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).

The MERITO Study: a multicentre trial of the analgesic effect and tolerability of normal-release oral morphine during 'titration phase' in patients with cancer pain.

Adequate and rapid pain control is one of the main goals of cancer pain treatment. The objective of this study was to assess the effect and tolerability of oral normal-release morphine during the initial phase of treatment in patients with moderate-to-severe cancer pain. Consecutive patients naïve to strong opioids received normal-release morphine 5 or 10 mg every 4 h during the titration phase (first 5 days), depending on previous analgesic therapy. Pain intensity was assessed using an 11-point Numerical Rating Scale (0-10), and data were recorded in a patient-compiled diary. The primary endpoint was the proportion of time with pain control (a reduction of at least 50% with respect to the baseline pain score) during the titration phase. A total of 159 consecutive patients (102 men; mean age 65 years) with cancer-related pain were enrolled. Pain control was observed for 75% (95% CI 70-80) of the follow-up period in the intent-to-treat population. Overall, 50% and 75% of patients achieved pain control within 8 and 24 h after starting normal-release morphine therapy respectively. The mean pain score was 7.63 points at baseline, and decreased to 2.43 and 1.67 points (both P<0.001) at days 3 and 5 respectively. The most commonly reported adverse events were somnolence (24% of patients), constipation (22%), vomiting (13%), nausea (10%) and confusion (7%). Normal-release morphine results in rapid and satisfactory pain control, and is well tolerated, during the strong-opioid titration phase in patients with moderate-to-severe cancer pain.

Drug-resistant cluster headache responding to gabapentin: a pilot study.

Prompted by the results of gabaergic drugs, such as valproate and topiramate, we performed this pilot study to assess the effect of gabapentin in cluster headache. Eight patients suffering from episodic cluster headache and four suffering from chronic cluster headache were studied. All of them had failed to respond to traditional prophylactic drugs. The design of the study was an open trial. The main parameter for effectiveness was the number of daily attacks. Gabapentin was given at the daily dosage of 900 mg. All patients were pain free after a maximum of 8 days after starting therapy, with a bout duration thus reduced to 16-40% of the average previous bouts (only applies to episodic cluster patients). We hypothesize that the gabaergic action of gabapentin, perhaps combined with other mechanisms, such as calcium channel blockade, may be responsible for its remarkable effects on cluster headache.

Assessing delirium in cancer patients: the Italian versions of the Delirium Rating Scale and the Memorial Delirium Assessment Scale.

To validate the Italian versions of the Delirium Rating Scale (DRS) and the Memorial Delirium Assessment Scale (MDAS), 105 cancer patients consecutively referred for neurological or psychiatric consultation for mental status change were evaluated using the Confusion Assessment Method (CAM), the DRS, the MDAS, and the Mini-Mental State Examination (MMSE). According to the CAM criteria and clinical examination, 66 patients were delirious, and 39 received diagnoses other than delirium. The DRS and the MDAS scores significantly distinguished delirious from non-delirious patients. The MDAS and the DRS were mutually correlated. When using the proposed cut-off scores for the two scales, the MDAS had higher specificity (94%) but lower sensitivity (68%) than the DRS (sensitivity = 95%, specificity = 61% for DRS cut-off 10; sensitivity = 80%, specificity = 76%, DRS cut-off 12). The MMSE showed high sensitivity (96%) and very low specificity (38%). Exploratory factor analysis of the DRS and the MDAS suggested a three-factor and two-factor structure, respectively. Both instruments in their Italian version proved to be useful for the assessment of delirium among cancer patients. Further research is needed to examine the use of the DRS and the MDAS in other clinical contexts.

Cancer patients as 'experts' in defining quality of life domains. A multicentre survey by the Italian Group for the Evaluation of Outcomes in Oncology (IGEO).

Although the subjective nature of quality of life is generally accepted, less attention has been paid to the procedure of selecting domains to be explored with questionnaires. To explore what contributes to cancer patients' quality of life, a survey was conducted with the aim of identifying contents of quality of life using cancer patients as 'experts'. A questionnaire with open-ended items aimed at exploring the meaning of quality of life and at determining the contents of health and not health related quality of life, was submitted to a sample of cancer patients stratified by residence, cancer site and stage of disease. The 248 questionnaires received were transcribed and broken down into phrases to allow coding. A content analysis was performed, using as a conceptual framework, the domains identified by the Italian Society of Psycho-Oncology. Overall, 43 domains and a list of symptoms were identified. The two most frequently reported symptoms were pain (21.4% patients) and fatigue (14.1% patients). Social relationships and psychological domains were heavily represented. Twenty sub-domains related to the domain 'psychological well-being'. This study suggests that information on the content of quality of life questionnaires to be submitted to people affected by a specific disease, should be derived by studying people suffering the specific disease. These results reinforce the criticism that available quality of life instruments are more likely to reflect the perspective of health professionals than patients.

