Lost in time and space? Multisensory processing of peripersonal space and time perception in people with frequent experiences of depersonalisation.

Perception of one's own body in time and space is a fundamental aspect of self-consciousness. It scaffolds our subjective experience of being present, in the here and now, a vital condition for our survival and well-being. Depersonalisation (DP) is characterized by a distressing feeling of being 'spaced out', detached from one's self, as well as atypical 'flat' time perception. Using an audio-tactile paradigm, we conducted a study looking at the effect of DP experiences on peripersonal space (PPS) - the space close to the body - and time perception. Strikingly, we found no difference in PPS perception in people with higher DP experiences (High DPe) versus low occurrences of DP experiences (Low DPe). To assess time perception, we used the Mental Time Travel (MTT) task measuring the individuals' capacity to take one's present as a reference point for situating personal versus general events in the past and the future. We found an overall poorer performance in locating events in time relative to their present reference point in High DPe. By contrast, Low DPe showed significant variation in performance when answering to relative past events, while High DPe did not. Our study sheds light on the close link between altered sense of self and egocentric spatiotemporal perception in individuals with DP experiences, the third most common psychological symptom in the general population.

Mixed selectivity in monkey anterior intraparietal area during visual and motor processes.

Classical studies suggest that the anterior intraparietal area (AIP) contributes to the encoding of specific information such as objects and actions of self and others, through a variety of neuronal classes, such as canonical, motor and mirror neurons. However, these studies typically focused on a single variable, leaving it unclear whether distinct sets of AIP neurons encode a single or multiple sources of information and how multimodal coding emerges. Here, we chronically recorded monkey AIP neurons in a variety of tasks and conditions classically employed in separate experiments. Most cells exhibited mixed selectivity for observed objects, executed actions, and observed actions, enhanced when this information came from the monkey's peripersonal working space. In contrast with the classical view, our findings indicate that multimodal coding emerges in AIP from partially-mixed selectivity of individual neurons for a variety of information relevant for planning actions directed to both physical objects and other subjects.

Emotional body postures affect inhibitory control only when task-relevant.

A classical theoretical frame to interpret motor reactions to emotional stimuli is that such stimuli, particularly those threat-related, are processed preferentially, i.e., they are capable of capturing and grabbing attention automatically. Research has recently challenged this view, showing that the task relevance of emotional stimuli is crucial to having a reliable behavioral effect. Such evidence indicated that emotional facial expressions do not automatically influence motor responses in healthy young adults, but they do so only when intrinsically pertinent to the ongoing subject's goals. Given the theoretical relevance of these findings, it is essential to assess their generalizability to different, socially relevant emotional stimuli such as emotional body postures. To address this issue, we compared the performance of 36 right-handed participants in two different versions of a Go/No-go task. In the Emotional Discrimination task, participants were required to withhold their responses at the display of emotional body postures (fearful or happy) and to move at the presentation of neutral postures. Differently, in the control task, the same images were shown, but participants had to respond according to the color of the actor/actress' t-shirt, disregarding the emotional content. Results showed that participants made more commission errors (instances in which they moved even though the No-go signal was presented) for happy than fearful body postures in the Emotional Discrimination task. However, this difference disappeared in the control task. Such evidence indicates that, like facial emotion, emotional body expressions do not influence motor control automatically, but only when they are task-relevant.

Mirror neurons 30 years later: implications and applications.

Mirror neurons (MNs) were first described in a seminal paper in 1992 as a class of monkey premotor cells discharging during both action execution and observation. Despite their debated origin and function, recent studies in several species, from birds to humans, revealed that beyond MNs properly so called, a variety of cell types distributed among multiple motor, sensory, and emotional brain areas form a 'mirror mechanism' more complex and flexible than originally thought, which has an evolutionarily conserved role in social interaction. Here, we trace the current limits and envisage the future trends of this discovery, showing that it inspired translational research and the development of new neurorehabilitation approaches, and constitutes a point of no return in social and affective neuroscience.

