From acute to chronic pain: tapentadol in the progressive stages of this disease entity

OBJECTIVE: Chronic pain is now recognized as a neural disease, which results from a maladaptive functional and structural transformation process occurring over time. In its chronic phase, pain is not just a symptom but also a disease entity. Therefore, pain must be properly addressed, as many patients still report unsatisfactory pain control despite on-going treatment. The selection of the therapy - taking into account the pathophysiological mechanisms of pain - and the right timing can result in a successful analgesic outcome. This review will present the functional and structural modifications leading to chronification of pain, focusing on the role of tapentadol in this setting. MATERIALS AND METHODS: For inclusion in this review, research studies were retrieved via a keyword-based query of multiple databases (MEDLINE, Embase, Cochrane). The search was last updated in November 2016; no limitations were applied. RESULTS: Functional and structural abnormalities of the nervous system associated with pain chronification have been reported in several conditions, including osteoarthritis, chronic back pain, chronic pelvic pain and fibromyalgia. Correct identification and treatment of pain in recurrent/progressive stage is crucial to prevent chronification and related changes in neural structures. Among analgesic drugs, tapentadol, with its dual mechanism of action (opioid agonist and noradrenaline reuptake blocker), has recently resulted active in pain control at both central and spinal level. CONCLUSIONS: Tapentadol represents a suitable candidate for patients at early progressive stage of pain who have developed neuroplasticity with modification of pain pathways. The availability of different doses of tapentadol may help clinicians to tailor treatment based on the individual need of each patient, with the aim to enhance therapeutic appropriateness in the treatment of musculoskeletal and neuropathic pain

The challenge of perioperative pain management in opioid-tolerant patients

The increasing number of opioid users among chronic pain patients, and opioid abusers among the general population, makes perioperative pain management challenging for health care professionals. Anesthesiologists, surgeons, and nurses should be familiar with some pharmacological phenomena which are typical of opioid users and abusers, such as tolerance, physical dependence, hyperalgesia, and addiction. Inadequate pain management is very common in these patients, due to common prejudices and fears. The target of preoperative evaluation is to identify comorbidities and risk factors and recognize signs and symptoms of opioid abuse and opioid withdrawal. Clinicians are encouraged to plan perioperative pain medications and to refer these patients to psychiatrists and addiction specialists for their evaluation. The aim of this review was to give practical suggestions for perioperative management of surgical opioid-tolerant patients, together with schemes of opioid conversion for chronic pain patients assuming oral or transdermal opioids, and patients under maintenance programs with methadone, buprenorphine, or naltrexone

Short-term withdrawal from repeated exposure to cocaine during adolescence modulates dynorphin mRNA levels and BDNF signaling in the rat nucleus accumbens

BACKGROUND: Early-life stressful events affect the neurobiological maturation of cerebral circuitries including the endogenous opioid system and the effects elicited by adolescent cocaine exposure on this system have been poorly investigated. Here, we evaluated whether cocaine exposure during adolescence causes short- or long-term alterations in mRNAs codifying for selected elements belonging to the opioid system. Moreover, since brain-derived neurotrophic factor (BDNF) may undergo simultaneous alterations with the opioid peptide dynorphin, we also evaluated its signaling pathway as well. METHODS: Adolescent male rats were exposed to cocaine (20\u2009mg/kg/day) from post-natal day (PND) 28 to PND42, approximately corresponding to human adolescence. After short- (PND45) or long-term (PND90) abstinence, prodynorphin-\u3ba-opioid receptor (pDYN-KOP) and pronociceptin-nociceptin receptor (pN/OFQ-NOP) gene expression were evaluated in the nucleus accumbens (NAc) and hippocampus (Hip) together with the analysis of BDNF signaling pathways. RESULTS: In the NAc of PND45 rats, pDYN mRNA levels were up-regulated, an effect paralled by increased BDNF signaling. Differently from NAc, pDYN mRNA levels were down-regulated in the Hip of PND45 rats without significant changes of BDNF pathway. At variance from PND45 rats, we did not find any significant alteration of the investigated parameters either in NAc and Hip of PND90 rats. CONCLUSIONS: Our results indicate that the short-term withdrawal from adolescent cocaine exposure is characterized by a parallel pDYN mRNA and BDNF signaling increase in the NAc. Given the depressive-like state experienced during short abstinence in humans, we hypothesize that such changes may contribute to promote the risk of cocaine abuse escalation and relapse