[Evaluation of quality of life in oncology. Rationale and objectives of the first phase of the Quality of Life in Oncology project]. / La valutazione della qualità di vita in oncologia. Razionale ed obiettivi della prima fase del progetto QvOnc.

Although the subjective nature of quality of life perception is generally accepted, less attention has been paid to the procedure of selecting domains to be explored with questionnaires. In most cases domains are selected by panel of experts. It is not known whether these domains are relevant for the patients. Moreover, questionnaires developed in 'foreign' countries may not be culturally sound or relevant for patients living in different cultural background. In order to explore what really contributes to quality of life of Italian patients, a survey was conducted with the aim of identifying any dimension of quality of life, positively or negatively impacted on from the illness and therapies. A sample of two hundred and eighty eight cancer patients with previously specified characteristics (primary tumor, stage of disease and place of residence) were identified. After consenting to partecipate to the study, a staff member (a physician, a nurse or a psychologist) asked the patient to complete an open-ended questionnaire in the out-patient clinic or at home. This questionnaire, partially derived from a study by Padilla et al. made up of 5 questions: 'What does the term quality of life mean to you?', 'What contributes to a good quality of life?', 'What contributes to a poor or bad quality of life?', 'Which either physical or psychological symptom interferes with your quality of life?', 'State any positive or negative change in your quality of life, due to illness or treatments'. The first question was asked to explore the meaning of quality of life for the patient; the second and third question were asked to determine the contents of quality of life not health related; the fourth question and the diary provided information about quality of life contents related to his own experience of disease. Two hundred and forty eight questionnaires (86.1%) were obtained from 7 Cancer Centres participating to the study (Genova, Milano, Roma, Perugia, Napoli, Cagliari, Palermo). All the questionnaires were transcribed and subsequently broken down in phrases on a form that allowed coding. Three raters (a research nurse, an oncologist and a clinical psychologist) made the content analysis using as conceptual framework the list of domains identified by the Italian Society of Psycho-Oncology. The present study shows the possibility to define the content domain of quality of life attributes for cancer patients, using patients as experts.

Biological indices predictive of survival in 519 Italian terminally ill cancer patients. Italian Multicenter Study Group on Palliative Care.

The knowledge of prognostic factors capable of subdividing cancer patients into groups having homogenous survival times is useful even in very advanced stages of illness. This prospective multicenter study assessed these prognostic factors in 530 terminal patients with solid tumors who were undergoing only palliative care. Thirteen hematological and urinary parameters were assessed on admission and every 28 days thereafter. In 519 assessable patients with a median survival of 32 days, six biological parameters demonstrated a statistically significant predictive prognosis. A poor prognosis was predicted by high total white blood count (WBC) (P < 0.0001), high neutrophil percentage (P < 0.0001), low lymphocyte percentage (P < 0.0001), low serum albumin level (P = 0.0015), low pseudocholinesterase level (P < 0.0001), and high proteinuria (P = 0.0064). Multiple regression analysis showed that only WBC, lymphocyte percentage and pseudocholinesterase level were independent predictors of survival. The individualization of biological parameters having an independent prognostic capacity is a useful step in the attempt to identify subsets of patients with a homogeneous prognosis. The biological factors needed are easily detected by means of a simple blood test and do not require invasive operations on patients who are already debilitated.

[The role of T2*-weighted gradient-echo magnetic resonance sequences in the study of suspected dorsal-lumbosacral vertebral metastases]. / Ruolo delle sequenze di Risonanza Magnetica gradient-echo T2*-pesate nello studio delle sospette metastasi vertebrali dorso-lombosacrali.

INTRODUCTION: Magnetic resonance (MR) imaging showed high reliability in detecting spine metastases with spin-echo (SE) sequences, T1-weighted sequences being generally more sensitive than T/-weighted ones. We investigated the value of T2*-weighted gradient-echo (GE) sequences in studying spine metastases. MATERIALS AND METHODS: Twenty patients with established diagnosis of primary carcinoma and clinically suspected thoracic and/or lumbosacral spine metastases underwent .5-T MR imaging and 99mTc-HDP bone scan. The disagreement of GET2*- versus SET2-weighted images as well as versus bone scan and the disagreement of total MR results versus bone scan results were evaluated by McNemar test. The agreement of GET2*- versus SET1-weighted images was evaluated by Cohen's kappa. RESULTS: Of a total of 111 MR signal abnormalities consistent with metastasis, 109 (98.2%) were T2*-hyperintense, whereas only 50 (45.1%) were T2-hyperintense (p < .0001) and 51 (45.9%) were detected with bone scan (p < .0001). Of a total of 121 MR and/or bone scan findings consistent with metastasis, 111 (91.7%) were MR positive, with high disagreement with 61 (50.4%) positive at bone scan (p < .00001). T2*-hyperintensity associated with T1-hypointensity (with or without T2-hyperintensity) was the most frequent pattern (104/111), 93.7%). CONCLUSIONS: T2*-weighted GE sequences seem to be more effective than T2-weighted SE sequences and as effective as T1-weighted SE sequences. MR imaging confirms its ability in detecting abnormalities consistent with spine metastases.

