The aim of this study was to evaluate the clinical response to a combination of intrathecal morphine and levobupivacaine in advanced cancer patients who were highly opioid-tolerant, being previously treated with multiple opioid trials unsuccessfully. Initial intrathecal morphine dose was calculated from the previous opioid consumption using a morphine oral-intrathecal ratio of 100:1. Then, doses of both drugs were modified during the treatment according to the clinical needs and balanced with adverse effects. Fifty-five patients were assessed during admission, before starting the intrathecal treatment, during the titration phase, and followed up to death, by frequent phone contacts or visits, as available. Pain and symptom intensities were recorded before starting the intrathecal treatment (T0), at time of hospital discharge (T dis), and then at 1 month (T1), 3 months (T3), 6 months (T6) intervals, and the last observation, at least 1 week before death (T death). Fifty-five patients were selected for starting an intrathecal treatment. Thirty-two patients were males. The mean age was 60 years (95% CI 57-63), and 65.4% of patients were under 65 years. The most frequent indication was the presence of adverse effects and poor pain control. Complete data with adequate follow-up until death were available in 45 patients. Statistical differences in pain intensity were found at the different time intervals examined until death. Statistical decreases in the intensity of drowsiness and confusion were found until 1 month after starting intrathecal therapy. Statistical differences were found in daily intrathecal morphine doses, with a 3-fold increase at time of hospital discharge. Subsequently, further increases in doses were not significant. Conversely, systemic opioids, expressed as oral morphine equivalents, significantly decreased at all the intervals examined until death. Early complications included mild bleeding in 2 patients, without consequences, headache in 4 patients, bladder catheterization in 6 patients, reoperation for bleeding or changes of catheter position in 4 patients, unrelated death in 1 patient, and stroke in another 1. Late complications included local infection in 2 patients, and discontinuation of intrathecal therapy due to spinal compression. In patients who had received multiple trial of opioids and routes of administration, the intrathecal treatment started with an oral-intrathecal morphine conversion ratio of 100:1, and local anesthetics at the most convenient clinical doses provided a long-term improvement of analgesia, with a decrease in adverse effects and opioid consumption until death.