[Interest of a geostatistical approach to analyze the geographical disparities in human papillomavirus vaccine coverage in France]. / Intérêt d'une approche géostatistique pour analyser les disparités géographiques de la couverture vaccinale contre les papillomavirus humains en France.

BACKGROUND: The use of geostatistical methods remains rare in health studies. In order to assess the usefulness of the geostatistical approach in epidemiology, we chose to apply these methods to the vaccination coverage rate (VCR) against human papillomavirus (HPV) in France. Indeed, HPV vaccine coverage remains low in France and geographical disparities are sizable. The objective of this study was to identify the socioecological factors that may explain these geographical variations. METHODS: Sociological, economic and behavioral data for 2016 have been gathered (demographics and public health database, web and social networks) and were correlated with the HPV VCR vaccine coverage over the French territory. Homogeneous geographical areas defined by strong correlations for groups of variables were selected. In each homogeneous area, principal component analysis was performed and a geostatistical approach provided an estimate predicting vaccine coverage at a given scale. RESULTS: HPV VCR spatial variations in France cannot be fully explained by a single model. In urban areas, a low rate of HPV VCR is preferentially associated with unfavorable socioeconomic factors (poverty, unemployment, immigration). In rural areas, HPV VCR is preferentially associated with sociocultural factors (socio-professional categories, education level, interest in alternative medicines the anti-vaccine movement). Two secondary geographical areas were defined: the Île-de-France region and 12 departments in northeastern France. In the Île-de-France region, the association with the economic factors one again appears as in urban areas in general. The northeasteran departments represent a particular case insofar as HPV VCR is relatively high, notwithstanding economic poverty indicators. CONCLUSION: Geostatistical modeling successfully identifies new potential explanations for HPV VCR geographical disparities in France. These results could help to adapt or develop future vaccination programs in specific areas by taking into account the sociological, economic and behavioral characteristics of their populations.

Human Papillomavirus (HPV) vaccination coverage among French adolescents: A claims data study.

BACKGROUND: The French cancer control strategy 2021-2030 aims to achieve 80 % human papillomavirus (HPV) vaccination coverage. Since 2021, HPV vaccination is also recommended for boys aged 11-14 years, with a catch-up vaccination recommended for unvaccinated adolescents aged ≤19 years. The PAPILLON study used claims data to monitor the evolution of HPV Vaccination Coverage Rate (VCR) in the French population. METHODS: The annual HPV VCR was described from 2017 to 2022. Partial vaccination was defined as the dispensing of at least one dose of HPV vaccination. Full scheme vaccination was defined according to the current French recommendations as two or three doses of HPV vaccine over an 18-month period. Annual HPV vaccine initiation rates were estimated on 11-14 and 15-19-year-olds adolescents. Cumulative VCR were estimated on adolescents aged between 11 and 19 years at the time of first vaccination. RESULTS: Overall, 1,773,900 females and 592,167 males initiated HPV vaccination between 2017 and 2022. Initiations occurred between 11 and 14 years for 67.3 % of females and 62.4 % of males with a median time between the first two doses of 195 days and 190 days, respectively. In girls, the cumulative vaccination rate for the partial scheme vaccination at 15 y.o. increased from 28.1 % in 2017 to 50.9 % in 2022. Similarly, the cumulative vaccination rate for the full scheme vaccination at 16 y.o. increased from 15.5 % in 2017 to 33.8 % in 2022. In 2022, the initiation rates for males were 12.6 % at age 14 and 1.9 % at age 19. CONCLUSIONS: HPV vaccination coverage increased between 2017 and 2022 among girls targeted by the recommendation but remains insufficient. The results of this study show a tentative but promising start to vaccination in boys. This study will monitor the effects of actions taken to improve vaccination, including the extension of vaccination competencies to community pharmacists since end of 2022.

[Outpatient laparoscopic hysterectomy in France: A monocentric randomized trial]. / Hystérectomie cœlioscopique ambulatoire en France : étude randomisée unicentrique.

