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.

Italian Oncological Pain Survey (IOPS): a multicentre Italian study of breakthrough pain performed in different settings.

OBJECTIVE: A survey of breakthrough pain (BTP) was performed in five palliative care units (PCU), seven oncology departments (ONC), and nine pain clinics (OPC). METHODS: A standard algorithm was used to confirm the diagnosis of BTP of patients refereed to different settings. RESULTS: 1,412 evaluable cancer patients were enrolled. 53.9% were males and the mean age was 63.7±13.1 years. The mean intensity of background pain was 2.8±0.73. Patients reported 2.4±1.1 BTP episodes/day with a mean intensity of 7.37±1.28. 80.6% patients reported that the BTP had a significant negative impact in everyday life. The majority of patients reported a fast onset of BTP, which was predictable in 50.7% of cases, while BTP with a gradual onset (>10 min) was less predictable (29%) (P=0.001). PCU patients were older, had lower Karnofsky levels, a lower number of BTP episodes/day, a slow onset of BTP onset, and a less predictable BTP. Cancer diagnosis was performed a mean of 23.5 months (SD±32.8) before the assessment. The mean duration of background pain was 3.5 months (SD±3.5), and the mean duration of any analgesic treatment was 2.5 months (SD±3). BTP started a mean of 2.2 months (SD±1.9) before the assessment. Characteristics of BTP were influenced by the course of disease, as well as the duration of background pain and initiation of BTP. Most patients took rapid onset opioids and were satisfied with the treatment. BTP diagnosis was prevalently made by ONC and OPC physicians, and rarely by GPs. CONCLUSION: This survey performed by an Italian observatory expert review group, has confirmed that the BTP represents a clinically relevant condition with a negative impact on the patient's quality of life. BTP was detected in all settings involved. A number of factors are associated with the BTP. Also factors regarding the course of disease and setting of care have been assessed. This information may help in stratifying patients or predicting the risk of development of BTP with specific characteristics.

Safety and efficacy of citrate anti-coagulation continuous renal replacement therapies in post-cardiac surgery patients with liver dysfunction.

The study's aim was to examine safety and efficiency of citrate anticoagulated continuous renal replacement therapies (CRRT) in cardiac surgery patients with acute kidney injury and associated liver dysfunction. The study was conducted on critical ICU patients, hospitalized after cardiac surgery, who developed renal and liver acute failures due to low-flow syndrome. CRRT in continuous veno-venous hemodiafiltration with regional citrate anticoagulation (RCA) was prescribed to address renal failure and avoid bleeding-risk. Patient Ca(++) was measured to monitor RCA safety, while thromboelastography (TEG) and circuit Ca(++) were used to verify efficacy. CRRT effectiveness was evaluated through creatinine and urea levels, while liver function was monitored through bilirubin, aspartate aminotransferase, glutamic oxaloacetic transaminase (AST GOT) and gamma glutamyl transferase (GT) levels. The study did not require ethical approval. Hepatic and renal failures were confirmed by baseline levels (total bilirubin=3.1 ± 3.37 mg/dL, AST GOT=153 ± 147 U/L and gamma GT=93.3 ± 86 IU/L, creatinine=1.97 ± 0.88 and blood urea nitrogen [BUN] 98.13 ± 71.34) assessed in 15 patients. During treatment, Ca(++) (patient and circuit) remained stable and within range for the whole therapy thanks to low citrate dose (2.8 ± 0.3 mmol/L of blood), while hepatic markers did not show any significant changes the therapy, although treatment with citrate is contraindicated in patients with hepatic failure. RCA quality was confirmed by TEG values, which showed an anticoagulated circuit with no effects on patients. These results involved a high filter lifespan (49.76 ± 22.10 h) and with an effective creatinine and BUN clearance. No episodes of citrate intoxication were reported (total/ionized calcium ratio remained stable and physiologic). RCA during CRRT with dilute solutions proved both effective and safe, even in patients with acute liver failure.

One-year follow-up of patients with long-lasting post-herpetic neuralgia.

