Non-pharmacological Interventions for Muscle Cramps and Pain in Patients With Cirrhosis: A Systematic Review

Despite the high prevalence of pain and challenges associated with traditional pharmacological pain management in patients with cirrhosis, little is known about the safety and effectiveness of non-pharmacological management of pain in this patient population. A systematic literature search of published studies was conducted in nine databases from inception through January 11, 2023, including any clinical trial, cohort, or case-control study of non-pharmacological pain interventions in adult patients with cirrhosis. Studies using nutritional supplements were included. The primary and secondary outcomes for this review were pain/analgesic effect and safety, respectively. Two reviewers independently performed data extraction and risk of bias assessment. Of the 4,087 studies initially screened, 11 studies representing 340 patients ultimately met inclusion criteria, including seven observational and four randomized controlled trials. Five studies reported muscle cramp severity, four reported muscle cramp frequency, and two reported non-cramp pain. Oral zinc sulfate, L-carnitine, and taurine were reported to decrease cramp frequency. Oral vitamin E, oral zinc sulfate, L-carnitine, taurine, and pickle juice decreased cramp severity. Curcumin supplementation, resistance training, and stretching and walking programs improved non-cramp pain. Mild adverse events were reported in four studies. The risk of bias was moderate to high for all studies, largely due to missing data, study design, and a lack of blinding of participants. Numerous nutritional and non-pharmacological interventions have been reported to be safe and effective for the treatment of pain and painful muscle cramps in patients with cirrhosis. However, further research is needed to better determine the efficacy, safety, and optimal frequency and dosage of interventions.


Introduction And Background
Cirrhosis is a growing public health concern in the US [1].According to provisional data from the National Vital Statistics System, chronic liver disease and cirrhosis ranked ninth as underlying causes of death in the US [2].Many patients with cirrhosis experience pain and/or painful muscle cramps, with approximately 80% of patients reporting pain and 75% reporting pain-related disability [3,4].Furthermore, chronic pain is experienced by over half of patients with cirrhosis [3].Fibromyalgia-like symptoms, depression, opioid use, sleep disturbance, and depression are also more prevalent in patients with liver disease [3,4].
The treatment of pain in cirrhosis patients is complicated by the absolute and relative contraindications to pharmacological therapies that must be considered in this patient population.Many analgesic treatment options, such as nonsteroidal anti-inflammatory drugs and paracetamol, are associated with drug-induced liver injury.Patients with chronic liver disease also have an increased risk of adverse drug reactions such as constipation, renal dysfunction, and oversedation as a function of altered drug metabolism in this population [1,4].Thus, pain control in patients with cirrhosis is often inadequately addressed.Despite the prevalence of pain and complications associated with pharmacological management in patients with cirrhosis, little is known about the effectiveness and safety of the management of painful symptoms with non-pharmacological interventions in this population.An in-depth investigation of the nonpharmacological management of patients with cirrhosis is needed to address this treatment deficit.Therefore, the objective of our study was to conduct a systematic review summarizing the published literature examining the effectiveness and safety of non-pharmacological interventions for pain in patients with cirrhosis.
The protocol for this study was pre-registered at PROSPERO (ID: CRD42023401414).We reported this study consistent with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [5] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [6] statements (Appendices A, B, and C).

Data Sources and Search Strategy
An exhaustive search of the literature was conducted by a medical research librarian (AG) in Ovid AMED, CINAHL, Cochrane Library, Google Scholar, Ovid Embase, Ovid MEDLINE, PubMed, Scopus, and Web of Science Core Collection databases to find relevant articles published from the inception of each database to January 13, 2023.Databases were searched using a combination of keywords and controlled vocabulary for cirrhosis and pain management or pain and pain management interventions.The search was conducted without restrictions on language, publication type, or publication year and was peer-reviewed by a second medical librarian, according to the Peer Review of Electronic Search Strategies (PRESS) [7].In order to identify additional relevant studies that may not have been retrieved by the database search, forward and backward citation chasing was performed using citationchaser [8].The detailed search strategy can be downloaded from Open Science Framework (https://osf.io/57tpc).

Study Selection
The Population, Intervention, Comparison, Outcomes and Study (PICO) [9] criteria were used to determine the eligibility of the articles based on the type of study design, type of population, type of exposure and outcome, number of participants, and follow-up period.Non-pharmacological interventions, including nutritional supplements, were the exposure.The primary outcome was pain/analgesic effect, and the secondary outcome was safety.Comparative study designs (randomized controlled trial (RCT), crosssectional, cohort, and case-control) that assessed the effectiveness and/or safety of nutritional and/or nonpharmacological interventions in patients with cirrhosis in adult populations were included.Studies in which the participants were children were excluded.Studies presenting unoriginal data and containing minimal information in the methods and results sections were not included.Studies of patients who had undergone liver transplants or were on a transplant list and studies using prescription medications as an intervention were also excluded.
All search results were imported into an Endnote 20 library.Duplicates were subsequently removed using the Yale Reference Deduplicator [10].All studies were then imported into Covidence, a systematic review software, for screening.All titles and abstracts were independently screened by two coauthors (RM and LB).A full-text review for ultimate inclusion was conducted on all abstracts included by either reviewer.Disagreements were settled by a third author (JD).

