Marinangeli, F., Ciccozzi, A., Aloisio, L., Colangeli, A., Paladini, A., Bajocco, C., . . . Varrassi. G. (2007). Improved cancer pain treatment using combined fentanyl-TTS and tramadol. Pain Practice, 4, 307–312.

To facilitate dose escalation of strong opioids by using an opioid-tramadol combination

Of 70 patients, 35 were treated conventionally, with increasing transdermal fentanyl (group F). The other 35 patients received oral tramadol added to their fentanyl before each increment of their transdermal opioid (group T). Patients started fentanyl therapy by taking 25, 50, 75, or 100 mcg/hour, the amount based on equianalgesic dosing. Maximum tramadol dose was 400 mg/day. Rectal tramadol was not used.

• The sample was composed of 70 patients with intractable cancer pain whose visual analog pain score was greater than 3.
• All patients were receiving palliative care and not in the active treatment phase of disease.

The study was conducted in Italy.

Randomized open-label, prospectively evaluated study

Authors used a visual analog scale (VAS) to measure pain.

• In group F, 33 patients completed the study; in group T, 34 patients completed the study.
• Pain was equal in both groups; VAS scores did not differ. However, pain control in the tramadol group was achieved at slower escalation of fentanyl dose. The combination of a strong opioid with a weak opioid, to treat severe cancer pain, allowed a more gradual increase of analgesic delivery. Therefore, the combination minimized periods of overdosing and underdosing.
• Application time for patches was significantly higher in group T. In group T, no patient's fentanyl patch dose changed before the patient reached the maximum tramadol dose of 400 mg per day.
• Regarding adequacy of treatment, patients’, relatives’, and physicians’ judgments did not differ.

The combination of a strong opioid and a weak opioid, to treat severe cancer pain, allowed a more gradual increase of analgesic delivery. Therefore, the combination treatment minimized periods of overdosing and underdosing. Combination treatment as specified is a useful alternative, especially when disease and pain progress quickly.

Severe nausea and vomiting occurred in six patients in group T and three in group F, possibly due to a synergistic effect between fentanyl and tramadol. This study was insufficiently powered to show statistically significant differences relating to uncommon or serious side effects.

The greater number of fentanyl dose changes associated with higher fentanyl consumption in group F may support the hypothesis that tolerance is a pharmacologic effect, rather than a result of the rapid progression of disease. Additional study of the synergistic effect of tramadol and fentanyl, with respect to severe nausea and vomiting, is needed.