Pain relief in hysterosalpingography

Akshay Hindocha; Lawrence Beere; Helena O'Flynn; Andrew Watson; Gaity Ahmad

doi:10.1002/14651858.CD006106.pub3

. 2015 Sep 20;2015(9):CD006106. doi: 10.1002/14651858.CD006106.pub3

Pain relief in hysterosalpingography

Akshay Hindocha ¹, Lawrence Beere ¹, Helena O'Flynn ¹, Andrew Watson ², Gaity Ahmad ^1,^✉

Editor: Cochrane Gynaecology and Fertility Group

PMCID: PMC8504987 PMID: 26387564

Abstract

Background

Hysterosalpingography (HSG) is a method of testing for tubal patency. However, women struggle to tolerate the procedure, as it is associated with some discomfort. Various pharmacological strategies are available that may reduce pain during the procedure, though there is no consensus as to the best method.

Objectives

To compare the effectiveness of different types of pharmacological interventions for pain relief in women undergoing HSG for investigation of subfertility.

Search methods

This review has drawn on the search strategy developed for the Cochrane Menstrual Disorders and Subfertility Group (MDSG). We searched the following databases to 15 April 2015: MDSG Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL and PsycINFO.

Selection criteria

All identified randomised controlled trials investigating pharmacological interventions for pain relief during HSG were investigated for selection.

Data collection and analysis

Four review authors independently extracted data. We combined data to calculate mean differences (MDs) with 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods.

Main results

The search identified 23 trials (1272 women) that were eligible for inclusion into the study.

Oral opioid analgesia versus placebo/no treatment

There was no evidence of effect for oral opioid analgesia in reducing pain during the procedure (MD −0.91, 95% CI −1.88 to 0.06, 1 study, n = 128, low quality evidence) or more than 30 minutes after the procedure (MD −0.99, 95% CI −1.75 to −0.23, 1 study, n = 128, moderate quality evidence)

No studies reported on the effect of oral opioid analgesia, when taken prior to the procedure, in reducing pain within 30 minutes after the procedure

There was insufficient evidence to reach conclusions regarding adverse effects.

Intravenous opioid analgesia versus placebo/no treatment

There was evidence that intravenous opioids may improve pain relief during the procedure compared to no treatment (MD −3.53, 95% CI −4.29 to −2.77, 1 study, n = 62, moderate quality evidence)

No studies reported on the effect of intravenous opioid analgesia, when taken prior to the procedure, in reducing pain within 30 minutes and more than 30 minutes after the procedure

In terms of adverse effects, one trial reported 1/32 participants had apnoea with intravenous remifentanil. Recovery time was nearly 4 minutes longer in the remifentanil group compared to the control.

Oral non‐opioid analgesia versus placebo/no treatment

There was no evidence of effect for oral non‐opioid analgesia in reducing pain during the procedure (MD −0.13, 95% CI −0.48 to 0.23, 3 studies, n = 133, I² = 61%, low quality evidence), less than 30 minutes after the procedure (MD −0.30, 95% CI −1.03 to 0.43, 2 studies, n = 45, I² = 97%, very low quality evidence), or more than 30 minutes after the procedure (MD −0.36, 95% CI −1.06 to 0.34, 3 studies, n = 133, I² = 58%, low quality evidence).

There was insufficient evidence to reach conclusions regarding adverse effects.

Topical anaesthesia versus placebo/no treatment

There was evidence that topical anaesthetics may reduce pain during the procedure (MD −0.63, 95% CI −1.06 to −0.19, 9 studies, n = 613, I² = 66%, low quality evidence).

There was no evidence of effect for topical anaesthesia, when applied prior to the procedure, in reducing pain less than 30 minutes after the procedure (MD 0.42, 95% CI ‐0.03 to 0.86, 5 studies, n = 373, I² = 59%, very low quality evidence).

There was evidence of effect for topical anaesthesia, when applied prior to the procedure, in reducing pain more than 30 minutes after the procedure (MD −1.38, 95% CI ‐3.44 to −0.68, 2 studies, n = 166, I² = 92%, very low quality evidence).

There was insufficient evidence to reach conclusions regarding adverse effects.

Locally injected anaesthesia versus placebo/no treatment

There was evidence of effect that locally injected anaesthetic can reduce pain during the procedure (MD −1.31, 95% CI −1.55 to −1.07, 2 studies, n = 125, I² = 0%, very low quality evidence).

There was no evidence of effect for locally injected anaesthesia, when applied prior to the procedure, in reducing pain less than 30 minutes after the procedure (MD −1.31, 95% CI −2.14 to −0.49, 2 studies, n = 125, I² = 46%, low quality evidence).

No studies were included into the analysis of the effect of locally injected anaesthesia, when injected prior to the procedure, in reducing pain more than 30 minutes after the procedure.

There was insufficient evidence to reach conclusions regarding adverse effects.

Any analgesic versus any other analgesic

There was no evidence of a difference between the groups when oral non‐opioid analgesia was compared to opioid analgesia for pain relief during the procedure (MD 1.10, 95% CI −0.26 to 2.46, 1 study, n = 91, low quality evidence); less than 30 minutes following the procedure (MD −0.30, 95% CI −1.00 to 0.40, 1 study, n = 91, low quality evidence); and more than 30 minutes following the procedure (MD −0.60, 95% CI −1.56 to 0.36, 1 study, n = 91, low quality evidence). Topical anaesthetics were found to be more effective than paracervical block for pain relief during HSG (MD −2.73, 95% CI −3.86 to −1.60, 1 study, n = 20, moderate quality evidence). This benefit did not extend to within 30 minutes following HSG (MD −1.03, 95% CI −2.52 to 0.46, 1 study, n = 20, low quality evidence); or 30 minutes or more after HSG (MD 0.31, 95% CI −0.87 to 1.49, 1 study, n = 20, low quality evidence).

There was insufficient evidence to reach conclusions regarding adverse effects.

Authors' conclusions

Topical anaesthetic applied before the procedure may be associated with effective pain relief during HSG, though the quality of this evidence is low. Intravenous opioids may also be effective in pain relief, though this must be weighed against their side effects and their effects on the recovery time. There is insufficient evidence to draw conclusions on the efficacy of other analgesics for HSG, or to reach any other conclusions regarding adverse effects.

Plain language summary

Drug treatments for pain relief in hysterosalpingography

Review question:

Which pain‐killers are effective at reducing the discomfort experienced with hysterosalpingography?

Background:

Hysterosalpingography (HSG) is a test used in investigating infertility in women. HSG involves a dye being introduced into the uterus and the connecting tubes, which enables them to be visualised using an x‐ray, allowing the clinician to assess how open the connecting tubes are. This can be a painful procedure. There is disagreement regarding the best form of pain relief during the procedure.

Study characteristics:

We identified 19 randomised controlled trials that compared a specific drug treatment to a placebo/no treatment. Four trials compared two different drug treatments to establish if one was better. All studies took place in a clinical setting. Age of participants ranged from 18 to 42 years. Studies took place in India, Australia, United Kingdom, United States of America, Turkey, Israel, Netherlands, Italy, Iran, Nigeria, Spain, Brazil, and Belgium (1272 women in total).

We included 15 of these trials in a meta‐analysis. The remaining eight trials, while eligible for inclusion, did not have data in a format that could be entered into meta‐analysis (seven compared a specific drug to a placebo/no treatment, one compared two different drug treatments). The evidence is current to April 2015.

Key results:

Topical anaesthetic was associated with a mild reduction in the pain experienced during HSG (low quality evidence). However, it has no effect on the discomfort experienced by participants following the procedure (very low quality evidence).

Locally injected anaesthetics, on the other hand, were not associated with any benefit. Only one study investigated this (moderate quality evidence).

One study directly compared locally injected anaesthetics to topical anaesthetics. This study found that topical anaesthesia was associated with improved pain relief during the procedure (moderate quality evidence)

No oral drug was found to be effective in reducing pain experienced during the procedure. This was true for both opioid (low quality evidence) and non‐opioid (low quality evidence) analgesia. One trial however reported that tramadol may be of benefit in reducing the pain experienced more than 30 minutes after the procedure (moderate quality evidence).

Quality of the evidence:

The quality of the combined results was mainly downgraded for two reasons: 1) studies having methods that may be at risk of bias/inaccuracy; 2) substantially different conclusions between studies that investigate the same drug.

The included studies did not report side effects in large enough numbers to make definitive conclusions regarding the side effects of particular drugs during the procedure.

Conclusions:

Only topical anaesthetics and intravenous opioids were found to be of benefit in reducing pain during the procedure, though the quality of this evidence is low to moderate, and there is no evidence that these are effective at relieving pain following the procedure. There is insufficient evidence for other drug treatments in reducing pain during HSG. There was insufficient evidence to reach any conclusions regarding adverse effects.

Summary of findings

Background

Description of the condition

Tubal diseases account for 14% of cases of subfertility (Hull 1985), and include tubal obstruction, peritubal adhesions secondary to infection, endometriosis and previous surgery. Hysterosalpingography (HSG) is a reliable indicator of tubal patency, with National Institute for Health and Care Excellence (NICE) guidelines recommending HSG to screen for tubal occlusion in the absence of co‐morbidities (NICE guidelines 2013). While it is an integral part of the infertility workup, it can be very painful. This pain peaks at the time of instillation of the contrast media until 5 minutes after the procedure and then starts to decrease rapidly between 5 and 10 minutes after the procedure, so that at 30 minutes, most women classify it as a discomfort (Owens 1985). The pain is due to several factors, including cervical instrumentation, uterine distension, and peritoneal irritation from contrast spill into the peritoneal cavity. Furthermore, grasping the cervix with a tenaculum (a type of forceps with a hook), as well as distending the uterus, may release local prostaglandins. These can initiate uterine cramps, which result in delayed pain after HSG. Pain from the cervix and lower portion of the uterus is carried by the pelvic splanchnics (a nerve relating to the viscera), whereas pain sensation from the fundus and body of the uterus (uterine cramps) is conducted via the hypogastric (lower part of the abdomen) nerves to the lower thoracic (area of the chest) segments (Moore 1985).

