Efficacy of flupirtine for postoperative pain: A systematic review and meta-analysis

Samarjit Dey; Indubala Maurya; Ayush Lohiya; Prateek Arora; Rizwan Suliankatchi Abdulkader; Sairem Mangolnganbi Chanu

doi:10.4103/ija.ija_599_22

. 2023 Mar 16;67(3):247–255. doi: 10.4103/ija.ija_599_22

Efficacy of flupirtine for postoperative pain: A systematic review and meta-analysis

Samarjit Dey ¹, Indubala Maurya ^1,^✉, Ayush Lohiya ², Prateek Arora ³, Rizwan Suliankatchi Abdulkader ⁴, Sairem Mangolnganbi Chanu ⁵

PMCID: PMC10220165 PMID: 37250521

ABSTRACT

Background and Aims:

Flupirtine has been used for various chronic pain conditions, but its utility in the perioperative period as an analgesic is still inconclusive. This systematic review and meta-analysis aimed to assess the efficacy of flupirtine for postoperative pain.

Methods:

PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) were explored for the randomised controlled trials (RCTs) which compared flupirtine with other analgesic/placebo for perioperative pain in adult patients undergoing surgery. The standardised mean difference (SMD) of pain scores, the need for rescue analgesia and all adverse effects were assessed. Heterogeneity was assessed using Cochrane’s Q statistic test and I² statistic. Cochrane Collaboration’s tool was used to evaluate the risk of bias and the quality of the RCTs.

Results:

A total of 13 RCTs (including 1,014 patients) that evaluated the use of flupirtine for postoperative pain were included in the study. The pooled SMD of postoperative pain scores revealed that flupirtine and other analgesics were comparable at 0, 6, 12 and 24 hours (P > 0.05), while at 48 hours, flupirtine showed poor pain control (P = 0.04) as compared to other analgesics. There were no significant differences at other time points and on comparison of flupirtine with placebo. The side effect profile was comparable between flupirtine and other analgesics.

Conclusion:

The current evidence suggests that perioperative flupirtine was not superior to other most commonly used analgesics and placebo for the treatment of postoperative pain.

Key words: Acute pain, flupirtine, non-opioid analgesic, post-operative pain

INTRODUCTION

The goals of postoperative pain management are early mobilisation, short duration of hospital stay and better patient comfort and satisfaction. Inadequate postoperative analgesia can have a significant impact on patients’ recovery. Traditionally, opioids are the mainstay for acute perioperative pain management to target central mechanisms involved in pain perception. Opioid-related concerns such as nausea/vomiting, persistent post-surgical pain, long-term opioid use, opioid epidemic led to the adoption of multimodal analgesia regimens. Multimodal analgesia helps to address these factors and optimise patient satisfaction. Thus, the evolution of non-opioid or opioid-sparing analgesia has begun. Various non-opioid analgesics and nerve blocks have been widely studied for incorporation into the multimodal analgesia regimen.^[1,2]

Flupirtine is a non-opioid, non-steroidal anti-inflammatory drug (NSAID) with analgesic, muscle relaxation, neuroprotection and antiapoptotic properties. It acts indirectly as an N-methyl-D-aspartate (NMDA) receptor antagonist by activating K+ channels. Activation of the K+ channel leads to hyperpolarisation of the neuronal membrane, and the neuron becomes less excitable.^[3,4] Although flupirtine is not yet approved by the United States Food and Drug Administration (US FDA), it is still used in many countries, including India. Traditionally, flupirtine has been used for chronic pain conditions like fibromyalgia, musculoskeletal pain, headache, cancer pain, neurogenic pain.^[5,6] Multiple studies have assessed the use of flupirtine as a postoperative analgesic.^[7-20] Some studies have shown that flupirtine is effective in reducing postoperative pain.^[16] However, some have shown that flupirtine is not effective as compared to other analgesics.^[7-15,17-20] Hence, the utility of flupirtine in managing postoperative pain is still not established and its role in postoperative multimodal analgesia regimens is still unclear.^[7]

We conducted this systematic review and meta-analysis of RCTs that compared flupirtine to other analgesics/placebo for the treatment of postoperative pain after surgery in adult patients to assess the effect on outcomes such as postoperative pain, rescue analgesic use and adverse effects.

METHODS

Registration details

The review protocol was registered with the international prospective register of systematic reviews (PROSPERO) – CRD42020206406 and the article was written according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline.

Search strategy

A comprehensive literature search was done to identify studies published till 30 September 2020. The following databases were searched: Medline via PubMed, Embase and Cochrane Library (Cochrane Database of Systematic Reviews Cochrane Central Register of Controlled Trials). Search strategies for PubMed, EMBASE and Cochrane Library are provided in the Supplementary Appendix.

Selection criteria

The studies were included in the review as per the PICOS (acronym for Population, Intervention, Comparator, Outcome, and Study) framework/process. The study population included patients aged 18 years or more who underwent any type of surgery (major/minor). The intervention for the study was perioperative oral flupirtine (any dose/schedule) for postoperative pain and the comparator was other analgesics or placebo for postoperative pain.

The primary outcome was the efficacy of flupirtine for postoperative pain compared to other analgesics or placebo assessed using any of the pain-assessment scales (4-point/5-point/11-point scale). The secondary outcome was the proportion of individuals experiencing drug-related side effects due to flupirtine and other analgesics/placebo. Animal model studies, case reports/series, abstracts, conference proceedings, reviews, studies with incomplete text and any study which used flupirtine for chronic pain were excluded.

Selection of studies

The articles retrieved from various databases were uploaded to the Rayyan software.^[21] Duplicates were removed, and the most recent and complete versions were included. Two independent reviewers (IM and AL) screened the titles and abstracts of the records. Studies were ‘included’ if selection criteria were satisfied, ‘excluded’ if selection criteria were not satisfied and in case of doubt, marked as ‘may be’. Disagreements about selection, if any, were resolved by the third author (SD). Full-text articles were retrieved for the included abstracts. Reference lists of the included studies were also searched for additional sources. The final inclusion in the review was based on the full-text reading.

