Meta-analysis of efficacy and safety of sustained release oxycodone hydrochloride rectal administration for moderate to severe pain.

OBJECTIVE: This study aims to evaluate the efficacy and safety of oxycodone hydrochloride (OxyContin) rectal administration in cancer pain patients. This is geared towards providing the research evidence for a novel route of OxyContin administration.
METHODS: Relevant randomized controlled trials (RCTs) were searched in electronic databases, including PubMed, Cochrane Library, Web of Science, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP database), Wanfang Data Knowledge Service Platform, and Chinese Biomedical Literature Database (CBM). Moreover, unpublished academic data were obtained by contacting the colleague, professor, or Institute of Traditional Chinese Medicine. The RCTs of transrectal Oxycodone administration of sustained-release tablets for moderate and severe pain patients were searched in the databases from inception to December 2020.
RESULTS: According to the inclusion criteria, a total of 8 RCTs were included, with a total of 648 patients. Meta analysis results showed that there was no statistically significant difference in the efficacy of moderate to severe pain control between the rectal administration group and the oral administration group (RR = 1.04, 95%CI: 0.99-1.10, p = 0.13>0.05). At the same time, the incidence of adverse reactions in the rectal administration group was low. In terms of constipation, the rectal administration group was less than the oral administration group, with a statistically significant difference (RR = 0.43, 95%CI: 0.31-0.58, p< 0.00001). In terms of nausea and vomiting, the rectal administration group was less than the oral administration group, and the difference was statistically significant(RR = 0.30, 95%CI: 0.21-0.42, p<0.00001). In terms of sleepiness, there was no significant difference between the two groups(RR = 0.54, 95%CI: 0.26-1.15, p = 0.11>0.05). In terms of dizziness, there was no statistically significant difference between the two groups (RR = 0.43, 95%CI:0.27-0.68, p = 0.31>0.05). In terms of dyuria, there was no statistically significant difference between the two groups (RR = 0.37, 95%CI: 0.02-7.02, p = 0.51>0.05). In terms of KPS scores there was no significant difference was noted between the rectal and oral administration groups (RR = 1.04, 95%CI: 0.89-1.21, p = 0.63>0.05).
CONCLUSION: In summary, we found no significant differences in efficacy between rectal administration of OxyContin and oral administration. Thus, rectal administration should be considered in managing cancer pain among patients with difficulty in oral OxyContin administration. PROSPERO REGISTRATION NUMBER: CRD42021209660.

Introduction

Clinical pain treatment adopts a three-step treatment plan by the World Health Organization (WHO). Using the NRS score as a standard, the pain was divided into mild pain (1-3points), moderate pain (4-6points), severe pain (7-10points) [1, 2]. Moderate to severe pain generally requires opioids for treatment. OxyContin is one of the commonly used opioids whose conventional administration route is oral. However, its clinical application has encountered challenges. The administration method of analgesic therapy requires non-invasiveness, and oral administration is the preferred treatment route. Nonetheless, a few patients cannot be administered orally because of severe nausea, vomiting, difficulty eating, gastrointestinal reactions, intestinal obstruction, etc. Notably, injection therapy causes iatrogenic pain and patient dependence on the hospital; it also affects the psychology of the patient. In addition, rectal administration is a non-invasive method of administration; it has few requirements to a certain extent and is suitable for nearly all patients experiencing pain. Although oral administration is the most convenient route, it cannot be applied as the first choice in many cases. Therefore, rectal administration is significant to patients with difficulty in oral administration. At present, many clinical studies utilize rectal administration to resolve the above problems, with effective treatment outcomes. Nevertheless, these studies used a small sample size, hence the findings are not convincing. Thus, it is necessary to systematically evaluate the efficacy and safety of rectal OxyContin administration in the management of moderate to severe pain. This work conducted a meta-analysis of the efficacy and adverse effects of rectal OxyContin administration, geared towards providing evidence-based information for a new route of OxyContin administration.

Materials and methods

This systematic review protocol is registered on PROSPERO (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021209660). The registration number is CRD42021209660. This is a literature-based study thus ethical approval was unnecessary.

