Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Europe: a report from the ESMO/EAPC Opioid Policy Initiative.

BACKGROUND: Many patients in Europe do not receive adequate relief of pain because of excessive regulatory restrictions on the availability and accessibility of opioids. This is a major public health problem. The aim of the study is to evaluate and report on opioid availability and the legal and regulatory barriers to accessibility across the countries of Europe. METHODS: European Society for Medical Oncology and European Association for Palliative Care national representatives reported data regarding survey of opioid availability and accessibility. Formulary adequacy is evaluated relative to the World Health Organization (WHO) essential drugs list and the International Association for Hospice and Palliative Care list of essential medicines for palliative care. Overregulation is evaluated according to the guidelines for assessment of national opioid regulations of the WHO. RESULTS: Data were reported on the availability and accessibility of opioids for the management of cancer pain in 21 Eastern European countries and 20 Western European countries. Results are presented describing the availability and cost of opioids for cancer pain in each surveyed country and nine forms of regulatory restrictions. CONCLUSIONS: Using standards derived from the WHO and International Narcotics Control Board, this survey has exposed formulary deficiencies and excessive regulatory barriers that interfere with appropriate patient care in many European countries. There is an ethical and public health imperative to address these issues.

Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes.

BACKGROUND: The European Pain in Cancer survey sought to increase understanding of cancer-related pain and treatment across Europe. PATIENTS AND METHODS: Patients with all stages of cancer participated in a two-phase telephone survey conducted in 11 European countries and Israel in 2006-2007. The survey screened for patients experiencing pain at least weekly, then randomly selected adult patients with pain of at least moderate intensity occurring several times per week for the last month completed a detailed attitudinal questionnaire. RESULTS: Of 5084 adult patients contacted, 56% suffered moderate-to-severe pain at least monthly. Of 573 patients randomly selected for the second survey phase, 77% were receiving prescription-only analgesics, with 41% taking strong opioids either alone or with other drugs for cancer-related pain. Of those prescribed analgesics, 63% experienced breakthrough pain. In all, 69% reported pain-related difficulties with everyday activities; however, 50% believed that their quality of life was not considered a priority in their overall care by their health care professional. CONCLUSIONS: Across Europe and Israel, treatment of cancer pain is suboptimal. Pain and pain relief should be considered integral to the diagnosis and treatment of cancer; management guidelines should be revised to improve pain control in patients with cancer.

Short-term effects of pamidronate on bone turnover: can bone markers be considered predictive of the analgesic response?

Few data are available on the ability of bone markers to predict the symptomatic response to bisphosphonate therapy in patients with painful bone metastases. We evaluated the levels of bone markers in patients with bone metastases receiving pamidronate and determined the corresponding analgesic response. Forty-two patients were administered two two-week cycles of intravenous pamidronate 60 mg/week with a three-week interval in between. Serum levels of bone formation, resorption and other bone-associated markers (osteoprotegerin, osteopontin and calcium) were measured. Levels of two urinary markers were also measured and the intensity of pain and analgesic drug consumption evaluated. A mixed effects linear modelling approach was adopted to account for possible correlation among marker levels and time on study or analgesic response. We created an indicator variable that classified the patients' analgesic response as 'improved/stationary' or 'worsened' determined by patient reported intensity of pain and analgesic drug consumption. Eighteen patients 'worsened' and 24 were 'improved/stationary'. The results of the mixed effects models for testing the association between marker levels and time on study or analgesic response showed: i) the changes in marker levels over time did not significantly differ between the two groups; ii) the overall test for time on study was not statistically significant for C-terminal telopeptide of type I collagen (ICTP), osteoprotegerin and osteopontin; iii) in contrast, ICTP and osteoprotegerin were significantly associated with analgesic response. Biochemical markers of bone turnover, in particular ICTP and osteoprotegerin seem promising for predicting and objectively assessing the analgesic response to pamidronate treatment.

Role of rectal route in treating cancer pain: a randomized crossover clinical trial of oral versus rectal morphine administration in opioid-naive cancer patients with pain.

