AIM: To objectively evaluate the effect of TJ-68 on colonic spasms during colonoscopy.

METHODS: One hundred and one patients subjected to screening colonoscopy were randomly assigned to two groups: TJ-68 in 51 subjects and saline as the control in 50. The endoscope was inserted into the sigmoid colon, then a spastic region was identified and the tip of the colonoscope was positioned at a distance of about 10 mm from the spastic region. The endoscopic view was recorded before and after direct spraying of the TJ-68 solution or warm saline. The intraluminal area of the spastic region was serially measured using a computer image analyzer and expressed as pixel counts. The area under the curve (AUC) was calculated from the pixel curve. Statistical significance was assessed by Wilcoxon’s test and Mann-Whitney U test.

RESULTS: The mean AUC of the spastic region before and after TJ-68 spraying was 29 128 and 121 943 pixels, respectively, while with saline, it was 31 635 pixels and 48 617 pixels, respectively. Thus, the AUC significantly increased after TJ-68 spraying compared with the spraying of saline (P<0.001).

CONCLUSION: Direct spraying of TJ-68 on the colonic mucosa suppressed colonic spasm and it may be useful during colonoscopy when anticholinergic agents are contraindicated.

In colonoscopy, it is often difficult to insert the endoscope and observation tends to be hampered because of colonic spasms. In patients with colonic spasm sometimes excess air is used to get a good view of the colonic mucosa causing discomfort and pain in the patient, and resulting in an unsuccessful colonoscopy.

Hyoscine n-butyl bromide (Hyoscine) is usually and widely used as an antispasmodic agent in colonoscopy and it is administered by intramuscular or intravenous injection. However, systemic use of Hyoscine sometimes causes many adverse reactions; namely palpitation, dry mouth, urinary retention, orthostatic hypotension, anaphylactic reactions, and temporary visual impairment. Hyoscine, in addition, often causes serious complications in patients with heart disease and it is contraindicated in such cases. For this reason, a safer means to obtain the necessary antispasmodic effect is required for colonoscopy. In this regard, peppermint oil and warm water have been investigated by directly spraying them onto the colonic wall, however, there are some limitations for their clinical use[1,2].

Shakuyaku-kanzo-to (TJ-68), a Chinese herbal medicine, is traditionally used in China and Japan, to treat patients with convulsions, spasms, a pain in the limb, etc. Recently, the analgesic and sedative effects of TJ-68 as a premedication have been reported in endoscopy[3]. Although the antispasmodic effects of TJ-68 during barium enema examination was studied, the usefulness of TJ-68 as an antispasmodic agent in colonoscopy has not been examined[4].

The aim of this study was to objectively evaluate the antispasmodic effect of TJ-68 by direct intraluminal spraying of TJ-68 solution during colonoscopy.

Representative endoscopic photographs of the spastic area in the sigmoid colon taken from one patient in each group before and after spraying of TJ-68 solution and normal saline are shown in Figures 3 and 4.

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Figure 3 Endoscopic view in the TJ-68 group. Serial endoscopic views of the spastic region at the sigmoid colon before and after spraying of the TJ-68 solution are shown (A-F). The white broken line demarcates the area of the spastic region. The spastic region started to relax 0.5 min after spraying of the TJ-68 solution and remained open for 3 min.

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Figure 4 Endoscopic view in the normal saline group. Serial endoscopic views of the spastic region at the sigmoid colon before and after spraying of normal saline are shown (A-F). The white broken line demarcates the area of the spastic region. The region showed only little relaxation and did not open significantly during the study.

Antispasmodic effects of the TJ-68 solution

The mean changes of intraluminal spastic area before and after spraying of the agents are shown in Figure 5. In the TJ-68 group, the intraluminal area varied from 8 954 to 13 181 pixels at each point during 3 min before spraying, showing no difference, but after spraying, an obvious increase was observed. The intraluminal area rapidly increased 1 min after spraying and the mean area 3 min after it was 56 063 pixels. The mean AUC before and after TJ-68 spraying was 29 127 and 121 942 pixels/min, respectively, showing significant difference (P<0.001).

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Figure 5 Pixel curve and area under the curve (AUC) before and after the administration of the TJ-68 solution and normal saline. The graph shows the mean AUC of the two groups before and after spraying of TJ-68 (*) and normal saline (**): the mean AUC in the TJ-68 group increased significantly from 29 127 to 121 942 pixels, but the control group did not show a significant increase.

The mean intraluminal spastic area in the control group varied from 10 696 to 15 246 pixels at each point during 3 min before spraying, showing no difference. Spraying of saline did not significantly affect the mean intraluminal spastic area, and there was no significant increase of the mean AUC after spraying: 31 635 and 48 617 pixels/min, respectively. Thus, the AUC significantly increased after TJ-68 spraying compared with the spraying of saline (P<0.001, Table 2).

	Mean AUC (pixels×min)
	Before	After
TJ-68	29 1271	121 942b,d
Control	31 635	4 86172

¹NS vs control (Mann–Whitney U test), ^bP<0.001 vs before (Wilcoxon’s test), ^dP<0.001 vs control after (Mann–Whitney U test), ²NS vs before (Wilcoxon’s test).

