Implications of analgesics use in osteoporotic-related pain treatment: focus on opioids.

Bone loss is asymptomatic and will progress without pain and other symptoms until the occurrence of a fracture. The occurrence of a breaking bone induce acute pain determined and supported by a mechanical, inflammatory and neuropathic component. Very often the acute component evolves in a chronic musculoskeletal component. Overall objectives of the analgesic therapy can be summarized in pain relief, improving sleep, improve mobility, reduce anxiety, emotional component and depression. Osteoporosis is predominantly a condition of the elderly, more likely to have coexisting cardiovascular disease and age-related decline in renal function, receiving treatment for one or more comorbid conditions, taking multiple medications. Analgesic treatment with NSAIDs has negative effects on skeletal health and healing of the injured skeleton and increase risk of adverse events especially in older patients. Despite all opioids therapy represents a mainstay in the treatment of patients with moderate to severe pain, it can induce an endocrinopathy, which may affect bone metabolism. The negative effects of opioids on hormonal axis are not the same for all molecule and the choice of drug can be crucial in the treatment of patients with chronic pain.

Pathogenesis and clinical aspects of pain in patients with osteoporosis.

Bone pain is one of the most frequent kinds of chronic pain, mainly in elderly patients. It causes a significant worsening of functional capacity and deterioration in the quality of life in people affected. Mechanisms of pain in osteoporosis are poorly known and often extrapolated by other pathologies or other experimental model. One of principal causes would be a "hyper-remodeling" of bone, that involves osteoclasts activity and pathological modifications of bone innervation. Several studies show that osteoclasts play a significant role in bone pain etiology. Pain in osteoporosis is mainly nociceptive, if it become persistent a sensitization of peripheral and central nervous system can occur, so underlining the transition to a chronic pain syndrome. Central sensitization mechanisms are complex and involve several neuromediators and receptors (Substance P, NMDA, etc.). Most common manifestations of osteoporosis are vertebral compression fractures that cause persistent pain, though to differentiate from pain originating in structures as joint or muscle. First manifestation can be an acute pain due to pathological fracture, those of hip often causes disability. Pain in osteoporosis is an important clinical challenge. Often its complications and consequences on patient quality of life are underestimated with not negligible social implications. A balanced and early multimodal pain therapy including opioids as necessary, even in cases of acute pain, improve the functional capacity of patients and helps to prevent neurological alterations that seems to contribute in significant way in causing irreversible pain chronic syndromes.

Use of opioids for treatment of osteoporotic pain.

The prevalence of osteoporosis increases markedly with age: currently it is estimated that over 200 million people suffer from osteoporosis worldwide. One of the most feared and more frequent complications of osteoporosis is pain, which affects 85% of patients. Commonly in the treatment of chronic pain the therapeutic strategy is based on a three-ladder approach, involving opioids for moderate and severe pain. As proposed by the World Health Organization (WHO), according to the intensity of chronic pain, analgesic treatment can be established. Despite the debate and updates to the analgesic ladder for pain published in 1986 by the WHO, the benefits resulting from its worldwide use are uncontested. In case the pain was not responsive to drugs of pain ladder, is necessary to resort to specialized practices (e.g. subarachnoid infusion of drugs). The oral route for administering analgesics should be preferred, provided that the patients are able to use it. About 50% of all opioid users experience at least one side effect, and more than 20% discontinued treatment due to a serious adverse event. Despite published guidelines and WHO's pain ladder for the management of chronic pain, the treatment of this condition remains suboptimal. Given the physiopsychopathology and complexity of the problems of chronic osteoporotic pain, a multimodal and multidisciplinary approach is still considered the best way to diagnose and treat this disease.

Palliative Care for Patients with Kidney Disease.