Description of the intervention

We have investigated the effect of any one type of pharmacological intervention for pain relief during HSG compared with another type or with a placebo.

How the intervention might work

The pain experienced during and after HSG can have a negative impact on the woman’s ability to co‐operate with the procedure, thus limiting the usefulness of the investigation, as well as negatively influencing the woman’s willingness to undertake similar diagnostic studies. Therefore, establishing the most effective analgesia to offer during this procedure is important to minimise these factors.

Why it is important to do this review

A survey of Obstetric and Gynaecology departments in the United Kingdom reported a wide variation of practice with regards to pain relief in HSG. There appears to be no consensus in terms of if analgesia is considered, which analgesic is used, and when this analgesic is to be administered (personal comm: Ahmad, 2006). This review aims to report the evidence available.

Objectives

To compare the effectiveness of different types of pharmacological interventions for pain relief in women undergoing HSG during investigation of subfertility.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials comparing any one type of pharmacological intervention for pain relief during HSG with another type or a placebo or no treatment.

Types of participants

Women attending for HSG to investigate tubal patency.

Types of interventions

The following interventions were analysed:

1) Any analgesic (oral or topical) versus placebo or no treatment

a) Opioid analgesics versus placebo or no treatment

b) Non‐opioid analgesics e.g. NSAIDs, paracetamol, local anaesthesia and topical analgesia versus placebo or no treatment

c) Other comparisons within classes

2) Any analgesic versus any other analgesic

a) Opioid analgesic versus non‐opioid analgesic

b) Use of topical analgesics (including local anaesthesia and topical spray, gel, and cream) versus oral analgesics

c) Other comparisons within classes

Types of outcome measures

Primary outcomes

Pain score during the procedure (validated pain scale)

Pain score after the procedure (validated pain scale)

- Within the first 30 minutes after the procedure
- More than 30 minutes after the procedure

If any study reported a mean pain score on two separate occasions within the same group the earliest mean pain score was used.

Secondary outcomes

Adverse effects and complications: nausea, vomiting, constipation, drowsiness, respiratory depression, hypotension, allergic reaction and infection.

Search methods for identification of studies

See: Cochrane Menstrual Disorders and Subfertility Group (MDSG) methods used in reviews. All randomised controlled trials investigating pharmacological pain relief during HSG were obtained using the search strategies described below.

The MDSG Specialised Register of controlled trials was searched for any trials with our key words in the title, abstract, or keywords sections (Appendix 1). See the Review Group module for more details on the make‐up of the Specialised Register.

Electronic searches

Electronic databases were searched using Ovid software: MEDLINE (1950 to April 2015), CENTRAL (January 2007 to April 2015), EMBASE (1980 to April 2015), CINAHL (1982 to April 2015), PsycINFO (1806 to April 2015), (see Appendix 2, Appendix 3, Appendix 4, Appendix 5, Appendix 6).

The MEDLINE search was combined with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials which appears in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0 chapter 6, 6.4.11) (Higgins 2011). The EMBASE and CINAHL searches are combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (http://www.sign.ac.uk/methodology/filters.html#random).

Pubmed was also searched for recent trials not indexed by Medline (see Appendix 7), while Web of Knowledge was searched for conference abstracts (see Appendix 8).

There was no language restriction in these searches, and reports were included regardless of their publication type.

Searching other resources

LILACS database trials from the Portuguese‐ and Spanish‐speaking world was searched with the key word "hysterosalpingography" or "HSG" or "HyCoSy". The Database of Abstracts of Review Effects from the Cochrane library was also searched for reference lists from non‐Cochrane reviews on similar topics.

In addition, the following trial registers were searched for ongoing and registered trials: 'ClinicalTrials.gov', a service of the US National Institutes of Health (http://www.clinicaltrials.gov), and 'The World Health Organisation International Trials Registry Platform search portal' (http://www.who.int/trialsearch/Default.aspx) with key words "hysterosalpingography", "HSG" and "HyCoSy".

Grey literature was also searched through OpenGrey, with key words "hysterosalpingography", "Salpingography" or "HSG and pain".

Reference lists of identified studies were also searched, and experts in the field were consulted with a view to identifying further studies.

There was no language restriction in these searches, and reports were included regardless of their publication type.

Data collection and analysis

Selection of studies

Five review authors (GA, AW, HO’F, AH and LB) independently assessed the trials for eligibility for inclusion, in accordance with the eligibility criteria. Disagreements were resolved by AW.

Data extraction and management

Four review authors (GA, HO’F, AH and LB) independently extracted data. Disagreements were resolved by AW. Trials were analysed for the following: source, eligibility, methodological details, interventions (routes of delivery, doses, timing), descriptive data of participants (age, co‐morbidities), outcomes, and funding sources. Data were managed within a Microsoft Access database, in the form of a data collection form, before input into RevMan.

Assessment of risk of bias in included studies

We used Cochrane's tool for assessing risk of bias to assess that risk for each study. We considered the domains of selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias. We assessed the following for each study: concealed randomisation; allocation concealment; technique of randomisation; time of randomisation (pre‐ or intra‐operatively); number of randomised participants; number of participants not randomised, with explanation; participant exclusion; blinding of participants; blinding of observer; blinding of outcome assessment; documentation of drop‐outs; standardisation of outcome assessment; incomplete outcome data; selective outcome reporting; and whether the intention‐to‐treat analysis was employed. Information was managed within a 'Risk of bias' table.

Four review authors (GA, HO’F, AH and LB) independently performed all assessments of the risk of bias of trials and extracted data. All discrepancies were resolved by AW. Additional information on trial methodology and trial data was sought from the authors of trials which appear to meet the eligibility criteria but had aspects of methodology that were unclear, or where the data were in a form that was unsuitable for meta‐analysis

Measures of treatment effect

For dichotomous data (e.g. adverse events), we used the numbers of events in the control and intervention groups of each study to calculate Mantel‐Haenszel odds ratios (ORs). For continuous data, if all studies reported exactly the same outcomes we calculated mean difference (MD) between treatment groups. If similar outcomes were reported on different scales we planned to calculate the standardised mean difference (SMD).

Any validated pain scale was acceptable for inclusion of a trial into the review. If a study reported a mean pain score on two separate occasions within the same group, the earliest mean pain score was used. This was used instead of the peak mean pain score as pain peaks from the time of distension until five minutes after the procedure, so that at 30 minutes most women classify the pain as a discomfort (Owens 1985).

When interpreting the results of the comparison of an intervention to a placebo, a negative MD indicates that an intervention is superior to a placebo and a positive MD indicates that a placebo is superior to an intervention, in terms of their ability to reduce levels of pain.

We analysed the data and compared them according to the timing of the pain. The three timing groups were: pain during the procedure; pain within the first 30 minutes of the procedure; and pain more than 30 minutes following the procedure.

Unit of analysis issues

The following were addressed.

Multiple observations for the same outcome ‐ validated scores were given preference. In the meta‐analysis, a VAS score was preferentially used if reported, as this was the one validated score consistently reported across the studies.
If there were multiple intervention groups, we would preferentially combine all relevant experimental intervention groups of the study into a single group, and combine all relevant control intervention groups into a single control group. This was the case for Stoop 2010, where we combined the metal cannula and balloon cannula groups to form one intervention arm and one placebo arm. If this was not possible, we would instead split the ‘shared’ group into two or more groups with smaller sample size, and include two or more (reasonably independent) comparisons. This was the case for Owens 1985, Unlu 2015 and Karasahin 2009, where double counting was avoiding by halving the number of participants in the control arm of the study.

Dealing with missing data

Where the data were found to be incomplete or unsuitable for analysis, we contacted the original investigators to request missing data. The potential impact of missing data on the findings of the review were addressed.

Assessment of heterogeneity

Four methods were used to assess heterogeneity:

1. We performed a Chi² test. If significant, it was adjudged that there would be a strong possibility of high heterogeneity

2. We calculated the I² statistic to help determine heterogeneity. As a guide, the following thresholds were used:

0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity;
75% to 100%: considerable heterogeneity.

3. Overlap of the confidence interval of individual trials

4. Variations in the point estimate of individual trials

These four methods were considered, and the authors made a judgement on whether there was significant heterogeneity in the meta‐analysis, and the reasons for this were detailed in the text.

Assessment of reporting biases

The authors aimed to minimise the potential impact of reporting bias by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. Information on individual studies is included in tables (see tables in the section: Characteristics of included studies).

Data synthesis

We performed statistical analysis in accordance with the guidelines for statistical analysis developed by Cochrane (Higgins 2011). Results for each study were expressed as mean difference (MD) with 95% confidence intervals (CI) unless differing validated scales were reported, in which case a standard mean difference (SMD) would be used, and combined for meta‐analysis with RevMan software. When interpreting the results of the comparison of an intervention to a placebo, a negative MD indicates that an intervention is superior to a placebo in terms of ability to reduce levels of pain and a positive MD indicates that a placebo is superior to an intervention. Adverse effects were reported as odds ratios, with a fixed‐effect model.

The comparisons in the review are:

1) Any analgesic versus placebo or no treatment

1.1) oral opioid analgesics versus placebo or no treatment;

1.2) intravenous opioid analgesics versus placebo or no treatment;

1.3) non‐opioid oral analgesics e.g. NSAIDs or paracetamol versus placebo or no treatment;

1.4) non‐opioid topical analgesics e.g. local anaesthesia and topical spray, gel, and cream versus placebo or no treatment;

1.5) locally injected anaesthetic versus placebo or no treatment.

1.6 ) other comparisons within classes

2) Any analgesic versus any other analgesic

a) opioid analgesics versus non‐opioid analgesics;

b) use of topical analgesics (including local anaesthesia and topical spray, gel and cream) versus oral analgesics;

c) other comparisons within classes.