OBJECTIVE: To demonstrate the feasibility of outpatient laparoscopic hysterectomy using the assessment of post-operative quality of life. METHODS: A prospective randomized single-center trial was performed in France between 2013 and 2016. A total of 42 patients needed laparoscopic hysterectomy was included. Postoperative quality of life was assessed using the standardized Euroquol questionnaire. Patients filled the score before the operation and then on the 3rd and 30th postoperative day. Secondary outcomes were assessment of postoperative pain, overall quality of life, analgesic use, and anxiety. The patients were randomized into two groups, group A with a conventional hospital stay of 2 to 3 days and group B with a short stay and a discharge the day after the intervention. RESULTS: Twenty-one patients were randomized to group A as well as group B. We did not find any significant differences between the two groups in our study either on our primary outcome or in the seconds ones. On day 3, the average of Euroquol score was 0.68 for group A against 0.50 for group B (P=0.05). Likewise, the scores for postoperative pain were similar with 70.6 in group A and 61.8 in group B (P=0.21). The trend was the same for quality of life score or anxiety. CONCLUSION: Our study shows the possibility and the safety of outpatient laparoscopic hysterectomy.

A prospective randomized study of two reminding strategies: telephone versus mail in the screening of cervical cancer in women who did not initially respond.

OBJECTIVE: To compare the efficacy and cost-effectiveness of two reminding strategies addressed to women who did not respond to a first invitation to undergo cervical cancer screening. STUDY DESIGN: A randomized study was carried out by a programme created in Alsace to organize cervical cancer screening. In total, 10,662 women who did not have a smear test 1 year after a first notice was sent, were randomly allocated to receive either a new letter with a reply coupon or a telephone call. The uptake of screening was measured using routine data. Efficacy and direct costs of the two methods were compared. RESULTS: Uptake at 8 months was 6.3% [95% confidence interval (CI) 5.6-7.0%] for telephone calls and 5.8% (95% CI 5.2-6.4%) for letters. The difference was not significant. More information was collected through telephone calls than by letters, but with less reliability. Furthermore, telephone calls were more costly. CONCLUSIONS: We found that in our region, a mail reminder was as effective as, and less expensive than, a telephone call; moreover, it was applicable to the whole population, including patients without a telephone.

Value of endoscopic third ventriculostomy instead of shunt revision.

BACKGROUND: The purpose of this study was to analyze the value of endoscopic third ventriculostomy (ETV) in patients with shunt malfunction or infection. METHODS: ETV was performed in 263 patients in Greifswald between 1993 and 2008. We reviewed the data of all patients with previous shunts who underwent ETV instead of shunt revision. The procedure was successful when subsequent shunt implantation was avoided. RESULTS: Neuroendoscopy was performed in 30/31 previously shunted patients. The average age of the patients was 26.4 years ranging from 6 months to 69 years (male/female ratio: 18/12). The primary cause of hydrocephalus was aqueductal stenosis in 11, myelomeningocele in 5, posthemorrhagic in 5, postmeningitic in 3, tumor-related obstruction in 2, supracerebellar arachnoid cyst in 2, posttraumatic in 1 and a complex congenital hydrocephalus in 1. ETV was successful in 18 patients (60%) with a mean follow-up period of 51 months. 12 patients (40%) did not benefit from ETV and required a permanent shunt. 11 of them received the shunt within 3 months after failed ETV. ETV failed in all children <2 years of age. A benefit of ETV without subsequent shunt procedures was recognized in 18/27 (66.7%) with an obstructive and 0/3 (0%) patients with a communicating cause of the hydrocephalus. Complications occurred in 2 patients (6.7%). CONCLUSIONS: ETV is a potential treatment option when shunts fail in patients with obstructive hydrocephalus. If MR imaging shows no obstruction, a shunt revision is recommended. Patients with a posthemorrhagic and postmeningitic hydrocephalus are poor candidates for ETV.

European guidelines for clinical management of abnormal cervical cytology, part 2.

The current paper presents the second part of chapter 6 of the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening. The first part of the same chapter was published in a previous issue (Cytopathology 2008;19:342-54). This part provides guidance on how to manage and treat women with histologically confirmed cervical intraepithelial neoplasia. The paper describes the characteristics, indications and possible complications of excisional and ablative treatment methods. The three options to monitor the outcome after treatment (repeat cytology, HPV testing and colposcopy) are discussed. Specific recommendations for particular clinical situations are provided: pregnancy, immuno-suppression, HIV infection, post-menopause, adolescence and cyto-colpo-histological disparity. The paper ends with recommendations for quality assurance in patient management and some general advice on how to communicate screening, diagnosis and treatment results to the woman concerned. Finally, a data collection form is attached.