Literature resources

Inclusion criteria

The inclusion criteria included; clinical trials analyzing the transrectal administration of OxyContin for moderate to severe pain management; a randomized controlled trial; The control group treated with oxycodone sustained-release tablets.

Exclusion criteria

Clinical trials excluded included; Case reports; animal experiments; basic research; personal experience and review literature; incomplete data; Duplicate literature; Baseline conditions not evaluated.

Data extraction

All the records were fed into the EndNote X8 software after the electronic search stage. Data were independently extracted by 2 researchers (CTF and WD) using a predefined data extraction form. Two researchers independently screened titles and abstracts to establish the trials to be excluded. The full text was examined if necessary. The following aspects were considered: general information (year of publication, author’s details, etc.), participations, inventions, comparisons, outcomes, adverse events, and other information. Two authors resolved disagreement by discussion, and a third author (XH) arbitrated if there were further disagreements.

Intervening measure

The experimental group was administered with OxyContin (Oxycodone, Beijing Mengdi Pharmaceutical Co. LTD.) by rectum, while the control group was administered with oxycodone sustained-release tablets by mouth, with the same initial dose.

Search strategy and quality assessment

Document retrieval

Two reviewers (CDD and HXB) independently searched the studies in electronic databases based on the systematic review. Two retrieval personnel with "oxycodone, oxycontin, dosing, and anal rectum and anus" and "pain, cancer pain, pain, cancer pain", "randomized, RCT" as keywords, computer retrieving CNKI, VIP, CBM, Pubmed, Embase, the Cochrane library, retrieval of oxycodone Zyban rectum for drug efficacy and safety of the treatment of pain. The retrieval period was from the inception of the database to December 2020, and the relevant original data of the literature was extracted (Table 1).

Table 1

Pubmed search strategy.

Search number	Search Details	Results
9	(("Oxycodone"[MeSH Terms] OR (("Oxycone"[Title/Abstract] OR "oxycodone hydrochloride"[Title/Abstract]) OR "Oxycontin"[Title/Abstract])) AND ("administration, rectal"[MeSH Terms] OR (((("Drug"[All Fields] AND "administration anal"[Title/Abstract]) OR "drug administration rectal"[Title/Abstract]) OR ("Anal"[All Fields] AND "drug administration"[Title/Abstract])) OR "rectal administrations"[Title/Abstract]))) AND "Randomized Controlled Trial"[Publication Type]	3
8	"Randomized Controlled Trial"[Publication Type]	512,552
7	("Oxycodone"[MeSH Terms] OR (("Oxycone"[Title/Abstract] OR "oxycodone hydrochloride"[Title/Abstract]) OR "Oxycontin"[Title/Abstract])) AND ("administration, rectal"[MeSH Terms] OR (((("Drug"[All Fields] AND "administration anal"[Title/Abstract]) OR "drug administration rectal"[Title/Abstract]) OR ("Anal"[All Fields] AND "drug administration"[Title/Abstract])) OR "rectal administrations"[Title/Abstract]))	9
6	"administration, rectal"[MeSH Terms] OR (((("Drug"[All Fields] AND "administration anal"[Title/Abstract]) OR "drug administration rectal"[Title/Abstract]) OR ("Anal"[All Fields] AND "drug administration"[Title/Abstract])) OR "rectal administrations"[Title/Abstract])	3,127
5	"Oxycodone"[MeSH Terms] OR "Oxycone"[Title/Abstract] OR "oxycodone hydrochloride"[Title/Abstract] OR "Oxycontin"[Title/Abstract]	2,419
4	((("Drug"[All Fields] AND "administration anal"[Title/Abstract]) OR "drug administration rectal"[Title/Abstract]) OR ("Anal"[All Fields] AND "drug administration"[Title/Abstract])) OR "rectal administrations"[Title/Abstract]	610
3	"administration, rectal"[MeSH Terms]	2,531
2	"Oxycone"[Title/Abstract] OR "oxycodone hydrochloride"[Title/Abstract] OR "Oxycontin"[Title/Abstract]	382
1	"Oxycodone"[MeSH Terms]	2,282

Quality assessment

Quality assessment was conducted using the Cochrane collaboration’s risk of bias tool. Two authors (CBX and WYY) estimated the domain risk of bias as follows: Sequence generation of randomized, allocation concealment, blinding of participants, personnel and outcome assessment, incomplete outcome data and selective outcome report, and other sources of bias. Any disagreements were resolved by a third author (CHZ).

