Nausea and vomiting side effects with opioid analgesics during treatment of chronic pain: mechanisms, implications, and management options

A B S T R A C T Objectives. Gastrointestinal (GI) side effects such as nausea and vomiting are common following opioid analgesia and represent a significant cause of patient discomfort and treatment dissatisfaction. This review examines the mechanisms that produce these side effects, their impact on treatment outcomes in chronic pain patients, and counteractive strategies. Results. A number of mechanisms by which opioids produce nausea and vomiting have been identified. These involve both central and peripheral sites including the vomiting center, chemoreceptor trigger zones, cerebral cortex, and the vestibular apparatus of the brain, as well as the GI tract itself. Nausea and vomiting have a negative impact on treatment efficacy and successful patient management because they limit the effective analgesic dosage that can be achieved and are frequently reported as the reason for discontinuation of opioid pain medication or missed doses. While various strategies such as antiemetic agents or opioid switching can be employed to control these side effects, neither option is ideal because they are not always effective and incur additional costs and inconvenience. Opioid-sparing analgesic agents may provide a further alternative to avoid nausea and vomiting due to their reduced reliance on mu-opioid signalling pathways to induce analgesia. Conclusions. Nausea and vomiting side effects limit the analgesic efficiency of current opioid therapies. There is a clear need for the development of improved opioid-based analgesics that mitigate these intolerable effects

Characterization of Antiallodynic Actions of ALE-0540, a Novel Nerve Growth Factor Receptor Antagonist, in the Rat1

There is growing evidence that nerve growth factor (NGF) may function as a mediator of persistent pain states. We have identified a novel nonpeptidic molecule, ALE-0540, that inhibits the binding of NGF to tyrosine kinase (Trk) A or both p75 and TrkA (IC50 5.88 6 1.87 mM, 3.72 6 1.3 mM, respectively), as well as signal transduction and biological responses mediated by TrkA receptors. ALE-0540 was tested in models of neuropathic pain and thermally-induced inflammatory pain, using two routes of administration, a systemic i.p. and a spinal intrathecal (i.th.) route. Morphine was also tested for comparison in the antiallodynia model using mechanical stimuli. We show that either i.p. or i.th. administration of ALE-0540 in rats produced antiallodynia in the L5/L6 ligation model of neuropathic pain. The calculated A50 values (and 95% confidence intervals) for ALE- 0540 administered i.p. and i.th. were 38 (17.5– 83) mg/kg and 34.6 (17.3– 69.4) mg, respectively. ALE-0540 given i.th., at doses of 30 and 60 mg, also blocked tactile allodynia in the thermal sensitization model. Although morphine displayed greater potency [A50 value of 7.1 (5.6–8.8) mg/kg] than ALE- 0540 in anti-allodynic effect when given i.p. to L5/L6-ligated rats, it was not active when administered i.th. These data suggest that a blockade of NGF bioactivity using a NGF receptor antagonist is capable of blocking neuropathic and inflammatory pain and further support the hypothesis that NGF is involved in signaling pathways associated with these pain states. ALE-0540 represents a nonpeptidic small molecule which can be used to examine mechanisms leading to the development of agents for the treatment of pain

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT1B/1D receptors. The discovery that the serotonin 1F (5-HT1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT1B receptors, the activation of 5-HT1F receptors does not cause vasoconstriction. The potency of different serotonergic agonists towards 5-HT1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites. Lasmiditan activation of CNS-located 5-HT1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways

Endogenous Opioid Activity in the Anterior Cingulate Cortex Is Required for Relief of Pain

Pain is aversive, and its relief elicits reward mediated by dopaminergic signaling in the nucleus accumbens (NAc), a part of the mesolimbic reward motivation pathway. How the reward pathway is engaged by pain-relieving treatments is not known. Endogenous opioid signaling in the anterior cingulate cortex (ACC), an area encoding pain aversiveness, contributes to pain modulation. We examined whether endogenous ACC opioid neurotransmission is required for relief of pain and subsequent downstream activation of NAc dopamine signaling. Conditioned place preference (CPP) and in vivo microdialysis were used to assess negative reinforcement and NAc dopaminergic transmission. In rats with postsurgical or neuropathic pain, blockade of opioid signaling in the rostral ACC (rACC) inhibited CPP and NAc dopamine release resulting from non-opioid pain-relieving treatments, including peripheral nerve block or spinal clonidine, an α(2)-adrenergic agonist. Conversely, pharmacological activation of rACC opioid receptors of injured, but not pain-free, animals was sufficient to stimulate dopamine release in the NAc and produce CPP. In neuropathic, but not sham-operated, rats, systemic doses of morphine that did not affect withdrawal thresholds elicited CPP and NAc dopamine release, effects that were prevented by blockade of ACC opioid receptors. The data provide a neural explanation for the preferential effects of opioids on pain affect and demonstrate that engagement of NAc dopaminergic transmission by non-opioid pain-relieving treatments depends on upstream ACC opioid circuits. Endogenous opioid signaling in the ACC appears to be both necessary and sufficient for relief of pain aversiveness