[Use of HPV virologic test for atypical glandular cells in Alsace between 2014 and 2016]. / Recours au test virologique HPV dans la prise en charge des atypies glandulaires en Alsace entre 2014 et 2016.

OBJECTIVES: The new recommendations by the National Institute of Cancer (January 2017) recommend the use of a complementary human papillomavirus (HPV) virologic test during the diagnosis of atypical glandular cells in pap smear. The aim of this study was the performance analysis of the HPV virologic test for the detection of significant histological cervical abnormalities (CIN2 or more) in case of atypical glandular cells before the new recommendations were published. METHODS: We performed a descriptive and retrospective cohort study in Alsace between January 2014 and December 2016. We have included, from the EVE-association database, the patients with atypical glandular cells in pap smear. RESULTS: In total, 1074 patients had a pap smear with atypical glandular cells ; 0.18% of total pap smears. This study included 152 patients who had a HPV test. We observed 6 cases of CIN2 (3.9%) and 12 cases of CIN3 (7.9%). No in situ adenocarcinoma nor invasive carcinoma were detected. The sensitivity of the HPV test was 88.9% (95% CI: [0.65; 0.99]), the specificity was 65.9% (95% CI: [0.55; 0.76]), the positive predictive value was 34% (95% CI: [0.21; 0.49]) and the negative predictive value was 96.8% (95% CI: [0.89; 0.99]). CONCLUSION: The detection of HPV in atypical glandular cells seems to be powerful with an excellent negative predictive value but, because of moderate sensitivity and due to the risk of histologic lesion progression, the current recommendations should to be applied with care.

European guidelines for quality assurance in cervical cancer screening: recommendations for clinical management of abnormal cervical cytology, part 1.

The current paper presents the first part of Chapter 6 of the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening. It provides guidance on how to manage women with abnormal cervical cytology. Throughout this article the Bethesda system is used for cervical cytology terminology, as the European guidelines have recommended that all systems should at least be translated into that terminology while cervical intraepithelial neoplasia (CIN) is used for histological biopsies (Cytopathology 2007; 18:213-9). A woman with a high-grade cytological lesion, a repeated low-grade lesion or with an equivocal cytology result and a positive human papillomavirus (HPV) test should be referred for colposcopy. The role of the colposcopist is to identify the source of the abnormal cells and to make an informed decision as to whether or not any treatment is required. If a patient requires treatment the colposcopist will decide which is the most appropriate method of treatment for each individual woman. The colposcopist should also organize appropriate follow-up for each woman seen. Reflex testing for high-risk HPV types of women with atypical squamous cells (ASC) of undetermined significance with referral for colposcopy of women who test positive is a first option. Repeat cytology is a second possibility. Direct referral to a gynaecologist should be restricted to special circumstances. Follow-up of low-grade squamous intraepithelial lesion is more difficult because currently there is no evidence to support any method of management as being optimal; repeat cytology and colposcopy are options, but HPV testing is not sufficiently selective, unless for older women. Women with high-grade squamous intraepithelial lesion (HSIL) or atypical squamous cells, cannot exclude HSIL (ASC-H) should be referred without triage. Women with glandular lesions require particular attention. In a subsequent issue of Cytopathology, the second part of Chapter 6 will be presented, with recommendations for management and treatment of histologically confirmed intraepithelial neoplasia and guidance for follow-up of special cases such as women who are pregnant, postmenopausal or immunocompromised.

Laparoscopic pelvic lymphadenectomy in patients with intermediate-risk endometrial cancer: Is it worth it?

OBJECTIVE: The main aim of this study is to evaluate operative and postoperative morbidity of laparoscopic pelvic lymphadenectomy as well as its potential impact on the postoperative management in patients with an intermediate-risk of endometrial cancer. METHODS: We did a retrospective study between January 2009 and December 2013. We included all patients operated by laparoscopy for endometrial cancer presumed to have an intermediate-risk of recurrence. Pelvic lymphadenectomy in this group of patients was performed at the discretion of operating surgeons. Patients were consequently divided into two groups according to whether or not pelvic lymphadenectomy was performed. We made a comparative analysis between these two groups. RESULTS: Overall, 116 patients were managed for endometrial cancer presumed to be intermediate-risk. Among these, 93 received treatment with laparoscopy and were included in the study. Patients' characteristics did not differ between the two groups. The mean duration of surgery was significantly longer when pelvic lymphadenectomy was performed. The average number of retrieved lymph nodes was 13 and we had seven patients with positive lymph nodes (10%). CONCLUSION: Pelvic lymphadenectomy allows a better postoperative classification for some patients without more complication.