Subgroup analysis and investigation of heterogeneity

No subgroup analysis was done.

Where significant heterogeneity was identified, we explored the causes using the random‐effects model, and by performing sensitivity analyses.

Sensitivity analysis

We planned to conduct sensitivity analyses for the primary outcomes to determine whether the conclusions would have differed if eligibility were restricted to studies without high risk of bias.

Overall quality of the body of evidence: 'Summary of findings' table

We have prepared 'Summary of findings' tables using GRADEPRO or Guideline Development Tool software. These tables have evaluated the overall quality of the body of evidence for the main review outcomes (pain score during and post procedure, rate of completion of procedure and adverse events), using GRADE criteria (study limitations (i.e. risk of bias), consistency of effect, imprecision, indirectness and publication bias). Judgements about evidence quality (high, moderate or low) have been justified, documented, and incorporated into reporting of results for each outcome.

Results

Description of studies

See Characteristics of included studies and Characteristics of excluded studies

Results of the search

We retrieved 410 records by database searching, and retrieved 6 additional records by hand searching. We identified 297 records after duplicates were removed, and from these we assessed 25 full text articles for eligibility. We subsequently excluded two of these trials (as both were not deemed randomised trials). Overall, we included 23 randomised controlled trials (See Figure 1 and Characteristics of excluded studies).

Included studies

Study Design and Setting

All studies were randomised controlled trials investigating pain relief during HSG in the outpatient setting. Studies took place in India (Chauhan 2013; Gupta 2008), Australia (Costello 2002), United Kingdom (Elson 2000), United States of America (Bachman 2014; Frishman 2004; Jacobs 1991; Owens 1985; Robinson 2007), Turkey (Cengiz 2006; Hacivelioglu 2014; Hassa 2014; Kafali 2003; Karasahin 2009; Unlu 2015), Israel (Liberty 2007), Netherlands (Peters 1996), Italy (Anserini 2008), Iran (Kalantari 2014), Nigeria (Bello 2008), Spain (Arnau 2014), Brazil (de Mello 2006), and Belgium (Stoop 2010).

Power calculation was only stated in six trials (Arnau 2014; Costello 2002; Frishman 2004; Kalantari 2014; Stoop 2010; Unlu 2015).

Intention to treat was referred to in two studies (Owens 1985; Stoop 2010).

Participants

All participants were women attending for HSG in the outpatient setting for investigation of infertility.

The age of participants ranged from 18 to 42 years. However, only 19 studies provided information regarding the age of the participants (Anserini 2008; Arnau 2014; Bachman 2014; Bello 2008; Cengiz 2006; Costello 2002; de Mello 2006; Frishman 2004; Gupta 2008; Hacivelioglu 2014; Hassa 2014; Kalantari 2014; Karasahin 2009; Liberty 2007; Owens 1985; Peters 1996; Robinson 2007; Stoop 2010; Unlu 2015).

Other individual characteristics of participants were recorded inconsistently between studies, with different parameters being used. Therefore, they cannot be summarised easily. Instead, they have been detailed in the individual study's Characteristics of included studies table.

Interventions and Comparisons

We identified 19 randomised controlled trials that investigated the use of an analgesic versus placebo or no treatment for HSG, with a total of 1061 individual women investigated (Anserini 2008; Arnau 2014; Bachman 2014; Bello 2008; Cengiz 2006; Chauhan 2013; Costello 2002; de Mello 2006; Elson 2000; Frishman 2004; Hassa 2014; Kafali 2003; Kalantari 2014; Karasahin 2009; Liberty 2007; Owens 1985; Robinson 2007; Stoop 2010; Unlu 2015). Four RCTs were included that investigated the use of any analgesic versus any other analgesic for HSG, with a total of n = 533 (Table 9) (Gupta 2008; Hacivelioglu 2014; Jacobs 1991; Peters 1996).

1. Characteristics of included studies.

Study ID	Duration of follow up	Primary outcome	Power calculation	Intervention
Chauhan 2013	1 minute	Pain during and 1 minute after the procedure.	Not stated	Topical lidocaine versus no treatment.
Guzel 2010	30 minutes	Pain during, at 5 minutes and at 30 minutes post procedure.	Not stated	Oral flurbiprofen versus placebo.
Stoop 2010	30 minutes	Pain during and at 30 minutes post procedure.	Stated but unclear	Oral tramadol versus placebo.
Karashin 2009	End of procedure	Pain during the procedure	Not stated	Topical lidocaine versus placebo
Gupta 2008	30 minutes	Pain immediately after procedure and at 30 minutes post procedure	Present	Topical lignocaine versus oral naproxen.
Liberty 2007	End of procedure	Pain during and immediately after the procedure.	Present	Topical EMLA (lidocaine‐prilocaine) cream versus placebo
Fisherman 2004	10 minutes	Pain during, after 10 minutes	Present	Intrauterine lidocaine versus placebo
Costello 2002	10 minutes	Pain score during and after 10 minutes	Present	Intrauterine lignocaine versus placebo
Elson 2000	7 days	Pain score during, delayed pain score: 24 h and 7 days	Not stated	Paracetamol versus placebo
Jacobs 1991	120 minutes	Pain score during, immediately after (15, 30 minutes), delayed pain score (1, 2 h)	Not stated	Topical application of lidocaine versus paracervical block
Kafali 2003	30 minutes	Pain score during, immediately after, and 30 minutes	Not stated	Intrauterine lidocaine gel versus placebo
Owens 1985	1 h	Pain score during 5, 10, 15, 30, 45 minutes delayed (1 h)	Not stated	Aspirin versus Fenoprofen versus placebo
Peters 1996	24 h	Pain score immediately after the procedure, delayed pain score: 4, 8, 24 h	Not stated	Naproxen versus Tramadol

