Recent experimental data suggest a possible use of an opioid combination to improve analgesia. In cancer patients, a rapid opioid escalation due to either worsening of the pain condition or the development of tolerance is a critical phase, as this condition is associated with a negative prognosis. The aim of this study was to assess the effects of adding a second opioid at low doses in patients with a poor analgesic benefit after dose escalation. Fourteen patients receiving strong opioids who had increased their dosage more than 100% in the last week unsuccessfully were randomly chosen to add a second opioid to the first using an initial equivalent dosage of 20% of the previous therapy. The dose of the second opioid was then changed according to the clinical situation to obtain an acceptable pain control with minimal adverse effects. Pain and symptoms associated with opioid therapy were assessed, and an opioid escalation index (OEI) was calculated at weekly intervals. OEI significantly decreased after adding the second opioid, and this trend was also maintained for the following weeks. Similarly, pain intensity was significantly improved and maintained at acceptable levels for the following weeks. The second opioid did not induce significant opioid-related adverse effects. The opioid combination was able to break opioid escalation in patients with pain syndromes with a poor response to the previous opioid. It allowed for a regaining of analgesia, regardless of the opioid combination used. These preliminary observations should be confirmed in further studies.