Chronic Cancer Pain: Opioids within Tumor Microenvironment Affect Neuroinflammation, Tumor and Pain Evolution.

Pain can be a devastating experience for cancer patients, resulting in decreased quality of life. In the last two decades, immunological and pain research have demonstrated that pain persistence is primarily caused by neuroinflammation leading to central sensitization with brain neuroplastic alterations and changes in pain responsiveness (hyperalgesia, and pain behavior). Cancer pain is markedly affected by the tumor microenvironment (TME), a complex ecosystem consisting of different cell types (cancer cells, endothelial and stromal cells, leukocytes, fibroblasts and neurons) that release soluble mediators triggering neuroinflammation. The TME cellular components express opioid receptors (i.e., MOR) that upon engagement by endogenous or exogenous opioids such as morphine, initiate signaling events leading to neuroinflammation. MOR engagement does not only affect pain features and quality, but also influences directly and/or indirectly tumor growth and metastasis. The opioid effects on chronic cancer pain are also clinically characterized by altered opioid responsiveness (tolerance and hyperalgesia), a hallmark of the problematic long-term treatment of non-cancer pain. The significant progress made in understanding the immune-mediated development of chronic pain suggests its exploitation for novel alternative immunotherapeutic approaches.

Chronic cancer and non-cancer pain and opioid-induced hyperalgesia share common mechanisms: neuroinflammation and central sensitization.

Neuroinflammation, a peculiar form of inflammation that occurs in response to noxious stimuli in peripheral and central nervous system (CNS), consists in altered vascular permeability followed by leukocyte recruitment and activation in the inflamed tissue, release of inflammatory mediators including cytokines and chemokines, and finally in the activation of microglia and astrocytes in the spinal cord and CNS. This phenomenon mediates and even worsen the inflammatory pain in many painful states and is responsible for central sensitization leading to pain chronicity. We describe the major neuroinflammatory mechanisms shared by cancer and non-cancer pain. Particular attention is given to two different chronic inflammatory painful diseases such as the complex regional pain syndrome and the rheumatoid arthritis as prototypes of neuroinflammatory diseases (gliopathies). In addition, we describe the complexity of tumor microenvironment, their main cellular components (tumor cells, tumor infiltrating leukocytes and sensory neurons) and their reciprocal interactions that characterize different forms and intensity of cancer pain. We also hypothesize that one type of cancer pain, the breakthrough pain, can be attributable to receptor-mediated interaction of opioids with tumor cells and intratumoral leukocytes. Surprisingly, long-term opioid treatment shares the same neuroinflammatory potential responsible for the chronicity of both cancer and non-cancer pain; thus, resulting in paradoxical worsening rather than relieving pain. This paradox has upset the world of pain therapy, with neuroinflammation now being a main target of emerging therapies.

The ambiguity of opioids revealed by immunology is changing the knowledge and the therapeutic approach in cancer and non-cancer pain: A narrative review.

Herein, we summarize the steps of a common scientific path taken by the two Guest Editors, an Anesthesiologist (EA) and an Immunologist (AS), and started 25 years ago at the National Cancer Institute in Rome. When in 1980 WHO codified the usage of opioids for cancer pain relief, it was matter of debate whether only disease progression rather than opioid tolerance were the driving force of opioid escalation. The selective intratumoral accumulation of morphine observed in an experimental xenograft model - the initial scenario of our scientific collaboration - revealed a surprising interaction between the opioid and the opioid receptors expressed by cells of tumor microenvironment. This link could explain the peculiar opioid tolerance and likely hyperalgesia that were observed in the emerging clinical experience of cancer paradoxical pain and suggestive of opioid ambiguity. More elegant cancer pain experimental models, in particular of bone cancer, demonstrated the relevance of inflammatory mediators produced and released by tumor microenvironment cells. These factors were the words of an immune-mediated cross-talk between the tumor and the peripheral and central nervous systems leading to neuroinflammation and consequent pain hypersensitivity, chronicization of acute pain and maladaptive neuroplasticity. Immunology identified in the microglia activation a crucial hub of neuroinflammation and pain centralization. Subsequently the discovery of TLR-4 capacity to bind to opioids on glial cells revealed that they shared the same neuroinflammatory mechanisms underlying cancer and non cancer pain, and could also worsen pain for which they were used. The late awareness of this knowledge and the poor integration between immunological and pain sciences contributed to the recent severe opioid crisis in the USA (opioid epidemic) with a consequent limitation of long-term use of these drugs in non cancer pain, and generated a new wave of opiophobia. Immunological evidence-based pain therapies are currently quite sophisticated, but only little clinically exploited yet. To save the analgesic use of opioids would require the overcome of their intrinsic ability to cause both analgesia and hyperalgesia in a very ambiguous manner. At moment not to hijack and not to usurp the immune system appears still a very far goal.

