BACKGROUND: The presence of pain during interventional pain management such as prolotherapy and intramuscular stimulation is stressful to patients and can affect the treatment outcome. We studied the safety and efficacy of two drug regimens: midazolam alone and midazolam/alfentanil for sedation anesthesia during prolotherapy and intramuscular stimulation. METHODS: Fifty three patients received either midazolam 0.04-0.08 mg/kg (Group M) or midazolam 0.01-0.02 mg/kg with alfentanil 4-8microgram/kg (Group A) for prolotherapy or intramuscular stimulation. We recorded the pain response, sedation score and side effects during the procedure, as well as amnesia, satisfaction and time to discharge after the procedure. RESULTS: Both drug regimens had significant sedation scores, amnesia and overall provided patient satisfaction. The treatment of pain was superior in Group A. Respiratory depression of three patients occurred in Group A. The time to discharge was longer in Group M. CONCLUSIONS: Midazolam and midazolam/alfentanil used for sedation anesthesia during prolotherapy and intramuscular stimulation were both effective; however, midazolam alone was the safer approach.