Topical Anaesthetic versus placebo or no treatment for Pain relief in hysterosalpingography
Participant or population: Women being investigated for infertility  Settings: Outpatient setting  Intervention: Topical Anaesthetic
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo or no treatment	Topical Anaesthetic
Mean Pain Score During HSG   VAS Scale (0 to 10)	The mean pain score during HSG in the topical anaesthetic groups was 0.63 lower (1.06 to 0.19 lower) than in the placebo or no treatment groups.			613  (9 studies)	⊕⊕⊝⊝  low^1,2,3,4,5
Mean Pain Score Less Than 30 minutes After HSG   Visual analogue Scale (0 to 10)	The mean pain score less than 30 minutes after HSG in the topical anaesthetic groups was 0.42 higher (0.3 lower to 0.86 higher) than in the placebo or no treatment groups.			373  (5 studies)	⊕⊝⊝⊝  very low^1,3,5,6,7
Mean Pain Score More Than 30 minutes After HSG   Visual analogue Scale (0 to 10)	The mean pain score more than 30 minutes after HSG in the topical anaesthetic groups was 1.38 lower (3.44 lower to 0.68 higher) than in the placebo or no treatment groups.			166  (2 studies)	⊕⊝⊝⊝  very low^{1,3, 7, 8}
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Oral Opioid analgesics versus placebo or no treatment for Pain relief in hysterosalpingography
Participant or population: Women being investigated for infertility  Settings: Outpatient setting  Intervention: Opioid analgesics
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Opioid analgesics
Mean Pain Score During HSG   Visual analogue Scale (0 to 10)	The mean pain score during HSG in the oral opioid analgesic groups was 0.91 lower (1.88 lower to 0.06 higher) than in the placebo or no treatment groups.			128  (1 study)	⊕⊕⊕⊝  Low^1,2,3,4,5	SMD −0.33 (−0.68 to 0.02)
Mean Pain Score More Than 30 minutes After HSG   Visual analogue scale (0 to 10)	The mean pain score more than 30 minutes after HSG in the oral opioid analgesic groups was 0.99 lower (1.75 to 0.23 lower) than in the placebo or no treatment groups.			128  (1 study)	⊕⊕⊕⊝  moderate^1,2,3,4
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Intravenous Opioid Analgesics versus placebo or no treatment for pain relief in HSG
Participant or population: Women being investigated for infertility  Settings: Outpatient setting  Intervention: Opioid versus Non‐Opioid Analgesics
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Opioid versus Non‐Opioid Analgesics
Mean Pain Score During HSG   Visual analogue scale (10 cm)	The mean pain score during HSG in the intravenous opioid analgesic groups was 3.53 lower (4.29 to 2.77 lower) than in the placebo or no treatment groups.			62  (1 study)	⊕⊕⊕⊝  moderate^1,2,3,4,5	SMD 0.33 (−0.09 to 0.74)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Oral non‐opioid analgesics versus placebo or no treatment for pain relief in hysterosalpingography
Participant or population: Women being investigated for infertility  Settings: Outpatient setting  Intervention: Oral Non‐Opioid analgesics
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Oral Non‐Opioid analgesics
Pain Score During HSG   Visual analogue scale (0 to 10)	The mean pain score during HSG in the oral non‐opioid analgesic groups was 0.13 lower (0.48 lower to 0.23 higher) than in the placebo or no treatment groups.			133  (3 studies)	⊕⊕⊝⊝  low^1,2,3,4
Pain Score Less Than 30 minutes After HSG   Visual analogue scale (0 to 10)	The mean pain score less than 30 minutes after HSG in the oral non‐opioid analgesic groups was 0.30 lower (−1.03 lower to 0.43 higher) than in the placebo or no treatment groups.			45  (2 studies)	⊕⊝⊝⊝  very low^1,3,4,5
Mean Pain Score More Than 30 minutes After HSG   Visual analogue Scale (0 to 10)	The mean pain score more than 30 minutes after HSG in the oral non‐opioid analgesic groups was 0.36 lower (1.06 lower to 0.34 higher) than in the placebo or no treatment groups.			133  (3 studies)	⊕⊕⊝⊝  low^1,3,4,6
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Locally injected anaesthetic versus placebo or no treatment for pain relief in HSG
Participant or population: Women being investigated for infertility  Settings: Outpatient setting  Intervention: Locally Injected Anaesthetic
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Locally Injected Anaesthetic
Mean Pain Score During HSG Visual analogue scale	The mean pain score during HSG in the locally injected anaesthetics groups was 1.31 lower (1.55 to 1.07 lower) than in the placebo or no treatment groups.			125  (2 studies)	⊕⊕⊝⊝  low^1,2,3
Mean Pain Score Less Than 30 minutes After HSG Visual analogue scale	The mean pain score less than 30 minutes after HSG in the locally injected anaesthetics groups was 1.31 standard deviations lower (2.14 to 0.49 lower) than in the placebo or no treatment groups.			125  (2 studies)	⊕⊕⊝⊝  low^1,2,4
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Oral opioid versus oral non‐opioid analgesics for pain relief in HSG
Participant or population: Women being investigated for infertility  Settings: Outpatient setting  Intervention: Opoid versus Non‐Opoid Analgesics
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Non‐Opioid Analgesics	Opioid Analgesics
Mean Pain Score During HSG   Visual analogue Scale (0 to 10)	The mean pain score during HSG in the opioid analgesics groups was 1.10 higher (0.09 lower to 0.74 higher) than in the non‐opioid groups.			91  (1 study)	⊕⊕⊝⊝  low^1,2,3,4
Mean Pain Score Less Than 30 minutes After HSG   Visual analogue Scale (0 to 10)	The mean pain score less than 30 minutes after HSG in the opioid analgesics groups was 0.30 lower (1.00 lower to 0.40 higher) than in the non‐opioid groups.			91  (1 study)	⊕⊕⊝⊝  low^1,2,3,4
Mean Pain Score More Than 30 minutes After HSG   Visual analogue Scale (0 to 10)	The mean pain score more than 30 minutes after HSG in the opioid analgesics groups was 0.60 lower (1.56 lower to 0.36 higher) than in the non‐opioid groups.			91  (1 study)	⊕⊕⊝⊝  low^1,2,3,4
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Topical anaesthetic versus paracervical block for pain relief in HSG
Participant or population: Women being investigated for infertility  Settings: Outpatient setting  Intervention: Topical Anaesthetic versus Para‐Cervical Block
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Paracervical Block	Topical Anaesthetic
Mean Pain Score During HSG   Visual analogue scale (0 to 10)	The mean pain score during HSG in the topical anaesthetic group groups was 2.73 lower (−3.86 to −1.60 lower) than the paracervical block group.			20  (1 study)	⊕⊕⊕⊝  moderate^1,2,3,4	SMD −2.03 (−3.16 to −0.91)
Mean Pain Score Less Than 30 minutes After HSG   Visual analogue scale (0 to 10)	The mean pain score less than 30 minutes after HSG in the topical anaesthetic group was 1.03 lower (−2.52 lower to 0.46 higher) than the paracervical block group			20  (1 study)	⊕⊕⊝⊝  low^1,2,3,4,5	SMD −0.58 (−1.48 to 0.32)
Mean Pain Score More Than 30 minutes After HSG   Visual analogue scale (0 to 10)	The mean pain score more than 30 minutes after HSG in the topical anaesthetic group was 0.31 standard deviations higher (0.87 lower to 1.49 higher) than the paracervical block group			20  (1 study)	⊕⊕⊝⊝  low^1,2,3,4,5	SMD 0.22 (−0.66 to 1.1)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Topical anaesthetic versus non‐opioid analgesics for pain relief in HSG
Participant or population: Women being investigated for infertility  Settings: Outpatient setting  Intervention: Topical Anaesthetic versus Non‐Opioid Analgesics
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Non‐Opioid Analgesics	Topical Anaesthetic
Mean pain score within 30 minutes after HSG   Visual analogue scale	The mean pain score within 30 minutes after HSG in the topical anaesthetic groups was 0.60 higher (0.20 lower to 1.40 higher) than the non‐opioid analgesics group.			100  (1 study)	⊕⊝⊝⊝  very low^1,2,3,4	SMD 0.29 (−0.1 to 0.69)
Mean pain score more than 30 minutes after HSG   Visual analogue scale	The mean pain score more than 30 minutes after HSG in the topical anaesthetic groups was 0.58 standard deviations higher (0.01 lower to 1.17 higher) than the non‐opioid analgesics group.			100  (1 study)	⊕⊝⊝⊝  very low^1,2,3,4	SMD 0.38 (−0.01 to 0.78)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Date	Event	Description
5 May 2015	New search has been performed	Review has been updated. An updated search was carried out current to April 2015, with 16 new trials being incorporated into the review (Anserini 2008; Arnau 2014; Bachman 2014; Bello 2008; Cengiz 2006; Chauhan 2013; de Mello 2006; Gupta 2008; Hacivelioglu 2014; Hassa 2014; Kalantari 2014; Karasahin 2009; Liberty 2007; Robinson 2007, Stoop 2010; Unlu 2015;). One trial included in the last published version was found not to be randomised and has been excluded (Lorino 1990).  The review and the analyses have also been revised to meet up‐to‐date Cochrane guidance. As a result, the conclusions of the report have been substantially re‐worked.
5 May 2015	New citation required but conclusions have not changed	The conclusions of the review have not changed with the addition of 16 new trials.

Date	Event	Description
7 November 2008	Amended	Converted to new review format.
7 February 2007	New citation required and conclusions have changed	Substantive amendment

#	Query	Results
S51	S49 AND S50	1
S50	EM 2014* or EM 2015*	439,602
S49	S34 AND S48	8
S48	S35 OR S36 or S37 or S38 OR S39 OR S40 OR S41 OR S42 OR S43 OR S44 OR S45 OR S46 OR S47	954,513
S47	TX allocat* random*	4,243
S46	(MH "Quantitative Studies")	13,282
S45	(MH "Placebos")	9,173
S44	TX placebo*	33,620
S43	TX random* allocat*	4,243
S42	(MH "Random Assignment")	38,985
S41	TX randomi* control* trial*	85,907
S40	TX ( (singl* n1 blind) or (singl n1 mask) ) or TX ( (doubl n1 blind) or (doubl n1 mask) ) or TX ( (tripl n1 blind) or (tripl n1 mask) ) or TX ( (trebl n1 blind) or (trebl n1 mask*) )	763,614
S39	TX ( (trebl* n1 blind) or (trebl n1 mask*) )	114
S38	TX ( (trebl* n1 blind) or (trebl n1 mask*) )	0
S37	TX clinic* n1 trial*	170,899
S36	PT Clinical trial	77,668
S35	(MH "Clinical Trials+")	186,062
S34	S7 AND S33	11
S33	S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32	77,879
S32	(MM "Tramadol") OR "Tx Tramadol"	494
S31	TX EMLA	282
S30	(MM "Lidocaine")	1,990
S29	TX lidocaine‐prilocaine	47
S28	(MM "Naproxen") OR "naproxen"	700
S27	(MM "Ibuprofen") OR "ibuprofen"	1,786
S26	(MM "Diclofenac")	527
S25	TX diclofenac	1,192
S24	TX nonsteroidal antiinflammator*	651
S23	(MM "Antiinflammatory Agents, Non‐Steroidal")	4,285
S22	TX NSAID*	3,242
S21	TX paracetamol	1,210
S20	TX (pain N2 relief)	9,262
S19	TX morphine	6,686
S18	TX(hypnovel or midazolam)	2,441
S17	TX (nerve block)	5,744
S16	TX (fentanyl or remifentanil)	4,413
S15	(MM "Nerve Block")	4,067
S14	TX opioid	14,654
S13	TX (lidocaine or lignocaine)	4,393

Methods	Randomised double‐blind, placebo‐controlled trial taking place between December 2011 and April 2012. 15 control, 15 study group. None lost to follow up. Single centre at Philadelphia, USA.
Participants	Women undergoing HSG. Mean age 33.8 years. Pre‐procedure ibuprofen was recommended (taken by 94% in intervention group and 87% in placebo group ‐ the rest took paracetamol). Women were excluded if they had a positive pregnancy test on the day of the HSG, or if they reported hypersensitivity to benzocaine or related analgesic agents. The following characteristics were measured (% of study group, unless otherwise stated): race (47% Caucasian, 37% Black, 13% Asian, 3% Mixed), nulligravid (57%), nulliparous (80%), history of dysmenorrhoea (43%), history of chronic pelvic pain (13%), bilateral obstruction (10%) and unilateral obstruction (23%). The study found no significant difference between control and study group in each of these characteristics.
Interventions	Topical anaesthetic versus placebo. Benzocaine spray (concentration not stated) compared to saline. Both were sprayed on the anterior lip of cervix prior to application of tenaculum. Participants were followed up for 30 minutes post procedure. Ibuprofen was used as a co‐intervention (taken by 100% in treatment group and 86.7% in intervention group).
Outcomes	Mean pain score taken immediately after the procedure, and at 5 and 30 minutes post procedure. Outcomes included a visual analogue scale (10 cm) and a validated satisfaction survey (5 point scale).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was performed by the Investigational Drug Service at the Hospital of the University of Pennsylvania via computer‐generated random‐number sequence in blocks of four. Drug canisters were blinded to both patient and clinician". Comment: blocked randomization method using computer generated sequence. Likely low risk of bias.
Allocation concealment (selection bias)	Unclear risk	Quote: "Randomization was performed by the Investigational Drug Service at the Hospital of the University of Pennsylvania via computer‐generated random‐number sequence in blocks of four. Drug canisters were blinded to both patient and clinician". Comment: method used to protect allocation sequence before and until assignment not specifically outlined in text.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Quote: "Drug canisters were blinded to both patient and clinician". Comment: participants and healthcare providers were stated as blinded from the contents of the drug canisters. Probably adequate.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "Only 29 patients received either benzocaine or placebo saline spray due to a single canister malfunction". Comment: participant was part of treatment group. Intention‐to‐treat analysis used. Malfunction unlikely to be connected to subsequent outcome, and thus deemed low risk.
Selective reporting (reporting bias)	High risk	Comment: only median pain scores and range reported in trial. No means or standard deviations. Furthermore, no adverse effects data was provided in the study.
Other bias	Low risk	No other bias

