Current Pharmaceutical Design - Volume 18, Issue 37, 2012

Opioids induce respiratory depression via activation of μ-opioid receptors at specific sites in the central nervous system including the pre-Bötzinger complex, a respiratory rhythm generating area in the pons. Full opioid agonists like morphine and fentanyl affect breathing with onset and offset profiles that are primarily determined by opioid transfer to the receptor site, while the effects of partial opioid agonists such as buprenorphine are governed by transfer to the receptor site together with receptor kinetics, in particular dissociation kinetics. Opioid-induced respiratory depression is potentially fatal but may be reversed by the opioid receptor antagonist naloxone, an agent with a short elimination half-life (30 min). The rate-limiting factor in naloxone-reversal of opioid effect is the receptor kinetics of the opioid agonists that requires reversal. Agents with slow dissociation kinetics (buprenorphine) require a continuous naloxone infusion while agents with rapid kinetics (fentanyl) will show complete reversal upon a single naloxone dose. Since naloxone is non-selective and will reverse analgesia as well, efforts are focused on the development of compounds that reverse opioid-induced respiratory depression without affecting analgesic efficacy. Such agents include ampakines and serotonin agonists which are aimed at selectively enhancing central respiratory drive. A novel approach is aimed at the reduction of respiratory depression from opioid-activation of (micro-)glia cells in the pons and brainstem using micro-glia cell stabilizers. Since this approach simultaneously enhances opioid analgesic efficacy it seems an attractive alternative to the classical reversal strategies with naloxone.

Opioid consumption is associated with a wide range of side effects. Potential interference of opioids with bone and joint activity has emerged in the last few years. Opioids increase the risk of fracture, especially in elderly patients. Moreover, opioids interfere with the endocrine system, and their chronic use is a recognized risk factor for osteoporosis. Pathogenetic mechanisms at the basis of the interference of opioids with bones and joints are analysed in this review.

The therapeutic action of opioid analgesics is compromised by peripheral adverse effects among which opioid-induced constipation (OIC) is the most disabling, with a prevalence reported to vary between 15 and 90 %. Although OIC is usually treated with laxatives, there is insufficient clinical evidence that laxatives are efficacious in this indication. In contrast, there is ample evidence from double- blind, randomized and placebo-controlled trials that peripheral opioid receptor antagonists (PORAs) counteract OIC. This specific treatment modality is currently based on subcutaneous methylnaltrexone for the interruption of OIC in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the prevention of OIC in the treatment of non-cancer and cancer pain. Both drugs counteract OIC while the analgesic effect of opioids remains unabated. The clinical studies show that more than 50 % of the patients with constipation under opioid therapy may benefit from the use of PORAs, while PORA-resistant patients are likely to suffer from non-opioid-induced constipation, the prevalence of which increases with age. While the addition of naloxone to oxycodone seems to act by preventing OIC, the intermittent dosing of methylnaltrexone every other day seems to stimulate defaecation by provoking an intestinal withdrawal response. The availability of PORAs provides a novel opportunity to specifically control OIC and other peripheral adverse effects of opioid analgesics (e.g., urinary retention and pruritus). The continuous dosing of a PORA has the advantage of few adverse effects, while intermittent dosing of a PORA can be associated with abdominal cramp-like pain.

Administration of opioids for analgesia may produce pruritus. It was believed, that this effect is mediated centrally by activation of μ-opioid receptors (MOR). However, recent data suggested that opioids may also mediate pruritus directly in the skin. A number of skin cell types, including keratinocytes, dermal mast cells, fibroblasts or macrophages, were shown to express both MOR as well as other opioid receptors. It was demonstrated, that the activation of MOR in the skin elicited pruritus, while activation of cutaneous µ- opioid receptors had anti-pruritic effect. Moreover, activation of opioid receptors in the skin modulated not only pruritus, but also inflammatory response. Taking these observations into consideration it could be suggested, that substances acting solely on peripheral opioid receptors could be potent anti-pruritic or even anti-inflammatory drugs, but devoided of typical side effects related to the activation of central opioid system.