BACKGROUND: Recent information on epidemiology and management of post-herpetic neuralgia (PHN), a painful complication of zoster, is scarce. METHODS: This study was conducted at the Pain Clinic of the Policlinico Tor Vergata, Rome, Italy, on eighty-five immunocompetent patients with a clinical diagnosis of PHN. At enrollment (time 0, T0), the patients were interviewed by physicians to obtain demographic data and information about their zoster clinical history and underwent a blood test for VZV-DNA research. DN4 and SF-12 questionnaires were used to assess the neuropathic nature of pain and the overall health status, respectively. A one-year follow-up was planned for enrolled cases, who were visited at regular intervals of at least 3 months. RESULTS: At T0 all the patients were at least 6 months from the episode of acute zoster and still presented with intense pain (mean VAS =6.7; mean DN4 = 5.7). Using antivirals within 72 hours from the rash onset was associated to a significant reduction of pain at T0 (p = 0.006 vs untreated patients). Only 2.6% of patients treated with antivirals during acute zoster but 18.6% of the untreated ones presented with neuropathic pain at T12 (p =0.007), even though the two groups were similar at T0. VZV-DNA was found in 5 out of the 50 available blood samples. At the last follow-up visit, PCS and MCS scores of the PHN patients were found to be recovered over those of the historical age-matched healthy controls. Undesirable side effects of analgesic therapies were observed in 15.3 to 28.8% of the patients. CONCLUSIONS: Patients who six months after acute zoster still have significant neuropathic pain, have a high probability of suffering from chronic pain in the subsequent months/years. The initial antiviral treatment has a significant impact on the pain. Current strategies of analgesic therapy are effective to achieve relief of pain in PHN patients, but they are burdened with heavy and undesirable side effects.

Feasibility of frequency-modulated wireless transmission for a multi-purpose MEMS-based accelerometer.

Recent advances in the Micro Electro-Mechanical System (MEMS) technology have made wireless MEMS accelerometers an attractive tool for Structural Health Monitoring (SHM) of civil engineering structures. To date, sensors' low sensitivity and accuracy--especially at very low frequencies--have imposed serious limitations for their application in monitoring large-sized structures. Conventionally, the MEMS sensor's analog signals are converted to digital signals before radio-frequency (RF) wireless transmission. The conversion can cause a low sensitivity to the important low-frequency and low-amplitude signals. To overcome this difficulty, the authors have developed a MEMS accelerometer system, which converts the sensor output voltage to a frequency-modulated signal before RF transmission. This is achieved by using a Voltage to Frequency Conversion (V/F) instead of the conventional Analog to Digital Conversion (ADC). In this paper, a prototype MEMS accelerometer system is presented, which consists of a transmitter and receiver circuit boards. The former is equipped with a MEMS accelerometer, a V/F converter and a wireless RF transmitter, while the latter contains an RF receiver and a F/V converter for demodulating the signal. The efficacy of the MEMS accelerometer system in measuring low-frequency and low-amplitude dynamic responses is demonstrated through extensive laboratory tests and experiments on a flow-loop pipeline.

Breakthrough pain in patients with controlled or uncontrolled basal pain: an observational study.

BACKGROUND: Breakthrough pain (BTP) is traditionally defined as a pain exacerbation in patients with chronic controlled pain. However, this definition has recently been challenged. OBJECTIVES: To evaluate the prevalence of unsatisfactory control in patients with chronic cancer pain, and investigate the frequency and intensity of BTP episodes. METHODS: A total of 665 patients with chronic cancer pain attending 21 pain therapy units in Italy were evaluated for baseline pain intensity and number of BTP episodes over a 30-day period. All patients started, continued or modified treatment for BTP at enrollment, according to medical judgment. RESULTS: The number of BTP events was higher in patients with uncontrolled baseline pain, although the intensity and duration of episodes were similar. In patients with uncontrolled baseline pain, the number of events decreased with time and reached values comparable with those reported in patients with controlled pain. Both the intensity of the pain and the duration of the BTP events exhibited similar values in the two groups at all time points, following increased monitoring and the prescription of analgesic medication. CONCLUSION: Patients with uncontrolled baseline pain experienced BTP flares with higher frequency, but similar intensity and duration with respect to patients with controlled pain at baseline. Notably, a close follow-up and adequate management of the BTP episodes led to an improvement of BTP in the observed patients.

Long-term efficacy of OROS® hydromorphone combined with pregabalin for chronic non-cancer neuropathic pain.