No complication was encountered in this study.

The TJ-68 solution caused the relaxation of the spastic colonic region as early as 0.5 min after spraying, and the relaxation was maintained for 3 min, or more. This phenomenon was sought to be as the local effects of the TJ-68 on the colonic wall. While in the control, the spastic area did not increase significantly after spraying of saline. Judging from the increase in the number of pixels in the control, this increase seemed to be simply attributable to a volume load. While the increase in the TJ-68 group was attributable to the active relaxing effect of TJ-68, and relaxation of the spastic area was observed within 0.5 min after spraying. We think there is a close correlation between the intraluminal movement of a spastic region and the intraluminal pressure. Actually, Asao et al. reported that the changes of the endoscopic findings by the intraluminal administration of the peppermint oil solution is correlated well with the intraluminal pressure measured by the Barostat[1]. Based on this phenomenon, we assume that TJ-68 will permeate and be absorbed through the colonic wall, and directly act on the myenteric plexus.

Since TJ-68 solution has a light brown color, blinding of the study is thought to be difficult in the strict sense. But selection of the patients or assignment of the agents to each group was performed in a strictly blind fashion. Furthermore, as relaxation of spasms was evaluated objectively, we believe that discernment of the agent after spraying had only a little influence on the outcome.

TJ-68 is an extract powder composed of Shakuyaku (Paeoniae radix) and Kanzo (Glycyrrhizae radix) combined at a ratio (g) of 1:1. TJ-68 inhibits acetylcholine-induced contraction and the contractile machinery of the smooth muscle by Kanzo and that of neurogenic contraction by Shakuyaku in guinea pig ileum[5,6]. Furthermore, the two components of TJ-68 exert synergistic effects[5].

Peppermint oil and warm water were examined in a way, analogous to our study, for their relaxing effect on the colonic wall after direct spraying[1,2]. Peppermint oil was reported to have a direct relaxing effect on the colonic smooth muscle when used in endoscopy or barium enema examination[1,7,8]. We also studied the antispasmodic effect of peppermint oil on the colonic wall using our method of evaluation and compared it to that of TJ-68. As a result, TJ-68 was found to have an antispasmodic effect similar or stronger than that of peppermint oil (data not shown). Peppermint oil is not sold via a regular medical distribution system. Furthermore, it is sometimes difficult to get and prepare the peppermint oil solution[1]. On the other hand, TJ-68 is available in any medical facility in Japan, because it is a regular medical prescription sold via a regular medical distribution system. In addition, the preparation of TJ-68 solution is easy and simple: only mixing TJ-68 with saline.

Church reported that warm water irrigation significantly reduced discomfort related to colonoscopy, but there was no difference regarding insertion time, total duration of colonoscopy, dose of midazolam administered, or frequency of severe spasm. Decrease of the patient’s discomfort was the parameter of effectiveness of warm water in their study. But their study had some limitations because they used a sedation drug (midazolam) as premedication[2]. Moreover, warm water has basically no direct antispasmodic effect on the colonic wall.

Colonic relaxation by antispasmodic drugs has been evaluated using various parameters: pain score, colonic spasm score, difficulty of the procedure scored by an endoscopist, and dose of drugs used for sedation[1,2,9-14]. However, these parameters were considered to be subjective, moreover, most studies were performed under sedation[2,9-14]. In the present study, we evaluated colonic relaxation quantitatively. In addition, we did not use any drugs to induce sedation. But the clinical relevance of TJ-68 in colonoscopy should be investigated in subsequent studies, although our preliminary study showed significant differences between the TJ-68 group and the control group in total colonoscopy time and patient’s pain score (data not shown).

Contrary to the ordinary use of antispasmodic age-nts, we sprayed TJ-68 directly on the colonic wall. Antispasmodic agents are generally administered intra-muscularly or intravenously, but systemic administration sometimes prevents the insertion of the endoscope because the muscle tone of the colon is excessively reduced[13]. Colonoscopy is difficult to carry out at the spastic region but not every spasm affects the examination. Ideally, the examiner expects to obtain effective relaxation in only some of them. In this respect, direct spraying of the antispasmodic agent TJ-68 is one of the meaningful ways of administration. But administration of this agent by spraying differed from the common oral administration. Since this was the first attempt to spray this agent directly onto the colonic wall, we had essentially no idea about the adverse effects. But the total amount of TJ-68 used in this study was no more than 2.5 g, that is to say one third of the oral dose: 7.5 g. In fact, no complication was experienced in this study.

In this study, we set the concentration of the TJ-68 solution at 10^-2 mg/dL. Significant relaxation of the guinea pig distal colon was obtained with this concentration of TJ-68 in our preliminary experimental study; thus this concentration was thought to be effective enough to depress colonic spasm during colonoscopy.

In conclusion, we objectively demonstrated that intraluminal direct spraying of TJ-68 solution on the colonic mucosa could lower the colonic spasm. Additional studies are needed to determine the time required for colonoscopy or to assess patient’s compliance before TJ-68 can be definitively recommended as a useful antispasmodic agent for use in colonoscopy.