Data extraction

A pretested spreadsheet-based data extraction form was used to collect information on authors, year of publication, study setting, inclusion criteria, study methodology, details of intervention and comparator group, pain assessment, rescue analgesic requirement and side effects. Extraction was done by two authors (IM and AL) independently and checked for consistency by the third author (SD). The main outcome of the study was postoperative pain scores. We extracted pain scores for the time periods mentioned in the respective publication. If recorded data timings were non-specific timings, they were approximated to a specific time by a mutual discussion with the two authors (IM and AL).

Risk of bias assessment

Cochrane Collaboration’s tool was used to assess the quality of the randomised controlled trials (RCTs) included in the systematic review and meta-analysis. Risk of bias was assessed in the following domains: (1) random sequence generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective reporting and (7) other bias. Our judgements on these domains were categorised as ‘low’ risk of bias, ‘high’ risk of bias or ‘unclear’ risk of bias. Two independent reviewers (IM and AL) evaluated the risk of bias in all the included studies in the review. Any disagreement was resolved by the third author (RSA).

Data synthesis and statistical analysis

For meta-analysis of continuous outcomes, it is essential to have mean, standard deviation (SD) and number of participants in each intervention group. Hence, wherever medians (interquartile range (IQR)) were given, we converted them to mean (SD) using the formula suggested in the Cochrane Handbook for Systematic Reviews of Interventions.^[22,23] We provided summary estimates of standardised mean difference (SMD) of pain scores between intervention and comparator groups with 95% confidence intervals (CI). The SMD was used as a summary statistic as all studies assessed the same outcome, that is, pain, but used different scales for assessing the outcome. Hence, it was necessary to standardise the outcome. It was calculated as follows: SMD = (difference in mean pain score between groups)/(standard deviation of pain score among participants).^[23] We did not impute the missing data in the analysis. The estimates available in the published literature were used for the analysis.

Results were presented in the following two parts: 1) Flupirtine versus other analgesics and 2) Flupirtine versus placebo/inert substances. Heterogeneity was assessed by Cochrane’s Q statistic test and I² statistic (percentage of residual variation attributed to heterogeneity). I² value >50% was considered to indicate the presence of heterogeneity. Sensitivity analysis was performed to assess the effect of quality of studies on the outcomes. Pooled SMDs were assessed after excluding the studies with high ROB. Trial sequential analysis (TSA) was performed to assess the adequacy of sample size for making conclusions and to weigh type I and II errors in the meta-analysis.^[24] To summarise the levels of evidence, Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework was used.^[25] Random-effects meta-analysis was performed in RevMan v5. Visual inspection of funnel plots was done to assess the publication bias.

RESULTS

Study selection

A total of 371 articles were retrieved from the identified databases. After removing duplicates, 271 studies were screened using abstracts. In the next step, 20 full-text articles were screened. Finally, 13 studies satisfied the inclusion criteria and were included in this systematic review and meta-analysis.^[8-20] [Figure 1, Table S1].

Table S1.

List of articles excluded from the review with reasons

Author	Title	Journal	Year	Reason for exclusion
Galvin et al.	Pharmacological interventions for the prevention of acute postoperative pain in adults following brain surgery	The Cochrane Database of Systematic Reviews	2019	Review article
Luben et al	Treatment of tumor pain with flupirtine. Results of a double-blind study versus tramadol	Fortschritte der Medizin	1994	Outcome was chronic cancer Pain
Yadav et al	Role of flupirtine in reducing preoperative anxiety of patients undergoing craniotomy procedure	Saudi Journal of Anaesthesia	2017	Outcome was anxiety
Riethmüller- Winzen	Flupirtine in the treatment of post-operative pain	Postgraduate Medical Journal	1987	Study population was of pediatric age group
Bloomfield et al	Flupirtine and acetaminophen analgesia after episiotomy	Clinical pharmacology and therapeutics	1985	Procedure was episiotomy
Überall et al	Efficacy and safety of flupirtine modified release for the management of moderate to severe chronic low back pain: results of SUPREME, a prospective randomized, double-blind, placebo- and active-controlled parallel-group phase IV study	Current Medical Research and Opinion	2012	Outcome was chronic back pain
Banerjee et al.	Comparative study of efficacy and tolerability of flupirtine versus tramadol in non-steroidal anti-inflammatory drug intolerant mechanical low back pain	Indian Journal of Rheumatology	2012	Outcome was chronic back pain

Open in a new tab

Characteristics of studies included in the meta-analysis

All included studies were RCTs.^[8-20] Three out of 13 studies were published in the 1980s; the rest were published between 2010 and 2020.^[12-14] The majority of studies were from India and included males as well as females. In seven studies, analgesics were administered for abdominal procedures.^{[8,10-12,15,19,20]} The number of participants in the included studies varied from 40 to 390 [Table 1].

Table 1.