Statistic analysis

Outcome indicator

Primary outcomes. Regarding the effective rate of pain control, clinical efficacy was considered the primary outcome indicator. The therapeutic efficacy standard was divided into 4 grades based on the WHO pain treatment remission (PAR) [3], i.e., Complete remission (CR): No pain after treatment; Partial relief (PR): the pain was significantly relieved compared to that before treatment, sleep was undisturbed, and normal life could be achieved; Mild relief (MR): The pain was less than before treatment, but the pain was still felt, and the sleep is disturbed; No relief (NR): No change in pain compared to before treatment. Effective rate = (CR+PR) number of cases/total cases × 100%.

Secondary outcomes. The secondary outcomes were any adverse events including constipation, nausea, vomiting and dizziness, and quality of life, which were measured using the Karnofsky scale.

Meta-analysis

The RevMan5.3 software was used for statistical analyses. The evaluation index of the study was the data of dichotomous variables, including the effective rate of pain control and incidence of adverse reactions. The risk ratio (RR) was used as the analysis statistic, and the 95% confidence interval (CI) was calculated. RR was analyzed by the Z test. P < 0.05 was considered a statistically significant difference in evaluation indices between the two groups.

Heterogeneity test

Based on the test level of α = 0.05, there was inter-study heterogeneity if P < 0.05. At the same time, heterogeneity of I2 was quantitatively analyzed, I2≥50% and the inter-study heterogeneity was large. In the absence of heterogeneity, a fixed-effect model was selected for combined effect analysis, while a random effect model was used.

Assessment of reporting bias

Funnel plots were used to assess the presence of publication bias. Reporting bias was also assessed using Egger’s test and Begger’s analysis.

Sensitivity analysis

With the availability of sufficient trials, sensitivity analysis was performed by sequentially eliding each trial to examine the robustness of the final results.

Strategy for data synthesis

The RevMan V.5.3 software was used for data synthesis. Dichotomous data were expressed in RR and continuous data in mean difference (MD). The fixed-effect model was used if I2<50% or I2>75%, I2<50% had low heterogeneity, whereas those with I2>75% had high heterogeneity. A subgroup analysis or a sensitivity analysis was performed when I2>75%.

Result

Document retrieval process

A total of 175 related literature were retrieved (CNKI = 28; VIP = 36; Wanfang = 76; CBM = 26; Pubmed = 3; Embase = 2; Cochrane Library = 4); 86 repeated references were excluded; 2 references on exclusion system evaluation; 41 references with unrelated research contents, 27 with different intervention measures; 2 with non-randomized controlled trials; 6 with non-oxycontin treatment were excluded, and 8 were included in the meta-analysis [3-10]. (Fig 1).

Fig 1

Flow diagram of the literature search.

Basic information of literature

The major characteristics of all included studies were showed on Tables 2 and 3. Our analysis include the effective rate of pain control and any adverse events including nausea, vomiting and dizziness, constipation, dysuria and lethargy.

Table 2

Characteristics of the adverse reactions.

Author	EG					CG					Total
	Nausea	Dizziness	Constipation	Dysuria	Lethargy	Nausea	Dizziness	Constipation	Dysuria	Lethargy
Zhang 2013 [4]	12	3	18	1	-	28	30	35	12	-	34/105
Yin 2013 [5]	1	-	1	-	0	6	-	10	-	0	2/16
Wu 2014 [6]	3	-	6	-	3	12	-	13	-	10	13/37
Han 2017 [7]	25					42					25/42
Chen 2018 [8]	2	-	1	-	2	2	-	1	-	1	5/4
Liu 2018 [9]	4	3	6	0	1	9	4	14	0	1	14/28
Liu 2019 [10]	6	5	2	-	3	37	4	7	-	3	16/51
Du 2020 [11]	5	10	3	3	0	17	11	7	2	2	24/41

EG: experimental group; CG: control group.

