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.

Strategies to manage the adverse effects of oral morphine: an evidence-based report.

Successful pain management with opioids requires that adequate analgesia be achieved without excessive adverse effects. By these criteria, a substantial minority of patients treated with oral morphine (10% to 30%) do not have a successful outcome because of (1) excessive adverse effects, (2) inadequate analgesia, or (3) a combination of both excessive adverse effects along with inadequate analgesia. The management of excessive adverse effects remains a major clinical challenge. Multiple approaches have been described to address this problem. The clinical challenge of selecting the best option is enhanced by the lack of definitive, evidence-based comparative data. Indeed, this aspect of opioid therapeutics has become a focus of substantial controversy. This study presents evidence-based recommendations for clinical-practice formulated by an Expert Working Group of the European Association of Palliative Care (EAPC) Research NETWORK: These recommendations highlight the need for careful evaluation to distinguish between morphine adverse effects from comorbidity, dehydration, or drug interactions, and initial consideration of dose reduction (possibly by the addition of a co analgesic). If side effects persist, the clinician should consider options of symptomatic management of the adverse effect, opioid rotation, or switching route of systemic administration. The approaches are described and guidelines are provided to aid in selecting between therapeutic options.

Indoprofen, a new analgesic and anti-inflammatory drug in cancer pain.

Evaluation of the analgesic activity of indoprofen was carried out in patients with cancer pain under double-blind conditions and compared with aspirin and placebo. A randomized experimental design was followed. Single oral doses were given of the test drug (100 and 200 mg), aspirin (600 and 1,000 mg), and placebo. For measuring analgesia, 5-point pain intensity and pain relief semiquantitative scales were used. Potency ratio between drugs was calculated on SPID (sum of pain intensity differences) and TOTPAR (total pain relief) and resulted in 10.3 by combination of estimates. In a group of only 24 patients, the data supported the following conclusions: indoprofen at 100 and 200 mg single doses is effective in relieving cancer pain; it displays a dose-related analgesic effect comparable to that of aspirin with only one-tenth the dose.

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.

A new international framework for palliative care.

In spite of recent advances in anti-cancer treatments, most adult cancer patients still ultimately die from their disease. There should therefore be free access to palliative care around the clock and seven days a week, for all cancer patients, as a fundamental human right. At present, the implementation of palliative care and patients' access to it are inconsistent across Europe and many other parts of the world. The World Health Organisation (WHO) made an important advance in 1986 by first defining palliative care and, then updating this definition in 2002. However, this definition could benefit from further refinement in order to reflect the increasing multi-professional specialisation in this subject, and to recognise the different models for delivering this type of care. We recommend that palliative care should be defined as follows: Palliative care is the person-centred attention to symptoms, psychological, social and existential distress in patients with limited prognosis, in order to optimise the quality of life of patients and their families or close friends. Based on this definition, we propose two further types of palliative care which reflect the reality of how palliative care is actually delivered: Basic palliative care is the standard of palliative care which should be provided by all healthcare professionals, in primary or secondary care, within their normal duties to patients with life-limiting disease. Specialised palliative care is a higher standard of palliative care provided at the expert level, by a trained multi-professional team, who must continually update their skills and knowledge, in order to manage persisting and more complex problems and to provide specialised educational and practical resources to other non-specialised members of the primary or secondary care teams. If a patient has difficult symptoms which cannot be controlled by his/her current healthcare team, he/she has a right to be referred, and the current healthcare provider has an obligation to refer, to the local palliative care team. Important priorities to ensure the standardisation of, and uniform access to, palliative care for all cancer patients include: Integration of palliative care services with the primary care and oncology teams. Establishment of a specialised palliative care service in each major cancer centre. Establishment of educational programmes covering palliative care for undergraduates, oncologists, primary care team members and specialists training in palliative care. Support for research using appropriate methodologies to underpin the scientific basis of palliative care. Establishment of quality assurance programmes. Recognition of palliative medicine as a medical specialty. Establishment of academic centres of excellence with chairs of palliative medicine and palliative care nursing. Removal of unnecessary restrictions on all drugs which are proven to be of benefit in symptom control, especially improving access to strong opioids. Improved information for patients and family carers to allow them to make choices and exercise autonomy.