Characteristics of included studies

Author	Study design	Study period	Study Site	Randomisation	Allocation concealment	Blinding	Age group of participants	Gender	ASA	Type of surgery	Duration of surgery
Ojha 2018 [19]	Prospective randomised	May 2016-December 2016	India	Yes	Yes	Double blind	16-60 years	Females	1,2	Diagnostic laparoscopy for gynaecological surgeries under general anaesthesia	Not mentioned
Saumya 2017[16]	Prospective randomised	January 2015- July 2016	India	Yes	Not mentioned	Open sup	18-50	Males and females	1,2	lower limb surgery	<2 hours in both the groups. Non-significant difference
Karan 2016[20]	Prospective randomised	March 2014-January 2016	India	Yes	Not mentioned	Double blind	15-65 years	Males and females	NA	Inguinal hernia surgery	Not mentioned
Thapa 2016[11]	Prospective, randomised,	February 2013-June 2014	India	Yes	Not mentioned	Double blind	30-60 years	Females	1,2	Total abdominal hysterectomy	Not mentioned
Yadav 2015[8]	Prospective randomised	August 2012- April 2013	India	Yes	Not mentioned	Double blind	18 to 70 years	Males and females	1, 2	Laparoscopic cholecystectomy	Not mentioned
Joginder Pal 2015[10]	Prospective randomised	February 2012-October 2013	India	Yes	Not mentioned	Double blind	18-65 years	Males and females	1,2	Elective abdominal surgeries under Spinal anaesthesia	Not mentioned
Ahuja 2015[12]	Prospective randomised	January 2013-August 2013	India	Yes	Not mentioned	Double blind	18-70 years	Females	1,2	Gynaecological ambulatory surgeries under general anaesthesia	<30 minutes in both the groups. Non-significant difference
Yadav 2014[9]	Prospective randomised	December 2010- January2013	India	Yes	Not mentioned	Double blind	18 to 70 years	Males and females	1, 2	Craniotomy	Not mentioned
Jain 2013[17]	Prospective randomised	December 2009 -January 2011	India	Yes	Not mentioned	Double blind	18–70	Females	1, 2, 3	CA Breast	1.5 hrs in both groups. Non-significant difference
Naser 2012[18]	Prospective randomised	Not mentioned	India	Yes	Not mentioned	Double blind	18–65	Males and females	Not mentioned	Short duration general surgeries	<45 minutes in both groups. Non-significant difference.
Galasko 1985[13]	Prospective randomised	Not mentioned	UK	Yes	Not mentioned	Double blind	>18 years	Males and females	Not mentioned	Elective surgery for prosthetic hip joint replacement	Not mentioned
Mastronardi 1988[14]	Prospective randomised	Not mentioned	Italy	Yes	Not mentioned	Double blind	>18 years	Males and females	Not mentioned	Planned for elective orthopaedic surgery	Not mentioned
Moore 1983[15]	Prospective randomised	Not mentioned	UK	Yes	Not mentioned	Double blind	>18 years	Females	Not mentioned	Total abdominal hysterectomy	Not mentioned

Open in a new tab

Details of intervention

Flupirtine was administered orally in all the studies.^[8-20] Only in 1 study, 200 mg (single dose) of flupirtine was given; in the rest of the studies, 100 mg per dose of flupirtine was administered.^[8] Only in two studies a single dose of flupirtine was given.^[8,11] The rest of the studies repeated flupirtine doses for pain relief for 1–5 days. The interval between two doses of flupirtine varied between 4 and 24 hours. Flupirtine was administered postoperatively in eight studies^{[9,10,13-16,18,20]} pre-operatively in two studies,^[8,11] and both pre- and postoperatively in three studies^[10,12,17] [Table S2].

Table S2.

Interventions in included studies

Author	Intervention drug	Dose (mg)	Mode of administration	Total no of doses administered	Average doses/day	Interval between 2 doses	Timing of starting drug (pre/post)	Time of starting drug	Last post-op dose given on
Ojha_2018	Flupirtine	100	Oral	4	3	8 hr	Pre-operative and Post-operative	8 hr after	24 hr Post op
	Ibuprofen	800	Oral	4	3	8 hr	Pre-operative and Post-operative	8 hr after	24 hr post op
Saumya 2017	Flupirtine	100	Oral	10	2	12 hr	Post-operative only	6 hr after	Day 5
	Piroxicam	20	Oral	10	2	12 hr	Post-operative only	6 hr after	Day 5
Thapa 2016	Flupirtine	100	Oral	1	1	NA	Pre-operative only	1 hr before	NA
	Empty gelatin capsule	NA	Oral	1	1	NA	Pre-operative only	1 hr before	NA
Karan_2016	Flupirtine	100	Oral	NA	NA	NA	Post-operative only	NA	NA
	Diclofenac	50	Oral	NA	NA	NA	Post-operative only	NA	NA
Yadav 2015	Flupirtine	200	Oral	1	1	NA	Pre-operative only	2 hr before	NA
	B complex	NA	Oral	1	1	NA	Pre-operative only	2 hr before	NA
Joginder Pal 2015	Flupirtine	100	Oral	20	4	6 hr	Post-operative only	12 hr after	Day 5
	Diclofenac	50	Oral	20	4	6 hr	Post-operative only	12 hr after	Day 5
Ahuja 2015	Flupirtine	100	Oral	7	3	8 hr	Pre-operative and Post-operative	1 hr before & 8 hr after	Day 2
	Ibuprofen	800	Oral	7	3	8 hr	Pre-operative and Post-operative	1 hr before & 8 hr after	Day 2
Yadav 2014	Flupirtine	100	Oral	6	3	8 hr	Post-operative only	48 hr after	Day 4
	Diclofenac	50	Oral	6	3	8 hr	Post-operative only	48 hr after	Day 4
	B complex	NA	Oral	6	3	8 hr	Post-operative only	48 hr after	Day 4
Jain 2013	Flupirtine	100	Oral	2	1	24 hr	Pre-operative and Post-operative	2 hr before and 24 hr after surgery	Day 1
	Placebo capsule	NA	Oral	2	1	24 hr	Pre-operative and Post-operative	2 hr before and 24 hr after surgery	Day 1
Naser 2012	Flupirtine	100	Oral	15	3	8 hr	Post-operative only	24 hr after	Day 5
	Tramadol	50	Oral	15	3	8 hr	Post-operative only	24 hr after	Day 5
Mastronardi 1988	Flupirtine	100	Oral	Not available	2.3	Minimum 45 minutes, maximum permissible dose is 400 mg	Post-operative only	On request	Not available
	Diclofenac	50	Oral	Not available	2.7	Minimum 45 minutes, maximum permissible dose is 200 mg	Post-operative only	On request	Not available
Galasko 1985	Flupirtine	100	Oral	Not available	2.6 (day 1), 2.3 (day 2), 1.8 (day 3), 1.5 (day 4)	Minimum 4 hr	Post-operative only	24 hr after	Day 4
	Pentazocine	50	Oral	Not available	3.3 (day 1), 2.4 (day 2), 1.7 (day 3), 1.5 (day 4)	Minimum 4 hr	Post-operative only	24 hr after	Day 4
Moore 1983	Flupirtine	100	Oral	Not available	2.6 (day 1), 3.0 (day 2), 1.3 (day 3)	Minimum 4 hr	Post-operative only	On request	Day 3
	Dihydrocodeine	60	Oral	Not available	2.5 (day 1), 3.0 (day 2), 1.5 (day 3)	Minimum 4 hr	Post-operative only	On request	Day 3