BACKGROUND AND OBJECTIVES: Treatment for chronic non-cancer neuropathic pain can be complicated by side effects and drug interactions. Combining opioid analgesics and calcium channel modulators may overcome these and improve efficacy. The objective of the present study was to evaluate the efficacy and safety of OROS® hydromorphone combined with pregabalin in patients with chronic non-cancer neuropathic pain. METHODS: This retrospective observational study was conducted on clinical records from patients aged ≥18 years with chronic non-cancer neuropathic [>4 on the Douleur Neuropathique en 4 questions (DN4) scale] pain of ≥6 months duration, with severe intensity [>4 on the Numerical Rating Scale (NRS); range 0-10], who attended all visits and had ≥12 months of follow-up at the Tor Vergata University Polyclinic Hospital, from November 2008 to February 2011. Patients received an oral combination of OROS® hydromorphone and pregabalin. Pain was evaluated at each visit (months 1, 3, 6, 9, and 12) using the NRS and DN4 scale; Patients' Global Impression of Change (PGIC) was administered at months 1, 6, and 12. Dosage and side effects were recorded at each visit. RESULTS: Of 1,292 patients (32 % men, mean ± SD age 67.6 ± 11.9 years), 1,126 attended all visits. Seventeen percent (n = 224) had purely neuropathic pain. Initial mean dosage was 6.06 ± 2.00 mg/day for OROS® hydromorphone, 113.02 ± 21.94 mg/day for pregabalin. Dosages increased up to month 6, and returned to near initial dosages at month 12 (range 4-120 mg/day for OROS® hydromorphone; 75-600 mg/day for pregabalin). NRS pain scores (mean ± standard deviation) were 7.25 ± 1.34 at baseline and 1.85 ± 1.36 at 12 months (p < 0.0001); DN4 scores were 6.19 ± 1.65 at baseline, reduced to 1.84 ± 1.25 at 12 months (p < 0.0001), reductions of 74.4 and 70.2 %, respectively. More than 90 % of patients had a ≥50 % score reduction on both scales after 12 months. The PGIC scale showed that >75 % of patients felt improvement at 1 month, increasing to 91 % and 93 % at 6 and 12 months. The incidence of side effects was similar between elderly (aged >65 years) and younger subjects; there were no cases of addiction. CONCLUSIONS: The OROS® hydromorphone and pregabalin combination was efficacious for chronic non-cancer neuropathic pain and well tolerated, providing significant pain reduction without the risk of addiction and with a good tolerability profile, regardless of age.

Beyond the traditional definition of breakthrough pain: an observational study.

INTRODUCTION: Breakthrough pain (BTP) is traditionally defined as a transitory pain flare in opioid-treated patients with chronic background pain. This definition has, however, been challenged in recent years. This study aimed to analyze BTP prevalence in different pain conditions. METHODS: This was a prospective, non-interventional, observational study conducted from June to September 2011 in two Italian pain treatment reference centres. Consecutive patients aged >18 years with oncological or non-oncological pain were eligible for this study; background pain was acute/ subacute (<3 months) or chronic (>3 months). The characteristics of pain were evaluated by means of a structured interview by physicians, and patients were asked to complete a dedicated clinical study form. The following outcomes were assessed: chronic pain duration (in patients with chronic pain), BTP prevalence, and number and severity of daily BTP episodes. All outcomes were assessed in four populations of patients with: (a) chronic oncological pain; (b) chronic non-oncological pain; (c) non-chronic oncological pain; (d) non-chronic non-oncological pain. The correlation between BTP and gender was also investigated. RESULTS: Of 1,270 patients with chronic pain, 1,086 had non-oncological pain (85.5%). Most patients (68.6%) with non-oncological pain were female (P = 0.001). Pain duration was significantly longer in non-oncological pain versus oncological pain groups (P = 0.002). BTP prevalence was lower in non-oncological patients (P < 0.001). No differences were reported in terms of number and severity of daily BTP episodes. BTP was more frequent in females with non-oncological pain (P = 0.04). Females had a significantly higher pain severity (P = 0.02) than males. CONCLUSION: BTP is frequently reported in patients who do not have BTP according to the traditional definition. BTP frequency and severity is similar in oncological and non-oncological pain.

Prolonged-release oxycodone/naloxone in nonmalignant pain: single-center study in patients with constipation.