Local toxicity with subcutaneous methadone. Experience of two centers.

We report on 8 patients treated with subcutaneous methadone for cancer-related pain at 2 institutions. The success of other subcutaneous agents for pain control has been well demonstrated. It was felt that methadone would be useful due to its low cost. Unfortunately, 7 of the 8 patients experienced adverse reactions at the subcutaneous sites requiring cessation of subcutaneous methadone.

Trazodone for deafferentation pain. Comparison with amitriptyline.

We report a clinical multicentre experience with antidepressant agents (trazodone and amitriptyline) in the treatment of chronic pain due to deafferentation. Forty five patients were admitted to the study; most of them with oncological peripheral nerve lesions. Almost all of them were already being treated with NSAID in association with weak or strong opioids. A random double blind study was performed: 23 patients were treated with trazodone, 22 with amitriptyline. In the assessment of results, pain intensity, hours of sleep, hours standing and lying, side effects, mood, anxiety and weakness were all taken into consideration. The therapeutic analgesic efficacy of the two drugs proved to be similar.

Skin problems in advanced and terminal cancer patients.

Disturbances caused by skin problems may compromise the quality of life of cancer patients. The main complications affecting the skin comprise the dermatologic toxicity of anticancer therapy, bedsores, malignant ulcers, sores due to nonmetastatic cancer, pruritus, and infections. Most of the information available about these entities has been acquired in the cancer patient without advanced disease. The little currently known about the epidemiology and physiopathology of such lesions in the advanced phase of cancer is presented, and approaches to management are suggested.

Prognostic value of quality of life scores in terminal cancer patients.

A multicenter cross-sectional study of 115 terminal cancer patients in eight home-care units assessed the prognostic value of quality of life scores, as measured by the Therapy Impact Questionnaire (TIQ). The analysis of the questionnaires completed by 100 patients revealed an association between survival and many of the scales: fatigue, gastrointestinal symptoms, global health status, functional impairment, emotional status, and cognitive status. This association was also observed for some specific physical symptoms, such as confusion, weakness, and loss of appetite, and the overall number of symptoms reported by the patient. Adjusting for some possible confounding factors, only confusion (among the physical symptoms), cognitive status, and global health status (among TIQ primary scales) showed independent prognostic value. As regards the latter two scales, median survival time was distributed differently for patients with no impairment of either (137 days), with impairment of one scale (50 days) and with impairment of both scales (17 days). The judgment expressed by the patient about subjective perception of general malaise and cognitive difficulties can give the clinician important prognostic information.

Organic brain syndromes and opioid administration for cancer pain.

To clarify the range of potential etiologies that may contribute to organic brain syndrome in patients receiving systemic opioids for cancer pain, we describe 15 patients who presented this complication. In 11 cases, concomitant conditions were found that could contribute to the onset of organic brain syndrome. These data illustrate that multiple causes often play a role in the development of mental status changes in advanced cancer. Opioids are seldom the only causal factor implicated.

Continuous subcutaneous infusion of hyoscine butylbromide reduces secretions in patients with gastrointestinal obstruction.

We describe the use of hyoscine butylbromide as a subcutaneous infusion in 3 patients with inoperable malignant bowel obstruction. An objective reduction of drainage from the gastrointestinal tract was observed with the hyoscine butylbromide infusion (60-120 mg/day). We suggest that this effect can be useful in the palliative treatment of vomiting in inoperable bowel obstruction.

Clinical observations on controlled-release morphine in cancer pain.