Interest in palliative care has increased in recent times, particularly in its multidisciplinary approach developed to meet the needs of patients with a life-threatening disease and their families. Although the modern concept of palliative simultaneous care postulates the adoption of these qualitative treatments early on during the life-threatening disease (and potentially just after the diagnosis), palliative care is still reserved for patients at the end of their life in most of the clinical realities, and thus is consequently mistaken for hospice care. Patients with acute or chronic kidney disease (CKD) usually experience poor quality of life and decreased survival expectancy and thus may benefit from palliative care. Palliative care requires close collaboration among multiple health care providers, patients, and their families to share the diagnosis, prognosis, realistic treatment goals, and treatment decisions. Several approaches, such as conservative management, extracorporeal, and peritoneal palliative dialysis, can be attempted to globally meet the needs of patients with kidney disease (e.g., physical, social, psychological, or spiritual needs). Particularly for frail patients, pharmacologic management or peritoneal dialysis may be more appropriate than extracorporeal treatment. Extracorporeal dialysis treatment may be disproportionate in these patients and associated with a high burden of symptoms correlated with this invasive procedure. For those patients undergoing extracorporeal dialysis, individualized goal setting and a broader concept of adequacy should be considered as the foundations of extracorporeal palliative dialysis. Interestingly, little evidence is available on palliative and end of life care for acute kidney injury (AKI) patients. In this review, the main variables influencing medical decision-making about palliative care in patients with kidney disease are described, as well as the different approaches that can fulfill the needs of patients with CKD and AKI.

A Longitudinal Study of Breakthrough Cancer Pain: An Extension of IOPS-MS Study.

The aim of this study was to longitudinally assess the characteristics of background pain and breakthrough pain (BTcP), analgesic treatment, and satisfaction with treatment four weeks after the first assessment. METHODS: Adult cancer patients with a diagnosis of BTcP were included. At T0, age, gender, visit setting, cancer diagnosis, the extent of the disease, ongoing anticancer treatments, and Karnofsky level were recorded. The background pain intensity in the last 24 h (on a numerical scale 0-10), opioids used for background pain, and their doses, expressed as oral morphine equivalents (OME), as well as other analgesic drugs, were recorded. The number of BTcP episodes, their intensity, predictability and precipitating factors, onset duration of untreated episodes, and interference with daily activities were collected. Analgesics and doses used for BTcP, and the mean time to meaningful pain relief after taking medication, were assessed. The level of satisfaction with BTcP medication was also assessed. Adverse effects to be attributed to these medications were also recorded. At T4, the same data were evaluated. RESULTS: After one-month follow-up, patients had a lower number of BTcP episodes and peak intensity, possibly due to the optimization of background analgesia. The principal characteristics of BTcP did not change significantly. CONCLUSION: A careful and continuous assessment should be guaranteed to all patients to limit the burden induced by BTcP, other than treating BTcP episodes with short-onset opioids.

Oxycodone/Acetaminophen: The Tailoring Combination Treatment for Specific Clinical Profile of Opioid Well-Responsive Cancer Pain.

BACKGROUND: International guidelines recommend moderate-to-severe cancer pain to be treated with strong opioids. However, pain management remains an unsolved matter, at least in the demanding oncology and palliative care setting. Although cancer pain consists of multiple components, which interact in complex ways where combination therapy can better intercept multiple pain characteristics, few studies have used a non-opioid/opioid association to exploit possible synergistic actions. Even the efforts of a recent approach emphasizing appropriate pain assessment and accurate classification to obtain personalized pain management have not produced a satisfactory analgesic strategy. OBJECTIVE: This analysis was intended to evaluate the effectiveness of the immediate release fixed combination of oxycodone/acetaminophen (OxyIR/Par) for the treatment of moderate-to-severe intensity background pain used alone or in combination with other strong opioids in cancer patients with breakthrough cancer pain (BTcP). This is a secondary analysis of a wider observational, prospective, multicenter study [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] performed on 179 patients treated with opioids for cancer pain who received the fixed combination of oxycodone/acetaminophen (OxyIR/Par) for the treatment of background pain (BGP). RESULTS: Cancer patients with breakthrough cancer pain and controlled BGP (Background Pain) were classified according to the presence of analgesic therapy with tablets of fixed combination OxyIR/Par alone (group A, n=120) or tablets of fixed combination OxyIR/Par combined with other strong opioids (group B, n=59). Clinical features of group A were different to group B: higher mean Karnofsky Performance Status Index 70.3% (95% CI=67.2-73.5; median=70, CI=60-80) vs 58.3 (95% CI=53.4-63.2; median=50, CI=45-70) (P<0.001), and mainly group A patients were treated in an ambulatory setting (55.0% group A vs 33.9% group B) (p<0.001). Both groups had managed BGP with similar mean dosages (group A: 12.0, CI=10.5-13.4; group B: 13.1, CI=11.0-15.1) and frequencies of OxyIR/Par alone for group A and in association to other opioids for group B, but Breakthrough cancer Pain (BTcP) exhibited different characteristics in the two groups, showing a lower mean intensity numerical rating scale (NRS) of 7.5 (95% CI=7.2-7.7; median=7, CI=7-8 group A) vs 7.9 (95% CI=7.6, 8.2; median= 8, CI=7-9 group B) (P=0.04) and a higher percentage of patients had a faster onset, defined as the maximum intensity reached in less than 10 minutes, 81.7% (N=98) in group A vs 59.3% (n=35) in group B (P=0.002). CONCLUSION: This is the first analysis about the efficacy of an immediate-release fixed combination of OxyIR/Par in the real world for moderate-to-severe background cancer pain and breakthrough cancer pain. The oral fixed combination OxyIR/Par provided an adequate level of analgesia for moderate-severe background cancer pain, in a different cohort of cancer patients with different performance status, both in ambulatory and palliative settings. The low dosage of fixed combination OxyIR/Par was effective alone or in association with other opioids.