Table 3

Characteristics of the included studies.

Author	Number of patients	Gender (M/W)		Study	Interventions		EG				CG
	EG/CG	EG	CG		EG	CG	CR	PR	MR	NR	CR	PR	MR	NR
Zhang 2013 [4]	44/44	-	-	RCT	Rectal drug delivery20mg	Oral20mg	37	6	1	0	21	15	7	1
Yin 2013 [5]	30/30	-	-	RCT	Rectal drug delivery-	Oral-	11	16	2	1	12	16	1	1
Wu 2014 [6]	30/30	17/13	18/12	RCT	Rectal drug delivery10-20mg	Oral10-20mg	11	15	-	4	12	15	-	3
Han 2017 [7]	64/64	38/26	33/31	RCT	Rectal drug delivery10mg	Oral10mg	60			5	59			4
Chen 2018 [8]	40/40	25/15	24/16	RCT	Rectal drug delivery10-20mg	Oral10-20mg	29	8	-	3	24	6	-	10
Liu 2018 [9]	34/34	23/11	24/10	RCT	Rectal drug delivery10-20mg	Oral10-20mg	18	11	-	5	17	13	-	4
Liu 2019 [10]	42/42	-	-	RCT	Rectal drug delivery10mg	Oral10mg	21	18	-	3	23	17	-	2
Du 2020 [11]	40/40	30/10	28/12	RCT	Rectal drug delivery10mg	Oral10mg	37			18	22			3

EG: experimental group; CG: control group.

Literature quality evaluation

The bias risk assessment of the included studies were showed on Figs 2 and 3. Fig 2 shows the proportion of studies assessed as low, high or unclear risk of bias for each risk of bias indicator. Fig 3 shows the risk of bias indicators for individual studies. The method of randomization was described by all eight trials which have no describe allocation concealment methods.

Fig 2

Graph of bias risk ratio.

Fig 3

Summary chart of quality evaluation.

Meta analysis results

Bias test

A funnel plot (Fig 4) was drawn to investigate a publication bias. P = 0.553 > 0.05 based on Egger linear regression method and P = 0.548 > 0.05 based on the Begg rank correlation test suggested significant publication bias in the included literature.

Fig 4

Funnel plots to test for publication bias.

Effective rate of pain control

All 8 literature reported an effective rate of pain control. After the heterogeneity test, I2 = 71%>50%, and p = 0.001<0.1, indicating that the heterogeneity among the selected pieces of literature was statistically significant, and a heterogeneity search was required. Sensitivity analysis was conducted on the 8 literature, and we found that du yajuan 2020 had a significant effect on heterogeneity. After removing this study, heterogeneity test analysis was repeated, and the results indicated that the remaining 7 [4-10] literature had no heterogeneity (I2 = 41%, p = 0.12 > 0.1). After the exclusion, meta-analysis was conducted with fixed effects. The RR of the 7 studies was 1.04 with the 95% confidence interval of 0.99–1.10, which was statistically significant (z = 1.53, p = 0.13 > 0.05, Fig 5); this suggests no statistical difference between the efficacy of oxycodone sustained-release oxycodone tablets (oxycontin) for rectal administration of moderate to severe pain and oral administration.

Fig 5

Forest plot of effective rate of pain control between experimental and control group.

Security analysis

Adverse reactions were reported in all the 8 literature, primarily nausea and vomiting, constipation, drowsiness, and dizziness. The incidence of nausea, vomiting, and constipation was lower in rectal administration group than that of oral oxycodone sustained-release tablets, and the difference was statistically significant (p < 0.05). No significant difference was noted between the two groups in drowsiness, dizziness, and dyspnea. Besides the above five major adverse reactions, Wu Reported psychiatric symptoms, and the rectal administration group was less than the oral administration group. Du Yajuan reported skin itching, rectal administration of excess oral medication in the group. In terms of compliance, the rectal administration group was superior to the oral administration group, with a statistically significant difference. In addition, no adverse reactions including addiction, hypotension, and respiratory depression appeared in the statistics.

