The validity and reliability of the global index of safety (GIS)

OBJECTIVE: The global index of safety (GIS) is an adverse event (AE) based instrument designed to evaluate the safety profile of drugs. This paper presents the evaluation of the inter-rater reliability and validity of a 94-item GIS for antipsychotics through Rasch analysis. RESEARCH DESIGN AND METHODS: A total of 194 psychiatrists participating in an outpatient pharmacoepidemiologic study of olanzapine in schizophrenia rated the severity that each AE would have on a 5-point scale. Reliability was determined through a paired comparison design involving the new independent ratings of 101 different psychiatrists participating in another study of olanzapine in acute inpatient units. Spearman's, Pearson's and Intra-class correlation (ICC) coefficients were used to estimate the inter-rater reliability of the AE weights. Validity was analyzed through the Rasch rating scale model. RESULTS: Reliability coefficient estimates were excellent (Spearman = 0.99, Pearson = 0.99, ICC = 0.98), supporting the inter-rater reliability of the item weights. Through goodness-of-fit statistics and the investigation of the hierarchy of item calibrations, Rasch analysis confirmed the validity of the instrument. CONCLUSION: The data presented here on inter-rater reliability estimates of adverse events related to antipsychotic drugs indicate that GIS is a promising alternative for the evaluation of the safety profile of drugs.     

Inter--rater and test--retest reliability of the Japanese version of the subjective deficit syndrome scale

The subjective deficit syndrome scale (SDSS) was established in 1990 by Jaeger et al. to assess systematically subjective experiences of schizophrenic patients. It was translated into Japanese in 1999 by this paper's second author (T.I.). In this study, the inter-rater reliability of this Japanese version (SDSS-J) was examined. The subjects studied were 13 schizophrenic patients (male 6, female 7; respective average ages at study entry and disease onset: 41 and 25 years), who were being followed up at the outpatients' service of the Department of Neuropsychiatry, Hyogo College of Medicine. Four psychiatrists attended together, the systematic interview with each subject to rate the SDSS-J and independently rated 19 items. The severity scales of the items assessed by these raters ranged from 0 to 4 for 12 items and from 0 to 3 for 7. The ANOVA ICC inter-rater reliability values for the 19 individual items ranged from 0.67 to 0.96. The ANOVA ICC test-retest reliability values achieved by two raters were also high overall, ranging from 0.72 to 1.00, except for one item (item 13) assessed by one rater. Our results suggest that the SDSS-J is a potentially useful rating scale for evaluating subjective experiences of schizophrenic subjects.     

Quality of Information on Referrals to Colorectal Surgeons: Towards Consensus

Summary

Objectives: To produce a valid, reliable instrument to gauge the extent to which GPs document relevant signs, symptoms and risk factors in referral letters to colorectal surgeons.

Design: GPs and colorectal surgeons were invited to participate in a two-part questionnaire survey about the ideal contents of a referral letter. In the second round participants were asked to reconsider the questionnaire in the light of the group's collective replies in the first round. The instrument was tested for predictive validity and inter-rater reliability.

Setting: GPs in North Nottinghamshire Health Authority and colorectal surgeons in North Trent.

Participants: 125 GPs registered in two districts with North Nottinghamshire Health Authority and nine colorectal surgeons in North Trent were invited to participate.

Main outcome measures: Mean scores in the second round of the questionnaire were used to produce an instrument in which marks could be ascribed to each item mentioned on a GP referral letter.

Results: There was a 68.6% response rate to the questionnaire survey. The instrument had substantial inter-rater reliability (r= 0.77). Higher scores predicted cases that would be offered urgent appointments by the specialist (OR = 1.06, 95% CI = 1.01 to 1.10). Cases with pathology were not referred with more thorough documentation of pre-referral assessment (score 33 vs. 31, mean difference 2.3, p = 0.06 (t-test), 95% CI = -0.07 to 4.02).

Conclusions: In some cases, patients with pathology are entering secondary care with communications from GPs in which the relevant history and examination are not fully documented. Explicit documentation of GP assessment prior to referral may have a significant impact on how cases might be managed in secondary care.     

A Double-blind,Randomised Comparative Trial of Amisulpride Versus Olanzapine in the Treatment of Schizophrenia: Short-term Results at Two Months

Summary

Objective: To compare the efficacy and safety of the atypical antipsychotics amisulpride and olanzapine in the treatment of acute psychotic exacerbations of schizophrenia.

Design and setting: A multinational, double-blind randomised clinical trial.

