C. Ripamonti

Morphine and alternative opioids in cancer pain: the EAPC recommendations.

An expert working group of the European Association for Palliative Care has revised and updated its guidelines on the use of morphine in the management of cancer pain. The revised recommendations presented here give guidance on the use of morphine and the alternative strong opioid analgesics which have been introduced in many parts of the world in recent years. Practical strategies for dealing with difficult situations are described presenting a consensus view where supporting evidence is lacking. The strength of the evidence on which each recommendation is based is indicated.

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

PURPOSEnTo 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.nnnPATIENTS AND METHODSnA 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 Pearsons correlation coefficient, scatter plots, and Cuzicks test for trend respectively.nnnRESULTSnBefore 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 (Pearsons 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.nnnCONCLUSIONnThe 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.

The role of bisphosphonates in the treatment of painful metastatic bone disease: a review of phase III trials

Abstract Metastatic bone disease is a frequent cause of morbidity in advanced cancer patients with a subsequent high incidence of skeletal complications (fractures, hypercalcemia, spinal cord compression) and severe pain. The osteolytic process is mainly characterized by an osteoclastic activity of bone resorption and inflammatory activity provoked by various cytokines and prostaglandins. Bisphosphonates represent a new class of drugs with inhibitory activity on bone resorption and on inflammatory processes which revealed themselves to be efficacious in a series of clinical conditions such as tumour‐induced hypercalcemia, Pagets disease, osteoporosis and metastatic bone disease. The aim of this review of the literature is to show the analgesic efficacy of the different bisphosphonates in phase III studies carried out on patients with metastatic bone disease. Medline and Cancerlit database from January 1984 to February 1998 have been considered. From the analysis of the published studies it appears that bisphosphonates and, in particular, intravenous Disodium Pamidronate, are not only able to slow down the progression of the disease and to reduce the onset of skeletal complications but also have an analgesic effect and the possibility of improving the quality of life, above all in patients with osteolytic metastases due to breast cancer and multiple myeloma. Bisphosphonates represent a further valid therapy to add to an already consolidated list of therapies such as radio, chemo and endocrine therapy, analgesic drugs, orthopaedic and physiatric in the pain management of patients with bone metastases. These drugs meet with the patients compliance, are well‐tolerated as well as having a good cost/efficacy profile. It still remains to be seen if the newer and more potent bisphosphonates such as Ibandronate and Zoledronate can be administered differently from the intravenous route such as by mouth or by patch which are readily accepted by the patient and, moreover, if these more potent drugs are able to prevent or delay the onset and/or the progression of bone metastases.

Edmonton symptom assessment scale: Italian validation in two palliative care settings.

In the palliative care setting, the Edmonton Symptom Assessment Scale (ESAS) was developed for use in daily symptom assessment of palliative care patients. ESAS considers the presence and severity of nine symptoms common in cancer patients: pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being and shortness of breath plus an optional tenth symptom, which can be added by the patient. The aim of this study was to validate the Italian version of ESAS and to evaluate an easy quality of life monitoring system that uses a patient’s self-rating symptom assessment in two different palliative care settings: in-patients and home patients. Eighty-three in-patients and 158 home care patients were enrolled. In the latter group, the Italian validated version of the Symptom Distress Scale (SDS) was also administered at the admission of the patients. The two groups of patients have similar median survival, demographic and clinical characteristics, symptom prevalence and overall distress score at baseline. ESAS shows a good concurrent validity with respect to SDS. The correlation between the physical items of ESAS and SDS was shown to be higher than the correlation between the psychological items. The association of ESAS scores and performance status (PS) showed a trend: the higher the symptom score was, the worse was the PS level. Test–retest evaluation, applied in the in-patient group, showed good agreement for depression, well-being and overall distress and a moderate agreement for all the other items. In conclusion, ESAS can be considered a valid, reliable and feasible instrument for physical symptom assessment in routine “palliative care” clinical practice with a potentially different responsiveness in different situations or care settings.

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

PURPOSEnThe 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.nnnPATIENTS AND METHODSnIn 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.nnnRESULTSnA 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.nnnCONCLUSIONnOral 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.

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

BACKGROUNDnOral 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.nnnPATIENTS AND METHODSnIn 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnThe 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.

