Pain, symptoms and therapy satisfaction in adult oncologic patients at admission to palliative care: An Italian prospective, multicenter, observational study.

BACKGROUND: Pain in cancer patients is a complex clinical problem. Pain is systematically assessed and treated during palliative care, but little is known about how it is addressed before starting palliative care. AIM: This study primarily analyzed pain, symptoms, ongoing therapy at patients' admittance to the palliative care unit, and the relationships between pain and tumor, comorbidities, performance status and quality of life (QoL). Notably, patient satisfaction with the received antalgic therapy was assessed. METHODS: A multicentric, prospective, observational study was conducted in seven Italian palliative centers. The population consisted of adult cancer patients admitted to specialist palliative care units in hospice and home care. RESULTS: The sample consisted of 476 patients. Ninety-three patients reported moderate pain of 4.0 and worst pain of 5.9 at the initial medical examination. The pain was high, and QoL was lower in breakthrough pain. The pain was lower in older subjects when it was discontinuous and when it was also treated with corticosteroids. A total of 61% of the patients were unsatisfied with the prescribed pain therapy. CONCLUSIONS: Before the beginning of palliative care, physicians do not manage pain adequately. We support the idea that palliative care is not only intended for the last days of life but must be started early and simultaneously with oncological treatments. All that, in our opinion, is often ignored, and we hope that our study could have a positive influence and that the study results stimulate further research in this area with in-depth studies.

Opioid switching and variability in response in pain cancer patients.

INTRODUCTION: Opioid switching is a possible strategy for inadequate analgesia or unmanageable side effects. Its effectiveness ranges from 50 to 90% and is still debated. PURPOSE: We analyzed the impact of opioid switching in a cancer pain population treated with strong opioids for pain. METHODS: This is a post hoc analysis from a multicenter, randomized, four-arm, controlled, phase IV clinical trial. Outcome variables included the percentages of switches, the reasons for the switch, the dose changes before and after the switch, depending on the starting opioid, the response in case of inadequate analgesia, and unmanageable toxicity, and the variability of response among and within patients. RESULTS: We analyzed 498 patients. The opioid was switched in 79 patients (15.9%) 87 times, mainly for uncontrolled pain (52.3%), adverse opioid reactions (22.1%), both of these (4.8%), and dysphagia (20.8%). The reasons for switching varied depending on the starting opioid. Pain reduction was good after 51.45% of switches and control of opioid side effects was good after 43.5%. The relief of opioid-induced toxicity varied among adverse events and within each patient. The daily doses were higher after switching oral opioids and lower after transdermal drugs. CONCLUSIONS: Half of the patients who underwent switching experienced improved relief of pain or amelioration of opioid toxicity. The switch can help in the management of some cases but with many limits and uncertainties.

A comparison between the administration of oral prolonged-release oxycodone-naloxone and transdermal fentanyl in patients with moderate-to-severe cancer pain: a propensity score analysis.

BACKGROUND: Opioids are the most important pharmacological treatment for moderate-to-severe cancer pain, but side effects limit their use. Transdermal fentanyl (TDF) and oral prolonged-release oxycodone-naloxone (OXN-PR) are effective in controlling chronic pain, with less constipation compared to other opioids. However, TDF and OXN-PR have never been directly compared. PATIENTS AND METHODS: Cancer patients with moderate-to-severe chronic pain were consecutively enrolled in two prospective 28-day trials, received either TDF or OXN-PR, and were assessed at baseline and after 7, 14, 21, and 28 days. The primary endpoint was 28-day analgesic response rate (average pain intensity decrease ≥30% from baseline). Other outcome measures included opioid daily dose changes over time; need for adjuvant analgesics; number of switches; premature discontinuation; presence and severity of constipation; and other adverse drug reactions. To compare the efficacy and the safety of TDF and OXN-PR, we used the propensity score analysis to adjust for heterogeneity between the two patient groups. RESULTS: Three hundred ten out of 336 patients originally treated (119 TDF and 191 OXN-PR) were included in the comparative analysis. The amount of responders was comparable after TDF (75.3%) and OXN-PR administration (82.9%, not significant [NS]). The final opioid daily dose expressed as morphine equivalent was 113.6 mg for TDF and 44.5 mg for OXN-PR (p<0.0001). A daily opioid dose escalation >5% was less common after OXN-PR (19.3%) than after TDS administration (37.9%, p<0.0001). Opioid switches and discontinuation were similar in both groups. Severe constipation in the two groups was comparable (32.6% after TDF vs 24.7% after OXN-PR, NS). Nausea, vomiting, and dry mouth were significantly less frequent in the OXN-PR group than in the TDF group. CONCLUSION: Despite a similar analgesic activity in moderate-to-severe cancer pain, OXN-PR is characterized by lower daily dosages, less need for drug escalation, and fewer side effects compared to TDF.