Constipation. Seven studies [3–6, 8–10] reported the incidence of constipation with no heterogeneity between studies. The fixed-effect model was used for analysis, and the difference was statistically significant (RR = 0.43, 95%CI: 0.31–0.58, p< 0.00001, Fig 6).

Fig 6

Forest plot of the incidence of constipation between experimental and control group.

Nausea and vomit. Seven studies [3–6, 8–10] reported the incidence of nausea and vomiting with no heterogeneity between studies. The fixed-effect model was used for analysis, and the difference was statistically significant (RR = 0.30, 95%CI: 0.21–0.42, p < 0.00001, Fig 7).

Fig 7

Forest plot of the incidence of nausea and vomiting between experimental and control group.

Lethargy. Five studies [6, 8–11] reported the incidence of narcolepsy, with no heterogeneity between studies. The fixed-effect model was used for analysis, and we found no significant difference between the rectal and oral administration groups (RR = 0.54, 95%CI: 0.26–1.15, p = 0.11, Fig 8).

Fig 8

Forest plot of the incidence of lethargy between experimental and control group.

Dizziness. Four studies [4, 9–11] reported the incidence of dizziness, with inter-study heterogeneity (p = 0.003, I2 = 79%), and the random-effect model was used for analysis. No statistically significant difference was noted between the two groups (RR = 0.43, 95%CI: 0.27–0.68, p = 0.31 > 0.05, Fig 9).

Fig 9

Forest plot of the incidence of dizziness between experimental and control group.

Dysuria. Two studies [4, 11] reported the incidence of dysuria, with heterogeneity between studies (p = 0.03, I2 = 80%), and the random-effect model was used for analysis. No statistically significant difference was observed between the two groups (RR = 0.37, 95%CI: 0.02–7.02, p = 0.51 > 0.05, Fig 10).

Fig 10

Forest plot of the incidence of dysuria between experimental and control group.

Occurrence of adverse reactions. Adverse reactions were reported in all 8 studies, with the total frequency of adverse reactions occurring 133 times in the rectal administration group and 324 times in the oral administration group, about 2.4 times higher than that in the rectal administration group.

KPS score. KPS scores before and after treatment were reported in 2 studies [5, 9], with no heterogeneity between the studies. No significant difference was noted between the rectal and oral administration groups (RR = 1.04, 95%CI: 0.89–1.21, p = 0.63, Fig 11).

Fig 11

Forest plot of the KPS scores between experimental and control group.