The authors report the data from two studies on the use of controlled-release morphine sulphate tablets for cancer pain relief. This preparation allows just two administrations per day, in comparison with immediate release oral aqueous morphine solution. The first study, a randomized trial carried out on 70 patients suffering from advanced cancer pain, evaluated the analgesic efficacy and side effects of this drug. The second, an open study of 113 patients, assessed analgesic efficacy, incidence of side effects, and the effects of age on dose. The analgesia provided by controlled-release morphine administration proved to be superimposable to those of the oral aqueous morphine solution. Moreover, the use of controlled-release morphine was associated with a statistically significant reduction of some side effects. Ninety-one percent of patients needed controlled-release morphine every 12 hr, while 9% required it every 8 hr.

Issues in symptom control. Part 4. Oral complications in patients with advanced cancer.

Disturbances caused by lesions of the oral cavity play an important part in the alteration of the quality of life of cancer patients. The main complications affecting the oral cavity are infections (fungal, viral, bacterial), neutropenic ulcers, drug-induced stomatitis, dry mouth, and taste alteration. Most of the information available about these entities has been acquired in the cancer patient without advanced disease. The little knowledge about the epidemiology and physiopathology of such lesions in the advanced phase of cancer is presented, and approaches to management are suggested.

Subcutaneous octreotide in the treatment of pain in advanced cancer patients.

Octreotide is a synthetic somatostatin analogue that has been recently tested by various routes of administration as an analgesic drug for different types of pain. The authors evaluated the analgesic efficacy of a subcutaneous 200-ng bolus of octreotide on somatic and visceral pain from advanced cancer in a randomized, single-blind crossover study. The results in nine cases did not show an analgesic effect superior to that of a placebo. Pain relief was obtained in one case of postprandial visceral pain. This case is discussed in detail, and another possible clinical use for octreotide in a particular form of neoplastic pain is hypothesized.

A clinical study on the use of codeine, oxycodone, dextropropoxyphene, buprenorphine, and pentazocine in cancer pain.

The authors report a prospective study on 944 cancer pain patients treated with one of the following opioids: codeine, oxycodone, dextropropoxyphene, buprenorphine, and pentazocine. Level of analgesia, duration of treatment, side effects, and drop out were evaluated for each drug. Twenty-four percent of the patients still benefitted from treatment at the fourth week of study, even if high drug dosages were not used. Pentazocine did not show an evident analgesic effect during the first 2 wk of treatment. The other opioids were found to be valid therapeutic instruments for chronic cancer pain control in a limited number of patients.

Characteristics of terminal cancer patients who committed suicide during a home palliative care program.

Cancer patients may commit suicide at any stage of the disease and many risk factors of suicide have been described in the literature. To identify the possible vulnerability factors of suicide in five terminal cancer patients who committed suicide while they were cared for at home by well-trained palliative care teams, a psychological autopsy study was carried out by reviewing their medical records; their report of symptoms at the time of care; and with the caregivers', doctors', and nurses' recollection of events by means of a structured interview prepared ad hoc. We collected data regarding the physical, emotional, and social suffering of the patients, their personality profile, and their feelings with respect to the illness and disability. The interviews lasted for a mean of two hours and were performed from 2-8 years after the suicide events by the social worker at the Rehabilitation and Palliative Care Division. The interviews took place between June 1996 and January 1998. All the patients showed great concern about the lack of autonomy and independence, refused dependence on others and had fear/worry of losing their autonomy. Four patients presented functional and physical impairments, uncontrolled pain, awareness of being in the terminal stage, and mild to moderate depression. They had a feeling of hopelessness consequent to their clinical conditions, fear of suffering, and feeling of being a burden on others. They had a strong character and managerial professions. They had isolated themselves from others and they had previously talked about suicide. Before committing suicide, three patients had adverse physical/emotional consequences to the oncological treatments-they showed aggressiveness towards their family and one towards the home care physician. Multiple vulnerability factors were present simultaneously in all patients. However, the loss of, and the fear of losing, autonomy and their independence and of being a burden on others were the most relevant. The identification of a cancer patient at risk of committing suicide forms the first step for the prevention of and the setting up of adequate psychosocial rehabilitation of these patients whenever possible.