Multidimensional Statistical Technique for Interpreting the Spontaneous Breakthrough Cancer Pain Phenomenon. A Secondary Analysis from the IOPS-MS Study.

Breakthrough cancer pain (BTcP) is a temporary exacerbation of pain that "breaks through" a phase of adequate pain control by an opioid-based therapy. The non-predictable BTcP (NP-BTcP) is a subtype of BTcP that occurs in the absence of any specific activity. Since NP-BTcP has an important clinical impact, this analysis is aimed at characterizing the NP-BTcP phenomenon through a multidimensional statistical technique. This is a secondary analysis based on the Italian Oncologic Pain multiSetting-Multicentric Survey (IOPS-MS). A correlation analysis was performed to characterize the NP-BTcP profile about its intensity, number of episodes per day, and type. The multiple correspondence analysis (MCA) determined the identification of four groups (phenotypes). A univariate analysis was performed to assess differences between the four phenotypes and selected covariates. The four phenotypes represent the hierarchical classification according to the status of NP-BTcP: from the best (phenotype 1) to the worst (phenotype 4). The univariate analysis found a significant association between the onset time >10 min in the phenotype 1 (37.3%)' vs. the onset > 10 min in phenotype 4 (25.8%) (p < 0.001). Phenotype 1 was characterized by the gastrointestinal type of cancer (26.4%) with respect to phenotype 4, where the most frequent cancer affected the lung (28.8%) (p < 0.001). Phenotype 4 was mainly managed with rapid-onset opioids, while in phenotype 1, many patients were treated with oral, subcutaneous, or intravenous morphine (56.4% and 44.4%, respectively; p = 0.008). The ability to characterize NP-BTcP can offer enormous benefits for the management of this serious aspect of cancer pain. Although requiring validation, this strategy can provide many indications for identifying the diagnostic and therapeutic gaps in NP-BTcP management.

A Call to Action by the Italian Mesotherapy Society on Scientific Research.

Mesotherapy (local intradermal therapy, LIT) is a technique used to slowly spread drugs in tissues underlying the site of injection to prolong the pharmacological effect with respect to intramuscular injection. Recommendations for proper medical use of this technique have been made for pain medicine and rehabilitation, chronic venous disease, sport medicine, musculoskeletal disorders, several dermatological conditions, skin ageing, and immune-prophylaxis. Although mesotherapy is considered a valid technique, unresolved questions remain, which should be answered to standardize methodology and dosing regimen as well as to define the right indications in clinical practice. New randomized controlled trials are needed to test single products (dose, frequency of administration, efficacy and safety). Even infiltration of substances for dermo-cosmetic purposes must be guided by safety and efficacy tests before being proposed by mesotherapy. In this article, we put forth a preclinical and clinical research plan and a health technology assessment as a call to action by doctors, researchers and scientific societies to aid national health authorities in considering mesotherapy for prevention, treatment and rehabilitation paths.

Effects of opioid rotation in chronic pain patients: ORTIBARN study.