INTRODUCTION: Opioid treatment for chronic malignant and nonmalignant pain of moderateto-severe intensity is associated with bowel dysfunction leading to constipation; this often requires opioid dose reduction or interruption. Combination opioid agonist/antagonist therapy can restore normal bowel function. A prolonged-released (PR) fixed-dose combination of oxycodone and naloxone has been developed and efficacy has been demonstrated in phase 3 clinical trials. METHODS: This 2-month, retrospective, singlecenter, observational study assessed the effectiveness and safety of PR oxycodone/naloxone in consecutive nononcological patients with constipation and chronic pain despite analgesic treatment; specific subgroup analyses were performed in opioid-experienced or opioid-naïve patients and in age subgroups. Efficacy was assessed by: intensity of pain; bowel function; effective oxycodone/naloxone dose; Patients' Global Impression of Change (PGIC) scale; rescue paracetamol; and laxative use. Safety evaluations were also performed. RESULTS: Of 1,051 patients starting on the oxycodone/naloxone combination (32.0% male; mean age 67 ± 13 years, 53.9% opioid naïve), 1,012 completed 2 months of treatment. Overall, PR oxycodone/naloxone was associated with a significant decrease in pain intensity (P < 0.001), a reduced need for rescue paracetamol (P < 0.001), and PGIC score of "very much improved" or "much improved" in 84.0% of patients. Constipation markedly decreased (P < 0.001) despite reduced laxative use (P < 0.001 vs. baseline). The most frequent treatment-emergent adverse events were somnolence (2.0%), dizziness (1.1%), and confusion (1.0%). Clinical differences in endpoints were seen between opioid-naïve and opioid-experienced patients, and among agestratified groups, but efficacy was similar to the overall population. CONCLUSIONS: Fixed combination PR oxycodone/naloxone was effective and well tolerated in moderate-to-severe chronic pain in patients with constipation, providing analgesia and relief from bowel dysfunction. Consistent efficacy across patient subgroups provides guidance for daily management of chronic pain when therapy options are limited due to bowel dysfunction, regardless of age or previous medication. Supplementary material belonging to this paper is available on SpringerLink.

Palmitoylethanolamide in the treatment of chronic pain caused by different etiopathogenesis.

OBJECTIVE: To assess the efficacy and safety of palmitoylethanolamide (PEA), an endogenous fatty acid amide belonging to the N-acylethanolamines family, in reducing pain severity in patients with pain associated to different pathological conditions. METHODS: This was an observational study conducted on 610 patients who were unable to effectively control chronic pain with standard therapies. PEA (600 mg) was administered twice daily for 3 weeks followed by single daily dosing for 4 weeks, in addition to standard analgesic therapies or as single therapy. The primary outcome measure was the mean score pain severity evaluated by the numeric rating scale. Safety was also evaluated. RESULTS: PEA treatment significantly decreased the mean score pain intensity evaluated in all patients who completed the study. The PEA effect was independent of the pain associated pathological condition. PEA-induced decrease of pain intensity was present also in patients without concomitant analgesic therapy. Importantly, PEA showed no adverse effects. CONCLUSIONS: In this study, PEA was effective and safe in the management of chronic pain in different pathological conditions.

Role of mesotherapy in musculoskeletal pain: opinions from the italian society of mesotherapy.

Mesotherapy is the injection of active substances into the surface layer of the skin. This method allows a slower spread, higher levels, and longer lasting effects of drugs in the tissues underlying the site of injection (skin, muscle, and joint) compared with those following intramuscular injection. This technique is useful when a local pharmacological effect is required and relatively high doses of drug in the systemic circulation are not. Mesotherapy should only be undertaken following a complete clinical workup and subsequent diagnosis. Encouraging results have been reported in randomized, controlled clinical trials and in observational studies involving patients with various forms of musculoskeletal pain. Recommendations by experts from the Italian Society of Mesotherapy for appropriate use of mesotherapy in musculoskeletal pain and an algorithm for treating localized painful conditions are provided.

Breakthrough pain in patients referred to pain clinics: the Italian pain network retrospective study.

