Carla Ripamonti

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.

Episodic (Breakthrough) Pain Consensus Conference of an Expert Working Group of the European Association for Palliative Care

Breakthrough pain is transitory exacerbation of pain that occurs in addition to otherwise stable persistent pain. The wide differences in estimation of incidence reported in literature are probably because of different settings and meanings attributed to the definition of breakthrough pain.

Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan

BACKGROUND Screening of the oral cavity and dental care was suggested as mandatory preventive measures of osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BPs). We investigated the occurrence of ONJ before and after implementation of dental preventive measures when starting BP therapy. PATIENTS AND METHODS Since April 2005, 154 consecutive patients treated with BPs (POST-Group) have undergone a baseline mouth assessment (dental visit +/- orthopantomography of the jaws) to detect potential dental conditions and dental care if required. A retrospective review was also conducted of all consecutive cancer patients with bone metastases (PRE-Group) and treated for the first time with BPs from January 1999 to April 2005 in our clinic without receiving any preventive measure. Incidence proportion and incidence rate (IR) were used to estimate the incidence of ONJ. RESULTS Among the study population (966 patients; male/female=179/787), 73% had breast cancer. 25% of patients were given zoledronic acid (ZOL), 62% pamidronate (PAM), 8% PAM followed by ZOL and 5% clodronate. ONJ was observed in 28 patients (2.9%); we observed a reduction in the incidence of ONJ from 3.2% to 1.3%, when comparing-pre and post-implementation of preventive measures programme. Considering the patients exposed to ZOL, the performance of a dental examination and the application of preventive measures led to a sustained reduction in ONJ IR (7.8% in the PRE-Group versus 1.7% in the POST-Group; P=0.016), with an IR ratio of 0.30 (95% confidence interval 0.03-1.26). CONCLUSIONS ONJ is a manageable and preventable condition. Our data confirm that the application of preventive measures can significantly reduce the incidence of ONJ in cancer patients receiving BPs therapy. Dental exams combined to the identification of patients at risk in cooperation with the Dental Team can improve outcomes and increase the number of ONJ-free patients.

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.

Subcutaneous Morphine for Dyspnea in Cancer Patients

Dyspnea has been defined as an uncomfortable awareness of breathing [1]. It occurs in approximately 29% to 74% of patients with terminal cancer [2, 3] and is perceived as one of the most devastating symptoms by the patient and the family. Controlled single-dose trials have suggested that opioids are effective in the management of dyspnea associated with chronic obstructive lung disease [4]. However, opioids were poorly tolerated in these patients during repeated administration, mostly because of sedation and nausea [5]. These side effects usually disappear with the development of tolerance and are rarely a cause for discontinuing treatment among the approximately 80% of terminal cancer patients who receive opioids for pain [6]. However, the effects of opioids on the dyspnea of cancer have not been the focus of prospective studies. A previous uncontrolled study by our group suggested that subcutaneous morphine was able to decrease the intensity of dyspnea without statistically modifying oxygen saturation, respiratory rate, or the end tidal Paco 2 [7]. Methods The purpose of this study was to conduct a crossover, placebo-controlled trial to assess the effects of morphine on the intensity of dyspnea in 10 consecutive patients with terminal cancer. The mechanism of dyspnea was progressive lung tumor in 3 patients, lung metastases in 4 patients, pleural effusion in 1 patient, and carcinomatous lymphangitis in 1 patient, respectively. All patients were fully conscious, had normal cognitive status (score of 24 in the mini-mental state questionnaire) [8], were complaining of shortness of breath while in bed, and were receiving continuous oxygen using nasal prongs at a rate of 2 to 6 L/min. All patients received intermittent subcutaneous injections of morphine every 4 hours for the management of cancer pain. The morphine dose had not changed for at least 5 days, and all patients had good pain control (defined as no or mild pain most of the day and 2 extra analgesic doses/day). At 10:00 a.m. (time of their regular morphine dose) after at least 1 hour of bed rest, patients were randomized to receive subcutaneous injections of morphine or placebo. On the following day at 10:00 a.m. a crossover was made, and patients received the alternate treatment. Patients received an average dose of 34 12 mg of morphine. This dose was calculated to be 50% higher than the regularly scheduled dose in order to overcome potential development of tolerance. Dyspnea was assessed using a visual analog scale (0, no shortness of breath; 100, worst shortness of breath). Pain was assessed at baseline using a visual analog scale (0, no pain; 100, worst pain). Results Table 1 shows the results 30, 45, and 60 minutes after the injection of morphine or placebo. Baseline results were not different between day 1 and day 2. Improvement (P < 0.02) was seen in the intensity of dyspnea without any change in respiratory rate or oxygen saturation level measured by pulse oximetry. Table 1. Effect of Morphine and Placebo on Dyspnea, Oxygen Saturation, and Respiratory Rate* After the completion of the study, the patient and the investigator each blindly chose morphine as more effective for the patients dyspnea in 9 and 8 patients, chose placebo in 0 and 1 patient, and had no preference in 1 patient and 1 patient, respectively (P = 0.01 for patients, P = 0.044 for investigators, binomial distribution). After studying the effects of morphine in these initial controlled patients, we used morphine intermittently for dyspnea in 45 consecutive patients with terminal cancer. In all patients, morphine was prescribed on an as needed basis. All patients were already receiving regular morphine for cancer pain. The dose used for dyspnea was the same as the regular dose used for pain. Patients received a total of 312 subcutaneous doses. Good subjective response (no dyspnea or mild dyspnea) was documented by the nurse 30 minutes after the injection in 281 patients (90%), poor response was documented in 12 patients (4%) (moderate or severe dyspnea), and the response was not documented in 17 patients (5%). No patients had respiratory depression. Discussion Our results suggest that intermittent injections of morphine are safe and effective for the management of dyspnea in terminal cancer. Because our patients also had cancer pain, it is possible that some patients might have perceived less dyspnea after morphine, because it decreased the intensity of pain. An unpleasant sensation (dyspnea) could also be heightened by the presence of another unpleasant sensation (pain). However, this probably did not occur, because all patients had stable pain control (visual analog scale 21 27 on a 0-100 scale and had no change in morphine dose for 5 days). Future studies should determine the ideal dosage and modality of administration (as needed compared with regular dosing) of morphine, the relation between morphines effect on pain and the effect on dyspnea, and the safety on the approximately 20% of terminal cancer patients who are not receiving opioids.