[Imiquimod and immune response modifiers in gynaecology]. / Imiquimod et autres immunomodulateurs en gynécologie.

Immunomodulators have been used for some time in various medical specialities, but have only recently been used in gynaecology. The first drug in this therapeutic class, Immiquimod (Aldara), has been shown to be effective in treating lesions induced by Human Papillomavirus (HPV) such as genital warts or cervical and vulvar dysplasia, by stimulating the immune system of an infected individual. Thanks to its ease of use and its few side effects, Imiquimod would appear to be, in the future, the treatment of choice for these types of viral infections, alone or in association with therapeutic vaccines or physical abative therapies as a prevention of relapses. This review aims at summarizing and clarifying the mechanism of action of the different immunomodulators, their indications and their effectiveness in gynecologic practice.

[Left colon necrosis after endoscopic para-aortic lymph node exploration in a cervical carcinoma stage IIB]. / Nécrose colique gauche après un curage lomboaortique coelioscopique pour cancer du col utérin de stade IIB.

Authors report a left colon ischemia six days after laparoscopic para-aortic lymphadenectomy in the staging of advanced cervical carcinoma. Before surgery, positron emission tomography scanning was performed: there were no para-aortic nodal metastasis. The histologic examination confirmed the radiological staging. Positron emission tomography scanning could avoid surgery in the case of patients with high risks morbidity factors.

Cerebral aneurysms associated with von Recklinghausen's neurofibromatosis: report of a case and review of the literature.

The authors report a case of an intracranial aneurysm associated with von Recklinghausen's neurofibromatosis. A 34-year-old woman presented with a history of headaches, unconsciousness and neck rigidity. Widespread cutaneous neurofibromas were found. Investigations revealed an aneurysm of the anterior communicating artery. The authors discuss this case and review the relevant literature.

[Health-related quality of life in patients treated for ovarian cancer: tools and issues]. / Étude de la qualité de vie dans les néoplasies ovariennes : outils et enjeux.

Health-related quality of life (QoL) in patients treated for ovarian cancer is directly and heavily impacted by the natural history of cancer, its evolution and its therapeutic modalities. The evaluation and consideration of various parameters of QoL seems to be a major issue. Indeed, on the one hand, it is essential to take into account the opinion of patients in the choice of therapeutic strategies for this cancer with a poor prognosis and, on the other hand, more and more studies show that QoL is an independent prognostic factor in ovarian cancer. Improvement in this case, in addition to being an endpoint by itself, would potentially improve the overall survival of patients. To date there are several tools to assess QOL of patients with ovarian cancer. The 2 questionnaires most commonly used are: FACT-O and the EORTC QLQ-OV28. The aim of our study was to evaluate from a review of the literature, the reciprocal effects of ovarian cancer on QoL and QoL on ovarian cancer survival, as well as specificities of each of the 2 questionnaires most commonly used in assessing the QoL.

[Reliability of endocervical curettage after conservative treatment of intraepithelial neoplasia of the cervix]. / Fiabilité du curetage endocervical après traitement conservateur des néoplasies intraépithéliales du col utérin.

OBJECTIVE: To evaluate the reliability of endocervical curettage (ECC) in patients previously treated for CIN. PATIENTS AND METHODS: Retrospective analysis of data from 85 patients between January 1985 and December 2011 who received an ECC during monitoring after treatment of CIN. The reliability of the ECC was evaluated by comparison with the final histological analysis of the surgical specimen or the data for subsequent cyto-colpo-histological follow-up. RESULTS: Patients were referred to colposcopy either within the immediate post-treatment monitoring (n=42), meanly 9.7±5.3 months after treatment, or if cytological abnormalities were detected during long-term monitoring, meanly 78.6±52.4 months after treatment. Colposcopy was unsatisfactory in 75.3% of patients and normal colposcopic findings were found in 80% of patients. A perfect agreement between the ECC and the endocervical final diagnosis was noted in 68 patients (80%). For the diagnosis of severe cervical lesions (CIN 2+) ECC had a sensitivity of 86.2% (68.3-96.1), a specificity of 94.6% (85.1-98.9) and positive and negative predictive values of 61.4% (47.6-74.0) and 93% (83.0-98.1), respectively. CONCLUSION: The high sensitivity and negative predictive value of ECC for the diagnosis of severe post-therapeutic endocervical lesions avoid iterative treatment without increasing the risk of progression of a lesion to cancer.