Discussion

Pain is an unpleasant and emotional feeling, accompanied by substantial or potential tissue damage. It is a subjective feeling [12] and a common symptom among patients with advanced cancer. An estimated 40% of patients with early and mid-stage tumors and 90% with advanced tumors experience moderate to severe cancer pain, out of which 70% have not been effectively managed [13]. Opioids remain the primary clinical approach for pain management in patients with cancer-related pain; among them, OxyContin (Oshicontin) is widely administered. The current recommendations for OxyContin suggest an oral route of administration; nevertheless, it cannot be administered orally in a few patients including those with esophageal cancer having difficulties in eating. Thus, clinicians opt for rectal administration to treat pain among these patients. Moreover, unlike oral administration, rectal administration has other benefits. For example, Li Fei et al. [14] found that rectal administration minimizes the first-pass effect of the liver, prevents gastrointestinal reactions, and has a fast onset as well as enhanced safety. A total of 8 RCT studies were included in this systematic review. We found that rectal administration of OxyContin has a satisfactory clinical effect in the treatment of moderate to severe pain, with a low incidence of adverse reactions. Chen Weixian revealed that the NRS score of the observation group was better than that of the control group at 1 hour and 3 hours time points of administration, with a statistically significant difference. After 3hours, no difference was noted in the NRS score of the two groups at the statistical node. Wu Hanbing and Liu Min found no statistically significant difference in the NRS scores and pain relief efficacy between the two groups at different time points after medication. Liu Haibo and Yin Weijun noted no significant difference in the improvement of the KPS score (functional status score) between the two groups. Although treatment of cancer pain should follow oral administration principles recommended by the National Comprehensive Cancer Network (NCCN) guidelines, other administration routes may be considered for patients with eating difficulties or gastrointestinal dysfunction. For example, the use of controlled-release oral oxycodone hydrochloride (OxyContin) as a suppository has several benefits. First, it prevents the effect of nausea and vomiting caused by the primary disease on drug absorption. On the other hand, after rectal administration, the drug does not pass through the liver, thereby preventing the first-pass effect of the liver and increasing the blood drug concentration. Besides, the drug does not pass through the stomach and small intestine hence preventing its destruction by acid, alkali, and digestive enzymes, reducing its irritation in the stomach and intestines, and significantly improving its bioavailability. Using OxyContin as a suppository is cost-effective for the patient since it eliminates caregiver apprehension of high-tech equipment and supplies necessary for intravenous, intramuscular, subcutaneous, or intrathecal administration. It also affords the patient a relatively painless means of administration. Although most patients manage pain using oral analgesics, simple alternatives to oral medications in the near-terminal state remain unresolved. Intramuscular, intravenous, and subcutaneous injections are uncomfortable and expensive for patients; they are also impractical in the home environment. As a rectal suppository, OxyContin effectively manages pain, facilitates the administration of caregivers, and eliminates the breakthrough pain or excessive sedation that often occurs when changing drugs. Meanwhile, animal experiments indicate that rectal administration of opioids has higher bioavailability than that of oral administration [15]. Future developments of OxyContin require clinical trials investigating the bioavailability in both acute and chronic pain.

This study has compelling limitations, First, only domestic literature was included, hence lacking multi-center large sample clinical randomized controlled trial research data. Secondly, the eight included articles did not indicate allocation hiding and blinding. Thirdly, among the included literature, only Liu Haibo compared the pain control onset time and final drug dose between the two groups and found no significant difference. The remaining 7 pieces of works of literature did not indicate if there was a difference in the drug dose between the two groups during pain control. Furthermore, rectal administration has worth-mentioning limitations. First, only small doses of OxyContin are more suitable for pain control; if large doses are required, rectal administration operations will exhibit difficulties, thereby difficult acceptance by the patients. Secondly, its operation is more cumbersome than that of oral administration, and the drugs in the anus easily leak out hence requiring repeated administration.

In conclusion, the clinical application should be based on the actual situation to select the appropriate route of medication in the management of moderate to severe pain. Notably, OxyContin can be considered for rectal administration. At present, rectal administration of opioids in clinical practice has not been confirmed; rectal OxyContin administration of is off-label drug use. Therefore, future studies should conduct more in-depth clinical and experimental research on the rectal administration of OxyContin. Besides, we believe that special opioids will be discovered for transrectal administration.

PRISMA checklist.

(DOC)

Click here for additional data file.

26 Dec 2021

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Girish Sailor

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

This work was supported by the Science and Technology Project of Fenghua Science and Technology Bureau (NO: 20186515 ).

The funders had no influence on the study design, data collection and analysis, as well as the right to publish.

We note that you have provided additional information within the Acknowledgements Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4. Please amend your list of authors on the manuscript to ensure that each author is linked to an affiliation. Authors’ affiliations should reflect the institution where the work was done (if authors moved subsequently, you can also list the new affiliation stating “current affiliation:….” as necessary).

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The article is worthwhile as it addresses important clinical issues of pain management. In my professional opinion this paper will benefit the current clinical practice, however, I feel significant issues need to be seriously addressed. One of my main concern is the definition of moderate to severe pain that is not included. As this is part of the title, author must clearly define the term as per defined in all selected papers included in the review.

Initial paragraph in the discussion is repetitive to the information and phrases included in the introduction. Please revise the paragraph and assure that the there is no overlapping between these sections. The utilisation of short form for 1h and 3h that represent 'hour' should be avoided and written in full.

