A single oral dose of Silodosin and Diclofenac sodium is effective in reducing pain after ureteric stent removal: a prospective, randomized, double blind placebo-controlled study

Ureteral stents are associated with significant pain and discomfort (Joshi et al.
2002], 2003]; Pollard and Macfarlane 1988]). Joshi et al. reported that 80 % of patients experienced stent-related pain (Joshi
et al. 2003]). Numerous studies have been done to reduce stent-related pain and discomfort using
drugs like alpha blockers, anticholinergics, phosphodiesterase inhibitors etc., new
stent designs, stent materials and stent dimensions (Dellis et al. 2010]; Gupta et al. 2010]; Beddingfield et al. 2009]; Rane et al. 2001]; Deliveliotis et al. 2006]; Damiano et al. 2008]). Most of the available literature focuses on the stent-related morbidity when stent
was in situ. But to any urologist, it is not unusual to have patients complaining
of renal colic like pain after stent removal which often require additional analgesics
and admission due to the severity of pain. Pain during stent removal probably occurs
due to activation of nociceptors, the friction between stent and mucosa leading to
ureteral smooth muscle irritability, trigonal irritation as well as pressure-induced
changes in pelvi-calyceal system. However, this phenomenon of pain after stent removal
has remained neglected and unreported. Tadros et al. (2012]) first studied the efficacy of Rofecoxib in relieving pain after stent removal in
a placebo-controlled randomized study and found that a significant number of patients
complained of severe pain after stent removal in the placebo group and none in the
NSAID group (8). NSAIDs are considered the gold standard drugs for renal colic (Davies
and Anderson 1997]; Tankó and Tamás 1995]–1996; Hurault and Ryckelynck 1989]). Numerous animal studies as well human studies have shown that NSAIDs cause significant
decrease in ureteral contractility as well as decrease in renal blood flow (Chaignat
et al. 2008]; Perlmutter et al. 1993]). Chaignat et al. (2008]) have also demonstrated the presence of COX-1 and COX-2 receptors in human ureters.
Nakada et al. (2000]) reported that selective COX inhibitors and non-selective COX inhibitor led to significant
reduction in ureteral contractility in both porcine and human ureteral tissues. Also,
alpha blockers have been found to be effective in relieving stent-related pain (Deliveliotis
et al. 2006]; Damiano et al. 2008]). Alpha 1 receptors have been found to be widely distributed in human ureter and
bladder (Michel and Vrydag 2006]; Itoh et al. 2007]). Decrease in ureteral contractions as well as trigonal irritation are the likely
mechanisms for the relief of stent-related pain with alpha blockers. Beddingfield
et al. (2009]) also reported a significant reduction in stent-related pain as well as reduction
in narcotic dose with the use of Alfuzosin.

In our study, oral Diclofenac, which has a rapid onset of action and long t½ in inflamed
tissues (Davies and Anderson 1997]; Tankó and Tamás 1995]–1996; Hurault and Ryckelynck 1989]), significantly reduced pain after stent removal as compared to placebo (p ? 0.001).
There was also less incidence of severe pain and additional analgesics requirement
when compared to placebo but it was not statistically significant (p = 0.35, 0.56).
Thus, the pain relief observed with Diclofenac was probably due to its inhibitory
actions on ureteral contractility and renal blood flow as well as its analgesic and
anti-inflammatory properties. However, the inflammation and edema may takes days to
subside. So, this action probably plays a less significant role in the described setting.

In our study, there was significant reduction in pain in the Silodosin group as compared
to placebo (p ? 0.001). Patients had less severe pain in Silodosin group as compared
to placebo group but it was not statistically significant (p = 0.9). The mechanism
of pain relief described in previous studies probably explains the pain relief seen
with Silodosin in our study. The ureteral dilatory effect as well the decrease in
ureteral and detrusor contractility by Silodosin are the likely mechanisms responsible
for the pain reduction observed with Silodosin. There was also less incidence of suprapubic
pain in Silodosin group but the results were not statistically significant (p = 0.15).
This is probably related to Silodosin’s similar effect on lower urinary tract symptoms
(LUTS) in BPH patients.

There was no difference in pain relief between both Silodosin and Diclofenac groups
(p = 0.48). There was higher pain reduction seen with combination of Diclofenac and
Silodosin but it did not attain statistical significance (p = 0.9, 0.40). Possible
explanation is that there is probably certain overlap of different mechanisms of pain
reduction involved between both the drugs. however The incidence of severe pain (VAS  5)
was also least in the combination group (3.4 %) when compared to all the other groups,
but contrary to previous study, it was not statistically significant (p = 0.10). Tadros
et al. demonstrated significant reduction in analgesic requirement with NSAIDs. However,
the additional analgesics requirement in our study was least in combination arm but
it was not statistically significant (p = 0.70). However we did not keep any objective
criteria for use of additional analgesia and analgesics are used on demand basis.
So it is likely that these factors might have influenced on our result.

Use of both Diclofenac and Silodosin and their combination did not result in any significant
side effects in our study. Like other non-steroidal anti-inflammatory drugs, gastrointestinal
side effects are the most commonly reported adverse effects of Diclofenac and seen
in about 10 % of patients. These side effects have been found to be dose related (Lehtola
and Sipponen 1977]). These side effects with Diclofenac dose of 75–125 mg have been much lower than
with aspirin 3–5 g (Brogden et al. 1980]). Silodosin is comparatively a much safer drug with excellent side effect profile
due to its unmatched uro-selectivity (Van Dijk et al. 2006]). Silodosin has been reported to be frequently associated with abnormal ejaculation
however, its clinical relevance remains unclear, as subjects rarely discontinue treatment
due to this side effect (Marks et al. 2009]). Moreover, with the single dosing of both the drugs, these side effects are unlikely
to be of clinical significance, which is supported by our study results.

Thus our study supports the use of Diclofenac and Silodosin in reducing the pain after
stent removal. However, ours is a preliminary study and further research is required
in this field to better understand the phenomenon of pain after stent removal and
the mechanisms of pain reduction involved.

However, there are certain shortcomings to our study. We took the pain score only
after 24 h. If we could have taken more frequent pain scores before and even after
24 h, we could have better demonstrated and understood the pain dynamics involved.
Moreover, with studies with a larger sample size more clear conclusions could have
been derived.