Effects of caffeine as an adjuvant to morphine in advanced cancer patients. A randomized, double-blind, placebo-controlled, crossover study.

Psychomotor abnormalities are one of the complications of opioid therapy in advanced cancer patients. Caffeine has potential properties to counteract the central effects of morphine. Twelve patients receiving stable doses of slow release morphine with adequate pain relief were scheduled for this double-blind placebo-controlled crossover trial. The treatment consisted of an intravenous dose of 1/6 of the daily morphine dose, using an intravenous/oral conversion ratio of 1:3. The dose calculated was administered in 5 minutes. Patients were randomly divided to received in a double-blind manner an infusion of 200 mg of caffeine or saline solution intravenously over one hour. A crossover took place after 2-3 days. Patients were assessed immediately before the infusion and once at the end (one hour after). Each assessment included pain, nausea, confusion, and drowsiness intensity. Psychomotor tests, including tapping speed with 10-30 seconds trials, arithmetic tests, memory for digits, and visual memory were also performed. Caffeine infusion induced a significant decrease in pain intensity (from 25.3 to 16.3, p =0.003), but this was no different from the placebo. Caffeine increased both tapping speed tests (p = 0.041 and 0.010, respectively) in comparison with placebo treatment. No other significant differences were found in the other parameters examined. Caffeine showed a partial effect on the cognitive performance of advanced cancer patients on chronic morphine treatment who received a bolus of intravenous morphine. Further studies are necessary to evaluate whether higher doses of caffeine may be more effective and to establish the role of tolerance to caffeine in this group of patients.

When all else fails: stepwise multiple solutions for a complex cancer pain syndrome.

In the presence of insufficient pain relief and substantial adverse effects, application of alternative routes of administration and a change of opioid are the main methods used to improve the analgesic response. When all else fails, the result may further be optimized using adjuvant drugs by an alternative route, namely the intrathecal route. A stepwise approach with multiple drugs and routes of administration is described. This was implemented to resolve a complex pain syndrome otherwise considered uncontrollable. We found it possible to manage a very difficult pain situation by intrathecal home infusion through the efforts of a well-trained family and GP and a continuous exchange of information and advice with the pain relief team about changes in therapy to adapt to the clinical situation. A stepwise and a meaningful approach to clinical problems with use of advanced techniques and alternative drugs in the patient's home may be helpful in the treatment of conditions otherwise considered intractable.

Morphine versus methadone in the pain treatment of advanced-cancer patients followed up at home.

PURPOSE: The aim of this study was to evaluate the analgesic and adverse effects and the doses of methadone in comparison to morphine. PATIENTS AND METHODS: A prospective randomized study was performed in a sample of 40 patients with advanced cancer who required strong opioids for their pain management. Patients were treated with sustained-release morphine or methadone in doses titrated against the effect administered two or three times daily according to clinical need. Opioid doses, adjuvant medications, symptoms associated with opioid therapy, pain intensity, and pain mechanisms were recorded. The opioid escalation indices in percentage (OEI%) and milligrams (OEImg) were calculated. The effective analgesic score (EAS) that monitors the analgesic consumption-pain ratio was also calculated at fixed weekly intervals. RESULTS: differences in pain intensity were found. Patients treated with methadone reported values of OEI significantly less than those observed in patients treated with morphine. Seven patients in the methadone group maintained the same initial dosage until death, whereas only one patient in the morphine group did not require opioid dose escalation. A more stable analgesia in time in patients treated with methadone was shown by the low number of gaps in EASs reported. Symptom frequencies and intensities were similar in the two groups. CONCLUSION: Methadone is a drug of indisputable value in the treatment of cancer pain, and an unbalanced focus on the risks of inappropriate use rather than the benefits should not compromise the use of a relevant alternative to morphine in the management of cancer pain.

Ondansetron in nausea and vomiting induced by spinal morphine.

Nausea and vomiting induced by opioids are relatively frequent in advanced cancer patients, although other factors may play a role. These effects, which tend to disappear after repeated dosing, can usually be controlled with antiemetic drugs, including metoclopramide, haloperidol, and phenothiazines. Occasionally, nausea and vomiting persist, in spite of the prolonged administration of the antiemetic treatment. We report a patient who had nausea and vomiting that was resistant to common antiemetic treatments, change in opioid drugs, and change in route of administration, and who had a complete and immediate response to parenteral or oral ondansetron.

Opioid-sparing effect of diclofenac in cancer pain.

This study investigated the opioid-sparing effect of diclofenac using patient-controlled analgesia with oral methadone. Fifteen patients with advanced cancer participated. After achieving adequate analgesia with regular dosing of oral methadone (T1), patient-controlled analgesia with methadone was administered for 3 days (T2). Intramuscular diclofenac 75 mg twice daily was then added to this regimen for 3 days (T3). Compared to T2 values, methadone dose was significantly reduced at T2 and T2, and pain report (recorded on a visual analogue scale) was significantly reduced at T3. A reduction in methadone plasma concentration was also observed at T2 and T3, although it did not attain statistical significance. Significant decreases in the intensity of several symptoms other than pain were also found at T2 and T3. Diclofenac appears to have a relevant opioid-sparing effect when using patient-controlled analgesia with oral methadone.