Open in a new tab

Details of comparator

Comparator drug was another analgesic drug in nine studies,^{[10,12-16,18-20]} placebo or inert substance (like B-complex) in three studies^[8,11,17] and both placebo and other analgesic drugs in one study.^[9] The dosage, schedule and duration of administration of comparator drugs varied widely [Table S2].

Pain assessment

Eleven out of thirteen studies assessed pain using an 11-point scale,^{[8-12,14,16-20]} and one study each used a 4-point and 5-point pain assessment grading scale.^[13,15] The timing of pain assessment varied widely from 1 to 96 hours. We identified the following time points when the majority of studies have assessed and reported level of pain: 0 hour, 6 hours, 12 hours, 24 hours and 48 hours [Table S3].

Table S3.

Effect of interventions in included studies

Author	Scale				No. of patients screened	No. of patients participated	No. of patients analysed	Drug	No.
Ojha 2018	VNRS (11-point scale)				NA	NA	106	Flupirtine	53
								Ibuprofen	53
Saumya 2017	VAS (11-point scale)				76	76	71	Piroxicam	37
								Flupirtine	34
Karan 2016	VAS (11-point scale)				NA	NA	50	Flupirtine	25
								Diclofenac	25
Thapa 2016	VAS (11-point scale)				60	50	50	Empty gelatin capsule	25
								Flupirtine	25
Yadav 2015	VAS (11-point scale)				80	66	55	B complex	28
								Flupirtine	27
Joginder Pal 2015	VAS (11-point scale)				100	100	100	Diclofenac	50
								Flupirtine	50
Ahuja 2015	VNRS (11-point scale)				65	60	60	Ibuprofen	30
								Flupirtine	30
Yadav 2014	VAS (11-point scale)				390	390	371	Flupirtine	122
								Diclofenac	125
								B-complex	124
Jain 2013	NRS (11-point scale)				NA	NA	47	Placebo	24
								Flupirtine	23
Naser 2012	VAS (11-point scale)				NA	NA	104	Tramadol	50
								Flupirtine	54
Mastronardi 1988	VAS (11-point scale)				40	40	40	Diclofenac	20
								Flupirtine	20
Galasko 1985	Grading scale (0=none, 1=slight, 2=moderate, 3=severe, and 4=unbearable)				68	68	66	Pentazocine	31
								Flupirtine	35
Moore 1983	Four-point scale (0=none, 1=mild, 2=moderate, 3=severe)				50	50	50	Dihydrocodeine	25
								Flupirtine	25

Author	Mean (SD) score at 0 hr	Mean (SD) score at 6 hr	Mean (SD) score at 12 hr	Mean (SD) score at 24 hr	Mean (SD) score at 48 hr	Rescue analgesia drug		Rescue analgesia dose	Proportion administered rescue analgesia

Ojha 2018	0.184 (0.419)	0.438 (0.932)	NA	NA	NA	Diclofenac		NA	3%
	0.202 (0.473)	0.477 (0.842)	NA	NA	NA	Diclofenac		NA	9%
Saumya 2017	5.6 (1.7)		4.5 (1.6)	5.7 (1.4)	4.1 (1.5)	Tramadol		NA	52.90%
	5.8 (1.6)		5.3 (1.1)	4.8 (1.3)	4.4 (1.1)	Tramadol		NA	59.50%
Karan 2016	1.36 (1.77)	1.24 (2.18)	0.60 (1.65)	0.16 (0.62)	0 (0)	Tramadol		NA	20%
	2.2 (2.58)	1.40 (1.55)	1.28 (1.72)	0.28 (0.61)	0 (0)	Tramadol		NA	16%
Thapa 2016	NA	NA	NA	NA	NA	Morphine		47.0 (6.6)	NA
	NA	NA	NA	NA	NA	Morphine		40.4 (6.0)	NA
Yadav 2015	4, 1.5623	1, 1.5623	0.643, 0.7812	1, 1.5623	NA	Tramadol		19.7 (8.7)	NA
	1.3572, 0.7827	1, 1.5654	1, 1.5654	1, 1.5654	NA	Tramadol		15.9 (7.5)	NA
Joginder Pal 2015	6.3 (1.4)	4 (1.3)	2.8 (0.4)	1.5 (0.6)	NA	Tramadol		NA	20%
	6.6 (1.7)	4.1 (1.5)	2.8 (0.4)	1.4 (0.5)	NA	Tramadol		NA	16%
Ahuja 2015	0.2 (0.5)	0.5 (1)	0.3 (0.9)	0.1 (0.3)	0 (0)	Tramadol		NA	16.60%
	0.2 (0.6)	0.4 (0.9)	0.6 (1)	0.2 (0.5)	0 (0)	Tramadol		NA	3.30%
Yadav 2014	NA	NA	NA	NA	NA	Tramadol		NA	13%
	NA	NA	NA	NA	NA	Tramadol		NA	14%
	NA	NA	NA	NA	NA	Tramadol		NA	40%
Jain 2013	0.4656, 1.0245	1.4656, 2.6006	2, 1.5761	1.4656, 2.6006	0.3581, 0.7881	Morphine		19.8 (13.7)	NA
	0.717, 1.5803	1.3585, 2.3705	1.5377, 1.9754	1.3585, 2.3705	0, 0	Morphine		12.9 (10.4)	NA
Naser 2012	NA	NA	NA	5.0 (1.5)		Diclofenac		NA	2%
	NA	NA	NA	4.6 (1.8)		Diclofenac		NA	3.70%
Mastronardi 1988	5.1 (1.5)	NA	NA	NA	NA	No rescue analgesia		NA	NA
	4.8 (1.6)	NA	NA	NA	NA	No rescue analgesia		NA	NA
Galasko 1985	NA	NA	NA	1.5 (0.1)	1.2 (0.1)	No rescue analgesia		NA	NA
	NA	NA	NA	1.9 (0.1)	1.4 (0.1)	No rescue analgesia		NA	NA
Moore 1983	NA	NA	NA	2.2 (0.1)	2.1 (0.1)	Dihydrocodeine and papaverine		NA	NA
	NA	NA	NA	2.2 (0.1)	2.4 (0.1)	Dihydrocodeine and papaverine		NA	NA

