Topical nifedipine with lidocaine ointment versus active control for pain after hemorrhoidectomy: results of a multicentre, prospective, randomized, double-blind study.

BACKGROUND: Spasm through the internal anal sphincter is one of the supposed causes for pain after hemorrhoidectomy, a common and distressing experience. We hypothesized that the addition of topical nifedipine to lidocaine would improve pain control by causing a relaxation of the smooth muscle of the internal anal sphincter. METHODS: We conducted a multicentre randomized, double-blind trial to compare the efficacy of 0.3% nifedipine and 1.5% lidocaine ointment versus 1.5% lidocaine ointment alone in reducing pain after hemorrhoidectomy. A physician unaware of the treatment arm measured pain by use of the Analogue Chromatic Continuous Scale (ACCS) at baseline; soon after surgery; at 2, 4, 6, 8 and 24 hours after surgery; on day 7 after surgery; and at a final visit 14 days after surgery. The physician also noted the time to first analgesic administration within 24 hours after surgery. RESULTS: In all, 135 patients per group participated (270 total). Evaluation of the delta ACCS score versus basal value, a covariate for rescue analgesic administration time, revealed better pain control in the group that received nifedipine with lidocaine at 6 hours after surgery and on day 7 (p < 0.011 and p < 0.054, respectively). We noticed no difference between groups for time of administration of rescue analgesic, blood pressure, heart rate or frequency of headache. CONCLUSION: Although there was no difference between groups for time of administration of rescue analgesic after open hemorrhoidectomy, the patients' assessment of pain using ACCS showed that the use of topical nifedipine with lidocaine may provide a slight significant difference in favour of the study group at 6 hours and at day 7 after surgery. Narcotic analgesics and nonsteroidal anti-inflammatory drug administration should continue to be recommended. Further research focusing on these outcomes is warranted.

Pharmacokinetics of anorectal nifedipine and lidocaine (lignocaine) ointment following haemorrhoidectomy: an open-label, single-dose, phase IV clinical study.

OBJECTIVES: This study aimed to assess whether topical anorectal application of an ointment containing nifedipine (0.3% w/w) and lidocaine (lignocaine) [1.5% w/w] to patients undergoing Milligan-Morgan haemorrhoidectomy achieves pharmacologically relevant serum concentrations of the active ingredients and has any haemodynamic effects or adverse effects. METHODS: A single dose of 3 g of study ointment was circumferentially applied inside the anus to 24 patients (17 males and 7 females) aged 23-71 years (mean +/- SD: 42.9 +/- 4.9 years) during postoperative dressing after Milligan-Morgan haemorrhoidectomy from March 2007 to January 2008. Blood samples for the determination of nifedipine and lidocaine serum concentrations were drawn before surgery and at 20, 40, 60, 90, 120, 240, 360, 480 and 720 minutes after application. Serum concentrations of nifedipine and lidocaine were determined by a high-performance liquid chromatography method in order to calculate pharmacokinetic parameters. Patients' BP, heart rate and ECG readings were monitored during the study. RESULTS: Chromatographic signals of nifedipine were sporadically observed in only five patients (20.8%), consistent with therapeutically negligible concentrations and insufficient to permit calculation of any pharmacokinetic parameters. The serum concentrations of nifedipine in these five patients ranged from 5.9 to 18.8 ng/mL. Lidocaine concentrations were detectable in all patients. The means +/- SD and medians of pharmacokinetic parameters for lidocaine were as follows: maximum serum concentration (C(max)) 245.1 +/- 370.8 ng/mL, 73.6 ng/mL; time to reach C(max) (t(max)) 69.2 +/- 78.3 minutes, 40 minutes; area under the serum concentration-time curve from 0 to 6 hours (AUC(6)) 756.5 +/- 1254.1 ng.h/mL, 238.2 ng.h/mL. Only three patients had maximum serum concentrations above 1000 ng/mL (1037.8, 1044.75 and 1364.1 ng/mL). These outlier concentrations were four to five times lower than the threshold of CNS lidocaine toxicity (5000-6000 ng/mL). No serious local or systemic adverse events were observed throughout the study, and no subjects developed arrhythmias or significant ECG changes. Neither BP nor mean heart rate varied significantly after application of a single dose. CONCLUSIONS: This study demonstrates that single-dose topical application of an ointment containing nifedipine (0.3% w/w) and lidocaine (1.5% w/w) to patients undergoing Milligan-Morgan haemorrhoidectomy is safe to use. Following application onto damaged anorectal mucosa, nifedipine and lidocaine are absorbed into the bloodstream in small quantities that do not have any major implications for the safety of the product. Further studies are required to evaluate nifedipine and lidocaine concentrations in serum using a multiple-dose regimen.

Serum levels and possible haemodynamic effects following anorectal application of an ointment containing nifedipine and lignocaine : a study in healthy volunteers.

