Clinical experience with oral methadone administration in the treatment of pain in 196 advanced cancer patients.

PURPOSE: The aims of this study were to describe the analgesia, side effects, and dosage and the causes of suspension of treatment in a large sample of advanced cancer patients with pain after treatment with oral methadone from 7 to 90 days. PATIENTS AND METHODS: In a retrospective study, data collected for 196 advanced cancer outpatients with moderate to severe pain treated at 8-hour intervals with oral methadone in solution form from February 1993 to February 1995 were analyzed at baseline (time 0) and then at 7, 15, 30, 45, 60, and 90 days. The following parameters were assessed: Karnofsky Performance Status, intensity of pain (using the Integrated Pain Score [IPS], intensity of pain, insomnia, drowsiness, confusion, dry mouth, nausea, vomiting, constipation, and dyspnea (using the Therapy Impact Questionnaire [TIQ], mean daily dose of drug administered, and reasons for withdrawal from study. The period when pain was reduced by > or = 35% with respect to baseline was evaluated with the Palliation Index. The association of the degree of palliation of pain with the age of the patients, tumor site, analgesic treatment taken at baseline, and daily mean dose of methadone administered during the follow-up period was analyzed by means of the Kruskal-Wallis test. RESULTS: A reduction in pain intensity with respect to baseline occurred at each analysis time, and in 55.1% of the patients the reduction during the follow-up period was > or = 35% according to the Palliation Index. The mean dose of oral methadone ranged from 14 mg at day 7 to 23.65 mg at day 90. There was an overall worsening of the other symptoms, but a high percentage of the patients reported an amelioration of insomnia with respect to baseline. There was a statistically significant association (P < .0001) between the Palliation Index and the analgesic therapy administered at baseline. Only 11.2% of the patients withdrew from the study due to analgesic inefficacy and 6.6% due to methadone-related side effects (10 patients with drowsiness and three with severe constipation. CONCLUSION: Oral methadone administered every 8 hours was shown to be an appropriate analgesic therapy in the treatment of advanced cancer-related pain. The worsening of the other symptoms under study can be considered linked to the progression of the disease, and in fact, only a small percentage of the patients reported methadone-related side effects that warranted suspension of treatment. We consider oral methadone to be a useful analgesic therapy, and it should be considered in clinical practice for the treatment of cancer pain.

Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio?

PURPOSE: To define the dose ratio between morphine and methadone in relation to the previous morphine dose and the number of days needed to achieve the same level of analgesia in a group of patients with advanced cancer with pain who switched from morphine to oral methadone. PATIENTS AND METHODS: A cross-sectional prospective study of 38 consecutive cancer patients who switched from morphine to oral methadone was performed. The intensity of pain before, during, and after the switching period was assessed through a four-point verbal Likert scale. The relationship between previous morphine dose and the final equianalgesic methadone dose, dose ratio between morphine and methadone, and the number of days required to achieve equianalgesia have been examined by means of Pearson's correlation coefficient, scatter plots, and Cuzick's test for trend respectively. RESULTS: Before the switch, the median oral equivalent daily dose of morphine was 145 mg/d; after the switch, the median equianalgesic oral methadone dose was 21 mg/d. A median time of 3 days (range, 1 to 7 days) was necessary to achieve the equianalgesia with oral methadone; the lower the preswitching morphine dose, the fewer days necessary to achieve equianalgesia with oral methadone (P < .001). Dose ratios ranged from 2.5:1 to 14.3:1 (median, 7.75:1), which indicated that, in most cases, the dose ratio was much higher than that suggested by the published equianalgesic tables. A strong linear positive relationship between morphine and methadone equianalgesic doses was obtained (Pearson's correlation coefficient, 0.91). The dose ratio increased with the increase of the previous morphine dose with a much higher increase at low morphine doses. CONCLUSION: The results of our study confirm that methadone is a potent opioid, more potent than believed. Caution is recommended when switching from any opioid to methadone, especially in patients who are tolerant to high doses of opioids.

Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study.