The paper contains quite significant grammatical errors and sentences are not written in proper English, therefore, it is suggestible for the author to send the paper to be edited by professional native English editor. This is imperative as the paper contains information that is useful for reference in clinical practice.

Eg; 'On the one hand, it can avoid the influence of nausea and vomiting caused by the primary disease on drug absorption; on the other hand, after rectal administration, the drug does not pass through the liver, thereby avoiding the first pass effect of the liver and increasing the blood drug concentration; the drug does not pass through the stomach And the small intestine, avoid the influence and destruction of acid, alkali and digestive enzymes on the medicine, reduce the irritation of the medicine to the stomach and intestines, and greatly improve the bioavailability of the medicine.'

The information that is not properly written in professional English may impede future reference and citation, hence, affecting the quality of this paper. I believe if the paper can be improved to assure that it is publishable.

Reviewer #2: The authors has produce an excellent data for this study. It is a very good alternative way to administered the mentioned medicine especially for cancer patients with difficulty to swallow. This method also will reduce several unwanted effects.

The authors has thoroughly stated the methods. There are several minor formatting issues that need to be reviewed before being accepted.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Norsham Juliana

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

2 Mar 2022

Reviewer #1: The article is worthwhile as it addresses important clinical issues of pain management. In my professional opinion this paper will benefit the current clinical practice, however, I feel significant issues need to be seriously addressed. One of my main concern is the definition of moderate to severe pain that is not included. As this is part of the title, author must clearly define the term as per defined in all selected papers included in the review.

Answer：We would like to thank you very much for your recognition of our work and valuable comments. We've added definitions for mild, moderate, and severe pain to the Introduction.

Initial paragraph in the discussion is repetitive to the information and phrases included in the introduction. Please revise the paragraph and assure that the there is no overlapping between these sections. The utilisation of short form for 1h and 3h that represent 'hour' should be avoided and written in full.

Answer：We have truncated the repetition of the description in the introduction, modified '1h and 3h' and have written in full.

The paper contains quite significant grammatical errors and sentences are not written in proper English, therefore, it is suggestible for the author to send the paper to be edited by professional native English editor. This is imperative as the paper contains information that is useful for reference in clinical practice.

Eg; 'On the one hand, it can avoid the influence of nausea and vomiting caused by the primary disease on drug absorption; on the other hand, after rectal administration, the drug does not pass through the liver, thereby avoiding the first pass effect of the liver and increasing the blood drug concentration; the drug does not pass through the stomach And the small intestine, avoid the influence and destruction of acid, alkali and digestive enzymes on the medicine, reduce the irritation of the medicine to the stomach and intestines, and greatly improve the bioavailability of the medicine.'

The information that is not properly written in professional English may impede future reference and citation, hence, affecting the quality of this paper. I believe if the paper can be improved to assure that it is publishable.

Answer：We have already send the paper to be edited by professional native English editor. The article has corrected grammar and other errors in the original text.

Reviewer #2: The authors has produce an excellent data for this study. It is a very good alternative way to administered the mentioned medicine especially for cancer patients with difficulty to swallow. This method also will reduce several unwanted effects.

The authors has thoroughly stated the methods. There are several minor formatting issues that need to be reviewed before being accepted.

Answer：We thank you for your careful review of the manuscript and your constructive comments. We have modified the format of the article as required by the journal.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

28 Mar 2022

Meta-analysis of efficacy and safety of sustained release oxycodone hydrochloride rectal administration for moderate to severe pain

PONE-D-21-30242R1

Dear Dr. hou,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Girish Sailor

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The author has addressed all comments and the manuscript is ready for target audience. The article has been rewritten with proper grammar and easy to read.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Norsham Juliana

1 Apr 2022

PONE-D-21-30242R1

Meta-analysis of efficacy and safety of sustained release oxycodone hydrochloride rectal administration for moderate to severe pain

Dear Dr. Hou:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Girish Sailor

Academic Editor

PLOS ONE