Freye, E., Levy, J.V., & Braun, D. (2007). Effervescent morphine results in faster relief of breakthrough pain in patients compared to immediate release morphine sulfate tablet. Pain Practice, 7, 324–331.

To compare effervescent morphine to immediate release (IR) during breakthrough pain

Dosage adjustments of fixed schedule opioid could be made at the discretion of the investigator. Patients documented onset time, efficacy, and side effects of IR morphine given for breakthrough pain for one month. They were to take it within five minutes of breakthrough pain and titrate until sufficient relief, starting at 20 mg (equivalent to one effervescent tab). For the second month, the patients took effervescent morphine. They were instructed to take it within five minutes (they could take an additional one after 10 minutes) up to a max of four tabs for a single breakthrough pain episode. Patients could take non-investigational drugs for control of adverse effects (e.g., nausea, constipation, sedation). This was a long-term study that lasted up to six months.

• N = 76
• MALES: 41, FEMALES: 35
• KEY DISEASE CHARACTERISTICS: Patients with cancer with chronic pain being treated for breakthrough pain
• OTHER KEY SAMPLE CHARACTERISTICS: 86% of breakthrough pain was related to tumor, 5.3% of patients had neuropathic pain. For primary pain treatment, multiple sustained-released (SR) opioids were used—fentanyl patch, 38.2%; morphine SR, 32.8%; transdermal buprenorphine, 11.8%; oxycodone SR, 14.4%; and hydromorphone, 5.3%.

• LOCATION: Germany and the United States

• Open-label safety and efficacy study

• Time until pain relief, global satisfaction, side effects, efficacy, and long-term safety of effervescent formulation
• An episode was treated sufficiently when adequate pain relief occurred, defined as a visual analog scale (VAS) score of 3 on a 0–10 scale.
• Patients completed questionnaires and kept daily diaries.
• Number of breakthrough pain episodes
• Pain relief using VAS
• Global satisfaction scale using a five-point Likert scale from 0 (poor) to 4 (excellent)

During the IR morphine month, the mean VAS score was 8 and decreased to 3. During the effervescent morphine month, the mean VAS score of 7.8 decreased to 3.2. No statistically significant difference was seen between IR morphine and effervescent morphine; however, the difference was significant (p < 0.001) when comparing pain intensity prior to taking effervescent morphine. The time to relief with effervescent morphine was 13 minutes and 27 minutes with IR morphine (statistically significant, p < 0.001). Effervescent morphine decreased the number of breakthrough pain episodes from a mean of 3.3 per day to 2 per day. This was statistically significant (p < 0.01).

• Dosage adjustments of fixed-schedule opioids could be made at the discretion of the investigator. No formal guidelines were used to make these adjustments.
• The definition of pain relief was VAS of 3. This may not be an adequate pain relief level for all patients.
• The non-investigational drugs given to treat adverse effects were not standardized or monitored.
• Only opioid-responsive patients were included in the study.
• Historical data was used for the IR morphine month and was compared to the effervescent morphine month. The study should have used a concurrent, double-blinded, randomized, cross-over design.

Although effervescent morphine had a faster onset, it does not compare with the onset of transmucosal fentanyl citrate (7–10 minutes).