PURPOSE: To evaluate the clinical benefits of switching from morphine to oral methadone in patients who experience poor analgesia or adverse effects from morphine. PATIENTS AND METHODS: Fifty-two consecutive cancer patients receiving oral morphine but with uncontrolled pain and/or moderate to severe opioid adverse effects were switched to oral methadone administered every 8 hours using different dose ratios. Intensity of pain and adverse effects were assessed daily, and the symptom distress score (DS) was calculated before and after switching. RESULTS: Data were analyzed for 50 patients. Switching was considered effective in 80% of the patients; results were achieved in an average of 3.65 days. In the 10 patients who switched to methadone because of uncontrolled pain, a significant reduction in pain intensity (P <.005) and an average of a 33% increase in methadone doses necessary (P <.01) were found after an average of 3.5 days. DS significantly decreased from an average of 8.4 to 4.5 (P <.0005). In the 32 patients switching because of uncontrolled pain and morphine-related adverse effects, significant improvement was found in pain intensity (P <.0005), nausea and vomiting (P <.03), constipation (P <.001), and drowsiness (P <.01), but a significant increase in the methadone dose of an average of 20% (P <.004) was required. CONCLUSION: In most patients with cancer pain referred for poor pain control and/or adverse effects, switching to oral methadone is a valid therapeutic option. In the clinical setting of poor pain control, higher doses of methadone are necessary with respect to the equianalgesic calculated dose ratios previously published.

Effect of home care on the place of death of advanced cancer patients.

This study presents a prospective evaluation of the home care programme for patients with advanced cancer at the National Cancer Institute of Milan. Demographic, psychosocial and physical variables were evaluated. The Therapy Impact Questionnaire was used for symptom and quality of life assessment. The association of clinical and demographic variables with the place of death was investigated, considering that the aim of the home care programme is to follow up patients until death in their houses. Eighty-six per cent (86%) of patients died at home and 14% in hospitals. Multivariate analysis showed that only a higher degree of family support was associated with home death. Several changes in symptoms and quality of life items scores were seen, pain improved while physical debility and cognitive functions worsened throughout the home care duration to death. High intensity pain and dyspnoea were still present in, respectively, 23.8 and 15.3% of patients in the last week of life. Psychological distress was high at the end of life and did not seem to be affected by treatment. Home care is a feasible alternative for implementing palliative care in a selected population of patients with advanced cancer. Palliation of physical symptoms is more easily achieved than the control of psychological suffering. Family and economical issues implied by home care models should be part of the discussion in implementing palliative care for advanced cancer patients.

Megestrol acetate for anorexia in patients with far-advanced cancer: a double-blind controlled clinical trial.

The aim of this study was to evaluate a low-dose regimen of megestrol acetate (MA; 320 mg/day) on appetite in advanced cancer patients. Out-patients with far-advanced non-hormone responsive tumours and loss of appetite were randomised in a phase III trial, with two consecutive phases: a 14-day double-blind placebo controlled phase (phase A) and a 76-day open phase (phase B). During phase A, patients were treated with MA, two 160 mg tablets/day, or placebo. In phase B, the MA dose was titrated to clinical response in both groups. Appetite, food intake, body weight, performance status, mood and quality of life were evaluated with standardised measures; patients' global judgement about treatment efficacy was also requested. Of 42 patients entering the study, 33 (17 MA and 16 placebo) were evaluable for efficacy. The appetite score improved significantly with MA after 7 days (P = 0.0023), and this effect was still significant at 14 days (P = 0.0064). Patients judged the treatment with MA effective in 88.2% of cases (14th day), whilst placebo was considered effective by 25% (P = 0.0003). None of the other measures showed significant changes during treatment. The remarkable effect on appetite evident after 7 days, without serious side-effects, shows that MA can produce significant subjective effects at a low-dose even in patients with far-advanced disease.

Role of octreotide, scopolamine butylbromide, and hydration in symptom control of patients with inoperable bowel obstruction and nasogastric tubes: a prospective randomized trial.

Bowel obstruction may be an inoperable complication in patients with end-stage cancer. Scopolamine butylbromide (SB) and octreotide (OCT) have been successfully used with the aim of reducing gastrointestinal (GI) secretions to avoid placement of a nasogastric tube (NGT); however, there have been no comparative studies concerning the efficacy of these drugs. Furthermore, there is little information about the role played by parenteral hydration in symptom control of these patients. In a prospective trial that involved all 17 inoperable bowel-obstructed patients presenting to our services with a decompressive NGT, patients were randomized to OCT 0.3 mg/day or SB 60 mg/day for 3 days through a continuous subcutaneous infusion. Clinical data, survival time, and the time interval from the first diagnosis of cancer to the onset of inoperable bowel obstruction were noted. The intensity of pain, nausea, dry mouth, thirst, dyspnea, feeling of abdominal distension, and drowsiness were assessed by means of a verbal scale before starting treatment with the drugs under study (T0) and then daily for 3 days (T1, T2, T3). Moreover, daily information was collected regarding the quantity of GI secretions through the NGT, the oral intake of fluids, the quantity of parenteral hydration, and the analgesic therapy used. The NGT could be removed in all 10 home care and in 3 hospitalized patients without changing the dosage of the drugs. OCT significantly reduced the amount of GI secretions at T2 (P = 0.016) and T3 (P = 0.020). Compared to the home care patients, the hospitalized patients received significantly more parenteral hydration (P = 0.0005) and drank more fluids (P = 0.025). There was no difference in the daily thirst and dry mouth intensity in relation to the amount of parenteral hydration or the treatment provided (OCT or SB). Independent of antisecretory treatment, the patients receiving less parenteral hydration presented significantly more nausea (T0 P = 0.002; T1 P = 0.001; T2 P = 0.003; T3 P = 0.001) and drowsiness at T3 (P < 0.5). Pain relief was obtained in all 17 patients and only two patients required an increase in morphine dose at T1. All patients with inoperable malignant bowel obstruction should undergo treatment with antisecretory drugs so as to evaluate the possibility of removing the NGT. When a more rapid reduction in GI secretions is desired, OCT should be considered as the first choice drug. Parenteral hydration over 500 ml/day may reduce nausea and drowsiness.