Interplay between the endogenous opioid system and proteasome complex: Beyond signaling

Intracellular signaling mechanisms underlying the opioid system regulation of nociception, neurotransmitters release, stress responses, depression, and the modulation of reward circuitry have been investigated from different points of view. The presence of the ubiquitin proteasome system (UPS) in the synaptic terminations suggest a potential role of ubiquitin-dependent mechanisms in the control of the membrane occupancy by G protein-coupled receptors (GPCRs), including those belonging to the opioid family. In this review, we focused our attention on the role played by the ubiquitination processes and by UPS in the modulation of opioid receptor signaling and in pathological conditions involving the endogenous opioid system. The collective evidence here reported highlights the potential usefulness of proteasome inhibitors in neuropathic pain, addictive behavior, and analgesia since these molecules can reduce pain behavioral signs, heroin self-administration, and the development of morphine analgesic tolerance. Moreover, the complex mechanisms involved in the effects induced by opioid agonists binding to their receptors include the ubiquitination process as a post-translational modification which plays a relevant role in receptor trafficking and degradation. Hence, UPS modulation may offer novel opportunities to control the balance between therapeutic versus adverse effects evoked by opioid receptor activation, thus, representing a promising druggable target

Gray Matter Pathology in MS: A 3-Year Longitudinal Study in a Pediatric Population

RESULTS: At T0, GMf did not differ between cMS and NC (P .18), while it was lower in patients with aMS compared with both NCs (P .001) and patients with cMS (P .001). The number of patients with CLs, as well as CL number and volume, were higher in patients with aMS than in those with cMS (P .001). At T3, -GMf was higher in both patients with cMS (1.6% 0.5%; range 0.7%–3.4%; P .001) and aMS (1.6% 0.6%; range 0.6%–3.4%; P .001) compared with NCs (0.7% 0.2%; range 0.4%–1.1%), whereas no difference was observed between patients with cMS and aMS (P .93). -GMf significantly correlated with increased CL volume (cMS: r 0.46; aMS: r 0.48) and with the appearance of new CLs (cMS: r 0.51; aMS: r 0.49). CONCLUSIONS: Our findings suggest that focal (CLs) and diffuse (atrophy) GM damage are strictly associated with the biologic onset of MS, and proceed linearly and partly independently of WM pathology. ABBREVIATIONS: aMS adult-onset multiple sclerosis; CL cortical lesion; cMS childhoodonset multiple sclerosis; EDSS Expanded Disability Status Scale; GM gray matter; GMf gray matter fraction; -GMf delta gray matter fraction; -GMf_1 delta gray matter fraction at T1; -GMf_2 delta gray matter fraction at T2; -GMf_3 delta gray matter fraction at T3; NC healthy control; T0 baseline; T2WMLV T2 white matter lesion volum

The standardized Withania somnifera Dunal root extract alters basal and morphine-induced opioid receptor gene expression changes in neuroblastoma cells.