Open in a new tab

Primary outcomes: Effect of flupirtine on postoperative pain

The number of participants in each arm varied from 20 to 125. On comparison with other analgesic drugs, the pooled SMD of pain score was −0.01 (−0.20 to 0.18, P = 0.95, n = 212 [flupirtine] and 215 [other analgesics], I² = 0%, P = 0.66) at 0 hour, −0.03 (−0.25 to 0.20, P = 0.82, n = 158 [flupirtine and other analgesics], I² = 0%, P = 0.95) at 6 hours (certainty of evidence was high), 0.13 (−0.25 to 0.51, P = 0.50, n = 139 [flupirtine] and 142 [other analgesics], I² = 61%, P = 0.05) at 12 hours (certainty of evidence was high), 0.36 (−0.38 to 1.10, P = 0.34, n = 253 [flupirtine] and 268 [other analgesics], I² = 94%, P < 0.001) at 24 hours (certainty of evidence was low), and 1.69 (0.10 to 3.29, P = 0.04, n = 149 [flupirtine] and 148 [other analgesics], I² = 95%, P < 0.001) at 48 hours [Figure 2, Figure S1^{(167.4KB, tif)}, Table S4a].

Forest plots for individual outcomes – flupirtine versus other analgesics

Table S4a.

Comparison of standardised mean difference (SMD) of pain scores (Random effect model) – Flupirtine vs analgesics

Name	Flupirtine group			Control group				SMD	CI Start	CI End	Weight	Chi2	P- chi2	I- Square	Tau- Square	Z	P (Z)	df

	Mean	SD	n	Drug	Mean	SD	n
Pain score at 0 hr			212				215	-0.01	-0.2	0.18	100	3.27	0.66	0	0	0.06	0.95	5
Mastronadi 1988	4.8	1.6	20	Diclofenac	5.1	1.5	20	-0.19	-0.81	0.43	9.36
Karan_2016	1.36	1.77	25	Diclofenac	2.2	2.58	25	-0.37	-0.93	0.19	11.54
Ahuja 2015	0.2	0.6	30	Ibuprofen	0.2	0.5	30	0	-0.51	0.51	14.11
Saumya 2017	5.8	1.6	34	Piroxicam	5.6	1.7	37	0.12	-0.35	0.59	16.64
Pal 2015	6.6	1.7	50	Diclofenac	6.3	1.4	50	0.19	-0.2	0.58	23.41
Ojha 2018	0.18	0.42	53	Ibuprofen	0.2	0.47	53	-0.04	-0.42	0.34	24.93
Pain Score at 6 hrs			158				158	-0.03	-0.25	0.2	100	0.37	0.95	0	0	0.22	0.82	3
Karan_2016	1.24	2.18	25	Diclofenac	1.4	1.55	25	-0.08	-0.64	0.47	15.82
Ahuja 2015	0.4	0.9	30	Ibuprofen	0.5	1	30	-0.1	-0.61	0.4	18.97
Pal 2015	4.1	1.5	50	Diclofenac	4	1.3	50	0.07	-0.32	0.46	31.65
Ojha 2018	0.44	0.93	53	Ibuprofen	0.48	0.84	53	-0.04	-0.42	0.34	33.56
Pain score at 12 hrs			139				142	0.13	-0.25	0.51	100	7.62	0.05	60.64	0.09	0.68	0.5	3
Karan_2016	0.6	1.65	25	Diclofenac	1.28	1.72	25	-0.4	-0.96	0.16	21.94
Ahuja 2015	0.6	1	30	Ibuprofen	0.3	0.9	30	0.31	-0.2	0.82	23.9
Saumya 2017	5.3	1.1	34		4.5	1.6	37	0.57	0.1	1.05	25.27
Pal 2015	2.8	0.4	50	Diclofenac	2.8	0.4	50	0	-0.39	0.39	28.89
Pain score at 24 hrs			253				268	0.36	-0.38	1.1	100	94.86	0	93.67	0.92	0.96	0.34	6
Galasko 1985	1.9	0.1	35	Pentazocine	1.5	0.1	31	3.95	3.11	4.8	12.84
Karan_2016	0.16	0.62	25	Diclofenac	0.28	0.61	25	-0.19	-0.75	0.36	14.21
Moore 1983	2.2	0.1	25	Dihydrocodeine	2.2	0.1	25	0	-0.55	0.55	14.21
Saumya 2017	4.8	1.3	34	Piroxicam	5.7	1.4	37	-0.66	-1.14	-0.18	14.51
Ahuja 2015	0.2	0.5	30	Ibuprofen	0.1	0.3	50	0.26	-0.2	0.71	14.6
Pal 2015	1.4	0.5	50	Diclofenac	1.5	0.6	50	-0.18	-0.57	0.21	14.81
Naser 2012	4.6	1.8	54	Tramadol	5	1.5	50	-0.24	-0.62	0.15	14.83
Pain score at 48 hrs			149				148	1.69	0.1	3.29	100	40.84	0	95.1	1.88	2.08	0.04	2
Ahuja 2015	0	0	30	Ibuprofen	0	0	30	0	0	0	0
Karan_2016	0	0	25	Diclofenac	0	0	25	0	0	0	0
Moore 1983	2.4	0.1	25	Dihydrocodeine	2.1	0.1	25	2.95	2.13	3.77	32.23
Galasko 1985	1.4	0.1	35	Pentazocine	1.2	0.1	31	1.98	1.38	2.57	33.58
Saumya 2017	4.4	1.1	34	Piroxicam	4.1	1.5	37	0.22	-0.24	0.69	34.19

