Novel topical formulation of lidocaine provides significant pain relief for intrauterine device insertion: pharmacokinetic evaluation and randomized placebo-controlled trial.

OBJECTIVE: To investigate the pharmacokinetics, safety, and analgesic efficacy of a novel topical formulation of lidocaine at insertion of an intrauterine device (IUD). DESIGN: Randomized controlled trial; phase-I and phase-II studies. SETTING: University and public hospitals. PATIENT(S): Women aged ≥18 years who wanted to receive an IUD. Four women were parous in phase I; all in phase II were nulliparous. INTERVENTION(S): A single, 8.5-mL dose of lidocaine formulation (SHACT) was administered (to the portio, cervix, and uterus) with a specially designed applicator. MAIN OUTCOME MEASURE(S): The phase-I study (single-arm) was designed for pharmacokinetic assessment; the phase-II study (randomized) was intended for investigation of efficacy and safety. RESULT(S): From the phase-I study (15 participants), mean pharmacokinetic values were: maximum plasma concentration: 351 ± 205 ng/mL; time taken to reach maximum concentration: 68 ± 41 minutes; and area under the concentration-time curve from 0 to 180 minutes: 717 ± 421 ng*h/mL. Pain relief was observed with lidocaine vs. placebo in the phase-II study (218 women, randomized). Mean visual analog scale score for maximum pain during the first 10 minutes after IUD insertion was 36% lower with lidocaine than with placebo (28.3 ± 24.6 vs. 44.2 ± 26.0). Pain intensity was also significantly lower in the lidocaine group at 30 minutes. On average, 3 of 4 patients will have less pain with lidocaine than with placebo. Adverse events were similar in the placebo and lidocaine groups. No serious adverse events were reported. CONCLUSION(S): Lidocaine provides pain relief lasting for 30-60 minutes for women undergoing IUD insertion, without any safety concerns. Further studies of this lidocaine formulation, for IUD insertion and other clinical applications, are planned. CLINICAL TRIAL REGISTRATION NUMBER: 2011-005660-18 and 2011-006220-20 (EudraCT).

Changes in uterine innervation in pregnancy and during labour.

PURPOSE OF REVIEW: The present review highlights recent findings focusing on effects on the cervical innervation exerted by term pregnancy and labour. RECENT FINDINGS: The corpus uteri is almost denervated in term pregnancy, as demonstrated in both humans and rodents, whereas the cervical innervation remains dense throughout pregnancy and labour. In rats, fewer connections between sensory subdivisions in spinal cord segments and the cervix have been observed in late pregnancy as compared with the nonpregnant state. In term pregnancy an increased excitability of mechanosensitive afferents innervating the cervix has been demonstrated. The reasons for these seemingly contradictory findings may be clarified in further studies. Transient receptor potential vanilloid receptor, a key molecule in nociception, has been identified in the human cervix uteri in the nonpregnant state and during pregnancy and labour as opposed to the corpus, in which transient receptor potential vanilloid receptor disappears during pregnancy. These findings add evidence to the hypothesis that the uterine cervix is the main site from where labour pain propagates. SUMMARY: The conservation of the cervical innervation in term pregnancy and labour, in contrast to the corpus, and the large number of mediators involved in cervical ripening clearly indicate that the cervix plays a crucial role in pregnancy maintenance, labour initiation, labour pain and parturition.

Influence of pregnancy and labor on the occurrence of nerve fibers expressing the capsaicin receptor TRPV1 in human corpus and cervix uteri.