Methods	Randomised, double‐blind, placebo‐ controlled trial. 49 control, 39 study group. 12 lost to follow up. Single centre at Middlesex, UK.
Participants	Women undergoing HSG, age and previous work‐up not stated. Women were excluded if they had a history of allergy to paracetamol, or were taking analgesics, cold remedies or anti‐inflammatory medication on entry into the study. The following characteristics were measured (% of study group, unless otherwise stated): nulliparity (61%), technically difficult procedure (26%), sex of operator (40% male), experience of doctor (35% considered inexperienced), ethnicity (51% non‐Caucasian), abnormality on HSG (40%) The study found no significant difference between control and study group in each of these characteristics.
Interventions	Non‐opioid analgesic versus placebo or no treatment. 1 g of paracetamol versus placebo taken 30 minutes before HSG.  Duration of follow‐up 7 days post procedure. No co‐intervention.
Outcomes	Pain score during the procedure (mean pain score). Delayed pain score (mean pain score): 24h and 7 days, using visual analogue scale (10 cm).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The randomization of 1 g of paracetamol and identically matched placebo was undertaken by the hospital pharmacy department and coded in ascending numerical order" Comment: method of sequence generation not adequately detailed
Allocation concealment (selection bias)	Unclear risk	Quote: "The randomization of 1 g of paracetamol and identically matched placebo was undertaken by the hospital pharmacy department and coded in ascending numerical order. Patients received either paracetamol or placebo 30 min before the procedure." Comment: no mention of whether there were any efforts to ensure concealment of allocation.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Quote: simply states "this double blind randomized controlled trial" Comment: specific method of blinding is unclear. While trial is placebo controlled, there was no mention as to whether there were any steps to blind participants or operators to the allocation.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Quote: "88 out of 100 returned questionnaires". Comment: unclear why 12 participants did not return questionnaires, and whether this would affect the risk of bias.
Selective reporting (reporting bias)	Unclear risk	Comment: no evidence of adverse effects data being reported in the trial.
Other bias	Low risk	No other bias.

Methods	Randomised double‐blind trial taking place between 2011 and 2012. Participants: 57 control, 57 misoprostol group and 54 NSAID group. None lost to follow up. Single centre at Eskisehir, Turkey.
Participants	Females undergoing HSG for infertility, with mean age of 28.6. Participants were excluded based on "1) contraindication to misoprostol‐ cardiovascular disease, hypertension, severe asthma, glaucoma, renal failure, or allergy to prostaglandins; 2) contraindication to OH‐ cervical stenosis, active or recent cervical‐endometrial infection, profuse vaginal bleeding, known reproductive tract malignancy, pregnancy; 3) contraindications to NSAIDs‐ previously reported adverse reaction, known hypersensitivity, known gastroesophageal disease, genital bleeding; 4) other‐ history of cervical operation, presence of acute pelvic inflammatory disease, use of analgesics during the study period." The following characteristics were measured (% of study group, unless otherwise stated): BMI (mean 23.8), history of endometriosis (6%), total time of HSG (mean 2.6 min), volume of contrast infused (mean 11.7 ml), analgesic requirement after HSG (3%), vasovagal symptoms during HSG (5%). There was no significant difference in these characteristics between study groups.
Interventions	2 comparisons: 1: oral analgesic versus placebo. Oral NSAID (diclofenac potassium) 45 to 60 minutes before HSG versus no treatment. Duration of follow up 30 minutes post procedure. No co‐intervention. 2: oral analgesic versus placebo. Oral misoprostol (diclofenac potassium) 45 to 60 minutes before HSG versus no treatment. Duration of follow up 30 minutes post procedure. No co‐intervention.
Outcomes	Pain score during procedure (one value, written retrospectively post procedure), and pain score 30 minutes post procedure. Using visual analogue scale (10 cm). Vasovagal effects were reported as a secondary outcome.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "women were randomized into three groups using computer‐generated random numbers". Comment: probably adequate.
Allocation concealment (selection bias)	Unclear risk	Quote: "women were randomized into three groups using computer‐generated random numbers". Comment: no mention of steps taken to ensure concealment of allocation prior to randomization.
Blinding (performance bias and detection bias)   All outcomes	High risk	Quote: "Patients who did not receive any drug were enrolled into the control group". Comment: no placebo medication. No indication that study was blinded to either participant or operator.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: 168 participants randomised, with no drop‐outs during the study.
Selective reporting (reporting bias)	High risk	Comment: outcomes reported as median and interquartile range, with no means. Not enough evidence to rule out the possibility that the data may be skewed, so this was deemed high risk. Unclear if other adverse effects apart from vasovagal reactions occurred in the study.
Other bias	Low risk	No other bias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Oral opioid analgesic versus placebo or no treatment	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.1 Mean VAS pain score during HSG	1	128	Mean Difference (IV, Random, 95% CI)	‐0.91 [‐1.88, 0.06]
1.2 Mean VAS pain score more than 30 minutes after HSG	1	128	Mean Difference (IV, Random, 95% CI)	‐0.99 [‐1.75, ‐0.23]
2 Intravenous opioid analgesic versus placebo or no treatment	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.1 Mean VAS pain score during HSG	1	62	Mean Difference (IV, Random, 95% CI)	‐3.53 [‐4.29, ‐2.77]
3 Oral non‐opioid analgesic versus placebo or no treatment	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.1 Mean VAS pain score during HSG	2	133	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.48, 0.23]
3.2 Mean VAS pain score within 30 minutes after HSG	1	45	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐1.03, 0.43]
3.3 Mean VAS pain score more than 30 minutes after HSG	2	133	Mean Difference (IV, Random, 95% CI)	‐0.36 [‐1.06, 0.34]
4 Topical anaesthetic versus placebo or no treatment	7		Mean Difference (IV, Random, 95% CI)	Subtotals only
4.1 Mean VAS pain score during HSG	7	613	Mean Difference (IV, Random, 95% CI)	‐0.63 [‐1.06, ‐0.19]
4.2 Mean VAS pain score within 30 minutes after HSG	4	373	Mean Difference (IV, Random, 95% CI)	0.42 [‐0.03, 0.86]
4.3 Mean VAS pain score more than 30 minutes after HSG	2	166	Mean Difference (IV, Random, 95% CI)	‐1.38 [‐3.44, 0.68]
5 Locally injected anaesthetic versus placebo or no treatment	2	250	Mean Difference (IV, Random, 95% CI)	‐1.39 [‐1.59, ‐1.18]
5.1 Mean VAS pain score during HSG	2	125	Mean Difference (IV, Random, 95% CI)	‐1.31 [‐1.55, ‐1.07]
5.2 Mean VAS pain score within 30 minutes after HSG	2	125	Mean Difference (IV, Random, 95% CI)	‐1.31 [‐2.14, ‐0.49]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean VAS pain score during HSG	12		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.1 Oral opioid analgesic versus placebo or no treatment	1	128	Mean Difference (IV, Random, 95% CI)	‐0.91 [‐1.88, 0.06]
1.2 Intravenous opioid analgesic versus placebo or no treatment	1	62	Mean Difference (IV, Random, 95% CI)	‐3.53 [‐4.29, ‐2.77]
1.3 Non‐opioid analgesic versus placebo or no treatment	2	133	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.48, 0.23]
1.4 Topical anaesthetic versus placebo or no treatment	7	613	Mean Difference (IV, Random, 95% CI)	‐0.63 [‐1.06, ‐0.19]
1.5 Locally injected anaesthetic versus placebo or no treatment	2	125	Mean Difference (IV, Random, 95% CI)	‐1.31 [‐1.55, ‐1.07]
2 Mean VAS pain score within 30 minutes after HSG	6		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.1 Non‐opioid analgesic versus placebo or no treatment	1	45	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐1.03, 0.43]
2.2 Topical anaesthetic versus placebo or no treatment	4	373	Mean Difference (IV, Random, 95% CI)	0.42 [‐0.03, 0.86]
2.3 Locally injected anaesthetic versus placebo or no treatment	2	125	Mean Difference (IV, Random, 95% CI)	‐1.31 [‐2.14, ‐0.49]
3 Mean VAS pain score more than 30 minutes after HSG	5		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.1 Oral opioid analgesic versus placebo or no treatment	1	128	Mean Difference (IV, Random, 95% CI)	‐0.99 [‐1.75, ‐0.23]
3.2 Non‐opioid analgesic versus placebo or no treatment	2	133	Mean Difference (IV, Random, 95% CI)	‐0.36 [‐1.06, 0.34]
3.3 Topical anaesthetic versus placebo or no treatment	2	166	Mean Difference (IV, Random, 95% CI)	‐1.38 [‐3.44, 0.68]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Opioid versus non‐opioid	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.1 Mean VAS pain score during HSG	1	91	Mean Difference (IV, Random, 95% CI)	1.10 [‐0.26, 2.46]
1.2 Mean VAS pain score within 30 minutes after HSG	1	91	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐1.00, 0.40]
1.3 Mean VAS pain score more than 30 minutes after HSG	1	91	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐1.56, 0.36]
2 Topical anaesthetic versus para‐cervical block	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.1 Mean VAS pain score during HSG	1	20	Mean Difference (IV, Random, 95% CI)	‐2.73 [‐3.86, ‐1.60]
2.2 Mean VAS pain score within 30 minutes after HSG	1	20	Mean Difference (IV, Random, 95% CI)	‐1.03 [‐2.52, 0.46]
2.3 Mean VAS pain score more than 30 minutes after HSG	1	20	Mean Difference (IV, Random, 95% CI)	0.31 [‐0.87, 1.49]
3 Topical anaesthetic versus non‐opioid analgesics	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.1 Mean VAS pain score during HSG	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Mean VAS pain score within 30 minutes after HSG	1	100	Mean Difference (IV, Random, 95% CI)	0.60 [‐0.20, 1.40]
3.3 Mean VAS pain score more than 30 minutes after HSG	1	100	Mean Difference (IV, Random, 95% CI)	0.58 [‐0.01, 1.17]