The exact effect of opioid analgesics on sleep is to be determined. Although literature data are sporadically reported, the aim of this review is to summarize the already known effects of such medications on sleep. A variety of effects, both positive and negative, has been suggested, when opioids are used for pain treatment, but in the absence of pain as well. Although often thought to promote restful sleep, the reality is much more complicated. Sleep disturbances and alterations of sleep quantity and quality have been reported. In addition, their sedative effects have been relatively well established and opioids can cause respiration to slow and become irregular, leading to hypercapnia and hypoxia. As a result, their usage has been linked to irregular or ataxic breathing (Biot’s breathing) and their use has been associated with both central and obstructive sleep apnea. One could estimate that central apnea is a common complication of such chronic therapy, affecting between 30% and 90% of patients. Thus, sleep disturbances can be induced or deteriorated. On the other hand, extended release opioid formulations have been suggested to improve sleep due to no analgesic gaps and less walking because of breakthrough pain. Furthermore, several reports have shown significantly improved sleep quantity and adequacy, with reduced sleep disturbances. Still, as no prospective trials on the effect of opioid therapy on sleep are available and evidence is scarce, definitive conclusions cannot be drawn. Future studies with their effect on sleep as primary end-point are needed to draw permanent conclusions.

This review provides an overview of the immunological effects of commonly used analgesic opioid drugs, focusing mainly on two aspects: the mechanisms involved and the potential clinical relevance. The immunomodulatory effects of morphine have been characterized in animal and human studies. Morphine decreases the effectiveness of both natural and acquired immunity, interfering with intracellular pathways involved in immune regulation, both directly and indirectly via the activation of central receptors. The mechanisms and the targets at the basis of opioid-induced immunomodulation have started to be elucidated, demonstrating an interaction between opioid receptors and several molecules involved in the complex and well orchestrated immune response, such as transcription factors and receptors of both myeloid and lymphoid cells. Due to their widespread and expanding use, the immunological effects of opioid are receiving considerable attention because of concerns that opioid-induced changes in the immune system may affect the outcome of surgery or of variety of disease processes, including bacterial and viral infections and cancer. It is also emerging that not all opioids induce the same immunosuppressive effects and evaluating each opioid profile is important for appropriate analgesic selection. The impact of the opioid-mediated immune effects could be particularly dangerous in selective vulnerable populations, such as the elderly or immunocompromised patients. Indeed, it is evident that the possibility of reaching adequate and equivalent pain control by choosing either immunosuppressive drugs or drugs without an effect on immune responses may be an important consideration in opioid therapy.

Nausea and vomiting are common gastrointestinal symptoms following opioid administration, for either chronic or acute pain management. As a consequence, patients’ dissatisfaction has a negative impact on treatment efficacy. A number of mechanisms have been identified, involving both central and peripheral sites. This article will review the pathophysiology of opioid-induced nausea and vomiting and the various pharmacological treatments currently available for its management. Preventive strategies and therapeutic approaches are evaluated in the perioperative setting and in chronic pain. Newer drugs include second generation serotonin receptor antagonists (palonosetron) and neurokinin-1 (NK-1) antagonists (aprepitant).

Opioids are the gold standard for pain treatment but systemic opioid use is accompanied by central and intestinal side effects. As opioid receptors are expressed on peripheral sensory nerve endings, cutaneous and immune cells, local opioid application is being used for pain reduction in patients with inflammatory lesions such as burns, skin grafts, arthritis, acute or chronic wounds. In addition, peripherally active opioids have anti-inflammatory effects and can modulate wound healing. This review will cover anatomical, physiological and pathophysiological characteristics of opioid receptors and their ligands in peripheral tissues. We will then focus on mechanisms and the functional role of peripheral opioids in inflammation and wounds in experimental and clinical studies. Controversial results, methodological issues, implications for pharmacology, and therapeutic prospects for inflammatory diseases and wound healing will be discussed.