Patients and treatment:Three hundred and seventy-seven patients with predominantly positive symptomatology were treated for six months with either amisulpride (200-800?mg/d) or olanzapine (5-20?mg/d).

Main outcome measures: Short-term results were analysed after two months of treatment. The primary efficacy measure was the change of score on the Brief Psychiatric Rating Scale (BPRS). Other measures of efficacy and safety were also evaluated.

Results: Psychotic symptoms, as measured on the BPRS score, improved with both treatments, amisulpride being equivalent to olanzapine. All BPRS factor scores, as well as depressive symptoms, improved to a similar extent with both treatments. Less than five per cent of patients withdrew for adverse events, and there was no evidence for the emergence of extrapyramidal symptoms with either treatment. Statistically significant greater weight gain (2.7?±?3.9?kg) was observed during the study in the olanzapine group, compared with the amisulpride group (0.9?±?3.2?kg, p?<?0.0001).

Conclusions: Amisulpride and olanzapine show equivalent efficacy at 2 months in the treatment of acute psychotic exacerbations of schizophrenia. Amisulpride offers a significant advantage in preserving body weight.     

Reliability,validity and ability to detect change of the clinician-rated Personal and Social Performance scale in patients with acute symptoms of schizophrenia

ABSTRACT

Objective: To describe the measurement properties of the Personal and Social Performance scale (PSP), a clinician-reported measure of severity of personal and social dysfunction, in subjects with acute symptoms of schizophrenia.

Methods: Pooled data from three paliperidone extended-release clinical studies (n?=?1665) and data from a separate noninterventional, cross-sectional, validation study (n?=?299) were analyzed.

Results: The PSP showed good interrater (intraclass correlation coefficient [ICC]?=?0.87) and test–retest (ICCs?>?0.90) reliability. Pearson correlation coefficient for association between baseline PSP and Positive and Negative Syndrome Scale (PANSS) total scores was ?0.32 for subjects assessed by the same rater and ?0.29 for subjects assessed by different raters, suggesting low overlap in measurement constructs between the PANSS and PSP. Spearman Rank correlation coefficient for association between baseline PSP and Clinical Global Impression-Severity (CGI-S) scores was ?0.51 with the same rater and ?0.15 with different raters. Hypothesized relationships between the PSP and the PANSS or CGI-S based on levels of disease severity were prospectively defined. These hypotheses were confirmed by analyses showing statistically significant differences between baseline mean PSP scores in subjects grouped by severity rating on the CGI-S (mild or less vs. at least moderate) (p?<?0.001) and the PANSS (‘low symptom severity’ vs. ‘high symptom severity’) (p?=?0.005). The PSP was sensitive to change based on statistically significant correlations between change in the PSP and change in the CGI-S (p?<?0.001) and the PANSS (p?<?0.001). Limitations of analyses include pooling data across studies, interrater reliability assessment in the validation study only, post hoc assessment of test–retest reliability in the paliperidone ER studies, different raters for the PSP and PANSS not specified in the paliperidone ER studies, PSP validity assessment based on the PANSS and the CGI-S as comparators rather than another social function instrument.

Conclusion: These initial reliability and validity assessments suggest the PSP has promise as a measure of social functioning in patients with acute symptoms of schizophrenia.     

Development and testing of a neuropathic pain screening questionnaire: ID Pain

ABSTRACT

Objective: To develop a patient-completed screening tool to help differentiate nociceptive and neuropathic pain.

Research design and methods: A multicenter study was performed for item reduction (initial 89-item questionnaire) and model building. Patients (N = 586) with non-headache chronic pain completed the questionnaire and were referred to pain specialists for diagnosis. Factor and regression analyses were used to derive a final, 6-item questionnaire – ID Pain. A second multicenter study evaluated reliability and validity. Patients (N = 308) treated by pain specialists completed ID Pain and validation measures.

Main outcome measures: Sensitivity and specificity were assessed using receiver operating characteristic curves and the concordance c index. Reliability was assessed using a κ statistic and intraclass correlation coefficient.

Results: Final 6 items were: did the pain feel: (1) like pins and needles? (2) hot/burning? (3) numb? (4) like electrical shocks? (5) is the pain made worse with the touch of clothing or bed sheets? (6) is the pain limited to your joints? ‘Yes’ answers to questions 1–5 were scored as 1, while a ‘yes’ answer to question 6 was scored as –1. ‘No’ answers were scored as 0. Higher scores (–1 to 5) suggested a neuropathic component. The questionnaire accurately predicted diagnoses of neuropathic pain made by pain specialists. The concordance c indices in the studies were 0.73 and 0.69. The ICC was 0.742; the κ statistic ranged from 0.742 to 0.527.