Open in a new tab

Likewise, as compared to placebo/inert substances, the pooled SMD of pain score was −0.02 (−0.41 to 0.37, P = 0.92, n = 50 [flupirtine] and 52 [placebo/inert substances], I² = 0%, P = 0.92) at 6 hours, and −0.02 (−0.41 to 0.37, P = 0.92, n = 50 [flupirtine] and 52 [placebo/inert substances], I² = 0%, P = 0.92) at 24 hours [Figure 3, Figure S1^{(167.4KB, tif)}, Table S4b].

Forest plots for individual outcomes – flupirtine versus placebo

Table S4b.

Comparison of standardised mean difference (SMD) of pain scores (Random effect model) – Flupirtine vs placebo

Name	Flupirtine group			Control group				SMD	CI Start	CI End	Weight	Chi2	P- chi2	I-Square	Tau-Square	Z	P (Z)	df

	Mean	SD	n	Drug	Mean	SD	n
Pain Score at 6 hrs			50				52	-0.02	-0.41	0.37	100	0.01	0.92	0	0	0.1	0.92	1
Jain 2013	1.36	2.37	23	Placebo	1.47	2.6	24	-0.04	-0.61	0.53	46.07
Yadav 2015	1	1.57	27	B-complex	1	1.56	28	0	-0.53	0.53	53.93
Pain score at 24 hrs			50				52	-0.02	-0.41	0.37	100	0.01	0.92	0	0	0.1	0.92	1
Jain 2013	1.36	2.37	23	Placebo	1.47	2.6	24	-0.04	-0.61	0.53	46.07
Yadav 2015	1	1.57	27	B-complex	1	1.56	28	0	-0.53	0.53	53.93

Open in a new tab

Rescue analgesia was administered in 11 out of 13 studies.^[8-12,15-20] Drugs used for rescue analgesia were tramadol, morphine, diclofenac, dihydrocodeine and papaverine. [Table S3].

Secondary outcomes: Side-effect profile

1)
Sedation: As compared to placebo, an equal sedation score,^[8] lesser proportion^[17] and significantly higher sedation score^[11] were reported by one study each in the flupirtine group. One study reported a non-significant difference with the ibuprofen group.^[12] [Table S5]
2)
Postoperative nausea and vomiting (PONV): As compared to placebo, a higher proportion,^[9] equal score^[8] and lesser proportion of PONV^[17] was reported by one study each in the flupirtine group. As compared to other analgesics, two studies reported equal proportions (versus diclofenac),^[9,20] and one study reported a lesser proportion (versus tramadol)^[18] in the flupirtine group [Table S5].
3)
Nausea: As compared to placebo, one study reported a lesser nausea score at 48 hours.^[11] In comparison with analgesics, one study reported no significant difference with the ibuprofen group,^[12] another study reported a similar proportion (40% and 50%) in diclofenac and flupirtine groups^[10] and one study reported a higher proportion of nausea in flupirtine group as compared to diclofenac (4% versus 0%).^[20] [Table S5]
4)
Dizziness: Total three studies reported a lesser proportion of dizziness in comparison to placebo, tramadol and diclofenac groups.^[10,17,18] [Table S5]
5)
Gastritis: As compared to analgesic drugs, all six studies reported a lesser proportion of gastritis in the flupirtine group (versus diclofenac, piroxicam, ibuprofen, and tramadol).^{[10,14,16,18-20]}
6)
Liver enzyme elevation: None of the patients in two studies reported liver enzyme elevation in flupirtine group compared to placebo and diclofenac groups^[8,9] [Table S5].

Table S5a.

Side effect profile (1)