Opioids are among the oldest known and most widely used analgesics. The application of opioids has expanded over the last few decades, especially in the treatment of chronic non-malignant pain. This upsurge in opioid use has been accompanied by the increasingly recognized occurrence of opioid-associated endocrinopathy. This may arise after exposure to enteral, parenteral, or neuraxial opioids. Opioid-associated endocrinopathy consists primarily of hypothalamic-pituitary-gonadal axis or hypothalamic-pituitary-adrenal axis dysfunction and may manifest with symptoms of hypogonadism, adrenal dysfunction, and other hormonal disturbances. Additionally, opioid related endocrine dysfunction may be coupled with such disorders as osteoporosis and mood disturbances including depression. Undesirable changes in pain sensitivity such as opioid-induced hyperalgesia, and reduced potency of opioid analgesia may also be potential consequences of chronic opioid consumption. Few studies to date have been able to establish what degree of opioid exposure, in terms of dose or duration of therapy, may predispose patients to opioid-associated endocrinopathy. This article will review the currently available literature concerning opioid-associated endocrinopathy and will provide recommendations for the evaluation, monitoring, and management of opioid-associated endocrinopathy and its other accompanying undesired effects.

Opioids are increasingly used to manage not only acute but also chronic pain and heroine addiction. These patients usually receive many other medications that can interfere with the effects of opioids and vice versa. Patients often need combinations of drugs for their pain management, for treating opioid-related adverse effects or for other indications including depression and anxiety. Several antibiotics can also have interactions with opioids. It is important to understand what potential interactions exist between opioids and other drugs. Drug interactions can occur due to pharmacokinetic interactions including effects of absorption, metabolic pathways, drug transport through membranes and protein binding. Our knowledge of the metabolism of opioids has significantly increased over the last years and it is now possible to appreciate the role CYP enzymes, mainly CYP 2D6 and 3A4/5, in the metabolism of many commonly used opioids like codeine and oxycodone. Our knowledge regarding the role of the transporter proteins in drug interactions related to opioids is unfortunately meagre. Opioids inhibit the gastrointestinal system and can thus change the absorption of other drugs. Opioids can have synergistic or additive interactions with other drugs that have analgesic or sedative effects. Endogenous opioids control many physiological functions and exogenous opioids can have effects on all important transmitter systems (cholinergic, GABAergic, dopaminergic and serotonergic). The literature in this field is mainly based on case reports. Interindividual differences play an important role. Other potential interactions include prolongation of the QT-interval and lowering of the threshold for convulsions.

Opioid peptides and their G protein-coupled receptors (GPCRs) are important regulators within the cardiovascular system, implicated in modulation of electrophysiological function, heart rate, myocardial inotropy, vascular function, and cellular stress resistance. The opioid system is also involved in cardiovascular development, adaptation to injury and effects of advanced age. The significant roles of opioids are emphasized by the observation that the heart produces prodynorphin and proenkephalin, which are enzymatically processed from small to large active polypeptides. Indeed, depending on species, cardiac preproenkephalin mRNA levels are comparable to or higher than those found in the central nervous system. This review highlights and discusses current knowledge and recent findings regarding physiological and pathophysiological modulation of the heart and vessels by the opioid receptor system.