Risk of cervical stenosis after large loop excision or laser conization.

OBJECTIVE: To assess the frequency of cervical stenosis in patients treated by laser conization or the loop electrosurgical excision procedure and to determine the preoperative and therapeutic factors associated with its occurrence. METHODS: Two hundred fifty-five women treated by laser conization and 277 treated by loop electrosurgical excision procedure were followed regularly by postoperative colposcopy for mean periods of 38 and 16 months, respectively. Stenosis was defined as cervical narrowing that prevented insertion of a 2.5-mm Hegar dilator. RESULTS: Thirty-eight cases of cervical stenosis, of which seven were complete, were diagnosed up to 28 months after treatment. The risk of postoperative cervical stenosis was higher for patients over 50 years of age (relative risk [RR] 3.07, 95% confidence interval [95% CI] 1.30, 7.26; P = .031), for those with a totally endocervical lesion (RR 3.79, 95% CI 1.88, 7.62; P = .001), for those with an excision 20 mm high or greater (RR 2.96, 95% CI 1.63, 5.38; P = .005), and for those with laser conization (RR 2.35, 95% CI 1.24, 4.46; P = .009). Parity, menopause, previous treatment for cervical intraepithelial neoplasia, satisfactory colposcopy, size of the lesion, its histologic diagnosis, and the extent of excision did not increase the risk for cervical stenosis. Excision was not as high with loop electrosurgical excision as with laser conization (14.3 +/- 5.0 mm versus 20.2 +/- 6.0 mm). The height of excision (RR 1.95, 95% CI 1.02, 3.76; P = .04) and a totally endocervical lesion (RR 5.07, 95% CI 1.96, 14.44; P = .001) were the only independent factors associated with postoperative stenosis identified by a multivariate analysis using logistic regression. CONCLUSION: The height of excision and a totally endocervical lesion were the main factors associated with cervical stenosis. The decreased risk associated with the loop electrosurgical excision procedure seems to be due to a shorter endocervical excision.

Cytology and colposcopy after loop electrosurgical excision: implications for follow-up.

OBJECTIVE: To analyze risk factors associated with residual and recurrent lesions after loop electrosurgical excision procedure and to assess the reliability of cytology and colposcopy in detection of these lesions. METHODS: Cytology and colposcopy were used to follow up 288 women after treatment by loop electrosurgical excision 3-6 months, 9-15 months, and 24-36 months after the procedure. RESULTS: The mean (+/-standard deviation) postoperative follow-up was 39+/-13 months (range 24-68 months). Treatment failure, defined as the persistence or recurrence of a cervical lesion, was observed in 20 patients (6.9%). The endocervical localization of the initial lesion (adjusted relative risk [RR] 13.7; 95% confidence interval [CI] 1.3, 150.1; P < .05) and incomplete excision (adjusted RR 9.1; 95% CI 3.0, 27.3; P < .001) were the only independent risk factors for treatment failure. In six cases, a second treatment was performed before the first cytologic and colposcopic visit because of incomplete excisions. The remaining 14 treatment failures were diagnosed by postoperative cytology and colposcopy, ten after the first visit, three after the second, and one after the third. To diagnose the treatment failures, colposcopy and cytology provided complementary information at the first (P < .001) and second postoperative visits (P < .05). Although the sensitivity of cytology was not significantly improved by the association of both methods, the latter decreased the number of residual lesions overlooked by cytology alone and contributed to the diagnosis of 95% of treatment failures in less than 2 years. CONCLUSION: The high detection rate obtained by combining cytology and colposcopy during the first 2 postoperative years may allow more leisurely follow-up schedules after that time and may reduce the consequences of subsequent loss to follow-up.

Depression by morphine-6-glucuronide of nociceptive activity in rat thalamus neurons: comparison with morphine.