BACKGROUND: Behavioral studies demonstrated that the administration of Withania somnifera Dunal roots extract (WSE), prolongs morphine-elicited analgesia and reduces the development of tolerance to the morphine's analgesic effect; however, little is known about the underpinning molecular mechanism(s). In order to shed light on this issue in the present paper we explored whether WSE promotes alterations of \u3bc (MOP) and nociceptin (NOP) opioid receptors gene expression in neuroblastoma SH-SY5Y cells. METHODS: A range of WSE concentrations was preliminarily tested to evaluate their effects on cell viability. Subsequently, the effects of 5 h exposure to WSE (0.25, 0.50 and 1.00 mg/ml), applied alone and in combination with morphine or naloxone, on MOP and NOP mRNA levels were investigated. RESULTS: Data analysis revealed that morphine decreased MOP and NOP receptor gene expression, whereas naloxone elicited their up-regulation. In addition, pre-treatment with naloxone prevented the morphine-elicited gene expression alterations. Interestingly, WSE was able to: a) alter MOP but not NOP gene expression; b) counteract, at its highest concentration, morphine-induced MOP down-regulation, and c) hamper naloxone-induced MOP and NOP up-regulation. CONCLUSION: Present in-vitro data disclose novel evidence about the ability of WSE to influence MOP and NOP opioid receptors gene expression in SH-SY5Y cells. Moreover, our findings suggest that the in-vivo modulation of morphine-mediated analgesia by WSE could be related to the hindering of morphine-elicited opioid receptors down-regulation here observed following WSE pre-treatment at its highest concentration

Nociceptin/orphanin FQ prevents the antinociceptive action of paracetamol on the rat hot plate test

Nociceptin/orphanin FQ (N/OFQ) is involved in many behavioural patterns; in particular. it exerts a modulating effect on nociception. Like other proposed antiopiates, nociceptin/orphanin FQ has been shown to have analgesic, hyperalgesic as well as antianalgesic properties. Among the various effects proposed on nociceptive sensitivity at supraspinal level, the antagonistic activity toward morphine analgesia seems to be of interest. Therefore, we decided to investigate whether nociceptin/orphanin FQ and [Arg(14), Lys(15)] nociceptin/orphanin FQ (R-K, a nociceptin analogue) can have the same effect on the analgesia produced by nonopioid analgesics. in this study. we examined the antianalgesic effect of nociceptin/orphanin FQ and its analogue R-K on paracetamol-induced analgesia and evaluated by means of the hot plate test in rats. Nociceptin/orphanin FQ was intracerebroventricularly administered, anti. after 5 min, a dose of 400 mg/kg paracetamol was injected intraperitoneally, 30 min before the hot plate test. Nociceptin/orphanin FQ and R-K showed a dose-dependent antagonism on the antinociceptive effect of paracetamol, and the activity of both drugs was significantly reduced by the antagonist [Nphe(1)] Arg(14), Lys(15)-N/OFQ-NH2 (UFP-101). These data indicate that nociceptin/orphanin FQ and R-K have an antianalgesic effect on the analgesia produced by a nonopioid analgesic drug, like paracetamol, that seems to develop within the brain

Safe use of opioids in chronic kidney disease and hemodialysis patients. ips and tricks for non pain specialist

Abstract: In patients suffering from moderate-to-severe chronic kidney disease (CKD) or end-stage renal disease (ESRD), subjected to hemodialysis (HD), pain is very common, but often underestimated. Opioids are still the mainstay of severe chronic pain management; however, their prescription in CKD and HD patients is still significantly low and pain is often under-treated. Altered pharmacokinetics and the lack of clinical trials on the use of opioids in patients with renal impairment increase physicians’ concerns in this specific population. This narrative review focused on the correct and safe use of opioids in patients with CKD and HD. Morphine and codeine are not recommended, because the accumulation of their metabolites may cause neurotoxic symptoms. Oxycodone and hydromorphone can be safely used, but adequate dosage adjustments are required in CKD. In dialyzed patients, these opioids should be considered as second-line agents and patients should be carefully mon- itored. According to different studies, buprenorphine and fentanyl could be considered first- line opioids in the management of pain in CKD; however, fentanyl is not appropriate in patients undergoing HD. Tapentadol does not need dosage adjustment in mild-to-moderate renal impairment conditions; however, no data are available on its use in ESRD. Opioid- related side effects may be exacerbated by common comorbidities in CKD patients. Opioid- induced constipation can be managed with peripherally-acting-μ-opioid-receptor-antagonists (PAMORA). Unlike the other PAMORA, naldemedine does not require any dose adjustment in CKD and HD patients. Accurate pain diagnosis, opioid titration and tailoring are manda- tory to minimize the risks and to improve the outcome of the analgesic therapy