OBJECTIVES: This study aimed to assess whether topical anorectal application of an ointment containing nifedipine (0.3% w/w) and lignocaine (lidocaine) [1.5% w/w] to healthy adult volunteers gives rise to pharmacologically relevant serum levels of the active ingredients and has any haemodynamic effects or side effects. METHODS: A dose of 3g of the ointment was circumferentially applied inside the anus to 12 healthy volunteers every 12 hours for 7 days. Blood samples were collected at 0, 30, 60, 240, 480 and 720 minutes after the first application; in addition, blood samples were collected at days 1 and 7 after multiple applications. Serum concentrations of nifedipine, its main metabolites and lignocaine were determined by a new high-performance liquid chromatography method established for the purpose of the study. Volunteers' blood pressure, heart rate, ECG status and laboratory parameters were monitored throughout the study. RESULTS: Topical application of the ointment to healthy volunteers did not produce therapeutically significant serum levels of the active ingredients and/or their active metabolites. Indeed, chromatographic signals of the active ingredients and/or nifedipine metabolites were only sporadically observed, below the quantification limits for the method, and consistent with therapeutically negligible concentrations. No serious local or systemic adverse events were observed throughout the study, and no subjects developed arrhythmias or significant ECG changes. Neither blood pressure nor mean heart rate varied significantly after application of a single dose. After multiple doses, mean systolic and diastolic blood pressure remained close to baseline levels for the duration of the study. The mean heart rate after multiple doses was about 5% below baseline level at days 1 and 7; however, these differences were not statistically significant. CONCLUSION: This study demonstrates the safety of topical anorectal application of an ointment containing nifedipine (0.3% w/w) and lignocaine (1.5% w/w) to healthy volunteers.

Topical nifedipine with lidocaine ointment vs. active control for treatment of chronic anal fissure: results of a prospective, randomized, double-blind study.

PURPOSE: Chronic anal fissure may be treated by chemical or surgical sphincterotomy. The aim of this study was to test the efficacy of local application of nifedipine and lidocaine ointment in healing chronic anal fissure. METHODS: The study was performed according to a prospective, randomized, double-blind design. One hundred ten patients who gave informed consent were recruited. They received a clinical examination, a questionnaire to evaluate symptoms and pain, anorectal manometry, and anoscopy. Healing of anal fissure at Day 42 of therapy was defined as the primary efficacy variable of the study. Patients treated with nifedipine (n = 55) used topical 0.3 percent nifedipine and 1.5 percent lidocaine ointment every 12 hours for 6 weeks. The control group (n = 55) received topical 1.5 percent lidocaine and 1 percent hydrocortisone acetate ointment during therapy. Anal pressures were measured by recording resting and maximal voluntary contraction pressures at baseline and at Day 21. Long-term outcomes were determined after a median follow-up of 18 months. RESULTS: Healing of chronic anal fissure was achieved after 6 weeks of therapy in 94.5 percent of the nifedipine-treated patients (P < 0.001) as opposed to 16.4 percent of the controls. Mean anal resting pressure decreased from a mean value +/- standard deviation of 47.2 +/- 14.6 to 42 +/- 12.4 mmHg in the nifedipine group. This represents a mean reduction of 11 percent (P = 0.002). Changes of maximal voluntary contraction in nifedipine-treated patients were not significant. No changes in mean anal resting pressure and maximal voluntary contraction were observed in the control group. We did not observe any systemic side effect in patients treated with nifedipine. After the blinding was removed, recurrence of the fissure was observed in 3 of 52 patients in the nifedipine group within 1 year of treatment, and 2 of these patients healed with an additional course of topical nifedipine and lidocaine ointment. CONCLUSIONS: Our study clearly demonstrates that the therapeutic use of topical nifedipine and lidocaine ointment should be extended to the conservative treatment of chronic anal fissure.

Analysis of factors influencing the diagnostic failure of intraoperative fine needle aspiration cytology in pancreatic cancer.

Intraoperative fine-needle aspiration cytology (IFNAC) of pancreatic lesions provides a safe method of rapid tissue diagnosis. Few studies have included a thorough statistical analysis of the factors influencing the diagnostic failure of IFNAC. IFNAC was performed on 196 patients during surgical procedures for pancreatic and periampullary masses over an 18-year period. The sensitivity was 90.6% and the specificity 100%. There was a 0% puncture-related complication rate. In all, 6 clinicopathological factors were analyzed to elucidate correlations, if any, with IFNAC failure using statistical analysis. Statistical analysis of each of these clinicopathological factor showed that the cases of failure tended to be related to small tumour size (P < 0.0001), well-differentiated grading (P < 0.002) and a nuclear size similar to the surrounding RBCs (P < 0.0001). Age, gender, moderately or poorly differentiated tumours, and multiple punctures proved to be of no statistical significance in our analysis. We suggest that diagnostic failure of IFNAC seems to be caused mainly by a structural factor such as tumour size and an intrinsic one (a cellular low atypism factor such as well-differentiated grading and small nuclear size). However, we would caution that negative IFNAC cannot be relied on to definitively exclude a diagnosis of carcinoma and, in many instances, the justification for pancreatic resection cannot always be based on cytologic findings, but rather on clinical and laparotomy findings.