Are strong opioids equally effective and safe in the treatment of chronic cancer pain? A multicenter randomized phase IV 'real life' trial on the variability of response to opioids.

BACKGROUND: Guidelines tend to consider morphine and morphine-like opioids comparable and interchangeable in the treatment of chronic cancer pain, but individual responses can vary. This study compared the analgesic efficacy, changes of therapy and safety profile over time of four strong opioids given for cancer pain. PATIENT AND METHODS: In this four-arm multicenter, randomized, comparative, of superiority, phase IV trial, oncological patients with moderate to severe pain requiring WHO step III opioids were randomly assigned to receive oral morphine or oxycodone or transdermal fentanyl or buprenorphine for 28 days. At each visit, pain intensity, modifications of therapy and adverse drug reactions (ADRs) were recorded. The primary efficacy end point was the proportion of nonresponders, meaning patients with worse or unchanged average pain intensity (API) between the first and last visit, measured on a 0-10 numerical rating scale. (NCT01809106). RESULTS: Forty-four centers participated in the trial and recruited 520 patients. Worst pain intensity and API decreased over 4 weeks with no significant differences between drugs. Nonresponders ranged from 11.5% (morphine) to 14.4% (buprenorphine). Appreciable changes were made in the treatment schedules over time. Each group required increases in the daily dose, from 32.7% (morphine) to 121.2% (transdermal fentanyl). Patients requiring adjuvant analgesics ranged from 68.9% (morphine) to 81.6% (oxycodone), switches varied from 22.1% (morphine) to 12% (oxycodone), discontinuation of treatment from 27% ( morphine) to 14.5% (fentanyl). ADRs were similar except for effects on the nervous system, which significantly prevailed with morphine. CONCLUSION: The main findings were the similarity in pain control, response rates and main adverse reactions among opioids. Changes in therapy schedules were notable over time. A considerable proportion of patients were nonresponders or poor responders. CLINICAL TRIAL REGISTRATION: NCT01809106 (https://clinicaltrials.gov/ct2/show/NCT01809106?term=cerp&rank=2).

Assessing the response to opioids in cancer patients: a methodological proposal and the results.

PURPOSE: The efficacy of treatment with opioids in cancer pain is variable. To evaluate this variability, we (1) applied two parameters, changes in pain intensity (PI) and opioid daily doses (DDs), to distinguish different responses to opioids. The need to switch to another opioid was recorded. We then (2) evaluated the distribution of the responses depending on these parameters, alone and taken together, in cancer patients with pain. METHODS: The cutoffs between positive and negative responses related to PI and DD were defined on the basis of the literature. For PI, responders were patients who obtained simultaneously a decrease of 30% or more and a final score ≤4 points (numerical rating scale 0 to 10). For DD changes, we applied the opioid escalation index percentage, a positive response corresponding to a dose increase ≤5%. These criteria were applied to 201 cancer patients treated with WHO step III "strong" opioids for 21 days. The results were mainly analyzed case by case. RESULTS: Of the patients, 63.7% obtained a positive analgesic response and 80.1% a dose-related positive response. Combining the parameters, the response was double positive in 55.2% of cases, double negative in 11.4%, a good analgesic response with a large dose escalation in 8.5%, and no pain relief with a stable dose in 24.9%. Switches were made 21 times, 15 because of the lack of analgesia. CONCLUSIONS: Different degrees of response to opioids were observed, PI and DD changes both contributing. Only over half the patients had a full positive response.

Pharmacological and clinical differences among transmucosal fentanyl formulations for the treatment of breakthrough cancer pain: a review article.

Breakthrough pain (BTP) is highly prevalent (59.2%) in chronic cancer patients and normally needs rescue treatments' with opioids when pain flares up. Transmucosal oral/nasal fentanyl formulations are commonly used in clinical practice. The different methods of release influence the pharmacokinetics and clinical properties of these formulations. The aim of this review was to assess and weigh these differences. Clinical trials comparing one transmucosal fentanyl with placebo or another active drug were included. We searched Medline for the last ten years and analyzed 13 studies, totaling 1447 patients. Clinical data on efficacy and safety were compared. In parallel, we report the differences in delivery systems, bioavailability, maximum plasma concentration (Cmax), plasma half-life, and time to reach Cmax (tmax). Considerable variability emerged between formulations. This suggests some considerations on the choice of the fentanyl formulation in the light of the BTP features in each clinical case.