Conclusions: ID Pain appeared to accurately indicate the presence of a neuropathic component of pain. As a brief, self-administered screening tool, it could be useful in primary care settings.     

Pharmacy cost evaluation of risperidone,olanzapine, and quetiapine for the treatment of schizophrenia in acute care inpatient settings

SUMMARY

Objective: This study examines total pharmacy cost and usage patterns of schizophrenic patients in acute mental health inpatient settings for three atypical antipsychotics – risperidone, olanzapine, and quetiapine. Despite the readily available unit cost information for drugs, actual pharmacy costs may deviate significantly from ‘labeled costs’. Recent research findings indicate the need for more robust evaluation of such pharmacy costs.

Research design and methods: This study used data from non-randomized inpatient retrospective charts from three acute care inpatient mental health facilities. The final pooled sample included 327 patients, of which 120 received risperidone, 153 received olanzapine, and 54 received quetiapine. Medication cost was defined as the average wholesale price (AWP) as listed in the 2001 ‘Red Book’. Propensity scoring methodology and multinomial regression were employed to reduce treatment selection bias.

Results: The observed mean daily antipsychotic drug doses were 4.45?mg (SD 2.44) for risperidone, 14.04?mg (SD 5.55) for olanzapine, and 350.33?mg (SD 228.24) for quetiapine. The corresponding mean daily drug costs were $7.66(SD $4.20) for risperidone, $8.11 (SD $5.29) for quetiapine and, $12.10 (SD $4.79) for olanzepine. Numbers adjusted for treatment selection bias show that the average daily total pharmacy cost of risperidone was $4.35 lower than olanzapine (?p < 0.001) and $1.41 lower than quetiapine (?p = 0.38). The adjusted average daily pharmacy cost of olanzapine was $4.02 higher than quetiapine (?p < 0.001). After statistical adjustment there were no significant differences between study drugs in terms of length of stay or patient functioning.

Conclusion: This study provides the first US comparison of medication utilization patterns and pharmacy costs for olanzapine, risperidone, and quetiapine administered in acute mental health care inpatient settings. While this study did not estimate the full economic value of the three antipsychotics in these inpatient settings, it demonstrated that the mean daily costs for risperidone were lower than the mean daily costs for olanzapine (?p < 0.001) and quetiapine although the later difference was not statistically significant (?p = 0.38).     

Comparing the treatment patterns of patients with schizophrenia treated with olanzapine and quetiapine in the Pennsylvania Medicaid population

ABSTRACT

Objective: Compare treatment patterns for patients with schizophrenia treated with olanzapine versus quetiapine in the Pennsylvania Medicaid population.

Methods: Patients (18–64 years) with a diagnosis of schizophrenia (ICD-9-CM: 295.xx) and treated with olanzapine or quetiapine were identified from the Pennsylvania Medicaid claims database (1999–2003). Patients were continuously enrolled in the 12-month pre- and 12-month post-initiation periods. To control for selection bias, propensity score method with optimal matching algorithm was used to match patients from the two treatment groups. The key study outcomes including rates of augmentation, polypharmacy, discontinuation, and switching were analyzed using Kaplan-Meier survival analysis. Medication possession ratio and use of concurrent psychotropic drugs were also compared between the two groups.

Results: A total of 2321 quetiapine and 6929 olanzapine patients were identified. In all, 2321 pairs of patients were matched between the two groups and they had similar baseline characteristics. Over the 12-month study period, olanzapine patients had a better medication adherence (0.47 vs. 0.43; p?<?0.0001), and were less likely to use other psychotropic medications concomitantly (all p?<?0.05). Olanzapine patients had a significantly lower risk of augmentation and polypharmacy with other antipsychotics. The 6-month augmentation rates with antipsychotics were 12.9% and 16.7% for olanzapine and quetiapine, respectively (p?<?0.05); the polypharmacy rates with any antipsychotics were 12.5% and 18.6% for olanzapine and quetiapine, respectively (p?<?0.001). No significant differences were observed for discontinuation and switching between the two treatment groups. Sensitivity analysis with a 60-day minimum monotherapy requirement showed similar results.

Limitations: This study's limitations include the analysis of a single Medicaid state, which may limit the generalizability to the entire Medicaid population with schizophrenia or to all patients with schizophrenia.