Data Extraction and Quality Assessment
Data, including study populations, interventions, outcomes, quality, and follow-up period, were extracted from published articles into evidence tables by two coauthors (RM and LB) with oversight from additional coauthors (CG and JD).The primary and secondary outcomes for this review were pain/analgesic effect and safety, respectively.Study quality assessments were performed using two different quality assessment tools.The Newcastle-Ottawa Scale (NOS), which asks reviewers to score studies based on three elements (selection, comparability, and outcome) for a maximum score of nine points (lowest risk of bias), was used for included cohort studies [11].The Cochrane risk-of-bias tool for randomized trials (RoB 2), which assesses the risk of bias in five different domains as well as assigns an overall risk of bias scoring (low risk, some concerns, or high risk of bias), was used to assess quality in included randomized trials [12,13].Two authors individually assessed studies using the NOS (RM and LB) and RoB 2 (RM and CG) where appropriate.In both cases, authors completed assessments individually, and discrepancies between reviewers were resolved by consensus.

Analysis
Due to the heterogeneity of outcomes, pain and analgesic effects were assessed separately as cramp frequency, cramp severity, and non-cramp pain.Individual studies reported pain intensity using different scales, which were therefore analyzed using Hedge's standardized mean difference (MD) [14].In general, standardized MDs greater than 0.8 are considered to have large effects [15].Pain frequency was reported as muscle spasms per week and was analyzed using the raw MD between treatments and controls.Due to the heterogeneity of treatment interventions, we did not pool study results but created forest plots showing individual study results.Statistical analyses were performed using Stata/BE, version 17.0 (StataCorp LLC, College Station, Texas, US).
The studies included in our review demonstrated variability in pain assessments.Hansen et al. measured pain severity and pain interference using the Brief Pain Inventory [28], Nouri-Vaskeh et al. measured bodily pain using the 36-Item Short Form Survey (SF-36) [29], and Soldera et al. measured pain sensitivity using the SF-36 [24].Eight studies included assessments of muscle cramps [16][17][18][20][21][22]25,26].There was large variability in the measurement of the characteristics of cramps and the outcome measures used.Four studies measured the frequency of muscle cramps in days per week [17,18,20,22,25].Seven studies measured muscle cramp severity and intensity.Two studies measured severity as mild, moderate, or severe [16,17].Three studies measured severity on a 0-10 Visual Analogue Scale (VAS) [18,20,26].One study measured cramp intensity on a 1-10 point Likert scale [22].Three studies had a combined measurement based on the frequency and intensity of cramps.One study measured the proportion of cramp days with VAS less than five [26], and two used scoring systems based on frequency and intensity [16,25].One study measured the duration of muscle cramps in minutes per week [22].Finally, one study measured the time to cramp disappearance in days [17].

Safety
Mild adverse events were reported in four studies.One out of 12 participants reported epigastric discomfort but continued to take niushe-shen-qi-wan [17], one out of 12 participants reported mild watery stools while taking oral zinc sulfate [18], one of 10 participants experienced mild dyspepsia with oral taurine supplementation [25], and paracentesis was required in two participants (one in the intervention group and one in the control group) with a prior history of paracentesis before participating in the study [26] (Table 1).

Quality Appraisal
Overall, cohort studies were of similar quality (NOS score range: 3-4).Of the seven cohort studies, six scored four points, and one study scored three points [16][17][18][19][20][21]25].The main reasons cohort studies had a decrease in points were for how the study population was selected and/or for lacking a control group.Of the four randomized trials, two had some concerns and two had a high risk of bias [22][23][24]26].The main domain receiving scores of "some concerns" was missing outcome data, while the domain receiving the most scores of "high risk of bias" was the measurement of outcome due to a lack of blinding of study participants (Table 3). (

Key Findings
This systematic review found that limited information is available in the published literature assessing nutritional and non-pharmacological interventions for the treatment of pain in patients with cirrhosis.We included 11 studies, with the majority being cohort designs, assessing the impact non-pharmacological and nutritional interventions have on the frequency (four studies) and severity (five studies) of muscle cramps in patients with cirrhosis, and two studies assessing non-cramp pain.Multiple interventions were found to improve muscle cramp frequency and severity, with some mixed results.The risk of bias was moderate to high for all included studies, largely due to study design, missing data, and a lack of blinding of study participants.