BACKGROUND: Opioid rotation is currently the subject of considerable debate for two reasons: firstly as a strategy for pain treatment, and secondly because of the difficulty in determining equianalgesic doses. Switching from one slow-release (SR) opioid analgesic to another raises a number of critical issues, and there are no widespread studies that support a standard protocol. Initiation of opioid therapy must consider gradual dose titration of the drug until the minimum effective and maximum tolerated dosage for each patient is found. OBJECTIVE: This study aimed to evaluate the effects of SR opioid rotation after a stabilization period with normal-release (NR) morphine ('start therapy') in patients with cancer or non-cancer pain not controlled with their current SR opioid. METHODS: This is a multicentre, open-label, prospective study. A total of 326 consecutive patients were enrolled who were affected by chronic cancer or non-cancer pain that was not controlled by an SR opioid administered as either monotherapy or in combination with other analgesic drugs. Following start therapy with oral NR morphine at a dosage of 5 mg or 10 mg every 4 hours, rotation to an SR opioid of a different type from that previously administered was carried out. RESULTS: After about 3 days of start therapy with NR morphine, rotation to an SR opioid allowed a significant decrease of both baseline pain and daily episodes of breakthrough pain. No significant difference was detected between dosages and type of opioid administered, both prior to and after the start therapy period with NR morphine. CONCLUSIONS: Rotation to another opioid preceded by a brief period of opioid receptor resetting by start therapy with NR morphine allows a good level of pain control and avoids rotation to inappropriate opioid dosages or combinations analgesics.

Careful Breakthrough Cancer Pain Treatment through Rapid-Onset Transmucosal Fentanyl Improves the Quality of Life in Cancer Patients: Results from the BEST Multicenter Study.

OBJECTIVES: To explore the effect of breakthrough cancer pain (BTcP) treatment on quality of sleep and other aspects of the health-related quality of life (HRQoL) in patients with cancer pain. METHODS: In an observational, multicenter, cohort study, cancer patients from palliative care units, oncology departments, and pain clinics and affected by BTcP were included. Enrolled patients were assessed at the four visits: T0 (baseline), T7, T14, and T28. Stable chronic background pain (numeric rating scale, NRS ≤ 4) during the whole study period was mandatory. BTcP was treated through transmucosal fentanyl. Three questionnaires were used to measure the HRQoL: EORTC QLQ-C15-PAL, Pittsburgh Sleep Quality Index (PSQI), and the Edmonton Symptom Assessment System (ESAS). RESULTS: In 154 patients, the HRQoL showed a significant improvement for all physical and emotional characteristics in the EORTC QLQ-C15-PAL, except for nausea and vomiting (linear p-value = 0.1) and dyspnea (Linear p-value = 0.05). The ESAS and PSQI questionnaires confirmed these positive results (p < 0.0001 and p = 0.002, respectively). CONCLUSIONS: This prospective investigation by an Italian expert group, has confirmed that careful management of BTcP induces a paramount improvement on the HRQoL. Because in cancer patients there is a high prevalence of BTcP and this severe acute pain has deleterious consequences, this information can have an important clinical significance.

Breakthrough Cancer Pain Clinical Features and Differential Opioids Response: A Machine Learning Approach in Patients With Cancer From the IOPS-MS Study.

PURPOSE: A large proportion of patients with cancer suffer from breakthrough cancer pain (BTcP). Several unmet clinical needs concerning BTcP treatment, such as optimal opioid dosages, are being investigated. In this analysis the hypothesis, we explore with an unsupervised learning algorithm whether distinct subtypes of BTcP exist and whether they can provide new insights into clinical practice. METHODS: Partitioning around a k-medoids algorithm on a large data set of patients with BTcP, previously collected by the Italian Oncologic Pain Survey group, was used to identify possible subgroups of BTcP. Resulting clusters were analyzed in terms of BTcP therapy satisfaction, clinical features, and use of basal pain and rapid-onset opioids. Opioid dosages were converted to a unique scale and the BTcP opioids-to-basal pain opioids ratio was calculated for each patient. We used polynomial logistic regression to catch nonlinear relationships between therapy satisfaction and opioid use. RESULTS: Our algorithm identified 12 distinct BTcP clusters. Optimal BTcP opioids-to-basal pain opioids ratios differed across the clusters, ranging from 15% to 50%. The majority of clusters were linked to a peculiar association of certain drugs with therapy satisfaction or dissatisfaction. A free online tool was created for new patients' cluster computation to validate these clusters in future studies and provide handy indications for personalized BTcP therapy. CONCLUSION: This work proposes a classification for BTcP and identifies subgroups of patients with unique efficacy of different pain medications. This work supports the theory that the optimal dose of BTcP opioids depends on the dose of basal opioids and identifies novel values that are possibly useful for future trials. These results will allow us to target BTcP therapy on the basis of patient characteristics and to define a precision medicine strategy also for supportive care.

