Alicino, I., Giglio, M., Manca, F., Bruno, F., & Puntillo, F. (2012). Intrathecal combination of ziconotide and morphine for refractory cancer pain: A rapidly acting and effective choice. Pain, 153, 245–249.

To assess the efficacy and safety of an intrathecal (IT) combination of ziconotide and morphine in malignant pain refractory to high doses of oral uploads

Visual anolog scale of pain intensity (VASPI) scores and Karnofsky Performance Status Scale (KPSS) scores were recorded for each patient at the initial visit. An IT catheter was place under fluoroscopy with aseptic technique, with a 1 g dose of cefazolin to prevent infection. Patients continued their long-term oral morphine until the IT infusion started and asked to start a short-acting morphine dose of 10 or 30 mg if needed. VASPI and KPSS scores, vital signs, electrocardiograms (ECGs), and adverse events were evaluated at day 2, day 7, and weekly up to day 28. The ziconotide infusion titration was started at 2.4 micrograms per day and increased by 1.3 micrograms per day at day 7 in patients with a VASPI score greater than 30 at rest. IT morphine dose was calculated based on their daily dose, an oral-IT ratio of 400:1. Increases in IT morphine were based on the oral morphine consumption. Doses were adjusted for adverse events and analgesic effect. The mean VASPI score, mean change in VASPI score, and mean percentage change from baseline to each visit and to the last observation was calculated.

• N = 20   
• AGE = 18 years or older
• MALES: 35%   
• FEMALES: 65%
• KEY DISEASE CHARACTERISTICS: Disseminated cancer with bone metastasis involving vertebral bodies
• OTHER KEY SAMPLE CHARACTERISTICS: Participants had to have pain related to malignancy, prevalently nociceptive pain, a VASPI score greater than 70 mm at rest, or an occurrence of adverse events. Patients were excluded if they showed signs of sepsis or inadequately treated infection; uncontrolled heart failure; second-degree heart block; third-degree heart block; or history of dementia, delirium, hysteria, or untreated affective disorder.
   

• SITE: Single site   
• SETTING TYPE: Inpatient setting   
• LOCATION: Pain Centre at Italy Bari Policlinico Hospital, Bari, Italy

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Late effects and survivorship; end-of-life and palliative care
   

• Prospective, observational study
  • Used repeated measures

• KPSS
• VASPI
• Vital signs: blood pressure, heart rate, respiratory rate, and temperature
• 12-lead ECG
• Adverse events: Coding Symbols for Thesaurus of Adverse Reaction Terms (5^th ed.)
   

Prior to the study, participants had persistent pain for a mean of six months SD = two months) and took a mean daily dose of 320 mg per day (SD = 80 mg) of systemic opioids. The mean VASPI score at rest was 90 mm (SD = 7 mm), with a mean incidental VASPI score of 99 mm (SD = 3 mm), and a mean KPSS of 59 (SD = 10. 4). Patients had severe opioid-related side effects that did not permit an increase in systemic opioids. IT therapy started with morphine 0.82 mg per day (SD = 0.36 mg) with ziconotide 2.4 mcg per day. On day 2, the mean VASPI score at rest decreased to 55 mm (SD = 12 mm), a significant reduction (p < .001). For five patients, an increase in morphine was necessary. On day 7, the mean VASPI at rest was 44 mm (SD = 11 mm), a significant decrease (p < .001). Four patients had an increase in ziconotide daily. On day 28, mean VASPI was 34 (SD = 13), a significant decrease (p < .001). Eighty percent of patients reached the effective dose for morphine and ziconotide within two weeks. Only five patients survived until the third month with good pain control. The maximum dose of ziconotide was 5.2 mcg per day, and the maximum dose of morphine was 2 mg per day. Four patients developing adverse effects attributed them to the study drugs. Changes in serum creatinine kinase levels and vital signs were not significant. No infections correlated with IT catheter placement.

IT therapy with ziconotide and morphine is a helpful strategy in controlling malignancy-related pain refractory to high dose of systemic uploads. Using both drugs appears to have a synergistic effect and may benefit patients with cancer. Lower doses of each drug may be utilized with few adverse events and side effects. However, this study has a few limitations that impair generalizability, may have a potential for bias, and may not have captured the risk to patients being treated longer than a few months.

• Small sample (less than 30)
• No control group or comparison (potential for bias)
• No randomization, no blinding
• Sample size was 20 (less generalizable).
• Only five patients survived to three months.
• Oservation was limited to one month.
• The sample was small and the length of observation was limited, so observable adverse events and complications may have not been observed.

Combination IT ziconotide and morphine in patients with cancer with nociceptive bone pain refractory to systemic opioids may be a helpful strategy for controlling pain. Low doses of ziconotide are required with the use of morphine, as compared to higher doses of ziconotide alone. In turn, less adverse events may be observed with potentially better pain control. When considering drug stability, alternative agents for pain in combination with ziconotide may be considered in place of morphine, as pump refills are required with lower-stability agents.