Conclusion: This large Medicaid claims database analysis showed that olanzapine patients were significantly more compliant to treatment and less likely to augment or have polypharmacy with antipsychotics during the course of treatment compared to quetiapine patients.     

Linguistic adaptation and validation into Spanish of the Diagnostic Interview for Borderline Personality Disorders-Revised (DIB‐R)

ABSTRACT

Objective: This paper describes the linguistic adaptation and psychometric validation into Spanish of the Diagnostic Interview for Borderlines-Revised (DIB‐R) scale for diagnosing borderline personality disorder (BPD).

Methods: A conceptual equivalence approach was undertaken, including forward and backward translations of the scale and patient debriefing in a pilot phase. BPD and control patients were included in the validation study, and all of them were administered the scale by well trained interviewers, blinded to the clinical diagnosis. Reference diagnosis for BPD was done according to DSM‐IV criteria. The interview was independently administered in a subset of patients by different interviewer to test inter-rater reliability. Reliability and validity of the instrument were tested by calculating the Cronbach α and Guttman split-half coefficients and by receiver operating characteristic (ROC) curve analysis, kappa agreement coefficient determination and assessment of sensitivity and specificity of the scale.

Results: A cohort of 111 subjects, 84 BPD patients (33.6 ± 9.3 years) and 27 control subjects (34.9 ± 9.3 years), were included in the study. A cut-off point ≥ 7 showed a kappa agreement coefficient of 0.853 (95% confidence intervals: 0.739–0.967, p < 0.00001). The figures for sensitivity and specificity values were 0.964 (0.899–0.993) and 0.889 (0.708–0.977) respectively. Inter-rater reliability showed a kappa coefficient of 0.783 (?p < 0.0001).

Conclusion: The Spanish version of the DIB‐R showed adequate psychometric properties for diagnosing BPD in Spain.     

Long-acting atypical injectable antipsychotics in the treatment of schizophrenia: safety and tolerability review

Importance of the field: Although atypical antipsychotics have beneficial efficacy and tolerance, non-adherence and partial adherence remain in patients treated for schizophrenia. Long-acting injectable or depot atypical antipsychotics offer better medication adherence and tolerability advantages. Currently, two drugs are available for the treatment of schizophrenia, risperidone long-acting injectable (RLAI) and olanzapine pamoate (OP).

Areas covered in this review: Short- and long-term safety and tolerability data on RLAI and OP from January 2006 through September 2009 were reviewed by performing Medline and PubMed searches, reviewing abstracts and poster presentations, and viewing available material from the FDA and European Medicines Agency.

What the reader will gain: RLAI and OP show good short- and long-term safety when treating patients with schizophrenia, with uncommon discontinuation due to adverse effects. RLAI and OP data show rare problems with injection site reactions and patients exposed to injectable treatments prefer to continue injections. Infrequent but serious post-injection delirium sedation syndrome occurred after 1% of OP injections. Weight gain was generally higher among patients treated with OP versus RLAI.

Take home message: Healthcare providers, patients and family members should be made aware of the safety and benefits of long-acting injectable atypical antipsychotics in order to diminish the unnecessary restrictions of these therapies for patients with schizophrenia.     

The inter-rater reliability of the Japanese version of the Montgomery-Asberg depression rating scale (MADRS) using a structured interview guide for MADRS (SIGMA)

The inter-rater reliability of the Japanese version of MADRS (MADRSJ) was examined using the structured interview guide for MADRS (SIGMA) developed by our group. Two or more psychiatrists attended the systematic interview sessions with each subject to evaluate MADRSJ independently, using SIGMA. A total of 18 interviews was carried out for seven patients with DSM-IV major depressive disorder. The severity of each item assessed by the raters ranged from 0 to 6 for nine items and from 0 to 4 for one item. The analysis of variance intraclass correlation coefficient inter-rater reliability values for the individual items carried out by two trained personnel ranged from 0.91 to 1.00, while those achieved by three raters ranged from 0.85 to 1.00. The present results suggest that SIGMA is a potentially useful interview guide for assessing ten symptoms of MADRSJ precisely in patients with a depressive disorder.     

Antipsychotic switching: results from a one-year prospective,observational study of patients with schizophrenia

ABSTRACT

Objective: The Health Outcomes of a Canadian Community Cohort (HOCCC) study is a 1-year prospective observational study of outpatients with schizophrenia or related psychotic disorders. The purpose of the study was to compare effectiveness of antipsychotic treatment as measured by 1-year treatment completion rates.