3D bioactive composite scaffolds for bone tissue engineering

Bone is the second most commonly transplanted tissue worldwide, with over four million operations using bone grafts or bone substitute materials annually to treat bone defects. However, significant limitations affect current treatment options and clinical demand for bone grafts continues to rise due to conditions such as trauma, cancer, infection and arthritis. Developing bioactive three-dimensional (3D) scaffolds to support bone regeneration has therefore become a key area of focus within bone tissue engineering (BTE). A variety of materials and manufacturing methods including 3D printing have been used to create novel alternatives to traditional bone grafts. However, individual groups of materials including polymers, ceramics and hydrogels have been unable to fully replicate the properties of bone when used alone. Favourable material properties can be combined and bioactivity improved when groups of materials are used together in composite 3D scaffolds. This review will therefore consider the ideal properties of bioactive composite 3D scaffolds and examine recent use of polymers, hydrogels, metals, ceramics and bio-glasses in BTE. Scaffold fabrication methodology, mechanical performance, biocompatibility, bioactivity, and potential clinical translations will be discussed

A loaded self-managed exercise programme for patellofemoral pain: A mixed methods feasibility study

© 2019 The Author(s). Background: A novel loaded self-managed exercise programme that includes pain education and self-management strategies may result in better outcomes for people with patellofemoral pain (PFP). However, establishing program feasibility is an essential first step before testing efficacy. The purpose of this study was to evaluate the feasibility and acceptability of conducting a definitive RCT which will evaluate the clinical and cost-effectiveness of a loaded self-managed exercise programme for people with PFP compared with usual physiotherapy. Methods: In a mixed methods, pragmatic, randomised controlled feasibility study, 60 participants with PFP (57% female; mean age 29 years) were recruited from a physiotherapy clinic within a large UK teaching hospital. They were randomly allocated to receive either a loaded self-managed exercise programme (n = 30) or usual physiotherapy (n = 30). Feasibility indicators of process, resources, and management were collected through follow-up of standardised questionnaires six months after recruitment and semi-structured interviews with 20 participants and physiotherapists. Results: Recruitment rate was 5 participants per month; consent rate was 99%; adherence to intervention appointments was 87%; completeness of questionnaire data was 100%; and adherence to intervention delivery was 95%. Three exercise diaries were returned at six months (5%). At six months, 25 questionnaire booklets were returned (9 in the loaded self-managed group, 16 in the usual physiotherapy group), with a total retention rate of 42%. At six months, 56% (5/9) of respondents in the loaded self-managed group and 56% (9/16) in the usual physiotherapy group were classified as 'recovered'. Both groups demonstrated improvements in average pain (VAS), kinesiophobia, pain catastrophizing, general self-efficacy and EQ-5D-5 L from baseline to six months. Conclusion: The results of this feasibility study confirm that it is feasible and acceptable to deliver a loaded self-managed exercise programme to adults with PFP in an NHS physiotherapy outpatient setting. However, between group differences in lost to follow up and poor exercise diary completion mean we are uncertain on some feasibility aspects. These methodological issues need addressing prior to conducting a definitive RCT. Trial registration: ISRCTN 35272486. Registered 19th December 2016

The Perception and Endogenous Modulation of Pain

Pain is often perceived an unpleasant experience that includes sensory and emotional/motivational responses. Accordingly, pain serves as a powerful teaching signal enabling an organism to avoid injury, and is critical to survival. However, maladaptive pain, such as neuropathic or idiopathic pain, serves no survival function. Genomic studies of individuals with congenital insensitivity to pain or paroxysmal pain syndromes considerable increased our understanding of the function of peripheral nociceptors, and especially of the roles of voltage-gated sodium channels and of nerve growth factor (NGF)/TrkA receptors in nociceptive transduction and transmission. Brain imaging studies revealed a “pain matrix,” consisting of cortical and subcortical regions that respond to noxious inputs and can positively or negatively modulate pain through activation of descending pain modulatory systems. Projections from the periaqueductal grey (PAG) and the rostroventromedial medulla (RVM) to the trigeminal and spinal dorsal horns can inhibit or promote further nociceptive inputs. The “pain matrix” can explain such varied phenomena as stress-induced analgesia, placebo effect and the role of expectation on pain perception. Disruptions in these systems may account for the existence idiopathic pan states such as fibromyalgia. Increased understanding of pain modulatory systems will lead to development of more effective therapeutics for chronic pain