Inadequate blood flow in the retina (ischemia) is a common cause of visual impairment and blindness. Retinal ischemia plays a pivotal role in a number of ocular degenerative diseases such as diabetic retinopathy, glaucoma, and retinal artery occlusion. The sequence of events by which ischemia leads to retinal degeneration are not completely understood, but likely involve both necrotic and apoptotic processes. A variety of diverse chemical mediators (e.g., glutamate, oxygen free-radical, nitric oxide, and proinflammatory cytokines) have been implicated as participants in ischemic retinal injury. In the eye, experimental and/or clinical evidence has suggested roles for endogenous opioids and their receptors in the regulation of iris function, aqueous humor dynamics, corneal wound healing, and retinal development and neuroprotection. In numerous vital organs, opioid receptor activation prior to ischemia or severe hypoxia is neuroprotective. Recently, activation of opioid-receptors, particularly δ-opioid-receptors (DOR), has been demonstrated to suppress several steps in the deleterious cascade of events during ischemic/hypoxic stress. In providing neuroprotection against ischemia, opioid-receptor activation appears to block proinflammatory cytokines, such as TNF-α, and glutamate excitotoxicity. Depending on duration and severity of cellular stress, DOR activation can trigger different mechanisms at multiple levels to preserve neuronal survival, including: stabilized ionic homeostasis, augmented pro-survival signaling (e.g., PKC, ERK, PI3K/Akt) and enhanced anti-oxidative capacity. This review will summarize the potential roles of opioids in protecting the viability of ocular tissues. Special emphasis will be focused on enhancing the understanding of the molecular mechanisms of opioid actions in protecting the retina against ischemic/hypoxic injury.

Abuse-deterrent opioid formulations are receiving renewed interest in light of the increasing legitimate medical use of prescription opioids for the adequate treatment of pain. Unfortunately, there is an inevitable associated potential for misuse, diversion, and abuse. The challenges of deterrence are significant: opioid abusers are a heterogeneous population; studies on drug “liking” and opioid “attractiveness” are informative, but mainly rely on reports from users who are not reliable respondents; drug “liking” scores are useful, but it is unclear how much drug “liking” must be reduced in order to achieve an actual reduction in abuse levels; and the most popular drugs among opioid abusers appear to be those that meet a complex combination of both positive and negative criteria including things like availability, pricing, and how easily the drug’s illicit use can be concealed. Several abuse-deterrent formulations have been introduced or are in development. Epidemiological studies will have to be conducted to evaluate their effectiveness. Although there are currently more questions than answers, such products are clearly of medical and societal importance.

Opioids constitute the basis for pharmacological treatment of moderate to severe pain in cancer pain and non-cancer pain patients. Their action is mediated by the activation of opioid receptors, which integrates the pain modulation system with other effects in the central nervous system including cognition resulting in complex interactions between pain, opioids and cognition. The literature on this complexity is sparse and information regarding the cognitive effects of opioids in chronic pain patients is substantially lacking. Two previous systematic reviews on cancer pain and non-cancer pain patients only using controlled studies were updated. Fourteen controlled studies on the cognitive effects of opioids in chronic non-cancer pain patients and eleven controlled studies in cancer pain patients were included and analyzed. Opioid treatment involved slightly opposite outcomes in the two patient groups: no effects or worsening of cognitive function in cancer pain patients and no effect or improvements in the chronic non-cancer pain patients, however, due to methodological limitations and a huge variety of designs definite conclusions are difficult to draw from the studies. In studies of higher quality of evidence opioid induced deficits in cognitive functioning were associated with dose increase and the use of supplemental doses of opioids in cancer patients. Future perspectives should comprise the conduction of high quality randomized controlled trials (RCTs) involving relevant control groups and validated neuropsychological assessments tools before and after opioid treatment in order to further explore the complex interaction between pain, opioids and cognition.

Nampt/Visfatin/PBEF is a primary, rate-limiting enzyme involved in NAD+ biosynthesis, which serves as a pivotal substance for proteins, and is required for cell growth, survival, DNA replication and repair and energy metabolism. Growing researches have elucidated that it is a pleiotropic protein that functions not only as an enzyme, but also as an adipocytokin, a growth factor, and a cytokine. Additionally, accumulated evidences indicate that Nampt is correlated to various malignant tumors, and complicated mechanisms are proposed to be involved in the carcinogenesis, progression, invasion and metastasis of it, including regulation of energy metabolism and genome instability, promotion of proliferation, angiogenesis, and tumor-promoting inflammation, resistance in cell death and avoidance of immune destruction. APO866 and CHS-828 are recognized inhibitors of Nampt, known to block the intracellular and extracellular NAD+ synthesis pathway. Both of them are currently in clinical trials for the treatment of various malignant tumors and have been shown to represent novel promising antitumor chemotherapeutic agents.