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.

An update on the clinical use of methadone for cancer pain

Abstract Methadone is a synthetic opioid agonist considered a second choice drug in the management of cancer pain. Methadone has a number of unique characteristics including excellent oral and rectal absorption, no known active metabolites, high potency, low cost, and longer administration intervals, as well as an incomplete cross‐tolerance with respect to other mu‐opioid receptor agonist drugs. For these reasons, methadone has the potential of playing a major role in the treatment of cancer pain. However, its use is limited by the remarkably long and unpredictable half‐life, large inter‐individual variations in pharmacokinetics, the potential for delayed toxicity, and above all by the limited knowledge of correct administration intervals and the equianalgesic ratio with other opioids when administered chronically. Recent findings suggest that standard equianalgesic tables are unreliable for methadone titration in patients tolerant to high doses of opioid agonists and that switchovers should take place slowly and should be personalized. Future research has to better define the variation in both bioavailability and elimination of methadone in different patient populations, the interaction between methadone and the most commonly used drugs in cancer patients, the type and activity of potential methadone metabolites, and the equianalgesic doses between methadone and the most commonly used opioids.

Management of malignant bowel obstruction.

Malignant bowel obstruction (MBO) is a common and distressing outcome particularly in patients with bowel or gynaecological cancer. Radiological imaging, particularly with CT, is critical in determining the cause of obstruction and possible therapeutic interventions. Although surgery should be the primary treatment for selected patients with MBO, it should not be undertaken routinely in patients known to have poor prognostic criteria for surgical intervention such as intra-abdominal carcinomatosis, poor performance status and massive ascites. A number of treatment options are now available for patients unfit for surgery. Nasogastric drainage should generally only be a temporary measure. Self-expanding metallic stents are an option in malignant obstruction of the gastric outlet, proximal small bowel and colon. Medical measures such as analgesics according to the W.H.O. guidelines provide adequate pain relief. Vomiting may be controlled using anti-secretory drugs or/and anti-emetics. Somatostatin analogues (e.g. octreotide) reduce gastrointestinal secretions very rapidly and have a particularly important role in patients with high obstruction if hyoscine butylbromide fails. A collaborative approach by surgeons and the oncologist and/or palliative care physician as well as an honest discourse between physicians and patients can offer an individualised and appropriate symptom management plan.

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

Abstract 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.

Management of dyspnea in advanced cancer patients

Abstract Dyspnea is a frequent and devastating symptom among advanced cancer patients and is often difficult to control. However, there has been considerably less emphasis in the literature on the appropriate characterization and management of this symptom than of other cancer-related symptoms. The purpose of this paper is to review issues relating to the prevalence, causes, prognosis and treatment of dyspnea in patients with advanced cancer. A Medline search of the literature published from 1966 to February 1999 was conducted. Dyspnea occurs in 21–78.6% of advanced cancer patients and is reported to be from moderate to severe in 10–63% of the patients. The frequency and severity of dyspnea increase with the progression of the disease and/or when death is approaching. Lung cancer patients with dyspnea have shorter survival than patients with other types of cancer. Dyspnea can be a direct effect of the cancer, an effect of therapy or not related to the cancer or therapy. In addition to cancer, patients may suffer from chronic obstructive pulmonary disease, congestive heart failure, nonmalignant pleural effusion, pneumonitis, air flow obstruction, or bronchospasm associated with asthma. In the absence of lung or heart disease, dyspnea may be a clinical expression of the syndrome of overwhelming cachexia and asthenia or of severe asthenia. Many different causes may co-exist in a patient. Whenever possible, an attempt should be made to treat underlying cancer. Radiotherapy and chemotherapy may relieve dyspnea also in patients who fail to achieve a major objective response. Symptomatic measures in addition to specific treatments for the underlying cancer and/or other pulmonary and cardiovascular diseases are indicated. Oxygen therapy has proved effective in hypoxemic and nonhypoxemic patients. The role of transfusion therapy to relieve anemia-related dyspnea in advanced and terminal cancer patients is still controversial. Oral, subcutaneous and intravenous opioids are effective but underused in these patients, whereas currently available evidence does not support the clinical use of nebulized opioids. While benzodiazepines are frequently used in patients with dyspnea, these drugs were ineffective in four out of five randomized controlled trials. Other components of the symptom expression are better managed by supportive counseling, occupational therapy or physiotherapy. While the mechanism of breathing and the consequences of different pathologic conditions for both respiratory function and gas exchange are well known, the genesis and pathophysiology of dyspnea as a symptom are much less well understood. Palliative care assessment should be focused on dyspnea as a symptom rather than on the functional and gas exchange abnormalities. Increased research on the appropriate management of dyspnea is needed.