Opioid-Induced Tolerance and Hyperalgesia.

Opioids are very potent and efficacious drugs, traditionally used for both acute and chronic pain conditions. However, the use of opioids is frequently associated with the occurrence of adverse effects or clinical problems. Other than adverse effects and dependence, the development of tolerance is a significant problem, as it requires increased opioid drug doses to achieve the same effect. Mechanisms of opioid tolerance include drug-induced adaptations or allostatic changes at the cellular, circuitry, and system levels. Dose escalation in long-term opioid therapy might cause opioid-induced hyperalgesia (OIH), which is a state of hypersensitivity to painful stimuli associated with opioid therapy, resulting in exacerbation of pain sensation rather than relief of pain. Various strategies may provide extra-opioid analgesia. There are drugs that may produce independent analgesic effects. A tailored treatment provided by skilled personnel, in accordance with the individual condition, is mandatory. Any treatment aimed at reducing opioid consumption may be indicated in these circumstances. Interventional techniques able to decrease the pain input may allow a decrease in the opioid dose, thus reverting the mechanisms producing tolerance of OIH. Intrathecal therapy with local anesthetics and a sympathetic block are the most common techniques utilized in these circumstances.

Opioid-induced hyperalgesia after rapid titration with intravenous morphine: Switching and re-titration to intravenous methadone.

BACKGROUND: Rapid titration with intravenous morphine (IV-MO) provides fast and efficient pain relief in cancer patients with severe-excruciating pain. However, some patients, after an initially favourable response, can develop an hyperexcitated state unrelieved or worsened by further dose increments. METHODS: Eighty-one patients admitted on emergency basis titrated with IV-MO were assessed. RESULTS: 12 patients were unsuccessfully titrated with IV-MO. Switching to intravenous methadone (IV-ME) and titrating the doses proved to be successfully. CONCLUSIONS: In escalating opioid doses rapidly a recognition of the development of hyperalgesia should be suspected. Increasing doses of opioids may stimulate rather than inhibiting the central nervous system, with complex mechanisms already recognized in experimental studies. Switching to IV-ME and titrating the doses could be taken into consideration to break this vicious circle before pain conditions worsen irreversibly.

Pain in malignant hematology.

Pain is frequently experienced by patients with hematological malignancies, although it often receives little attention. Different underlying causes and mechanisms may sustain several pain syndromes in hematological malignant patients. Pain may be due to disease itself, to disease-related complications, to iatrogenic causes or may be associated with unrelated medical conditions. The management of pain in this setting requires a multidisciplinary approach, integrating analgesics and causal interventions. An accurate diagnostic assessment and the identification of the underlying causes and pathogenetic mechanisms may dictate the treatment approach. For most pain patients, the WHO's three-step analgesic scale for cancer pain relief can provide adequate relief with oral options, although difficult-to-treat pain syndromes, requiring a more complex treatment approach, may also be observed.

The use of fentanyl buccal tablets as breakthrough medication in patients receiving chronic methadone therapy: an open label preliminary study.