BACKGROUND: Cervical ripening is a prerequisite for a normal obstetrical outcome. This process, including labor, is a painful event that shares features with inflammatory reactions where peripheral nociceptive pathways are involved. The capsaicin and heat receptor TRPV1 is a key molecule in sensory nerves involved in peripheral nociception, but little is known regarding its role in the pregnant uterus. Therefore, the aim of this study was to investigate human corpus and cervix uteri during pregnancy and labor and non-pregnant controls for the presence of TRPV1. METHODS: We have investigated human uterine corpus and cervix biopsies at term pregnancy and parturition. Biopsies were taken from the upper edge of the hysterotomy during caesarean section at term (n = 8), in labor (n = 8) and from the corresponding area in the non-pregnant uterus after hysterectomy (n = 8). Cervical biopsies were obtained transvaginally from the anterior cervical lip. Serial frozen sections were examined immunohistochemically using specific antibodies to TRPV1 and nerve markers (neurofilaments/peripherin). RESULTS: In cervix uteri, TRPV1-immunoreactive fibers were scattered throughout the stroma and around blood vessels, and appeared more frequent in the sub-epithelium. Counts of TRPV1-immunoreactive nerve fibers were not significantly different between the three groups. In contrast, few TRPV1-immunoreactive fibers were found in nerve fascicles in the non-pregnant corpus, and none in the pregnant corpus. CONCLUSION: In this study, TRPV1 innervation in human uterus during pregnancy and labor is shown for the first time. During pregnancy and labor there was an almost complete disappearance of TRPV1 positive nerve fibers in the corpus. However, cervical innervation remained throughout pregnancy and labor. The difference in TRPV1 innervation between the corpus and the cervix is thus very marked. Our data suggest that TRPV1 may be involved in pain mechanisms associated with cervical ripening and labor. Furthermore, these data support the concept that cervix uteri may be the major site from which labor pain emanates. Our findings also support the possibility of developing alternative approaches to treat labor pain.

Presence of sensory nerve corpuscles in the human corpus and cervix uteri during pregnancy and labor as revealed by immunohistochemistry.

BACKGROUND: The uterus is exposed to changes such as enlargement and distension during pregnancy and labor. In these processes and in the process of cervical ripening, proprioceptive information is likely to be of great importance. Therefore, we wanted to study the possible existence of sensory nerve corpuscles in uterine corpus and cervix during pregnancy and labor. Studies on this aspect have not previously been perfomed. METHODS: Biopsies were taken from the upper edge of the hysterotomy during caesarean section at term (n = 8), in labor (n = 5) and from the corresponding area in the non-pregnant uterus after hysterectomy (n = 7). Cervical biopsies were obtained transvaginally from the anterior cervical lip. Serial cryostat sections were prepared for immunohistochemistry using polyclonal antibodies against nerve growth factor receptor p75, protein gene product 9.5 and S-100. RESULTS: Structures with the characteristics of sensory nerve corpuscles were observed in several specimens after staining for p75, PGP 9.5 and S-100. They were observed in specimens of the non-pregnant corpus and cervix and also in specimens of the pregnant cervix before onset of labor. However, they were absent in all specimens during labor. CONCLUSION: Sensory corpuscles have here for the first time been detected in the human corpus and cervix uteri. Studies on the importance of the corpuscles in relation to the protective reflex actions that occur in the uterus during pregnancy should be performed in the future.

Unaltered innervation of the human cervix uteri in contrast to the corpus during pregnancy and labor as revealed by PGP 9.5 immunohistochemistry.

OBJECTIVE: To examine the occurrence of the general neuronal marker protein gene product 9.5 (PGP 9.5) in the human corpus (isthmus region) and the cervix uteri during pregnancy and parturition STUDY DESIGN: Biopsies were taken from the upper edge of the hysterotomy during caesarean section (CS) at term (n=5), in labor (n=5) and from the corresponding area in the non-pregnant uterus after hysterectomy (n=5). Cervical biopsies were obtained transvaginally from the anterior cervical lip. Serial cryostate sections were prepared for immunohistochemistry using polyclonal antibodies to PGP 9.5. RESULTS: Nerve fibers displaying PGP 9.5 immunoreactivity were observed in all sections from the three groups examined. They were identified in muscle tissue, in the stroma, and around blood vessel walls. A 30-fold decline of immunoreactive nerve fibers was observed in the isthmus part of the corpus uteri at term compared to the non-pregnant. There were no significant differences between the immunoreactivity in the cervix uteri of the three groups CONCLUSIONS: The innervation of the cervix uteri is dense and unaltered throughout pregnancy and labor. In contrast, the corpus is almost denervated. Further studies are needed to clarify the reason and the impact of these findings.