INTRODUCTION: Despite breakthrough pain (BTP) being one of the most severe forms of pain, there are no definitive data on its prevalence. METHODS: The authors performed a retrospective survey of the prevalence of BTP in consecutive patients in four Italian pain clinics, subsequent to application of an Italian law mandating detailed clinical records on pain characteristics, treatment, and results. Mean pain intensity was assessed with a numerical rating scale from 0 to 10. RESULTS: The authors analyzed records of 1,401 patients (58% women, 33.1% patients with cancer). Transient episodes of severe pain or BTP were referred by 790 patients (56.4%), including 58.2% of the men (342 of 588) and 55.1% of the women (448 of 813). Among the 464 patients with cancer, 70.3% reported daily exacerbation of pain. The mean BTP intensity was 8.31 ± 1.58 and 31.1% of patients reported experiencing three episodes per day. CONCLUSION: Despite some limitations of the study, the authors show that transient episodes of severe pain or BTP are significantly present both in cancer and other diseases, and that many patients are not yet receiving appropriate opioid therapy. The authors need validated tools at international level for the diagnosis and treatment of BTP in patients with cancer and for transitory and patients with severe non-cancer pain. A survey at national level is needed to estimate the prevalence of BTP in different settings, to plan specific medical education.

Management of opioid-induced constipation in cancer patients: focus on methylnaltrexone.

Opioids are one of the most widely used therapies for the palliative treatment of cancer pain; however, despite their proven analgesic efficacy, they are associated with several adverse effects. Associated with psychological distress and multiple concomitant clinical concerns, constipation is the most commonly occurring adverse effect of chronic opioid therapy in cancer patients. Whilst prophylaxis remains the first-line management option, methylnaltrexone is a recommended treatment option for opioid-related constipation if administration of laxatives is ineffective. Due to its inability to cross the blood-brain barrier, methylnaltrexone exerts a peripheral inhibition of opioid-related effects without influencing the opioid-induced central effects; as a result, the analgesic effect of opioids is unaffected. Moreover, multiple clinical trials, albeit not always conducted specifically in cancer patients, have demonstrated that up to 4 months' treatment with either intravenous or subcutaneous methylnaltrexone provides effective relief from opioid-related constipation and is well tolerated. Preliminary evidence indicates that the addition of methylnaltrexone to standard care for opioid-related constipation may also be advantageous from a pharmacoeconomic perspective. In addition, preliminary data suggest that methylnaltrexone could be associated with some further clinical benefits other than the treatment of opioid-related constipation, such as the improvement of gastric emptying, the relief of nausea/vomiting, and the reduction of the risk of regurgitation and pulmonary aspiration. This narrative review examines the most recent evidence and evaluates the current role of methylnaltrexone in the management of opioid-related constipation, and its potential efficacy in cancer patients. The pharmacokinetics, pharmacodynamics, efficacy and tolerability of methylnaltrexone are discussed.

Adherence and long-term effect of oxycodone/paracetamol in chronic noncancer pain: a retrospective study.

INTRODUCTION: Long-term administration of opiates in patients with chronic noncancer pain (CNCP) is subject to debate due to insufficient clinical evidence to support efficacy and tolerability. METHODS: This retrospective analysis used hospital records to investigate the effects of low doses of the combination of oxycodone/paracetamol on CNCP in an outpatient clinic setting to verify adherence to therapy and long-term efficacy. All patients receiving therapy for CNCP were examined between May and September 2010 and information was collected on medication, duration of therapy, and static and dynamic pain measured using numeric rating scales (NRS) from relevant charts. RESULTS: Two hundred and thirty-one patients (157 men, 68%) with a mean (± SD) age of 66.4±15.5 years were analyzed. Pain indexes at baseline revealed a mean (± SD) static NRS (sNRS) of 3.5±1.77 and a mean dynamic NRS (dNRS) of 7.24±1.33. At last follow-up, mean (± SD) pain reductions versus baseline were 1.58±1.42 for sNRS and 3.04±1.43 for dNRS (P<0.0001 for both). Regarding the duration of therapy, 54 patients (23.4%) were treated for <4 months, and 177 patients (76.6%) for 4 months up to 23 months. Pain reduction was significant in all groups (P<0.0001) but was greatest in patients who had been receiving therapy for ≥4 months. Improvements in pain relief were not associated with an increase in daily dose, which remained stable or decreased slightly over time. DISCUSSION: The results of this study support the hypothesis that an opiate-based combination at low doses improves tolerability and adherence and results in patients obtaining long-term efficacy. Larger studies of the use of opiates in this setting and clinical monitoring on the regional and national level may convince clinicians to view opiates as efficacious analgesics and not as dangerous substances of abuse.