Methods	Randomised controlled trial taking place between March 2004 and April 2005. 44 Control group, 40 Study group. None lost to follow up. Single centre, Oyo State, Nigeria.
Participants	Women undergoing HSG for infertility. Mean age 31.5 years. Pre‐medication with 20 mg IV Hysocine N Butylbromide for all participants. Exclusion criteria not outlined by the study. The following characteristics were measured (% of study group, unless otherwise stated): indication (17% for primary infertility, 81% for secondary infertility, 2% for Asherman's syndrome), results (63% bilateral patent tubes, 24% bilateral blocked tubes, 9% unilateral blocked tubes, 4% unidentified). No significance calculation carried out between these characteristics.
Interventions	Intravenous opioid versus no treatment. 100 mg IV tramadol given 5 minutes before the procedure versus no treatment. Participants followed up 5 minutes after the procedure. Co‐intervention with 20 mg IV Hyoscine N Butylbromide for all participants.
Outcomes	Mean pain score during the procedure (one value only). Outcomes recorded on a 10 point numeric rating scale (a modified VAS).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The randomization of the patient and the pre‐medication with the appropriate drug was done by the consultant radiologist" Comment: method of randomization not outlined.
Allocation concealment (selection bias)	Unclear risk	Quote: "The randomization of the patient and the pre‐medication with the appropriate drug was done by the consultant radiologist" Comment: no detail on the steps taken to ensure concealment of allocation from the consultant radiologist prior to time of participant entry into the study.
Blinding (performance bias and detection bias)   All outcomes	High risk	Quote: "Group A... had pre‐medication with intravenous tramadol (100mg) and IV hyoscine N butylbromide. The second group (Group B) comprising of 44 women had pre‐medication with IV Hyoscine N butylbromide (20 mg) only." Comment: no placebo used. No mention of trial being single or double blinded. No mention of steps to ensure operator blinding. Likely that trial was not blinded.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: no mention of drop‐outs. Of the 84 women entered into the trial, all had outcomes reported.
Selective reporting (reporting bias)	High risk	Quote: "Numeric rating scale...has been discovered easier for subjects to be used, resulting in less missing and unclear responses". Comment: study authors adequately justified their use of the numeric pain score over the more commonly used VAS. However, no standard deviations reported in the trial. Furthermore, no adverse effects data was reported.
Other bias	Low risk	No other bias

Methods	Randomised controlled trial of unclear duration. 50 control, 50 study group. None lost to follow up. Single centre at Rohtak, India.
Participants	Females undergoing HSG for infertility, with mean age 25.62 and mean weight of 60kg. Exclusion criteria included a history of allergy to local anaesthetics or radio‐opaque dye, active pelvic inflammatory diseases, and active tuberculosis. The following characteristics were measured (% of study group, unless otherwise stated): weight (mean weight 60.1Kg), duration of infertility (mean 7.06 years), primary infertility (37%), secondary infertility (13%). The study found no significant difference between control and study group in each of these characteristics.
Interventions	Injected local anaesthetic versus no treatment. Compared 6 ml of 1% lidocaine versus no treatment. Lidocaine was injected into the cervix in divided doses of 1.5 ml each circumferentially at 12, 4, 6, 8 o’clock positions, and five minutes were allowed to elapse before proceeding to HSG. Duration of follow up 1 min post procedure. No co‐intervention.
Outcomes	Pain score taken before beginning the procedure (baseline), just after intracervical block, at the time of tenaculum placement, following counter traction on the tenaculum, on instillation of dye and one minute following the removal of instruments. Used the verbal descriptor scale and visual analogue scale (10 cm).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Once the women were found to meet enrolment criteria, they were divided randomly through a computer generated table into two groups of 50 women each". Comment: method is probably adequate
Allocation concealment (selection bias)	Unclear risk	Quote: "Once the women were found to meet enrolment criteria, they were divided randomly through a computer generated table into two groups of 50 women each." Comment: allocation concealment not directly addressed in the text.
Blinding (performance bias and detection bias)   All outcomes	High risk	Quote: "In the study group women received intracervical block along with premedication whereas the control group women received only premedication". Comment: blinding of participants and operator not done as no placebo injection was used in the control group.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: no mention of dropouts. Of the 100 participants entered into the trial, all had complete outcome data.
Selective reporting (reporting bias)	Low risk	Comment: though no power calculation was performed, there was no evidence of selective reporting, with all outcomes mentioned in the methods being reported in the results clearly.
Other bias	Low risk	No other bias.

Methods	Randomised, double‐blind, placebo‐controlled trial. 55 control, 55 study group. None lost to follow‐up. Single centre at Randwick, Australia.
Participants	Women undergoing HSG. Mean age 34 years. Participants instructed to take 2x 275 mg Naproxen 2 hours prior to HSG. No exclusion criteria were specified by the authors in the methods. The following characteristics were measured (% of study group, unless otherwise stated): nulliparous (77%), past vaginal delivery (14.5%), pre‐HSG Naproxen (93%), past cervical surgery (4.5%), cervical dilation required (12.7%), back leak of local saline (6.3%), volume of contrast infused (10.6mls), tubal obstruction (20%), Air bubbles in uterine cavity (16.3%). The study found no significant difference between control and study group in each of these characteristics.
Interventions	Intrauterine local anaesthetic versus placebo or no treatment. 2 ml of 2% plain lignocaine versus 2 ml of 0.9% NaCl solution topically into the uterine cavity.  Duration of follow‐up 10 minutes post procedure. Co‐intervention: 2 x 275 mg of naproxen sodium 2 h before HSG.
Outcomes	Mean pain score taken during the procedure and at 10 minutes after the procedure using verbal descriptor scale and visual analogue scale (20 cm).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was performed using a computer‐generated random numbers table" Comment: sequence generation method is likely adequate.
Allocation concealment (selection bias)	Unclear risk	Comment: authors did not mention if any measures were employed to ensure concealment of allocation.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Quote: "Both the physician performing the procedure and the subject were blinded to the treatment assignment." "solution was drawn up by the hospital pharmacy department". Comment: probably adequate.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "all 110 subjects successfully completed their allocated treatment and no patients withdrew from the study", "The subjects themselves recorded the pain scores." Comment: probably adequate, with no significant attrition.
Selective reporting (reporting bias)	Unclear risk	Comment: no exclusion criteria was stated by the authors, and there is no evidence to imply whether this was because there were no exclusions, or whether those that were excluded were not documented in the results. However, all outcomes mentioned in the methods were accounted for in the results, including the pain scores.
Other bias	High risk	Quote: "Both groups were similar in...number of patients correctly taking their pre‐HSG naproxen sodium tablets". Comment: in the lignocaine group, 6 of the 55 participants (10.9%) did not take pre‐HSG naproxen, while in the placebo group, only 1 of the 55 women (1.8%) did not take their pre‐proceedure naproxen. The authors argue that there was no significant difference between groups, as the P value calculated was 0.113. However, this high P value can also be due to the very small numbers of participants in each group and, on direct comparison, a much larger proportion of participants in the intervention group did not take their naproxen when compared to the control group. This, we feel, could in part explain why subjects in the lignocaine group were found to experience more pain at 10 minutes when compared to placebo, and thus could have influenced the conclusions of this report.

Methods	Randomised controlled trial undertaken between January and November 2003. 30 control, 29 study group. None lost to follow up. Single centre at Sao Paulo, Brazil.
Participants	Females undergoing HSG for infertility, with mean age 31.5 years. Exclusion criteria included the "use of any medications (except for the hyoscine butyl bromide and dipyrone) that increases or decreases neurologic thresholds of pain; and any disease process associated with increasing or decreasing thresholds of pain, whether central (such as depression or hypothyroidism) or local (such as endometriosis, constipation, chronic pelvic pain, lower back pain, or diabetes). Participant suspected of complete uterine synechiae or amenorrhoea after curettage and participants submitted to a technique other than the one designated for the specific day (in situations in which the use of another specific catheter was appropriate) were also excluded". The following characteristics were measured (% of study group, unless otherwise stated): constipation (39%), previous pelvic surgeries (34%), previous labour (47%), dysmenorrhoea (66%), tubal ligation (12%).
Interventions	Paracervical block versus no treatment. 3 ml 1% lidocaine injected in the vaginal cavity at the 2, 4, 8 and 10 o'clock positions compared to no treatment. Participants were followed up until immediately after the procedure. Oral hyoscine butylbromide and dipyrone used as co‐intervention in both groups. Third group was also analysed using a balloon cannula (as opposed to a metal cannula) without paracervical block. As it was not concerning pharmacological pain relief, it was not included as part of this systematic review.
Outcomes	Mean pain scores taken immediately after the procedure using the VAS (10 cm). Three level pain rating was also applied for specific steps throughout the procedure (no evidence of validation of this method).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Eighty‐nine patients were randomly assigned to one of three groups." Comment: method of randomization not detailed in the text
Allocation concealment (selection bias)	Unclear risk	Comment: there was no evidence on whether steps were taken to properly conceal allocation.
Blinding (performance bias and detection bias)   All outcomes	High risk	Quote: "In group 1, 30 patients underwent the technique performed with a metal cannula without anaesthetic; in group 2, 29 patients underwent the technique performed with a metal cannula with previous paracervical anaesthetic block". Comment: no placebo injection used to blind the paracervical anaesthetic injection. Study was therefore not blinded to operator, and was unlikely to be blinded to the participant.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: no mention of dropouts. Of the 89 participants entered into the trial, all had complete outcome data.
Selective reporting (reporting bias)	High risk	Quote: "The mean VAS score for group 1 (metal cannula technique without anaesthetic) was significantly higher than that for the other two groups". Comment: while mean VAS scores were reported, no standard deviations were given in the study, and review authors were unable to contact the authors regarding this. Furthermore, no adverse effects data was reported.
Other bias	Low risk	No other bias