BACKGROUND: Data on the treatment of breakthrough cancer pain (BTcP) in patients receiving methadone therapy are lacking. Whether methadone produces tolerance to other opioids, other opioids should be less effective when administered as a BTcP medication. AIM: The aim of this preliminary study was to assess the efficacy of fentanyl buccal tablets (FBT) for the treatment of BTcP in patients who receive methadone as a background analgesic. PATIENTS AND METHODS: A prospective study was carried out for a period of 1 year in a consecutive sample of 13 advanced cancer patients admitted to an acute pain relief and palliative care unit-patients who were receiving stable doses of oral methadone for their background analgesia. The dose of FBT was 100 µg for patients who were receiving 12 mg of oral methadone. For higher doses of methadone, proportional doses of FBT were given. For each episode, trained nurses collected changes in pain intensity (on numerical scale 0-10) and emerging problems when called for pain increases considered to be severe in intensity by patients) (T0) and 15 min after FBT administration (T15). RESULTS: The mean age was 58.1 (SD 9.9), and nine patients were males. Sixty-four events were treated with FBT (4.9 ± 3.1 for each patient, on average). Patients were receiving mean doses of oral methadone of 68 mg (range 15-240). In the majority of events, a decrease in pain intensity >33% and >50% was observed (n = 20 and n = 26, respectively), 15 min after the administration of FBT. Data on ten episodes were unavailable. Nine events were unsuccessfully treated. In all the patients, the level of adverse effects after FBT administration was mild and undistinguishable from that associated with basal opioid analgesia. CONCLUSION: FBT was effective as breakthrough pain medication in patients receiving methadone for their background analgesia, confirming that this group of patients are not inevitably resistant to other opioids.

When the progression of disease lowers opioid requirement in cancer patients.

OBJECTIVE: To describe 2 cases in which an abrupt progression of disease compromising pain pathways and inducing some relief of existing pain or limiting drug delivery to central nervous system. METHODS: Case reports which a significant decrease of opioid requirement was reported, either systematically and spinally. RESULTS: The progression of disease produced changes in pain input or limited the effects of opioids given spinally. DISCUSSION: The data presented suggest that physicians should be aware of the possibility that opioid doses have to be reduced, where presumably specific events related to the progression of disease can change the pain syndrome or reduce the delivery of opioids when using particular routes of administration. This problem needs to be recognized and treated appropriately when it occurs.

Opioid switching and burst ketamine to improve the opioid response in patients with movement-related pain due to bone metastases.

OBJECTIVE: To improve opioid repsonse in patients with movement-related pain by using opioid switching adding a burst of ketamine. METHODS: Two patients with incident bone pain who had adverse effects with increasing doses of opioids were switched to methadone and a burst of 100 mg/d of ketamine for 2 consecutive days was added. RESULTS: Basal pain and pain on movement significantly improved. CONCLUSIONS: The development of breakthrough pain due to movement (incident pain), associated with bone metastases is so rapid that no medication as needed has such a short onset to parallel this temporal pattern of pain firing. Experimental studies have shown that bone metastases are characterized by a specific pattern of spinal hyperexcitation requiring higher doses of opioids. Optimization of basal opioid regimen may improve mobilization. However, adverse effects may more likely occur. The role of opioid switching and burst ketamine to further improve the opioid response has never been assessed in this context. Further studies in animals could confirm these preliminary data, with specific design to parallel this clinical context.

Pharmacological management of cancer pain in the elderly.