How to evaluate the effect of pain treatments in cancer patients: results from a longitudinal outcomes and endpoint Italian cohort study.

BACKGROUND: Dealing with cancer pain implies assessing the intensity and other attributes of pain and identifying appropriate outcomes and endpoints to evaluate the effect of treatments. METHODS: In the context of an observational longitudinal prospective study, 1461 painful cancer patients were evaluated at baseline and weekly over 4 weeks. Four pain intensity (PI) measures (worst, average, least and right now: WP, AP, LP, and PRN), pain relief and patients' satisfaction with pain treatments were recorded. Starting from these data, we extrapolated the full responder (FR) subjects, whose PI decreased by ≥2 points, or by ≥30%, or who obtained a final score of ≤5 points, according to criteria previously suggested by literature. The receiver operating characteristics (ROC) curve analysis was used to estimate the predictive accuracy. RESULTS: All the PI measures decreased from the initial to final visit: the reduction was 1.9 as WP, 1.3, 0.8 and 1.2 as AP, LP and PRN, respectively. The proportion of FR differed from 47.8% to 88.3% depending on PI measures and the criterion adopted. ROC analysis showed an acceptable accuracy of all endpoints and confirmed the cut-offs recommended by the literature. The best criterion corresponded to a PI absolute value of ≤4 points when measured as AP. CONCLUSIONS: All measures applied seem able to profile the evolution of pain, with some differences. This implies the need of an appropriate choice of outcomes and endpoints according to the goal and objective of the intervention under evaluation.

Evaluation of the comparative analgesic effectiveness of transdermal and oral opioids in cancer patients: a propensity score analysis.

BACKGROUND: Transdermal delivery systems containing fentanyl or buprenorphine, despite the relatively lack of comparative studies, have reached an impressive share of the market in several countries. In the context of a wider observational study, we applied the propensity score to test the comparative effectiveness of the two routes of administration (oral vs. transdermal). METHODS: We applied the propensity score in a subgroup of patients (starting the World Health Organization third step therapy during the scheduled follow-up of 28 days) using pre-planned primary (pain intensity change) and secondary endpoints, such as increase in doses, need for switching and safety profile. Univariate and multivariate analyses were carried out. RESULTS: Three-hundred sixty-six eligible cases were analysed. We found a difference among the two groups in terms of variables potentially associated with therapy choice and outcomes. After adjusting for propensity score, results were in favour of transdermal delivery systems for the primary endpoint (odds ratio 1.68; p = 0.04). A similar trend was also present for the other secondary endpoints. Only in the case of nausea and vomiting, patients receiving transdermal delivery systems reported a higher frequency of events. CONCLUSION: The application of the propensity score has helped understand better the actual effectiveness of transdermal delivery systems that are at least equivalent to the oral opioids, and even more effective for pain intensity reduction.

Managing severe cancer pain: the role of transdermal buprenorphine: a systematic review.

Pain is a frequent and important symptom in cancer patients. Among the available strong opioids, transdermal buprenorphine has been licensed in Europe since 2002, and results from a few clinical studies suggest that it may be a good alternative to the other oral or transdermal opioids. To assess the best available evidence on its efficacy and safety, we carried out a systematic literature review with the aim of pooling relevant studies. We identified 19 eligible papers describing 12 clinical studies (6 randomized controlled trials and 6 observational prospective studies), including a total of about 5000 cancer patients. Given the poor quality of reports and the heterogeneity of methods and outcomes, pooling was not feasible as the type of data was not appropriate for combining the results statistically. A meta-analysis based on individual data is ongoing in the context of the Cochrane Collaboration. In conclusion, although the narrative appraisal of each study suggests a positive risk benefit profile, well designed and statistically powered controlled clinical trials are needed to confirm this preliminary evidence.

Pattern and quality of care of cancer pain management. Results from the Cancer Pain Outcome Research Study Group.