The role of somatostatin and octreotide in bowel obstruction: pre-clinical and clinical results.

Malignant bowel obstruction is a common complication in patients with advanced abdominal or pelvic cancer. Whereas surgery should be considered in all cases of malignant bowel obstruction, many advanced and terminal cancer patients are considered unfit for surgery. In such patients with a short life expectancy, gastrointestinal symptoms such as nausea, vomiting, continuous and/or colicky pain, can be controlled by using a pharmacologic approach made up of analgesics, antiemetics and antisecretory drugs, without the use of a venting nasogastric tube. Among the antisecretory drugs, octreotide has been shown to reduce nausea and vomiting in bowel-obstructed patients owing to a reduction of gastrointestinal secretions, thus allowing in most patients removal of the nasogastric tube and the associated distress. Preclinical and clinical studies that demonstrated the role of somatostatin and octreotide in bowel obstruction are reviewed.

Pain experienced by patients hospitalized at the National Cancer Institute of Milan: research project "towards a pain-free hospital".

According to the data of the literature, the prevalence of pain in cancer patients at various stages of the disease and the settings of care range from 38 to 51%, with an increase of up to 74% in the advanced and terminal stages. Despite published World Health Organization (WHO) guidelines for pain management, 42 to 51% of cancer patients receive inadequate analgesia and 30% receive no analgesics at all. A 3-year Research Project "Towards a Pain-free Hospital", which began one year ago, is ongoing at the National Cancer Institute of Milan. The research is organized in three subsequent steps. In the 1st one, a series of patient- and staff-oriented evaluation tools are used to assess the level of appropriateness of pain communication, assessment, management and control of the in-patients. The 2nd step will implement a number of continuing educational interventions aimed at improving patient awareness and staff knowledge of the appropriate pain assessment and management in order to respond to the patient's pain problem. In the 3rd step, all the assessment tools used in step one will be applied again to establish the prevalence of pain, the causes and intensity and patient satisfaction with pain management and to evaluate the impact of the interventions performed during the 2nd step regarding the overall ability of our hospital to tackle pain emergency in the hospitalized cancer population. The results relative to the 1st step are herein reported, in particular as regards the study on prevalence, causes, severity of pain, the interference of pain with sleep, mood and concentration, the use of pain medications and the relief obtained, the structural validity and internal consistency of the assessment tool used. A total of 258 patients hospitalized for at least 24 h were interviewed by 9 physicians using a brief structured questionnaire prepared ad hoc: 51.5% of the patients presented pain during the previous 24 h caused by surgery (49.6%) or by the tumor mass itself (29.3%). Out of the 133 patients with pain, a high degree (much or very much) of pain at rest was present in 27.1% and pain on movement in 30.8%; 31.6% did not take any analgesic treatment, and 14.3% of the latter reported a high degree of pain at rest and 21.4% on movement. Pain interfered with sleep from much to very much in 28.8% and with irritability and nervousness in 15.9% of the patients. In the 91 patients taking analgesics, 57.2% reported a high degree of pain relief. A high degree of pain and interference, however, was associated with low relief levels. The assessment tool used was shown to have a good structural validity and internal consistency (Chrombach alpha index of interference scale = 0.73). Although the Milan Cancer Institute has the longest tradition in Italy of pain assessment by means of validated tools and pain management according to the WHO guidelines and educational efforts in this field, the results of the study clearly show that it is necessary to persevere with continuing educational and informative programs in order to reduce the frequency and severity of pain and thus improve the quality of life of in-patients.