S No	Author	Sedation/Somnolence	PONV	Diarrhoea	Constipation	Bleeding	Depression	Respiratory depression	Nausea	Vomiting	Dizziness
1	Yadav 2015 (B-complex)	RSS score was same (2 vs 2) in both the groups.	Score using 4-point scale was same (0 vs 0) in both the groups	NA	NA	NA	NA	NA	NA	NA	NA
2A	Yadav 2014	NA	2.5% (Flupirtine) vs 2.4% (Diclofenac)	1.6% (Flupirtine) vs 0% (Diclofenac)	2.5% (Flupirtine) vs 3.2% (Diclofenac)	0.8% (Flupirtine) vs 0% (Diclofenac)	0%% (Flupirtine) vs 0% (Diclofenac)	NA	NA	NA	NA
2B	Yadav 2014	NA	2.5% (Flupirtine) vs 1.6% (B-complex)	1.6% (Flupirtine) vs 0.8% (B-complex)	2.5% (Flupirtine) vs 1.6% (B-complex)	0.8% (Flupirtine) vs 0.8% (B-complex)	0% (Flupirtine) vs 0% (B-complex)	NA	NA	NA	NA
3	Joginder Pal 2015	NA	NA	NA	NA	NA	NA	NA	40.0% (Flupirtine) vs 50.0% (Diclofenac)	12.0% (Flupirtine) vs 18.0% (Diclofenac)	2.0% (Flupirtine) vs 20.0% (Diclofenac)
4	Thapa 2016 (Placebo)	Sedation score upto 4 hour was higher in flupirtine group (P=0.02)	NA	NA	NA	NA	NA	NA	Mean (SD) cumulative categorical scoring system (CCS) at the end of 48 hr was 0.2 (0.5) in flupirtine group and 0.8 (0.5) in placebo group.	NA	NA
5	Ahuja 2015	No significant difference between flupirtine and ibuprofen group	NA	NA	No significant difference between flupirtine and ibuprofen group	NA	NA	No significant difference between flupirtine and ibuprofen group	No significant difference between flupirtine and ibuprofen group	No significant difference between flupirtine and ibuprofen group	NA
6	Jain 2013	0.0% (Flupirtine) vs 12.5% (Placebo)	13.0% (Flupirtine) vs 20.0% (Placebo)	NA	NA	NA	NA	NA	NA	NA	8.7% (Flupirtine) vs 12.5% (Placebo)
7	Naser 2012	NA	3.7% (Flupirtine) vs 10.0% (Tramadol)	NA	NA	0.0% (Flupirtine) vs 0.0% (Tramadol)	NA	NA	NA	NA	1.9% (Flupirtine) vs 4.0% (Tramadol)
8	Karan 2016	NA	4% (Flupirtine) vs 4% (Diclofenac)	NA	NA	NA	NA	NA	4% (Flupirtine) vs 0% (Diclofenac)	0% (Flupirtine) vs 4% (Diclofenac)	NA
9	Ojha 2018	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA

Open in a new tab

Table S5b.

Side effect profile (2)

S No	Author	Pain abdomen	Dry mouth	Gastritis	Rashes	Shivering	Liver enzyme elevation	Impaired taste	Pruritus	Hypotension	Headache	Cough
1	Yadav 2015	NA	NA	NA	NA	NA	None of the patient had reported.	NA	NA	NA	NA	NA
2A	Yadav 2014	NA	NA	NA	NA	NA	0%% (Flupirtine) vs 0% (Diclofenac)	NA	NA	NA	NA	NA
2B	Yadav 2014	NA	NA	NA	NA	NA	0% (Flupirtine) vs 0% (B-complex)	NA	NA	NA	NA	NA
3	Joginder Pal 2015	14.0% (Flupirtine) vs 0.0% (Diclofenac)	14.0% (Flupirtine) vs 26.0% (Diclofenac)	10.0% (Flupirtine) vs 62.0% (Diclofenac)	4.0% (Flupirtine) vs 6.0% (Diclofenac)	NA	NA	4.0% (Flupirtine) vs 58.0% (Diclofenac)	NA	NA	10.0% (Flupirtine) vs 10.0% (Diclofenac)	NA
4	Thapa 2016	NA	NA	NA	NA	0.0% (Flupirtine) vs 0.0% (Placebo)	NA	NA	0.0% (Flupirtine) vs 28.0% (Placebo)	NA	NA	NA
5	Ahuja 2015	NA	NA	NA	No significant difference between flupirtine and ibuprofen group	NA	NA	NA	NA	No significant difference between flupirtine and ibuprofen group	NA	NA
6	Mastronadi 1988	NA	NA	5.0% (Flupirtine) vs 15.0% (Diclofenac)	NA	NA	NA	NA	NA		NA	NA
7	Saumya 2017	NA	NA	2.9% (Flupirtine) vs 8.0% (Piroxicam)	NA	NA	NA	NA	NA		NA	NA
8	Jain 2013	NA	NA	NA	NA	NA	NA	NA	0.0% (Flupirtine) vs 4.0% (Placebo)		4.3% (Flupirtine) vs 0.0% (Placebo)
9	Naser 2012	NA	NA	0.0% (Flupirtine) vs 4.0% (Tramadol)	NA	NA	NA	NA	NA	NA	NA	0.0% (Flupirtine) vs 2.0% (Tramadol)
10	Karan 2016	0% (flupirtine) vs 8% (diclofenac)	NA	0% (flupirtine) vs 16% (diclofenac)	NA	NA	NA	NA	NA	NA	NA	NA
11	Ojha 2018	NA	NA	Significantly higher in ibuprofen group than flupirtine group	NA	NA	NA	Significantly higher in ibuprofen group than flupirtine group	NA	No significant difference between flupirtine and ibuprofen	NA	NA

Open in a new tab

ROB assessment

A total of 10 out of 13 studies had low risk,^[8-14,16-18] three studies had unclear risk of bias^[15,19,20] in the random sequence generation domain. In the domain of allocation concealment, five studies had low risk of bias,^{[11-13,19,20]} rest of the studies (eight) had unclear risk of bias.^[8-10,14-18] A total of five out of 13 studies had low risk,^{[8,11,15,17,19]} five studies had unclear risk,^{[9,10,12,14,18]} and three studies had high risk of bias^[13,16,20] in the domain of blinding of participants. In the domain of blinding of outcome assessment, seven studies had low risk of bias,^{[8,10,12,13,17,19,20]} rest of the studies (six) had unclear risk of bias.^{[9,11,14-16,18]} A total of nine out of 13 studies had low risk,^{[8-12,16,18-20]} two studies had unclear risk,^[14,15] and two studies had high risk of bias^[13,17] in the incomplete outcome domain. In the domain of selective reporting, nine studies had low risk of bias,^[9-13,15-18] rest of the studies (four) had unclear risk of bias.^[8,14,19,20] Two studies had low risk of bias in six out of seven domains of ROB assessment.^[11,12] One study had low risk of bias in only one domain while one study had low risk of bias in two out of seven domains of ROB assessment^[14,15] [Figure 4].