Factors Influencing the Clinical Presentation of Breakthrough Pain in Cancer Patients.

Background: The aim of this study was to identify potential variables influencing the clinical presentation of breakthrough cancer pain (BTP). Methods: Cancer patients with a diagnosis of BTP were enrolled. Demographic and clinical characteristics, as well as background pain and BTP characteristics were collected. Multivariate analyses were conducted to assess the correlation between BTP characteristics and the variables examined. Results: Data of 4016 patients were analysed. Average daily number of BTP episodes was 2.4, mean intensity was 7.5, and a mean duration was 43.3 min. A short onset BTP was observed in 68.9% of patients. In 30.5% of patients BTP was predictable. There were 86.0% of participants who reported a marked interference of BTP with their daily activities. Furthermore, 86.8% of patients were receiving opioids for the management of BTP. The average time to meaningful pain relief was 16.5 min and 70.9% of patients were satisfied with their BTP medications. Age, head and neck cancer, Karnofsky, background pain intensity, predictable and fast onset BTP were independently associated with the number of BTP episodes. BTP pain intensity was independently associated with background pain intensity, fast onset BTP, and Karnofsky. Neuropathic pain mechanism was independently associated with unpredictable BTP. Variables independently associated with a longer duration of BTP were age, place of visit, cancer diagnosis, disease-oriented therapy, background pain intensity and mechanism, and unpredictable BTP. Age, Karnofsky, background pain intensity, fast onset, and long duration of BTP were independently associated with interference with daily activity. Conclusions: BTP has a variable presentation depending on interdependent relationships among its different characteristics.

Assessment and treatment of breakthrough cancer pain: from theory to clinical practice.

Breakthrough cancer pain (BTcP) is a common condition in oncological patients. However, its management is still suboptimal. Improved knowledge of BTcP and its management in clinical practice may have immediate importance for all physicians involved in the supportive care of cancer patients. This review critically discusses the most important concepts for the correct diagnosis of BTcP and presents some intriguing cases of the management of this condition in clinical practice. Overall, the most appropriate therapeutic choice appears to be a rapid-onset opioid (ROO), and in particular, the nasal route of administration is the quickest and most convenient mode of administration for the management of BTcP, especially when the patient needs rapid resolution of pain. To this end, intranasal fentanyl spray may have a particular relevance in clinical practice. Future research should focus on accepted definitions of BTcP to investigate the optimal management of this highly heterogeneous pain condition. Therapeutic decision-making of patients, clinicians, and payers will likely be driven from results of well-designed clinical trials of ROOs.

Breakthrough Cancer Pain: Preliminary Data of The Italian Oncologic Pain Multisetting Multicentric Survey (IOPS-MS).

INTRODUCTION: An ongoing national multicenter survey [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] is evaluating the characteristics of breakthrough cancer pain (BTP) in different clinical settings. Preliminary data from the first 1500 cancer patients with BTP enrolled in this study are presented here. METHODS: Thirty-two clinical centers are involved in the survey. A diagnosis of BTP was performed by a standard algorithm. Epidemiological data, Karnofsky index, stage of disease, presence and sites of metastases, ongoing oncologic treatment, and characteristics of background pain and BTP and their treatments were recorded. Background pain and BTP intensity were measured. Patients were also questioned about BTP predictability, BTP onset (≤10 or >10 min), BTP duration, background and BTP medications and their doses, time to meaningful pain relief after BTP medication, and satisfaction with BTP medication. The occurrence of adverse reactions was also assessed, as well as mucosal toxicity. RESULTS: Background pain was well controlled with opioid treatment (numerical rating scale 3.0 ± 1.1). Patients reported 2.5 ± 1.6 BTP episodes/day with a mean intensity of 7.5 ± 1.4 and duration of 43 ± 40 min; 977 patients (65.1%) reported non-predictable BTP, and 1076 patients (71.7%) reported a rapid onset of BTP (≤10 min). Higher patient satisfaction was reported by patients treated with fast onset opioids. CONCLUSIONS: These preliminary data underline that the standard algorithm used is a valid tool for a proper diagnosis of BTP in cancer patients. Moreover, rapid relief of pain is crucial for patients' satisfaction. The final IOPS-MS data are necessary to understand relationships between BTP characteristics and other clinical variables in oncologic patients. FUNDING: Molteni Farmaceutici, Italy.