Treatment of postoperative pain: comparison between administration at fixed hours and 'on demand' with intramuscular analgesics.

From the data in the literature it can be seen that 40% of the surgical population has insufficient postoperative analgesia. Many reasons have been given for this: pain control delegated to the doctor on duty and/or the nursing staff; administration of drugs 'on demand', if the patient asks for them, or the nurses feel it to be necessary; fear of causing side effects such as respiratory insufficiency; or provoking addiction by giving narcotics. The aim of this paper is to evaluate the intensity of pain, the side effects, the degree of activity, anxiety, feeling of weakness and the mood of patients surgically treated for oncological diseases of the thorax and upper abdomen, comparing two different antalgic approaches. Thirty-five patients were studied. Pain was treated on demand with a narcotic, or an anti-inflammatory drug, or not treated at all; 20 patients were treated with analgesics given at predetermined hours, following the regime: methadone 10 mg intramuscularly (i.m.) every 12 h from the first to the third day following surgery and sodium diclofenac 75 mg (i.m.) every 12 h from the fourth to the seventh day. Results showed that patients treated with analgesics given intramuscularly at fixed hours have a significantly better pain control during the whole week of treatment (P less than 0.001), on average sleep more (P less than 0.001), spend more time standing or sitting and fewer hours lying down (P less than 0.001), have a higher performance status and feel less weak (P less than 0.05) than the group of patients treated with drugs 'on demand', or not treated at all.

Psychological aspects of genital human papillomavirus infection: a preliminary report.

Genital human papillomavirus (HPV) infection can lead to self-inflicted blame and hypochondriac fears as well as to problems with sexuality. The aim of this study was to assess the psychological and psychodynamic aspects of patients with widespread genital HPV infection entering into a clinical trial in which they were randomly assigned to three treatment groups: CO2 laser ablation, intramuscular interferon-alpha, CO2 laser ablation plus intramuscular interferon-alpha. Fifty-one patients were studied. Patients were asked to take a series of questionnaires which included a self-rating questionnaire for gathering information on sexuality, emotional relationship with the partner and social life. A visual analog scale was used to rate intensity of pain during sexual intercourse. Each patient went also through an in-depth interview with a clinical psychologist and filled out two personality tests to measure depression (CDQ = IPAT depression test) and anxiety (ASQ = IPAT anxiety test). Results indicated a high percentage of sexual impairments after therapy (28 cases), presence of fear of cancer (14 cases) and worsenings in the emotional relationship with the partner. No difference was found among groups of treatment.

Plasma morphine and morphine-6-glucuronide patterns in cancer patients after oral, subcutaneous, sublabial and rectal short-term administration.

Clinical studies on the effectiveness of morphine administered through different routes are contradictory. In order to further elucidate this point, the plasma concentrations of morphine and its 3- and 6-glucuronated metabolites were measured after short-term oral, sublabial, rectal and subcutaneous administration of the opiate. The bioavailability of free morphine and the 6-glucuronated active metabolite was comparable through the different routes. It was concluded that the choice of the route of morphine administration should be mainly guided by the needs of each individual patient.

[Alcohol infusion of the pituitary, high-dose medroxyprogesterone and their association as analgesics in advanced breast cancer (author's transl)]. / Effetto antalgico dell'alcoolizzazione ipofisaria, del medrossi-progesterone acetato ad alte dosi e della loro associazione nel carcinoma mammario in fase avanzata

The analgesic effects of alcohol infusion of the pituitary, high-dose progesterone and their association on chronic intractable pain in TxN+M+ breast cancer patients no longer responsive to combination chemotherapy, radiotherapy and hormone therapy are assessed. The antalgic effect of medroxyprogesterone proved to be more lasting than that of alcohol infusion of the pituitary. Moreover, 6 of the 20 patients treated with the former presented regression of the disease whereas none of those treated with alcohol did so.