PURPOSE: The aim of this double-blind, double-dummy, crossover study was to compare the efficacy, tolerability, and time of onset of analgesia after the administration of 10 mg of morphine hydrochloride via the oral and rectal routes in opioid-naive cancer patients with pain. PATIENTS AND METHODS: Thirty-four patients with cancer pain and no previous opioid treatment were randomized to receive morphine hydrochloride 10 mg orally or rectally (in the form of a microenema) for 2 days. During days 3 and 4, a crossover took place. The scores of pain, nausea, and sedation (visual analog scale of 0 to 100) calculated as the percentage change from baseline (before opioid administration) were assessed at different intervals up to 240 minutes. The number of vomiting episodes was recorded. Parity tests and analysis of variance (ANOVA) were performed to compare the two administration routes. RESULTS: A significant difference in pain intensity was achieved 10 minutes after rectal administration compared with 60 minutes after oral administration. There was still a significant reduction in pain via the rectal route after 180 minutes versus via the oral route after 120 minutes. No significant difference was observed in the intensity of sedation, nausea, or number of vomiting episodes between the oral and rectal routes. CONCLUSION: A liquid solution of morphine is well absorbed via the rectal route. Rectal morphine is safe, effective, easy to manage, and inexpensive, with a rapid onset of action. Rectal morphine can be considered a valid alternative route for opioid administration and may also be used when rescue doses of morphine are required in patients regularly treated with oral or parenteral opioids.

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.

Palliative care research.

Most of the research in palliative medicine is of a descriptive nature. Clinical practice is based upon clinical experience rather than upon research. The level of appropriate research reduces the chance for improvement of palliative care. Ethical and methodological obstacles seem to be prominent in palliative care research. The Declaration of Helsinki is generally accepted as an ethical code of practice for clinical research and it also applies to palliative care. In order to obtain reliable data, standardisation of data collection is needed. Improvement of quality of life is the primary endpoint in most studies in palliative care. The existing validated quality of life instruments such as the European Organization for Research and Treatment of Cancer (EORTC) quality of life (QLQ)-C30 can be used until the patient is too sick to complete the questionnaire. New approaches are needed and must be developed for the dying patients. Palliative care research needs proper funding; specific programmes supporting research on a European level are needed. The European Association for Palliative Care (EAPC) is capable of conducting and coordinating collaborative research in palliative care on a European level.

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.

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.

Propofol in terminal care.

In advanced cancer patients close to death, delirium, multifocal myoclonus, and restlessness may occur. Multi-organ failure and related metabolic changes are mostly responsible for these symptoms. A pharmacologic approach to manage the delirium is necessary in the majority of cases. Benzodiazepines, neuroleptics, and barbiturates are the most common drugs used. In the case reported, propofol administered at very low doses provided good control of neuropsychiatric symptoms. After a loading dose of 20 mg, an infusion of 50-70 mg per hr was started. The patient died peacefully after 8 hr of propofol infusion, without requiring opioids. Propofol seems to be a promising drug in treating the terminal agitated state that can be associated with the dying process.

Visual disturbances in advanced cancer patients: clinical observations.

Visual disturbances in advanced cancer patients are very rarely signaled, evaluated, or adequately treated. The main causes of sight disturbances are primary eye tumors, ocular metastases, and some paraneoplastic syndromes. Sight alteration can also be associated with asthenia, fatigue, anemia, and hypovitaminosis. These symptoms can be monocular or binocular, and their gravity and evolution can vary. Based on a survey of 156 patients, we estimate the prevalence of visual disturbances to be 12% in advanced cancer patients.

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.

Gabapentin as an adjuvant to opioid analgesia for neuropathic cancer pain.

Gabapentin was administered as an "add on" therapy to 22 patients with neuropathic cancer pain only partially responsive to opioid therapy. Global pain, burning pain, shooting pain episodes, and allodynia were assessed separately. Gabapentin was given for at least a week and efficacy was assessed after 7 to 14 days of therapy. Global pain score decreased from a mean (+/- SD) of 6.4 (+/- 1.5) to 3.2 (+/- 1.3) (95% confidence interval of the baseline minus final score differences [95% CI] = 1.0-2.4). Burning pain intensity decreased from a mean (+/- SD) of 5.1 (+/- 3.6) to 2.0 (+/- 2.3) (95% CI = 1.5-3.8), and episodes of shooting pain decreased in frequency from 7.2 (+/- 3.7) to 2.2 (+/- 2.2) daily episodes (95% CI = 1.8-4.3). Allodynia was found in 9 patients and disappeared in 7 during gabapentin administration. Twenty patients judged the new drug efficacious in relieving their symptoms. The potential role of gabapentin as an adjuvant to opioid analgesia in cancer pain is discussed.

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.

Tolerability of ketorolac administered via continuous subcutaneous infusion for cancer pain: a preliminary report.

We evaluated the local and systemic tolerability of ketorolac administered through continuous subcutaneous infusion in ten cancer patients. The patients were monitored daily for the severity and duration of pain, and the development of other symptoms. The duration of injection site varied from 1 to more than 7 days. No patients complained of local discomfort or pain. Mild local bleeding at the site of drug injection was observed in seven cases. No increase in the intensity of symptoms was observed during the infusion of ketorolac.