Risk of bias assessment of included studies

Sensitivity analysis

To assess the effect of quality of studies on the primary outcome, we excluded two studies on the basis of risk of bias and assessed the SMD of pain scores at 24 hours.^[14,15] However, the pooled SMD of pain score on comparison with other analgesics was 0.43 (−0.43 to 1.29, P = 0.33, n = 228 [flupirtine] and n = 243 [other analgesics], I² = 95%, P < 0.001).

Publication bias

Visual inspection of funnel plots revealed no publication bias [Figure S1^{(167.4KB, tif)}].

Trial sequential analysis

TSA revealed that the cumulative z statistic line of outcomes at 6, 12 and 24 hours was falling in the ‘inner wedge’ area which denotes that further studies will hardly be able to change the no-effect results^[24] [Figure S2^{(344.5KB, tif)}].

Level of evidence

The article was written according to PRISMA guidelines. The assessment of level of evidence was done using GRADE framework.^[25] The certainty of evidence was high for pain score at 6 and 12 hours. However, the certainty was low for the pain assessment at 24 hours [Table S6].

Table S6.

GRADE (Grading of Recommendations, Assessment, Development and Evaluations) framework for summary of levels of evidence

Outcomes	Risk with Flupirtine	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Pain score at 6 hours assessed with: Pain assessment scale	SMD 0.03 SD lower (0.25 lower to 0.2 higher)	-	250 (5 RCTs)	⨁⨁⨁⨁ High	Flupirtine results in little to no difference in pain score at 6 hours.
Pain score at 12 hours assessed with: Pain assessment scale	SMD 0.13 SD higher (0.25 lower to 0.51 higher)	-	281 (4 RCTs)	⨁⨁⨁⨁ High	Flupirtine results in little to no difference in pain score at 12 hours.
Pain score at 24 hours assessed with: Pain assessment scale	SMD 0.36 SD higher (0.38 lower to 1.1 higher)	-	521 (8 RCTs)	⨁⨁ Low^{a, b}	Flupirtine may result in little to no difference in pain score at 24 hours.

Open in a new tab

GRADE (Grading of Recommendations, Assessment, Development and Evaluations) framework for summary of levels of evidence

DISCUSSION

Flupirtine provided comparable analgesia at 0, 6, 12 and 24 hours in the postoperative period compared to active analgesics, while at 48 hours, the analgesic effect of flupirtine was poor than other analgesics. Compared to placebo, flupirtine did not provide an analgesic advantage at 6 and 24 hours. There was insufficient information for analysis of the safety profile. Flupirtine has been reported to cause liver toxicity or a rise in liver enzymes. There were no reports related to liver toxicity or any other serious adverse event in these trials.

There are no systematic reviews/meta-analyses on flupirtine for acute postoperative pain management. A systematic review was done by Schüchen et al. to assess the effect of non-opioid analgesics in the palliative medicine.^[26] The review concluded that there is moderate quality evidence for substantial pain relief in cancer patients by flupirtine for chronic pain.^[23] The review also showed that flupirtine was associated with fewer side effects as compared to placebo or other analgesic use for chronic pain.^[26] However, our study assessed the effect of flupirtine on acute postoperative pain. Hence, the different outcomes could be the reason for the difference in efficacy. Poor perioperative pain control predisposes to chronic post-surgical pain (CPSP). Nociceptive stimuli activate NMDA receptors and have an essential role in central sensitisation, wind up and pain memory. The mechanism by which flupirtine produces analgesia differs from other commonly used analgesics.^[27] Flupirtine activates the selective neuronal potassium channel openers leading to indirect NMDA receptor antagonism. This NMDA receptor antagonism prevents hyperalgesia and sensitisation and may reduce the incidence of CPSP.

Extensive literature search and risk of bias assessment are two major strengths of this study. Our study included trials which used flupirtine for postoperative pain without defining flupirtine dose/schedule, type and duration of surgeries and study size. We included 13 studies in our review. Various studies used flupirtine in different doses and schedules (200 mg versus 100 mg, single-dose versus multiple-dose) following various surgical procedures and compared postoperative analgesia with placebo/other analgesic drugs. The comparator drugs also varied in pharmacological action, dosage and schedule. We used standard Cochrane tool for assessing risk of bias in the included studies. It was followed by sensitivity analysis to assess the effect of studies with high risk of bias on the results of the study.

Our study has several limitations. First, the evidence supporting the use of flupirtine for postoperative pain is weak due to a limited number of studies included in the quantitative analysis. The studies involved participants who had undergone various surgical procedures, including abdominal, limb surgeries, craniotomy and superficial surgeries. Though they represent the adult populations excluding pregnancy, the interpretation from a relatively smaller group of patients with varied flupirtine dosing schedules should be interpreted with caution. Second, the majority of the studies were from the Indian subcontinent. Though approval by the US-FDA is pending, flupirtine has been used in European and Asian countries. Due to the risk of liver toxicity with flupirtine, its use has been prohibited in Europe since 2018.^[28] If flupirtine clears Food and Drug Administration approval for trials, it would be possible to study in a variety of populations to elucidate its role in perioperative pain management. Flupirtine can be considered an alternative to another non-opioid analgesic in patients in whom NSAIDs are contraindicated, such as advanced age, borderline renal function, and non-responsive to routine opioid medications.

CONCLUSIONS

In summary, the current evidence suggests that the analgesic effect of other analgesics used to treat moderate or severe postoperative pain is not inferior to flupirtine. To establish the analgesic superiority of flupirtine over other analgesics, there is a need to have further studies with better standardisation of dose and frequency to limit all potential sources of heterogeneity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Figure S1

Funnel plots

IJA-67-247_Suppl1.tif^{(167.4KB, tif)}

Figure S2

Trial sequential analysis

IJA-67-247_Suppl2.tif^{(344.5KB, tif)}