This work presents the development of quantitative structure activity relationship (QSAR) model to predict the antimalarial activity of artemisinin derivatives. The structures of the molecules are represented by chemical descriptors that encode topological, geometric, and electronic structure features. Screening through QSAR model suggested that compounds A24, A24a, A53, A54, A62 and A64 possess significant antimalarial activity. Linear model is developed by the multiple linear regression method to link structures to their reported antimalarial activity. The correlation in terms of regression coefficient (r2) was 0.90 and prediction accuracy of model in terms of cross validation regression coefficient (rCV2) was 0.82. This study indicates that chemical properties viz., atom count (all atoms), connectivity index (order 1, standard), ring count (all rings), shape index (basic kappa, order 2), and solvent accessibility surface area are well correlated with antimalarial activity. The docking study showed high binding affinity of predicted active compounds against antimalarial target Plasmepsins (Plm-II). Further studies for oral bioavailability, ADMET and toxicity risk assessment suggest that compound A24, A24a, A53, A54, A62 and A64 exhibits marked antimalarial activity comparable to standard antimalarial drugs. Later one of the predicted active compound A64 was chemically synthesized, structure elucidated by NMR and in vivo tested in multidrug resistant strain of Plasmodium yoelii nigeriensis infected mice. The experimental results obtained agreed well with the predicted values.

Lung cancer, of which non-small-cell lung cancer (NSCLC) is the most common form, remains the leading cause of cancerrelated mortality worldwide, with many patients presenting with advanced disease at initial diagnosis. In advanced NSCLC patients whose tumors harbor activating epidermal growth factor receptor (EGFR) mutations, the use of EGFR tyrosine kinase inhibitors (TKIs) as first-line treatment has provided an unusually large progression-free-survival (PFS) benefit, a significantly high response rate (RR) and decreased toxicity when compared with cytotoxic chemotherapy in several phase III randomized trials; however, resistance invariably occurs. There are multiple mechanisms defined by which tumor cells may become independent of EGFR such as the well-characterized example of mesenchymal-epithelial transition factor (MET) amplification. Upon initial diagnosis of NSCLC, MET gene amplification is uncommon; however, acquired MET amplification has been noted in up to 20% of EGFR-mutated tumors that have been pretreated with an EGFR TKI. In tumors containing MET gene amplification, stimulation of the tumor occurs via the co-receptor HER-3 resulting in activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway, thereby circumventing the effects of an EGFR TKI. Recently, the targeting of the MET pathway has been attempted with small molecules and with monoclonal antibodies. This review will explain the MET signaling pathway and biology in cancer and the recent clinical development and advances of MET/HGF targeting agents in the treatment of advanced NSCLC.

In the last two decades a tremendous development has been noticed in our understanding of the purinergic system, consisting of heterogeneously expressed purinoceptor subtypes and its classical agonists: e.g., adenosine triphosphate, uridine triphosphate or complex dinucleoside polyphosphates. These agonists exert multiple effects on the vascular system: they regulate the relaxation and constriction of arterial blood vessels, lead to proliferation and migration in endothelial cells and vascular smooth muscle cells, and mediate potent proinflammatory responses or phenotypic cell changes. This review focuses on the P2 purinoceptor subtype P2Y and its pleiotropic effects in the vascular wall under physiological and pathophysiological condition. Various experimental and clinical studies provide evidence that pharmacological targeting of P2Y might be effective in reducing vascular alterations under disease conditions.