Existing studies indicate a high prevalence rate and poor management of cancer pain in the elderly. Pain is often considered an expected concomitant of aging, and older patients are considered more sensitive to opioids. Despite the well known pharmacokinetic changes in the elderly, the complex network of factors involved in the opioid response make the evaluation of a single element, such as age, more difficult. Notwithstanding such difficulties, appropriate analgesic treatment is able to control cancer pain in the elderly in most cases. Skills necessary to optimise pain control in older cancer patients include the ability to objectively assess functional age (not necessarily related to chronological age since the rate of decline is variable), understand the impact of coexisting conditions, carefully manage the numbers and types of drugs taken at the same time and adequately communicate with patients and relatives. The most common treatment of cancer pain consists of the use of regularly given oral analgesics. The elderly are at increased risk of developing toxicity from NSAIDs, and the overall safety of these drugs in frail elderly patients should be considered. When older patients have clear contraindications to NSAIDs, manifest signs of toxicity from these agents, or find that pain is no longer controlled with this class of drugs, opioids should be started. A variety of opioids are available, and they differ widely with respect to analgesic potency and adverse effects among the elderly. Although the aged population requires lower doses of opioids, only careful titration based on individual response can ensure the appropriate response to clinical demand. Elderly patients are potentially more likely to be affected by opioid toxicity because of the physiological changes associated with aging. Nevertheless, appropriate dosage and administration may limit these risks. Cancer patients with pain who do not respond to increasing doses of opioids because they develop adverse effects before achieving acceptable analgesia may be switched to alternative opioids. Despite the favourable effects reported with opioid switching, monitoring is crucial, particularly in the elderly or patients who are switched from high doses of opioids. Adjuvant analgesics, including antidepressants, antiepileptics, corticosteroids and bisphosphonates may help in the treatment of certain types of chronic pain. With an appropriate and careful approach, it should be possible to reduce or eliminate unrelieved cancer pain in most elderly patients and, consequently, to enhance their quality of life. Older patients with cancer should be continuously assessed for cancer pain, both before and after analgesic treatment.

Opioids in pain management of blood-related malignancies.

Opioids are basic analgesics used in the treatment of moderate to severe pain in patients affected by blood-related malignancies. They should be sequentially administered according to the World Health Organisation scale for cancer pain. Initial treatment and titration with opioids should be based on immediate-release preparations, to be administered at appropriate intervals in order to relieve pain and to satisfy the individual opioid requirement. Once a relatively good pain control has been achieved, a slow release formulation at equivalent doses can be given. Most patients can be adequately managed using oral formulation opioids. However, a small group, such as those presenting severe mucositis or requiring a rapid pain relief, should be managed by intravenous continuous infusion and/or by a patient-controlled analgesia system; while for patients in the community, there are distinct advantages to using the subcutaneous route. Other available routes of administration for opioids, can be used in selected circumstances, including rectal, transdermal, epidural, intrathecal and intramuscular. The invasive neuraxial route has a very limited role in patients with haematological malignancies, given the high risk of infection and bleeding. Through a close observation and a careful management, opioid-related side effects can be effectively prevented and treated. This article reviews the principles of opioid therapy and how opioids can be adapted for patients with pain due to haematological malignancies.

Low morphine doses in opioid-naive cancer patients with pain.

Cancer pain can be managed in most patients through the use of the analgesic ladder proposed by the World Health Organization. Recent studies have proposed to skip the second "rung" of the ladder by using a so-called "strong" opioid for moderate pain. However, usual doses of strong opioids commonly prescribed for the third rung of the analgesic ladder may pose several problems in terms of tolerability in opioid-naive patients. The aim of this multicenter study was to evaluate the efficacy and tolerability of very low doses of morphine in advanced cancer patients no longer responsive to nonopioid analgesics. A sample of 110 consecutive opioid-naive patients with moderate-to-severe pain were given oral morphine at a starting dose of 15 mg/day (10 mg in those older than 70 years). Doses were then titrated according to the clinical situation. Pain intensity, morphine doses, symptom intensity, quality of life, and the requirement for dose escalation were monitored for a period of 4 weeks. The treatment was effective and well tolerated by most patients, who were able to maintain relatively low doses for the subsequent weeks (mean dose 45 mg at Week 4). Only 12 patients dropped out due to poor response or other reasons. The use of very low doses of morphine proved to be a reliable method in titrating opioid-naive advanced cancer patients who were also able to maintain their dose, in a 4-week period, below the dose level commonly used when prescribing strong opioids.