Comparison of octreotide and hyoscine butylbromide in controlling gastrointestinal symptoms due to malignant inoperable bowel obstruction.

In advanced cancer patients with inoperable bowel obstruction, the administration of antisecretive and antiemetic drugs has proved to be effective in controlling gastrointestinal symptoms caused by bowel obstruction. However, controlled studies concerning the most effective antisecretive drug are lacking. The aim of this randomized controlled study was to determine whether octreotide or hyoscine butylbromide was the more effective antisecretive drug for use in states of inoperable bowel obstruction. Eighteen patients with inoperable bowel obstruction randomly received octreotide 0.3 mg daily (n = 9) or hyoscine butylbromide (HB) 60 mg daily (n = 9) s.c. The following parameters were measured: episodes of vomiting, nausea, drowsiness, continuous and colicky pain, using a Likert scale corresponding to a numerical value: (none 0, slight 1, moderate 2, severe 3) recorded before starting the treatment (T0) and 24 h (T1), 48 h (T2) and 72 h after (T3), and the mean daily amounts of fluids administered i.v. or s.c. during the period of study. Three patients dropped out of the study because data were incomplete. Octreotide treatment induced a significantly rapid reduction in the number of daily episodes of vomiting and intensity of nausea compared with HB treatment at the different time intervals examined. No relevant changes were found in dry mouth, drowsiness and colicky pain. Lower levels of hydration were associated with nausea regardless of the treatment. At the doses used in this study, octreotide was more effective than HB in controlling gastrointestinal symptoms of bowel obstruction. Further studies are necessary to understand the role of hydration more clearly in such a clinical situation.

Equianalgesic dose/ratio between methadone and other opioid agonists in cancer pain: comparison of two clinical experiences.

BACKGROUND: Oral methadone is considered to be a valid opioid analgesic alternative to morphine and hydromorphone in treating cancer pain. However, the use of methadone could be complicated by the limited knowledge of the equianalgesic dose/ratio with the other analgesic opioids when switching in tolerant patients. PATIENTS AND METHODS: In two Palliative Care Units, data collected regarding 88 advanced cancer patients with pain switched from different opioids to oral methadone were reviewed and compared with the aim of determining the equianalgesic dose ratio in relation to the dose of opioid previously administered. RESULTS: The results of this retrospective study suggest that: (1) methadone is much more potent than previously described in literature, (2) the dose ratio between hydromorphone and methadone is higher than as suggested by equianalgesic tables, and (3) the ratio correlates with total opioid dose administered before switching. CONCLUSIONS: The fact that methadone ratio is different according to the opioid dose used previously should be taken into careful consideration by the clinician in order to avoid severe toxicity or death during switchover. Prospective studies should be carried out in order to better define our findings.

The role of disodium pamidronate in the management of bone pain due to malignancy.

A number of controlled studies have recently demonstrated the role of disodium pamidronate in the prevention of skeletal complications in patients with metastatic bone disease due to breast cancer and multiple myeloma. They have also shown that it relieves pain and is well tolerated. The aim of this open prospective study was to evaluate the acceptability of a new schedule of pamidronate infusion and to assess pain, analgesic consumption and the Karnofsky Performance Status (KPS) in patients with metastatic bone pain treated with pamidronate in association or not with chemotherapy, radiotherapy, and hormone therapy. Patients with different types of cancer and at least one painful bone metastasis were treated with two cycles of 60 mg intravenous (iv) pamidronate weekly for three consecutive doses, with a 3-week interval between the two cycles (six infusions over 7 weeks), followed by one infusion every 3 weeks for a total of 24 infusions. Two hundred patients were enrolled in the study, of whom 94 received at least the first six infusions; 25 patients received all 24 infusions. Pamidronate was well tolerated in the majority of the patients both during the first six infusions and during the whole study period. In the patients under study, pain intensity decreased compared with T0 after the first two infusions (second week of treatment). The mean equivalent daily dose of oral morphine required ranged from 21.5 to 41.5 mg/day and was low and stable during the study. For the patients who remained in the study, the KPS remained around 70 during the whole treatment period and intrasubject analysis showed a substantial stability of the KPS within each subject. A first fracture occurred within 321 days in 25% of the whole population under study. Pamidronate represents a further valid therapy to add to an already consolidated list of therapies such as radiotherapy, chemotherapy, hormone therapy and orthopaedic intervention in the pain management of patients with bone metastases. Future studies are necessary to evaluate the role of pamidronate and the appropriate schedule in patients with advanced or terminal cancer who are no longer being treated with oncological therapies.