Patients with pain VAS ≥ 7 experienced better pain relief with the mixture as compared to patients with baseline pain VAS score < 7, no matter the pain origin nor the subjacent cause of pain. Further studies with a greater sample size and specific visceral pain conditions could clarify better use of the mixtures of NSAIDs and spasmolitics in specific visceral pain conditions.

Visceral pain related to smooth muscle spasm is one of the most common symptoms observed in many gastrointestinal (GI) and genitourinary (GU) disorders. Though the cause of visceral pain is not fully known, the symptomatic treatment of abdominal cramping pain and biliary and renal colic may include the use of spasmolytic agents or NSAIDs. Spasmolytic agents are used due to their smooth muscle relaxing effect and NSAIDs due to their known clinical effectiveness in biliary and renal colic conditions. Mixtures of NSAIDs and spasmolytic agents such as dypirone, lysine clonixinate or ibuprofen plus hyoscine butylbromide are used in some countries for the symptomatic treatment of abdominal pain associated with cramping. The theoretical rational basis for using these mixtures in several visceral pain conditions arise from the participation of a spastic process of smooth muscle in the affected viscera, plus the potential participation of prostaglandins through visceral pain hypersensitivity.

Rationale behind research

• The evidence of superior effectiveness of combination of spasmolytic and NSAIDs over individual drugs is scarce and controversial
• Therefore, this double-blind, randomized, clinical trial was conducted to assess the efficacy of combination over individual drugs

Objective

To characterize the analgesic effect and safety of ketorolac and hyoscine butylbromide against hyoscine butylbromide alone in patients with ambulatory acute cramping pain of gastrointestinal and genitourinary origin.

Study outcomes

• Pain level in patients was evaluated after first administration of drugs. Pain measurements were done using visual analog scale (VAS) on a 10-cm horizontal line paper sheet that had words ‘‘no pain’’ and ‘‘worst imaginable pain’’ at its left and right ends, respectively. VAS pain intensity was arbitrarily set at the middle of the pain level interval of 4–10, in < 7 or ≥ 7.
• Adverse events reported by patients were also recorded

Time points

• Efficacy: Baseline, 0.5, 1, 2, 4, 6, 24 and 48h after administration of drugs

Baseline: Treatment groups were well balanced with no significant baseline differences. 

Outcomes

• Both treatments produced significant reductions of VAS pain values in a gradual and similar manner from the first 30 min until 6th h. Pain values were decreased more at 24 h, and practically were 0 at 48 h. There were no significant differences between treatments at any time nor in the number of patients with a complete pain relief at 6, 24, and 48 h (43, 67 and 74 vs. 35, 59 and 71, for combination and monotherapy, respectively).

• Both groups of patients with a VAS pain intensity ≥ 7 showed gradual reductions of VAS pain values during the 48 h of treatment, the combination showed a better pain relief profile, with significant differences at the 1, 2, 4, 6, 24 and 48 h, in comparison with hyoscine butylbromide alone. Concordantly, the AUC (area under curve) pain score-time of ≥ 7 ketorolac/hyoscine butylbromide treatment was significantly lesser than corresponding value observed in ≥ 7 hyoscine nts with hyoscine butylbromide treatment. butylbromide group (26.3 ± 3.25 cm/h vs. 41.9 ± 3.67 cm/h, respectively) and also a greater significant number of patients of double therapy achieved a complete relief of pain in comparison with monotherapy at 6 and 24 h (23 and 36 vs. 12 and 25 patients, respectively). Overall, the patients with intense pain (≥7) and double therapy had 62.7 % less pain than patients

• There were no significant differences in AUC pain level time in both groups with GI pain (28.6 ± 3.9 cm/h vs. 33.5 ± 5.0 cm/h) or GU pain (28.7 ± 4.6 cm/h vs. 32.0 ± 5.1 cm/h) groups. Number of patients with a complete pain relief at 6, 24, and 48 h neither were different between GI ketorolac/hyoscine butylbromide (33, 50, 54) vs. GI hyoscine butylbromide (26, 45, 53) or GU ketorolac/hyoscine butylbromide (10, 17, 20) vs. GU hyoscine butylbromide (9, 14, 18) groups.

• There were significant differences in AUC pain level – time in GI ≥ 7 ketorolac/hyoscine butylbromide vs. GI ≥ 7 hyoscine butylbromide (24.6 ± 3.71 cm/h vs. 46.1 ± 7.68 cm/h), but not in GU ≥ 7 ketorolac/hyoscine butylbromide vs. GU ≥ 7 hyoscine butylbromide (29.3 ± 6.21 cm/h vs. 32.1 ± 5.26 cm/h). In AUC values, patients with intense pain (≥ 7) from GI origin and double therapy reported 53.4 % less pain than patients with intense pain (≥ 7) from GI origin treated only with hyoscine butylbromide.

Overall, in patients with a pain VAS ≥ 7, better pain relief was observed with the mixture, in comparison with those patients whose baseline pain VAS score was < 7, no matter the pain origin nor the subjacent cause of pain. This could be an important finding, since further studies with a greater sample size and specific visceral pain conditions could clarify therapeutic potential of NSAIDs in other indications of visceral pain such as colitis and irritable bowel syndrome, according with the intensity of pain, and better use of mixtures of NSAIDs and spasmolitics in specific visceral pain conditions.