Methods	Randomised placebo‐controlled trial. 40 control, 40 study group. 0 drop‐outs. Single centre at Tehran, Iran.
Participants	Women undergoing HSG for investigation of infertility. Mean age 29.65 years. The study excluded women with a history of cervical surgery and with known hypersensitivity to topical analgesics. Women were excluded if: 1) they had a history of hypersensitivity to local anaesthetics or were strictly prohibited to use local anaesthetics; 2) they had used oral analgesics before the procedure; 3) they had a history of chronic pelvic pain or dysmenorrhoea; 4) they could not cooperate or if there was any problem during the procedure such as difficulty in instrument application or difficulty in uterine expansion when there was need for more contrast injection. No data on participant characteristics were reported.
Interventions	Topical anaesthetic versus placebo. 5 g of EMLA cream versus placebo cream applied 15 minutes prior to the procedure. Participants were followed up until 30 minutes after the procedure. No co‐intervention.
Outcomes	Participants were asked to record their pain scores on speculum application, cervical instrumentation, at the end of uterine filling, on speculum and cannula withdrawal, and 30 minutes after the procedure ended. Pain was measured using a Visual Analogue Scale (10 cm).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomized to EMLA or control groups by a computer generated random allocation. We used block randomization without stratifying on confounder variables. A statistician generated the allocation sequence." Comment: random sequence method adequately detailed.
Allocation concealment (selection bias)	Low risk	Quote: "Before completing a questionnaire, participants were randomly allocated by specifying numbers on questionnaires by a secretary. The people who generated the allocation scheme were not involved in ascertaining eligibility, performing the procedure, and assessing the outcome." Comment: allocation adequately concealed using a third party.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Quote: "Both the HSG operator and the patient were blinded to the randomization. A researcher and HSG operator blinded to the randomization recorded the pain score specified by the patient at each stage of the procedure", "In the control group, a placebo cream identical in colour, smell and texture was used". Comment: blinding probably adequate.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: flow diagram in study indicated no dropouts after allocation. Therefore, deemed low risk.
Selective reporting (reporting bias)	Unclear risk	Comment: no evidence of selective reporting with pain outcomes. However, no adverse effects data was reported.
Other bias	Low risk	No other bias.

Methods	Randomised placebo controlled trial. 27 control, 27 study group. None lost to follow up. Single centre at Ankara, Turkey.
Participants	Women undergoing HSG for investigation of infertility. Mean age 27.65 years. The study excluded women with a history of cervical surgery and with known hypersensitivity to topical analgesics. The following characteristics were measured (% of study group): nulliparity (27%), dysmenorrhoea (52% moderate/severe), previous endometrial biopsy (34%), previous PID (19%), previous HSG (21%), difficult instrumentation (25%), difficult filling pressure during HSG (35%), and uterine position (49% anteverted). The study found no significant difference between control and study group in each of these characteristics.
Interventions	2 comparisons: 1‐ Topical analgesia versus placebo. 10 mg lidocaine HCl 10% compared to a sterile saline solution, both of which were sprayed onto the cervix 3 minutes prior to the procedure. Followed up until the end of the procedure. No co‐intervention. 2‐ Topical analgesia versus placebo. 20 mg lidocaine HCl 10% compared to a sterile saline solution, both of which were sprayed onto the cervix 3 minutes prior to the procedure. Followed up until the end of the procedure. No co‐intervention.
Outcomes	Participants were asked to record their expected pain scores pre‐HSG, their pain during uterine traction (after the tenaculum had been applied), and their pain during contrast medium injection. Pain was measured using a Visual Analogue Scale (10 cm)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "We randomly assigned the patients to three groups using the closed envelope method" Comment: while authors state that study was randomised, method of sequence generation was not detailed.
Allocation concealment (selection bias)	Unclear risk	Quote: "We randomly assigned the patients to three groups using the closed envelope method" Comment: state using a closed envelope method, but are unclear if this means sequential opaque envelopes
Blinding (performance bias and detection bias)   All outcomes	High risk	Comment: trial is not described in the text as blinded. Furthermore, methods show no evidence of any attempt to blind the study participants or outcome assessors. Probably not done.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: no mention of any drop‐outs. Of the 81 women entered into the trial, all had outcomes reported in the final results.
Selective reporting (reporting bias)	Low risk	Comment: while no power calculation was reported, no evidence of any selective reporting was noted. All outcomes mentioned in the methods were reported clearly and unambiguously.
Other bias	Low risk	No other bias

Methods	Randomised double‐blinded placebo controlled trial. 42 in intervention group and 40 in placebo group. No loss to follow up. Single centre trial at Ben‐Gurion University of Negev, Beer Sheba, Israel.
Participants	Women undergoing HSG for infertility investigation. Mean age of 30 years in both intervention and placebo group. Women were excluded if they had a known hypersensitivity to local anaesthetics, or used oral analgesics prior to the procedure. The following characteristics were measured (% of study group unless otherwise stated): infertility duration (mean 1.8 years), primary infertility (42%), nulliparity (65%), dysmenorrhoea (51%), dyspareunia (19%), past PID (4%), previous gynaecological operation (29%), previous vaginal delivery(34%), past caesarian (10%), past abortion (32%). The study found no significant difference between control and study group in each of these characteristics.
Interventions	3 ml of EMLA or placebo cream applied to cervix 30 minutes before procedure. No co‐intervention.
Outcomes	Pain score after speculum application, after cervical instrumentation, at the end of uterine filling with contrast media, at the end of tubal spillage and at the end of the procedure. 10 cm visual analogue scale used.
Notes	No re‐inclusion of drop out into final analysis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomized to EMLA or control groups using computer generated random numbers" Comment: probably adequate
Allocation concealment (selection bias)	Unclear risk	Quote: "The allocation was concealed until the statistical evaluation of the results", "Both the HSG operator and the patient were blinded to the randomization" Comment: though the authors state that the allocation was concealed, the method of concealment was not stated.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Quote: "double‐blinded prospective study", "In both groups, cervical cups (PRODIMED, NEUILLY EN THELLE, France) were filled with 3 ml of creams, identical in colour, smell and texture‐ according to randomization. An independent medical staff not performing the HSG prepared and dispensed either EMLA or placebo to the doctor that were blinded to the randomization" Comment: blinding of participants and operators is likely adequate.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Quote: "During the procedure, one patient from the EMLA‐treated group and three from the control group dropped out due to lack of patient co‐operation (NS)" Comment: 3/40 dropped out in placebo compared to 1/40 in intervention. However, there was no evidence that the study was analysed on an intention to treat basis.
Selective reporting (reporting bias)	Low risk	.Comment: no evidence of selective reporting was noted. All outcomes detailed in the methods were reported in the results in a clear manner.
Other bias	Low risk	Comment: no difference was found in terms of technical difficulties by the operator between control and intervention group. However, the authors re‐analysed the results without those cases in which the operators experienced difficulty at instrumentation, or those cases where the VAS score was high at baseline, in an attempt to exclude bias. As this analysis was not part of the original protocol, we decided not to use it in our meta‐analysis, rather, basing our results on the analysis which included all participants who completed the trial, which was also clearly documented in the report.

PERMALINK

Pain relief in hysterosalpingography

Akshay Hindocha

Lawrence Beere

Helena O'Flynn

Andrew Watson

Gaity Ahmad

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Overall quality of the body of evidence: 'Summary of findings' table

Results

Description of studies

Results of the search

1.

Included studies

1. Characteristics of included studies.

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Topical anaesthetic versus placebo or no treatment for pain relief in hysterosalpingography.

Summary of findings 2. Oral opioid analgesics versus placebo or no treatment for pain relief in HSG.

Summary of findings 3. Intravenous opioid analgesics versus placebo or no treatment for pain relief in HSG.

Summary of findings 4. Oral non‐opioid analgesics versus placebo or no treatment for pain relief in HSG.

Summary of findings 5. Locally injected anaesthetics versus placebo or no treatment for pain relief in HSG.

Summary of findings 6. Opioid versus non‐opioid analgesics for pain relief in HSG.

Summary of findings 7. Topical anaesthetic versus paracervical block for pain relief in HSG.

Summary of findings 8. Topical anaesthetic versus non‐opioid analgesics for pain relief in HSG.