Treatment of pain in chronic bowel subobstruction with self-administration of methadone.

Chronic treatment with opioids in cancer patients with chronic intestinal obstruction is hazardous, as uncontrolled constipation may result in definitive bowel obstruction. Intermittent use of opioids adjusted for fluctuating pain levels may enable patients to take the lowest opioid doses that will have sufficient effect, with a consequently lower risk of intestinal side effects. Methadone has many pharmacokinetic characteristics that fit it for use in this clinical situation. In two patients with recurrent episodes of bowel obstruction, methadone used at low doses and at flexible intervals regulated by the patients according to their pain level avoided the occurrence of new episodes of intestinal obstruction. Oral patient-controlled analgesia with methadone may be a simple, safe and cheap method of treating patients with pain associated with subtotal intestinal obstruction.

Subcutaneous fentanyl infusion in a patient with bowel obstruction and renal failure.

Inoperable bowel obstruction in patients with renal failure is a difficult clinical situation. In the last days of life, an accumulation of morphine metabolites in patients with impaired renal function may cause opioid toxicity, including terminal agitation. The use of an alternative drug may prevent morphine metabolite accumulation in uremic patients. Fentanyl may be an alternative to morphine. It has a large apparent volume of distribution, a short plasma half-life, and extensive biotransformation without active metabolites. A patient with acute renal impairment and bowel obstruction was successfully treated with a subcutaneous continuous infusion of fentanyl (25 micrograms/hr) and boluses of 12.5 micrograms for the last 2 days of life, limiting the worsening of the dramatic clinical picture of bowel obstruction combined with renal impairment. No local toxicity was evidenced.

Patient-controlled analgesia with oral methadone in cancer pain: preliminary report.

BACKGROUND: Methadone is a very useful drug in cancer pain because of its low cost, lack of active metabolites, high oral availability, and the rapid onset of its analgesic effect. It seems to be well tolerated in patients with difficult pain syndromes who are receiving high doses of opioids, and it may deter the development of tolerance, but a high individual variation in terminal elimination half-life can result in different rates and extents of drug accumulation. For this reason, oral patient-controlled analgesia with methadone was used in 24 advanced-disease patients with pain. PATIENTS AND METHODS: A regimen of self-administered oral methadone at fixed doses and flexible patient-controlled dosage intervals to achieve adequate analgesia, while avoiding toxic effects of methadone accumulation, was used in 24 patients requiring opioid therapy. After a priming period of three days with fixed doses of 3-5 mg three times a day for naïve patients and 50% of the morphine equivalent of methadone in patients switched from morphine, patients and relatives were instructed to maintain the night-time dose and to administer a second dose when the pain recurred. When more than four doses of methadone a day were used, an increase of the dosage was prescribed. Continuous pain assessment and monitoring of symptoms were offered. RESULTS: The majority of patients achieved good pain relief until death, and three were switched to very low doses of subcutaneous morphine in their final days. The methadone escalation index was about 2% a day, with a mean dosage increase of 0.3 mg a day for an average of 60 days of treatment at doses ranging from 9 to 80 mg. The plasma concentration in 14 patients ranged from 0.013 to 0.273 mcg/ml with dosages of 20-80 mg during chronic treatment. A mean of 2.4 doses a day was reported, including the fixed night-time dose. The extent of side effects was considered acceptable. CONCLUSION: Patient-administered analgesia with oral methadone appears to be a simple, cheap and relatively safe technique for controlling cancer pain, permitting individualization by the patient him- or herself and avoiding the risk of accumulation. Continuous assessment is necessary.

Long-term ketamine subcutaneous continuous infusion in neuropathic cancer pain.

Neuropathic cancer pain may be less responsive to opioids than other pain. Several studies suggest that N-methyl-D-aspartate (NMDA)-receptor antagonists could play a role in the treatment of neuropathic pain. Ketamine is an NMDA-receptor antagonist that is used as an anesthetic and has been suggested as a useful drug for neuropathic pain. Subanesthetic doses of ketamine can yield analgesia without hypnosis. We describe a patient who developed neuropathic cancer pain unresponsive to opioid escalation and spinal administration of a combination of bupivacaine-morphine and was subsequently treated by subcutaneous continuous ketamine infusion. A starting dose of 150 mg/day provided good pain relief and a dramatic reduction of the oral morphine dose (from 5 g to 200 mg). A slow and progressive increase of ketamine and morphine dosage (400 mg and 200 mg by the subcutaneous route, respectively) continued to provide adequate pain relief after 13 months of therapy despite signs of progressive disease.