Interpretation
Oral taurine [22,25], vitamin E [16], oral zinc sulfate [18], L-carnitine [20], and pickle juice [26] decreased cramp severity.Cramp frequency decreased with vitamin E [16], oral zinc sulfate [18], L-carnitine [20], niushe-shen-qi-wan [17], electroacupuncture [21], and oral taurine [22,25] interventions, while the duration of cramps decreased with vitamin E [16] and oral taurine administration [22].However, some interventions showed mixed effects.One study by Jang et al. [25] found treatment with oral taurine did not have a significant effect on cramp frequency, while another by Vidot et al. found taurine to significantly decrease cramp frequency [22].Furthermore, Tapper et al. [26] found a pickle juice intervention to decrease cramp severity (assessed via VAS) but found the difference between intervention and control groups for the proportion of cramp days with VAS less than five to be statistically non-significant.
Only two included studies evaluated the use of nutritional and non-pharmacological interventions to address non-cramp pain.Curcumin was found to improve bodily and joint pain [23].Additionally, resistance training and low-intensity stretching and walking programs improved pain sensitivity [24].More research is needed in this area, as previous work has found the prevalence of pain in patients with end-stage liver disease to be as high as 79% and the prevalence of muscle cramps to be as high as 68% [30].
Our study also found only minor adverse events associated with interventions.Adverse events were mild, rare, and consisted of reports of epigastric discomfort and dyspepsia.These results suggest that the use of nutritional and non-pharmacological interventions for pain and cramping in patients with cirrhosis is safe.However, several different treatments were included in this review, and sample sizes were often small.More studies, with larger sample sizes, are needed to better understand the safety of nutritional and nonpharmacological interventions in this population.
There was significant heterogeneity in the interventions used in the included studies.Only two of the 11 studies used the same intervention (oral taurine) [22,25].Many interventional studies had small sample sizes and often did not include a control or comparison group.More studies should be conducted using each intervention with larger sample sizes and the inclusion of control groups to gain a better understanding of the efficacy of nutritional and non-pharmacological interventions.Furthermore, we found a lack of standardization of outcome measures and pain characteristics assessed across studies.Future work could benefit from the inclusion of both cramp and non-cramp pain assessments, as well as the validation of painrelated outcome measures in this population.

Limitations and Future Research Directions
The limitations of this work are that we only included published studies and studies written in English and therefore may have excluded some results.Furthermore, many participants in these studies had medical comorbidities that may have affected the results.The risk of bias was moderate to high for the included studies and may have impacted the results.Selection of study populations, studies lacking control groups, and difficulties with blinding (e.g., pickle juice intervention) were all sources of bias that warranted careful interpretation of study findings.Finally, nutritional and non-pharmacological interventions were short in duration, leaving unanswered questions about the efficacy and safety of long-term use.
Continued research in the realm of nutritional and non-pharmacological interventions for pain management in patients with cirrhosis can benefit from standardization in treatment delivery and definitions of pain outcomes.Large-scale longitudinal studies evaluating the association of nutritional and nonpharmacological interventions for pain management are needed, and examination of potential subgroups at higher risk for safety concerns based on severity of liver disease and/or comorbidities is warranted.Many patients request nutritional and non-pharmacological treatments for chronic pain conditions, and more research is needed in this area.

Conclusions
This systematic review found that the frequency and severity of muscle cramps were more frequently investigated than non-cramp pain in patients with cirrhosis.The findings suggest that nutritional and nonpharmacological interventions may be safe and effective for the treatment of pain and painful muscle cramps in patients with cirrhosis.However, studies often did not contain control or comparator interventions, and only two studies examined the same type of treatment.Further research is needed to determine the efficacy, safety, and optimal frequency and dosage of nutritional and non-pharmacological interventions for pain and painful muscle cramps in patients with cirrhosis.Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

LN94-99
Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

LN102-103
Data items 10a List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

LN103-104 10b
List and define all other variables for which data were sought (e.g.participant and intervention characteristics, funding sources).Describe any assumptions made about any missing or unclear information.

LN103-104
Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.

TABLE 1 : Characteristics of the included studies
BPI, Brief Pain Inventory; ESLD, end-stage liver disease; MELD, model for end-stage liver disease; NR, not reported; RCT, randomized controlled trial; RET, resistance exercise training; SCB, Self-Care Behavior; SF-36, 36-item Short Form Health Survey; VAS, Visual Analogue Scale

TABLE 2 : Study outcomes
ACG, active control group (low intensity walking and stretching); BPI, Brief Pain Inventory; CG, control group; NR, not reported; RET, resistance exercise training group; VAS, Visual Analogue Scale

TABLE 3 : Study quality assessment
H, high risk of bias; L, low risk of bias; NOS, Newcastle-Ottawa Scale; RCT, randomized controlled trial; RoB, risk of bias; S, some concerns

TABLE 4 : PRISMA 2020 main checklist
Present results for main outcomes, preferably indicating the number of included studies and participants for each.If meta-analysis was done, report the summary estimate and confidence/credible interval.If comparing groups, indicate the direction of the effect (i.e. which group is favoured).Provide a brief summary of the limitations of the evidence included in the review (e.g.study risk of bias, inconsistency and imprecision).YesInterpretation 10 Provide a general interpretation of the results and important implications.

TABLE 5 : PRISMA abstract checklist
[27] et al. (2021)t al. (2021)[27]Qualifications of searchers (eg, librarians and investigators) 4 8 Search strategy, including time period included in the synthesis and key words 4, Suppl.Description of statistical methods (eg, complete description of fixed or random effects models, justification of whether the chosen models account for predictors of study results, dose-response models, or cumulative meta-analysis) in sufficient detail to be replicated