Oral tramadol and buprenorphine in tumour pain. An Italian multicentre trial.

In this multicentre trial tramadol and buprenorphine were compared for the treatment of neoplastic pain no longer responsive to non-steroidal antiinflammatory drugs. A total of 131 adults (86 M, 45F) were treated with tramadol (one 100-mg slow-release tablet every 8-12 h), or buprenorphine (one sublingual 0.2-mg tablet every 6-8 h). The trial was to continue for up to six months. Most patients started treatment with 2-3 tablets/day in both groups, and the mean treatment period was 58 days for tramadol and 51 for buprenorphine. Almost all dose changes needed were made in the first fortnight in both treatment groups, and the largest number of patients dropped out because of inadequate pain relief or progression of the underlying disease. The results achieved in the first two weeks persisted throughout the rest of the trial, and the investigator's assessments on each patient's clinical chart corresponded closely with those that patients made in their own daily diaries. In the four hours after the first dose both drugs virtually halved the severity of pain (measured using a visual analogue scale), and this relief lasted throughout treatment. By the end of the first week the proportion of patients with strong/unbearable pain in the tramadol group had fallen significantly (from 98.4% to 48.1%, p < 0.05), as compared to a drop from 92% to 66.7% for buprenorphine. The quality of sleep also tended to improve in the tramadol group, with the proportion of patients enjoying good or deep sleep rising from 37% to 50%, as compared to 33% to 40-44% with buprenorphine. Karnofsky's and Spitzer's indices reflecting the quality of life did not change in the tramadol group; in the buprenorphine group the Karnofsky index dropped slightly after a fortnight (p < 0.05 between treatments). In the first two months of the trial the number of patients with no/moderate pain rose continuously in the tramadol group (71% and 80% after one and two months); the rise was less marked in the buprenorphine group (number of patients with mild/moderate pain, 45% and 65%). In both the short term and in the longer term, it was found that the levels of efficacy and acceptability were always significantly better in the tramadol group than in the buprenorphine group. General and biological safety in both drugs was good. The most typical side-effects were those characteristic of opioids (nausea and/or vomiting, drowsiness). Adverse reactions were reported in 17 patients taking tramadol (25%) and in 16 taking buprenorphine (26%). There were six drop-outs in the first group (9%) and seven in the second (11%). Serious symptoms arose more frequently in the buprenorphine group (19% cf. 10%). No signs of dependence or tolerance were noted.

The incidence of narcotic-induced emesis.

Epidemiologic studies of the incidence of emesis induced by narcotic analgesics are lacking. The histories of 260 cancer patients receiving oral narcotic analgesics prescribed at the Pain Clinic of our Institute from December 1988 to December 1989 were reviewed. Of the 260 patients, 120 were women, median age 61 (range 30-90) yr and 140 were men, median age 62 (range 30-82) yr. Nausea and vomiting associated with assumption of the various narcotics were buprenorphine 8.3% and 22.7%, morphine 18.3% and 28%, codeine 16.2% and 29.7%, and oxycodone 10% and 40%, respectively. Since the use of narcotic analgesics can effectively relieve pain and improve quality of life in cancer patients, it is important to be aware of the incidence of narcotic-induced emesis in order to use appropriate prophylactic antiemetic therapy.

Disodium clodronate in the treatment of pain due to bone metastases.

Disodium clodronate (dichloromethylene bisphosphonate) a drug belonging to the class of bisphosphonates, inhibits osteoclastic bone resorption and therefore it may be used in the palliative treatment of patients affected by osteolytic bone metastases. The authors have evaluated the activity and tolerability of disodium clodronate in providing pain relief and improving the quality of life in patients with bone metastases, who were not improved by radiotherapy or chemotherapy. Out of 37 patients, 32 could be evaluated for pain relief. Of these, 62.5% had their pains improved by disodium clodronate administration without regard to the type of ongoing analgesic therapy, which had no implications on the outcome of the treatment.