Design and methods: Patients (N?=?929) were enrolled if in the course of usual clinical practice they switched to a second-generation antipsychotic (SGA). Observational data were collected for up to 1 year. The primary analysis compared 1-year treatment-completion rates for the olanzapine cohort with the other SGA cohort (quetiapine, risperidone, clozapine), using a chi-squared test.

Results: Of 929 patients enrolled, 64.8% (516/796) of evaluable patients completed 1 year of treatment. There was no statistically significant difference in the proportion of treatment completers between the olanzapine cohort (67.4%, 256/380) and the other SGA cohort (62.5%, 260/416). Treatment-completion rates were risperidone 62.0% (127/205), quetiapine 63.7% (123/193) and clozapine 55.6% (10/18). Antipsychotic polypharmacy was common. Patients treated with olanzapine or risperidone had significantly higher increases in BMI than quetiapine-treated patients. There were no major differences between olanzapine monotherapy and pooled other SGA monotherapy groups in status of extrapyramidal symptoms from baseline to endpoint.

Conclusions: Olanzapine and other SGAs exhibited similar rates of 1-year treatment completion. Further study of medication combinations is needed, given their perceived clinical value, and the high frequency of antipsychotic polypharmacy in clinical practice.

Limitations: As most patients received several psychotropics and power was reduced in monotherapy analyses, comparisons between cohorts must be interpreted cautiously. Comparisons between individual antipsychotics were post hoc and not powered a priori. Accuracy and completeness of adverse event information for drugs other than olanzapine is limited.     

Overall tolerability and analgesic activity of intra-articular sodium hyaluronate in the treatment of knee osteoarthritis

ABSTRACT

Objective: Viscosupplementation with intra-articular hyaluronic acid (HA) is an alternative to the treatment of symptomatic knee osteoarthritis (OA) with pain relieving drugs. Sinovial, is a sterile, non-pyrogenic 0.8% solution of highly purified sodium hyaluronate for intra-articular application. The aim of the present study was to investigate the safety and tolerability profile of this preparation in patients with symptomatic knee OA over 24 weeks.

Research design and methods: This was a single group, open-label study, including outpatients of both sexes, aged between 18 and 85 years, with symptomatic knee OA. All patients underwent weekly intra-articular injections of HA for 5 consecutive weeks and were followed-up for 19 additional weeks. The safety and tolerability profile (primary endpoint) was assessed by adverse event (AE) reporting. The secondary endpoint was efficacy evaluated by changes in the Western Ontario and McMaster Universities (WOMAC) score vs. baseline. Patient and physician satisfaction were also recorded.

Results: Intra-articular HA was generally well tolerated. The most frequent AE was pain at the injection site (5.8% of the injections); no serious treatment-related AE was reported. The WOMAC score was significantly reduced within the first 2 weeks of treatment (from 4.02 ± 1.90 to 3.55 ± 2.04, p = 0.0011), further decreased by the end of the injection series (week 6: 2.59 ± 1.90; p < 0.0001) and maintained during the follow-up (week 24: 2.44 ± 1.88; p < 0.0001). The WOMAC subscores were also significantly reduced from week 4 for ‘pain’ and from week 6 for ‘stiffness’ and ‘physical function’.

Conclusions: In the present study, intra-articular HA was well tolerated and safe in patients with symptomatic knee OA. Based on the sustained improvements in WOMAC score and subscores, a carry-over effect lasting for at least 19 weeks after the last injection may be proposed. These results further confirm the evidence of efficacy and safety of intra-articular HA in the management of knee OA.     

Systematic review and meta-analysis of the clinical safety and tolerability of ibuprofen compared with paracetamol in paediatric pain and fever

ABSTRACT

Objective: The main aim of this review was to compare the tolerability and safety between ibuprofen and paracetamol when used as anti-pyretic and analgesic agents in children up to 18 years of age.

Methods: MEDLINE (1950 to November 2008), EMBASE (1980 to November 2008), The Cochrane Library (2007, Issue 3), ACP Journal Club (1991 to November 2007) and Pascal (1987 to November 2007) were searched for randomised controlled trails (RCTs) (comparing ibuprofen and/or paracetamol with placebo), controlled observational studies and large case series comprised more than 1000 participants.

Main outcome measures: Adverse events (AEs) requiring discontinuation of medication; systemic reactions related to ibuprofen or paracetamol; serious AEs that are fatal, life-threatening or require hospitalisation; and serious AEs not requiring hospitalisation.