1 Any analgesic versus placebo or no treatment (organised by intervention)

1.1 Oral opioid analgesics versus placebo/no treatment

Primary outcomes

1.1.1 Mean pain score during the procedure (VAS)

1.1. Analysis.

1.1.2 Mean pain score within 30 minutes after the procedure (VAS)

1.1.3 Mean pain score more than 30 minutes after the procedure (VAS)

Secondary outcomes

1.1.4 Adverse effects

Methods	Randomised, double‐blinded trial. 91 study group. None lost to follow up. Multi centre at Leiden, Netherlands.
Participants	Women undergoing HSG. Aged between 22 and 38 years. Previous work‐up not stated. Women were excluded if they were pregnant or lactating or had significant clinical and/or laboratory evidence of any major disease, or if they had any contra‐indications to using the study drugs. Participants' characteristics were not reported in the study.
Interventions	Opioid analgesics versus non‐opioid analgesics. 500 mg Naproxen 30 min pre‐op, with up to 500 mg post‐op as required, versus 100 mg Tramadol 30 minutes pre‐op and up to 100mg post‐op. Follow up 24 h post procedure. No co‐intervention.
Outcomes	Pain score immediately after the procedure (mean pain score). Delayed pain score (mean pain score) ‐ 4 h, 8h and 24 h. Using visual analogue scale and verbal descriptor scale.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote ‐ "The randomization took place by computer stratified per centre" Comment: probably adequate
Allocation concealment (selection bias)	Unclear risk	Comment: the study did not mention if allocation concealment was attempted
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Quote: "The study was designed as a double blind, randomized controlled investigation using a double‐dummy technique" Comment: while the double‐dummy technique is well understood, steps to ensure operator blinding was not detailed in the study.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Quote: "The intention was to treat 50 patients in each group", "The 91 patients who completed the study". Comment: not explicitly mentioned. However, the report states that the intention was to get 50 participants in each group (100 in total), though only 91 actually completed the study. Whether this was because not enough participants were recruited, or whether there were drop‐outs is not mentioned.
Selective reporting (reporting bias)	Low risk	Comment: no evidence of selective reporting was noted. All of the outcomes mentioned in the methods were reported clearly in the results.
Other bias	Unclear risk	Comment: the specific participant characteristics were not reported in the study. Unclear if there was any difference between intervention groups

Methods	Randomised controlled trial. 38 in intervention group and 82 in control group. No loss to follow up. Single centre trial at Texas, USA
Participants	Women undergoing HSG for investigation of infertility. Mean age 31.02 years. Exclusion criteria "included a history of any allergies to local aesthetics, radio‐opaque dye, or anti‐inflammatory medications." The following characteristics were measured (% of study group): ethnicity (70% White, 12.5% Black, 2.5% Asian, 10.8% Hispanic, 4.2% Other or Unknown); smoking (15%); history of bilateral tubal ligation (19%); results of HSG (55% abnormal); number of patent tubes (22.5% had no patent tubes); hydrosalpinx (8%); intracavity filling defect (10%); cervical stenosis (2%); parity (0%) The study found no significant difference between control and study group in each of these characteristics.
Interventions	Intracervical block versus placebo or no treatment. 1% lidocaine 5 minutes before the procedure versus saline or no injection. Follow up 1 minute post procedure. All subjects took 800 mg ibuprofen 30 minutes prior to procedure.
Outcomes	Participants were asked to score pain before beginning the procedure; with placement of the last intracervical injection or speculum placement (whichever was applicable); after the placement of the cervical tenaculum; after counter traction on the tenaculum; with instillation of the dye; and 1 minute after the HSG was completed and the cannula and tenaculum were removed. VAS (10 cm) and five category verbal descriptive score used
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Once the patients were found to meet enrolment criteria, written informed consent was obtained. The women were then randomized by permuted block randomization using a random number table to one of the three groups." Comment: probably adequate
Allocation concealment (selection bias)	Low risk	Quote: "Sequentially numbered, opaque sealed envelopes were used to assign patients to receive either the intracervical block with 1% lidocaine, saline injection, or no injection. These envelopes were opened and viewed by the pharmacist preparing the medication, and the specific injection arms of the assignments were not available to the provider performing the HSG or to the patients." Comment: probably adequate
Blinding (performance bias and detection bias)   All outcomes	Low risk	Quote: "These envelopes were opened and viewed by the pharmacist preparing the medication, and the specific injection arms of the assignments were not available to the provider performing the HSG or to the patients. Unblinding of the injection arms of the study was not completed until the time of data analysis." Comment: probably adequate
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "Complete pain scores were collected from 116 participants. Four subjects were missing data points for a few of the times assessed. One patient in the saline group missed the verbal descriptive score for time points 3, 5, and 6 and VAS for time points 5 and 6. One patient in the control group missed one verbal descriptive score at time point 3, one patient missed VAS and verbal descriptive score for time point 6, and one patient missed data collection for time points 5 and 6 for VAS and verbal descriptive score. All subjects who were randomized and underwent the HSG and who recorded any pain scores were included as intention to treat for purposes of statistical analysis of the data points that were available" Comment: 3% dropout rate. No given reason as to why participants were unable to complete scores for these time points. However, relatively small proportion and ITT used, and therefore adjudged to be low risk.
Selective reporting (reporting bias)	High risk	Comment: only mean pain scores provided with no standard deviations being reported. No adverse effects data was provided.
Other bias	Low risk	No other bias

Methods	"This trial was performed at a single‐centre university hospital (Centre for Reproductive Medicine, Brussels, Belgium) between November 2008 and February 2009".
Participants	130 women randomised. Mean age was 33 years old. Participant demographics were comparable apart from a P value < 0.001 for previous abortion across the groups. The study excluded women with medical contraindications for tramadol, morphine or other opioids as well as for the use of monoamine oxidase inhibitors or other central nervous system‐acting drugs. Other exclusion criteria were allergy to radio‐contrast medium, cervical stenosis, presence of pelvic inflammatory disease or any other condition causing pelvic pain. The following characteristics were measured (% of study group unless otherwise stated): gravidity (0.81 Mean), parity (0.31 Mean), nulliparity (77%), previous vaginal delivery (12.5%), previous C‐section (7.8%), previous abortion (32%), previous dilation and curettage (14.8%), previous conization (3%), dysmenorrhoea (28.1%), dyspareunia (3.9%), previous abdominal surgery (14.1%). The study found no significant difference between control and study group in each of these characteristics, apart from prevalence of previous abortion (26% control group, 37% intervention group)
Interventions	Participants were administered either 50 mg of fast‐release oro‐dispersible tramadol (Meda Pharma, Brussels, Belgium) or placebo 30 min before the procedure. Participants were asked to score the pain at five stages of the procedure: (1) speculum application, (2) cervical instrumentation, (3) uterine filling, (4) tubal spillage, and (5) at 30 min after removal of the instrumentation.
Outcomes	Pain score reported during the procedure and at 30 minutes post procedure using the visual analogue scale.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Allocation was done by simple randomization" "computer‐generated randomization table allocated 128 patients into four groups to receive either tramadol or placebo and to the use of either a metal cannula or a balloon catheter as the HSG device" Comment: probably adequate
Allocation concealment (selection bias)	Unclear risk	Comment: no mention of any steps at allocation concealment
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Quote: "The patients were unaware of the type of cannula used and the medication received"... "Patients were administered either 50 mg of fast‐release oro dispersible tramadol (Meda Pharma, Brussels, Belgium) or placebo 30 min before the procedure". Comment: article stated as double blind, but no mention of any steps to blind the personal, and no mention of blinding regarding administration of the medication.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: there were 2 participants that were excluded prior to randomization. However, all 128 remaining participants who were randomised had outcomes reported and were included into the analysis.
Selective reporting (reporting bias)	Low risk	Comment: power calculation carried out. All outcomes mentioned in the methods were reported clearly.
Other bias	Low risk	No other bias

Methods	Randomised controlled trial. 18 in intervention groups and 7 in control group. 2 participants lost to follow up. Single centre trial at Afyonkarahisar, Turkey
Participants	27 participants randomised. Mean age was 28.6 years old. There was no significant differences between control and treatment group characteristics. The following were excluded: women who had a known stenotic cervical os, acute cervicitis, intense anxiety, a history of any allergy to local anaesthetics, radio‐opaque dye or anti‐inflammatory medications, any recent history of acute pelvic inflammatory disease, any vaginal discharge, any other cause of chronic pelvic pain, a positive beta‐HCG test, or were < 18 years old. The following characteristics were measured (% of study group unless otherwise stated): gravidity (33%), nulliparous (67%), education > 8 years (27%), education < 8 years (73%), The study found no significant difference between control and study group in each of these characteristics.
Interventions	3 Comparisons: 1‐Topical anaesthetic versus placebo or no treatment. 5% Lidocaine cream applied to the cervix 30 minutes before the procedure versus no cream. Follow up 15 minute post procedure. All subjects took 550 mg naproxen 1 hour prior to procedure. 2‐ Topical anaesthetic versus placebo or no treatment. 1% Intrauterine Lidocaine instillation 2 minutes before the procedure versus no instillation. Follow up 15 minute post procedure. All subjects took 550 mg naproxen 1 hour prior to procedure. 3‐ Locally injected anaesthetic block versus placebo or no treatment. 1% Lidocaine (2 to 4 mg/kg) injected into the cervix in divided doses of 1.5 ml circumferentially at 12, 4, 6 and 8 o'clock positions 5 minutes before the procedure versus no injection. Follow up 15 minutes post procedure. All subjects took 550 mg naproxen 1 hour prior to procedure.
Outcomes	Participants were asked to score pain before beginning the procedure, with speculum placement (whichever was applicable), after the placement of the cervical tenaculum, after counter traction on the tenaculum, with instillation of the dye, and 15 minutes after the HSG was completed and the cannula and tenaculum were removed. VAS (10 cm) was used.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "the remaining 75 patients were randomly divided into four groups" Comment: method of random sequence generation was not detailed in the text.
Allocation concealment (selection bias)	Unclear risk	Quote: "the remaining 75 patients were randomly divided into four groups" Comment: method of allocation concealment was not detailed in the text.
Blinding (performance bias and detection bias)   All outcomes	High risk	Quote: apart from Naproxen, "women in group 1 received no additional medication for pain relief" Comment: no evidence of topical placebo application in control group compared to topical application in the intervention group. Therefore, it is very likely the participant and the operator were unblinded.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Quote: "Subsequently, a total of five patients declined to participate in the study without providing a reason" Comment: 5 women dropped out after randomization in the entire study. 2 were in the topical anaesthetic cream group (10% dropout) and none were in the control group (0% dropout). The remaining 33 were in the other groups included in the study.
Selective reporting (reporting bias)	Unclear risk	Comment: no evidence of selective reporting for pain outcomes. However, no adverse effects data was provided in the trial.
Other bias	Unclear risk	Quote: "Women were self instructed to administer a single dose of 55omg of naproxen 1h before the scheduled time of the procedure" Comment: it is unclear if these women actually took the naproxen. No mention of whether investigators ensured that women entered into the trial had actually taken the tablets.

Study	Reason for exclusion
Costello 2005	This study compared the efficacy of different modes of delivery of lignocaine i.e. lignocaine spray versus lignocaine jelly.
Guzel 2010	Quasi‐randomised trial
Lorino 1990	Non‐randomised trial.