Estimation of baroreflex sensitivity during anesthesia induction with propofol.

This paper presents the analysis of the autonomic nervous system (ANS) control and cardiac baroreflex sensitivity in patients undergoing general anesthesia for major surgery, with the goal of evaluating the effects of anesthesia bolus induction with propofol on autonomic control of heart rate (HR) and arterial blood pressure (ABP). The increase in baroreflex gain in the LF band observed through two different methods hints at the fact that the baroreflex may increase heart period (HP) following a transient ABP decrease, but its response displays a larger amplitude, to compensate for the blunting of the sympathetic action on heart rate and vascular resistance.

Arterial blood pressure regulation following aorta clamping and declamping during surgery.

In this paper, we propose the use of black box models for the system identification of the cardiopulmonary baroreflex control of arterial resistance and of ventricular contractility and of arterial baroreflex control of heart rate (HR) from invasive, continuous measurements of arterial blood pressure (ABP) and central venous pressure (CVP), and non invasive, continuous recordings of ECG and respiration. Two crucial phases of the abdominal aortic aneurism (AAA) repair were investigated: the clamping and declamping of aorta. The objective of the present work is to evaluate and to test the ability to monitor baroreflex responses to clamping and declamping maneuvers preceding and following aneurism removal.

Intra- and inter-beat modeling of cardiovascular dynamics and control: assessing haemodynamic stability and responsiveness.

In critical care patient management, extensive and invasive patient monitoring is routinely performed in order to quantify patient status in view of therapeutic interventions. Little quantitative integration is performed when collecting information from multiple monitors, and processing algorithms are often based on little physiological understanding. Mechanistic modeling can offer insight into the mechanisms underlying patient stability and sensitivity to alterations in physiological variables. Starting from existing models, we construct an integrated model which combines detailed neural cardiovascular regulation with realistic circulation modeling, using Monte-Carlo techniques for reparameterisation when merging the two models. The combined model is analyzed in terms of its dynamical stability and sensitivity to parameter perturbations under simulated conditions of fluid deficit, anaesthesia, and dilatative cardiomyopathy. The results exemplify how a structural model can serve as a quantitative guide in assessing how different underlying patient states can alter the haemodynamics impact of external therapeutic intervention.

Oxycodone/paracetamol: a low-dose synergic combination useful in different types of pain.

The combination of two analgesic agents offers several advantages in the treatment of chronic pain. Paracetamol (acetaminophen) has central analgesic activity without a nonsteroidal anti-inflammatory drug (NSAID)-like or opioid-like effect. Oxycodone is a semisynthetic opioid agonist. The oral fixed-dose combination of oxycodone and paracetamol immediate-release formulation has a synergistic mechanism of action that is useful for moderate-to-severe pain and for nonresponders to NSAIDs or paracetamol alone. This fixed-dose combination offers several advantages: lower individual drug doses can be used because of their synergistic mechanisms of action, its opioid-sparing effect and it has a good efficacy and tolerability profile. Efficacy and safety of this fixed-dose combination were assessed in a wide range of clinical settings: in patients with osteoarthritis or chronic musculoskeletal pain, including when complicated by a neuropathic component; for chronic pain in elderly patients; cancer-related pain; postoperative pain; and for neuropathic pain, in the latter case usually given in combination with an NSAID or other drugs. The large variety of indications for which this fixed-dose combination may be useful can be attributed to the pharmacological synergy between oxycodone and paracetamol and because lower individual drug dosages can be used, suggesting that this should be a first-line agent for the treatment of chronic moderate-to-severe pain.

Idiopathic breakthrough pain: a new hypothesis.

Breakthrough pain (BTP) in treated patients with chronic pain states is neither well defined nor well understood. BTP is generally defined as a transient exacerbation of pain experienced by a patient with relatively stable and adequately controlled baseline pain. It is usually categorized as spontaneous, with no known cause, or incident, when initiated by voluntary or involuntary movements, or therapeutic procedures. Since pain is related to survival, it possibly cannot be completely and permanently controlled. It is hypothesized that glia are at least partially responsible for inducing pain spikes by attempting to reactivate unresponsive neurons. Therefore, compounds that modulate microglia may offer potential alternative therapeutic options in the control of idiopathic BTP.