Results: A total of 24 RCTs examined either ibuprofen and/or paracetamol versus placebo for AE data. Twelve other studies meeting our criteria were also included for AE data. Meta-analysis of systemic reactions demonstrated that tolerability and safety of ibuprofen was similar to placebo, as was paracetamol: ibuprofen versus placebo relative risk (RR) 1.39 (95% CI: 0.92, 2.10); paracetamol versus placebo RR 1.57 (95% CI 0.74, 3.33). A total of 2937 systemic AEs occurred in 21?305 patients taking ibuprofen compared with 1466 systemic AEs in 11?164 patients taking paracetamol: RR 1.03 (95% CI 0.98, 1.10). There was no significant difference between the two groups. Narrative analysis of AE data identified conflicting evidence regarding hepatic injury with paracetamol and group A streptococcal infections with ibuprofen or paracetamol treatment.

Conclusions: Ibuprofen, paracetamol and placebo have similar tolerability and safety profiles in terms of gastrointestinal symptoms, asthma and renal adverse effects. While the study data investigated here may not reflect over-the-counter use, these results are still relevant in the context of any safety concerns relating to general ibuprofen or paracetamol treatment in children.     

A crossover study on lipid and weight changes associated with olanzapine and risperidone

Rationale The results from case–control and retrospective studies revealed that olanzapine might be associated with more increased risks of metabolic dysfunction than risperidone. The crossover design can minimize the influence of individual variation in metabolic profiles and demographic variables, such as age, sex, concomitant medication use and personal life styles.Objectives We design a crossover study to evaluate the metabolic effect of olanzapine and risperidone.Methods Fifteen schizophrenic patients were shifted from olanzapine and risperidone or from risperidone and olanzapine due to poor treatment response. The body weights, lipid profiles and fasting glucose levels were assessed before medication switch and 3 months after crossover.Results In the seven patients taking risperidone at the time of inclusion (risperidone-first group), after shifting to olanzapine, there was a significant increase in triglyceride level (p=0.048) and body weight (p=0.008). In the other eight patients (olanzapine-first group), after shift to risperidone, there was a decrease in triglyceride level (p=0.009), body weight (p=0.049) and body mass index (BMI; p=0.04). When comparing the metabolic profiles in all patients after olanzapine and after risperidone (irrespective of the order of treatment), the mean triglyceride level (p=0.001), body weight (p=0.001) and BMI (p=0.015) were significantly higher in patients receiving olanzapine than in those receiving risperidone. Furthermore, there was a small increase in total cholesterol level (p=0.091) and a small decrease in high-density lipoprotein (HDL) level (p=0.061) in olanzapine group, but the differences did not reach a significant level. There was no significant difference between olanzapine and risperidone in fasting glucose and low-density lipoprotein (LDL).Conclusions This study confirms that elevated levels of triglyceride and body weight could be associated with the use of olanzapine as compared with risperidone. The changes in body weights and lipid profiles should be closely monitored in patients during treatment with atypical antipsychotic drugs.     

Advances in pharmacotherapy for opioid-induced constipation – a systematic review

Introduction: Opioid-induced constipation (OIC) is one of the most frequent and burdening adverse events (AE) of opioid therapy. This systematic review aimed to evaluate efficacy and safety of drugs in randomized controlled trials (RCTs) with adult OIC patients.

Areas covered: Efficacy assessment focused on objective outcome measures (OOMs): bowel movement (BM) frequency, BM within 4 h and time to first BM. Twenty-one studies examining seven drugs were identified. Methylnaltrexone showed improvements in all three OOMs. RCTs in naloxone and alvimopan tended to be effective for BM frequency measures. Naloxegol (≥ 12.5 mg) improved all OOMs. Though effectiveness of lubiprostone was demonstrated for all OOMs, group differences were small to moderate. CB-5945 and prucalopride tended to increase BM frequency, especially for 0.1 mg twice daily and 4 mg daily, respectively. Besides nausea and diarrhea, abdominal pain was the most frequent AE for all drugs (risk ratio, range: 1.52 – 5.06) except for alvimopan. Treatment-related serious AEs were slightly higher for alvimopan (cardiac events) and prucalopride (severe abdominal pain, headache). Pain scores for placebo and intervention groups were similar for all drugs.

Expert opinion: Finding a consensus definition and inclusion criteria for OIC plus a rational balance between efficacy and AEs of drugs remain future challenges.