Most patients with advanced or metastatic cancer experience pain and despite several guidelines, undertreatment is well documented. A multicenter, open-label, prospective, non-randomised study was launched in Italy in 2006 to evaluate the epidemiology, patterns and quality of pain care of cancer patients. To assess the adequacy of analgesic care, we used a standardised measure, the pain management index (PMI), that compares the most potent analgesic prescribed for a patient with the reported level of the worst pain of that patient together with a selected list of clinical indicators. A total of 110 centres recruited 1801 valid cases. 61% of cases were received a WHO-level III opioid; 25.3% were classified as potentially undertreated, with wide variation (9.8-55.3%) according to the variables describing patients, centres and pattern of care. After adjustment with a multivariable logistic regression model, type of recruiting centre, receiving adjuvant therapy or not and type of patient recruited (new or already on follow-up) had a significant association with undertreatment. Non-compliance with the predefined set of clinical indicators was generally high, ranging from 41 to 76%. Despite intrinsic limitations of the PMI that may be considered as an indicator of the poor quality of cancer pain care, results suggest that the recourse to WHO third-level drugs still seems delayed in a substantial percentage of patients. This delay is probably related to several factors affecting practice in participating centres and suggests that the quality of cancer pain management in Italy deserves specific attention and interventions aimed at improving patients' outcomes.

Illness awareness in terminal cancer patients: an Italian study.

The amount and quality of information and awareness in cancer patients' is a topic frequently debated, but few studies have focussed on terminal patients. This is the objective of the present study that involved two different palliative home-care units in Italy, which recruited 550 terminal cancer patients. Data from patients and their caregivers was prospectively collected with special attention to information patients were provided with when their cancer was diagnosed and patients' awareness of their current health condition. In the case of the information, 67.0% of patients reported they were previously informed about their diagnosis, but only 58.0% seemed to be aware of their terminal condition. The comparison between the caregivers opinions about the level of information provided to the patients and their present awareness and what the patients really know about their own disease shows a high degree of correspondence. Some variables such as age and education level of patients were associated with patient's awareness.

Guidelines on artificial nutrition versus hydration in terminal cancer patients. European Association for Palliative Care.

Whether a terminally ill cancer patient should be actively fed or simply hydrated through subcutaneous or intravenous infusion of isotonic fluids is a matter of ongoing controversy among clinicians involved in the care of these patients. Under the auspices of the European Association for Palliative Care, a committee of experts developed guidelines to help clinicians make a reasonable decision on what type of nutritional support should be provided on a case-by-case basis. It was acknowledged that part of the controversy related to the definition of the terminal cancer patient, since this is a heterogeneous group of patients with different needs, expectations, and potential for a medical intervention. A major difficulty is the prediction of life expectancy and the patient's likely response to vigorous nutritional support. In an attempt to reach a decision on the type of treatment support (artificial nutrition vs. hydration) which would best meet the needs and expectations of the patient, we propose a three-step process: Step 1: define the eight key elements necessary to reach a decision; Step II: make the decision; and Step III: reevaluate the patient and the proposed treatment at specified intervals. Step I involves assessing the patient concerning the following: 1) oncological/clinical condition; 2) symptoms; 3) expected length of survival; 4) hydration and nutritional status; 5) spontaneous or voluntary nutrient intake; 6) psychological profile; 7) gut function and potential route of administration; and 8) need for special services based on type of nutritional support prescribed. Step II involves the overall assessment of pros and cons, based on information determined in Step I, in order to reach an appropriate decision based on a well-defined end point (i.e., improvement of quality of life; maintaining patient survival; attaining rehydration). Step III involves the periodic reevaluation of the decision made in Step II based on the proposed goal and the attained result.

Effectiveness of levosulpiride versus metoclopramide for nausea and vomiting in advanced cancer patients: a double-blind, randomized, crossover study.

The antiemetic efficacy of levosulpiride (L) was compared to metoclopramide (M) in a double-blind, randomized, crossover study. Thirty patients with advanced cancer, who were no longer receiving antineoplastic therapy, were randomly assigned to receive either L 75 mg/day or M 30 mg/day. After 7 days, patients were crossed over to the alternate treatment, which was also given for 7 days. The hours with nausea were 1.08 (mean value/day/patient) during treatment with L and 2.01 with M (P = 0.002), independent of the order of administration. The nausea intensity was 0.76 (mean value/day/patient) with L and 1.42 with M (P = 0.0004). Complete control of nausea was obtained in 84.6% of patients receiving L and 42.3% of those treated with M (P = 0.0034). The number of vomiting episodes was 0.38 (mean value/day/patient) during treatment with L and 0.70 with M (P = 0.002), independent of the order of administration. Vomiting disappeared in 81.5% of patients receiving L and 51.8% of those treated with M (P = 0.041). There was a carry-over effect in favor of L. These data indicate that both L and M reduce nausea and vomiting, but L is more effective.

