Agra, Y., Sacristan, A., Gonzalez, M., Ferrari, M., Portugues, A., & Calvo, M.J. (1998). Efficacy of senna versus lactulose in terminal cancer patients treated with opioids. Journal of Pain and Symptom Management, 15, 1–7.

To compare senna versus lactulose in relation to efficacy and adverse events in patients with terminal cancer.

Lactulose, an osmotic laxative, is a synthetic disaccharide. Senna acts mainly in the large intestine, directly stimulating the myenteric plexus and increasing water and electrolyte secretions, thus stimulating peristaltic activity. Their action extends over six to 12 hours. Side effects are abdominal pain, nausea, vomiting, and diarrhea.

Group A received senna BID starting at 0.4 ml (12 mg). Group B received lactulose BID starting at 15 ml. Based on clinical response, doses were increased in increments of 0.4 ml and 15 ml, respectively, every three days. Max doses were 1.6 ml (48 mg) for senna and 60 ml (40 g) for lactulose.

When patients reached the ceiling of their respective laxative and had three days without defecation, they were maintained on that dose and, in the absence of side effects, were started on an initial dose of another laxative, which could then be increased at three-day intervals until reaching the experimental maximum. Enema or mechanical bowel evacuation was prescribed after a three-day period without defecation (for ethical reasons), and was recorded as a failure with increase in laxative dose. If no results occurred from mechanical evacuation after six hours, patients were held on standby outside of the study until defecation. 

The randomization schedule was stratified for age and gender (limit of eight per stratum). The study period was seven days to assess laxative efficacy on defecation days and at variable opioid dosage, and 27 days to assess mean morphine dose at which a laxative was necessary. Both laxative and opioid treatments were initiated simultaneously. Prescribers were blinded (single doses of identical volume in closed opaque flasks).

• The study reported on a sample of 91 patients with terminal cancer; 43 patients were assigned to the senna arm and 48 patients were assigned to the lactulose arm. 
• Patients were aged older than 18 years and were in a palliative care program from July 1, 1993, to July 1, 1995.
• Mean patient age was 67.8 years (range 41–93). 
• All patients had clearly documented terminal disease with a life expectancy less than six months, and caregivers in the home.
• Thirty percent had lung cancer, 11% had breast cancer, and 9% had stomach cancer. 
• Patients were excluded if they had contraindications to the experimental laxatives, including colectomy, steatorrhea, or aphagia; a Karnofsky performance status lower than 10%; or taken opioids (codeine or morphine) or laxatives within 72 hours prior to initiation of the study.

The study took place at a palliative care unit (PCU) in Madrid, Spain. The PCU assists patients who are released from the local hospital and is responsible for home care follow-up protocols.

This was a comparative study with a randomized, open, parallel-group design.

• Outcome measures were defecation-free intervals of 72 hours, number of days with defecation events, and general state of health (rated on a five-point Likert-type scale).
• Defecation days as a function of opioid dose and treatment cost also were examined.
• Laxative efficacy was analyzed by t-test and ANOVA.

• Of 91 patients, 75 completed the study for at least seven days and were evaluated in the analysis.
• Sixteen patients abandoned the study within four days and were not included in the analysis. Reasons for leaving were diarrhea (n = 1), noncompliance (n = 4), dying within the first 24 hours (n = 4), permanent hospitalization (n = 5), and moving out of the jurisdiction of the home care area (n = 2).
• Opioid dose did not determine laxative efficacy.
• By the end of the study, 37.5% of patients required both laxatives.

No difference existed between senna and lactulose in efficacy as measured by defecation-free intervals, days with defecation, or adverse effects. Senna use is recommend based on its lower cost. The description of the study design was very precise and detailed.

• Patients could differentiate medications by taste and texture.
• Data were based on self-report, which is not considered reliable.
• The study was done in Spain, so results may not be transferable to a U.S. population.
• The sample size was fewer than 100 patients in the final analysis.
• Baseline effects of diet, age, tumor type, and mobility were not discussed in relation to the results.