A randomized study on oral administration of morphine and methadone in the treatment of cancer pain

Abstract Over a period of 14 days, 54 patients with incurable chronic cancet pain were observed: 27 were randomized for treatment with morphine per os and 27 with methadone per os. Data regarding daily dosage, analgesic effects, hours of sleep, hours standing, performance status (PS) and side effects were collected during both treatments. The results show overlapping analgesic efficacy and side effects for both drugs, and confirm the hypothesis that lower doses of methadone are required than morphine. In the treatment with methadone, the initial average dose was 18 mg, and this dose was maintained throughout the entire period, whereas the initial average daily dose of morphine was 72.74 mg (±39.25), and the final average daily dose was 119.40 mg (±79.1). The findings in this study show that methadone is a valid alternative to morphine in cancer pain treatment even though, as a result of its pharmaceutical charcteristics, it requires a differnt titration for the patient.

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.

PURPOSEnThe 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.nnnPATIENTS AND METHODSnThirty-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.nnnRESULTSnA 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.nnnCONCLUSIONnA 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.

Is the use of transdermal fentanyl inappropriate according to the WHO guidelines and the EAPC recommendations? A study of cancer patients in Italy

BackgroundWorld Health Organization (WHO) guidelines, Agency for Health Care Policy and Research (AHCPR) clinical practice guidelines, and EAPC recommendations indicate oral route of opioid administration as the preferred route. Transdermal administration of opioids is considered an alternative when patients cannot take medications orally. Moreover, WHO and EAPC indicate orally administered morphine as the first-choice drug for the treatment of moderate to severe cancer-related pain. However, we can see that in Italy there is an increasing use of transdermal fentanyl (TF) as first-choice strong opioid (and route) even when oral administration of opioids is possible.AimsThe aims of this study are to describe the modality in the use of TF administration in two settings of care, taking into consideration (1) the drugs previously taken by the patients, (2) the reasons for switching from any drug to TF, (3) the conversion ratio used, and (4) the frequency of “inappropriate use of transdermal fentanyl according to the WHO guidelines and the EAPC recommendations”, i.e., switching to fentanyl patch from any drug, even if there were no contraindications in using oral morphine. The settings of care considered were the out-patient palliative care unit (OP-PCU) and the oncological wards (OWs) of the National Cancer Institute (NCI) of Milan.Patients and methodsThe clinical charts of 98 patients prescribed with and given fentanyl patch for the first time at the NCI of Milan in 2002 were reviewed and the data gathered were grouped according to the administration of fentanyl at the OP-PCU (63 out-patients) or at the OWs (35 in-patients). Summary descriptive statistics and bar and box plots have been used. Fisher two-tailed exact text was applied to test the differences between in- and out-patients.ResultsBefore switching to TF, (1) in-patients were more frequently treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and weak opioids (mostly tramadol) in respect to the out-patients (44.1 vs 25.8%) who were mostly treated with oral morphine (48.4 vs 20.6%) (p=0.045), and (2) 88.7% of the out-patients were treated with oral opioids and only 1.6% with parenteral opioids in respect to OWs where 69.7% were on oral opioids and 18.2% on parenteral opioids (p=0.006). In 29% of out-patients and in 53% of in-patients, changing to fentanyl patch was considered as “inappropriate” (p=0.028) according to the WHO guidelines and the EAPC recommendations. No statistically significant differences between the two settings were observed regarding the reasons for switching and the conversion ratio used.ConclusionsThere is a trend to use fentanyl patch as first-choice strong opioid in cancer patients in situations such as titration phase, in the presence of instable pain, and in the absence of dysphagia or gastrointestinal symptoms where the use of oral morphine is, however, not contraindicated.

A retrospective study on the use of oral morphine in cancer pain

Abstract The authors report a retrospective study of 390 cancer pain patients tested with oral morphine during a four-month period. Initial pain scores were reduced to one half after one week of treatment and then maintained throughout the study period. Mean daily dosages of morphine were lower in those patients 65 years and older. No significant changes in performance in relation to therapy were noted except for an increase in hours of sleep. An accurate titration of dosage and continued control of side effects are the main requirements of this method of administration. The presence of side effects and the cause of interruption of treatment are reported.