoses, marketing practices, prescribers, and patients - and education programs may help avert a public health crisis as opioid prescriptions increase.
Unlabelled:
Recent developments in the study of the structure and function of opioid receptors raise significant challenges for the definition of individual receptor types and the development of a nomenclature that precisely describes isoforms that may subserve different functions in vivo. Presentations at the 2013 meeting of the International Narcotics Research Conference in Cairns, Australia, considered some of the new discoveries that are now unravelling the complexities of opioid receptor signalling. Variable processing of opioid receptor messenger RNAs may lead to the presence of several isoforms of the μ receptor. Each opioid receptor type can function either as a monomer or as part of a homo- or heterodimer or higher multimer. Additionally, recent evidence points to the existence of agonist bias in the signal transduction pathways activated through μ receptors, and to the presence of regulatory allosteric sites on the receptors. This brief review summarizes the recent discoveries that raise challenges for receptor definition and the characterization of signal transduction pathways activated by specific receptor forms.
Linked articles:
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
Predictors of responsiveness to opioid analgesic medications are not well understood. This study tested whether individual differences in endogenous opioid (EO) function are associated with analgesic responsiveness to morphine. In randomized, counterbalanced order over three sessions, 45 chronic low back pain participants (CLBP) and 31 healthy controls received an opioid antagonist (8mg naloxone), morphine (0.08 mg/kg), or placebo. Participants then engaged in two laboratory evoked pain tasks (ischemic, thermal). Outcomes included pain threshold, pain tolerance, and pain ratings. Indexes of EO function and morphine analgesic responsiveness were derived for each measure as the difference in pain responses between the placebo condition, and naloxone or morphine conditions respectively. For all 7 pain measures across the two laboratory pain tasks, greater EO function was associated with significantly lower morphine analgesic responsiveness (p⩽.001 - p=.02). Morphine reduced pain responses of low EO individuals to levels similar to high EO individuals under placebo. Higher placebo condition evoked pain sensitivity was associated with significantly greater morphine analgesic responsiveness for 5 of 7 pain measures (p<.001 - p=.02). These latter associations were significantly mediated by EO function for 4 of these 5 pain outcomes (p's<.05). In the laboratory evoked pain context, opioid analgesic medications may supplement inadequate EO analgesia, with little incremental benefit in those with pre-existing high EO function. Implications for personalized medicine are discussed.
Clinical Question Do the benefits of opioid analgesics outweigh the risks in patients with persistent pain due to rheumatoid arthritis?
Bottom Line Weak opioids (such as codeine, dextropropoxyphene, and tramadol) may be effective in the short-term management of rheumatoid arthritis pain, but adverse effects are common and may outweigh the benefits; alternative analgesics should be considered first.
To assess the efficacy and safety of combination pain therapy for people with inflammatory arthritis (IA).
Systematic review of randomized controlled trials using Cochrane Collaboration methodology. Combination therapy was defined as at least 2 drugs from the following classes: analgesics, nonsteroidal antiinflammatory drugs (NSAID), opioids, opioid-like drugs, and neuromodulators (antidepressants, anticonvulsants, and muscle relaxants). The main efficacy and safety outcomes were pain and withdrawals due to adverse events, respectively.
Twenty-three trials (total of 912 patients) met inclusion criteria [22 in rheumatoid arthritis (RA) and 1 in a mixed population of RA and osteoarthritis]. All except 1 were published before 1990. All trials were at high risk of bias, and heterogeneity precluded metaanalysis. Statistically significant differences between treatment groups were reported in only 5/23 (22%) trials: in 3 trials combination therapy was better (2 trials with NSAID + analgesic versus NSAID only and 1 trial with 2 NSAID versus 1 NSAID), in 1 trial combination therapy was worse (opioid + neuromodulator versus opioid only), and in the fifth trial (NSAID + analgesic versus NSAID alone) reported results were mixed depending on the dosage used in the monotherapy arm. In general, there were no differences in safety and withdrawals due to inadequate analgesia between combination and monotherapy.
Based on 23 trials, all at high risk of bias, there is insufficient evidence to establish the value of combination therapy over monotherapy for pain management in IA. Well-designed trials are needed to address this question.