Ketorolac versus diclofenac sodium in cancer pain.

In a randomized single-blind study carried out simultaneously in five Departments for Pain Therapy and Palliative Care, the analgesic efficacy and side effects of oral ketorolac (ketorolac tromethamine, Tora-Dol, CAS 74103-07-4) and diclofenac sodium were compared in a population of 100 advanced cancer patients suffering from somatic and/or visceral pain. The treatment was carried out in agreement with the first step of the WHO pharmacological strategy in cancer pain. The administered dosage was 10 mg every 6 h for ketorolac and 50 mg every 8 h for diclofenac sodium. The study showed the efficacy of both drugs in cancer pain. A greater number of keterolac patients could pass to the second WHO step later than diclofenac patients. As to the tolerability, both drugs turned out to be similar, except for "sleepiness", which was four times more frequent (p < 0.05) in the diclofenac group.

Nimesulide and diclofenac in the control of cancer-related pain. Comparison between oral and rectal administration.

64 patients with pain associated with advanced cancer were treated with either nimesulide or diclofenac as initial analgesia. Patients were randomly allocated to 1 of 4 treatment groups: oral nimesulide 300 mg/day; oral diclofenac 150 mg/day; rectal nimesulide 400 mg/day; and rectal diclofenac 200 mg/day. After 1 week of treatment, both drugs provided an adequate degree of pain relief and allowed an increase in sleep duration. There were no significant differences in efficacy between the drugs or routes of administration. Fewer side effects were observed with nimesulide, giving this agent a better therapeutic index than the reference compound.

A new method of food intake quantification: application to the care of cancer patients.

Although it is commonly accepted that advanced cancer patients often suffer from malnutrition, there is little information available to quantify the extent of undernourishment and variations in food intake during the last weeks of life. To assess these factors, we developed a new method for measuring daily food intake, based on a self-descriptive record on which the patient chooses one of five different levels of food intake defined with a key word. This record was combined with a visual analogue scale and then administered to 100 healthy persons to assess if each key word can be attributed a numerical figure. Following this, the measurement method was applied to 75 cancer patients in the last weeks of life. The data confirmed and quantified the patients' undernutrition, and demonstrated a sharp and statistically significant increase in food intake when patients enter a palliative home care program. During the last 4 wk of life, the decrease in food intake became steady and irreversible.

Sodium naproxen versus sodium diclofenac in cancer pain control.

In a single-blind random study, simultaneously carried out by five Pain Therapy and Palliative Care Centres, the analgesic power and side-effects of sodium naproxen (CAS 26159-34-2) and sodium diclofenac (CAS 15307-86-5) by mouth were compared in a group of 100 advanced cancer patients. The patients complained of somatic and/or visceral pain and were treated with non-steroid anti-inflammatories as required. The dose administered amounted to 550 mg every 12 h for sodium naproxen and to 100 mg every 12 h for sodium diclofenac. The study stressed the similar analgesic effect of the two drugs--pain intensity and duration decreased by half in the first week of treatment--and a comparatively low morbidity rate.

Correlation between subjective labour pain and uterine contractions: a clinical study.

Fifteen primiparous women underwent tocography during the second phase of the first stage of labour in order to evaluate the main characteristics of their uterine contractions (intensity, duration and pattern). At the end of each contraction, for a total of about 8 contractions per woman and an overall total of 125 tocographic curves, each woman was asked to make a subjective evaluation of the pain felt during that contraction using a 10 cm visual analogue scale (VAS). All the tocographic curves corresponding to the contractions studied were elaborated mathematically to determine the peak (intensity), base (duration) and area under the curve (AUC). Lastly, correlations between the mathematical parameters of the curves and corresponding VAS scores were sought. In the population a general positive correlation between the 3 main parameters of tocographic curves and the VAS score was demonstrated; the AUC and the peak tended to be better correlated with VAS than duration. Within-subject comparison showed the existence of a significant correlation with VAS score in 12/15 women as far as peaks are concerned, in 10/15 as far as AUC is concerned and in 0/15 women as regards duration. The findings support the concept that perceived labour pain depends in most of the women on the intensity and pattern of the uterine contractions. The possible clinical and experimental applications of this finding are discussed.