To assess the contribution of the active metabolite of morphine, morphine-6-glucuronide (M6G), to the analgesic effect of systemically administered morphine, experiments were carried out on rats under urethane anesthesia in which nociceptive activity was evoked by electrical stimulation of afferent C fibers in the sural nerve and recorded from single neurons in the ventrobasal complex of the thalamus. Intravenous (i.v.) injections of morphine completely blocked the activity at doses of 500 and 1000 micrograms/kg, the ED50 being 44 micrograms/kg. M6G administered by i.v. injection reduced the evoked nociceptive activity only by about 40% at 80 and 160 micrograms/kg, the ED50 being 6 micrograms/kg. After intrathecal (i.t.) injection, morphine produced maximum depression of 55% of the control activity at 20 micrograms; the ED50 is 18 micrograms. M6G injected i.t. produced maximum depression of 40% at doses ranging from 0.2 to 10 micrograms. The ED50 of M6G i.t. is below 0.2 micrograms. The effects of morphine and M6G were reversed by naloxone (200 micrograms/kg i.v.). The results show that M6G is more potent than morphine, regardless of the route of administration, while morphine is more effective when injected i.v. Due to the low efficacy of M6G, it seems unlikely that this glucuronide contributes substantially to the analgesic effect of morphine when renal function is normal. The results also make evident that the maximum effect of morphine results from an action at spinal and supraspinal sites.

Depression of C fiber-evoked activity by intrathecally administered reactive red 2 in rat thalamic neurons.

To investigate the possible role of spinal purinoceptors in nociception, the potent P2-purinoceptor antagonist reactive red 2 was studied in rats under urethane anesthesia in which nociceptive activity was elicited by electrical stimulation of afferent C fibers in the sural nerve and recorded from single neurons in the ventrobasal complex of the thalamus. Intrathecal (i.t.) application of reactive red 2 (6-200 micrograms) caused a dose-dependent reduction of the evoked activity in thalamic neurons. The estimated ED50 was 30 micrograms, and the maximum depression of nociceptive activity amounted to about 70% of the control activity at a dose of 100 micrograms. Morphine, administered i.t. at a maximally effective dose (80 micrograms), inhibited the evoked nociceptive activity by only up to 55% of the control activity. An i.t. co-injection of reactive red 2 (100 micrograms) and morphine (80 micrograms) caused a maximum reduction of the evoked thalamic activity by up to 85% of the control activity, thus, exceeding significantly the effect elicited by either drug alone. Similarly, i.t. co-injection of almost equipotent dosages of reactive red 2 (30 micrograms) and morphine (30 micrograms) caused a maximum reduction of the evoked activity by up to 72% of the control activity, which again exceeded significantly the effect of either drug alone. The results suggest that in rats reactive red 2 exerts antinociception by blockade of P2-purinoceptors in the spinal cord and, hence, support the idea that ATP may play an important role in spinal transmission of nociceptive signals. An activation of the spinal opioid system does not seem to contribute to the effect of reactive red 2 but might act additive or even synergistically with its antinociceptive action.

No psychological dependence after oral administration of morphine to rats.

Rats subjected to forced oral self-administration of morphine solutions without or in combination with two daily i.p. injections of morphine preferred drinking water when this was offered in addition to morphine solutions. The daily intake of morphine during the terminal phase of self-administration of morphine was 50-80 mg/kg (oral application alone) or 270 mg/kg (oral and i.p. application). Morphine treated animals showed withdrawal symptoms on administration of naloxone 1 mg/kg i.p. during the period of self-administration, but not when they had started drinking exclusively water. The tail-flick test revealed no tolerance during prolonged treatment with morphine. The results indicate that no psychological dependence developed when morphine was applied orally and regularly.

Oral naloxone reduces constipation but not antinociception from oral morphine in the rat.

Oral administration of naloxone (10 mg/kg) antagonized the slowing of the intestinal transit caused by oral morphine (1, 2.5 and 5 mg/kg) in rats. Oral administration of naloxone (10 mg/kg) did not prevent the antinociceptive effect of orally administered morphine (2.5 mg/kg) in the tail-flick test carried out on rats. It is concluded that oral naloxone locally blocks the constipating effect of morphine, while it fails to reduce the central action of morphine due to extensive metabolization after oral administration.