Cirrhosis is morbid and intensely symptomatic. Although most of clinical practice is focused on the management of ascites and hepatic encephalopathy, these complications account for only a portion of the true burden of cirrhosis. Symptoms experienced by patients with cirrhosis include poor sleep, frailty, pruritus, and muscle cramps (1). Muscle cramps are common, afflicting 2 in 3 patients with cirrhosis, irrespective of disease severity (2). When we evaluated patient-reported outcomes among 305 patients with cirrhosis, muscle cramps, more than any other cirrhosis symptom, affected the quality of life (2).
Muscle cramps lead to a cascade of deleterious consequences. In a landmark study, Marchesini showed that, more so than the cardinal complications of cirrhosis, cramps had the strongest independent impact on most health-related quality of life (HRQOL) domains (3). Cramps cause pain, interfere with sleep, and limit mobility. Although the treatment of cramps has been explored in multiple studies (4), safe, effective treatments for cramps remain limited. Approaches trialed include quinidine (effective but potentially toxic) (5), baclofen (possibly effective but sedating) (6), albumin infusion (possibly effective but expensive) (7), and taurine (possibly effective but expensive and unregulated) (8). Better interventions and studies are needed.
We conducted a randomized controlled trial of pickle juice to reduce the symptoms and severity of muscle cramps in patients with cirrhosis. Even 1 tablespoon of pickle juice has been shown to abort experimentally induced cramps effectively and rapidly (9,10), before gastric emptying (11), by triggering the vagal tone through acidic stimulation of oropharyngeal nerves (9). In this article, we report the results of our trial enrolling 82 ambulatory subjects with cirrhosis.
We conducted a randomized controlled trial of pickle juice for the management of muscle cramps in persons with cirrhosis. We registered our trial in December 2020 before recruiting subjects (NCT04650295). The last subject was enrolled in November 2021. This study was approved after full review by the University of Michigan Institutional Review Board (HUM00185598).
Study population and recruitment
We included adults with cirrhosis (using clinical, histological, and imaging criteria) who had muscle cramps (painful muscle spasms, cramps, or charley horses that come on while resting) that occurred >4 times in the previous month and bothered the patient. We excluded persons with a history of cerebral palsy, stroke with paralysis, multiple sclerosis, and prior liver transplant. Patients were recruited through phone, email, or in-person. After enrolling 60 subjects, we opened our trial to patients at Beth Israel Deaconess Medical Center in Boston and Cedars-Sinai Medical Center in Los Angeles. Informed consent was obtained electronically through signNow or in-person. In 2 protocol deviations, we enrolled 1 patient with recurrent cirrhosis after transplant and 1 patient with refractory ascites due to noncirrhotic portal hypertension. Treating clinicians were notified of the trial and instructed not to adjust treatments during the 28-day period.
Intervention and randomization
Although many patients were enrolled at the time of a regularly scheduled visit, most were enrolled remotely. Patients were block randomized 1:1 using TATUM software to receive either pickle juice or tap water. As pickle juice is readily available, we did not mention pickle juice during the consent process, explaining that the trial was evaluating a “home remedy” and labeling the trial as “NICCles” (nonpharmaceutical intervention) to avoid contamination. After randomization, patients in the tap water arm were instructed to use sips of tap water. Patients in the pickle juice group received instruction to purchase 3 jars of brined pickled cucumbers of their choice. They were instructed to purchase dill or kosher pickles, not sweet or bread and butter. As all brined pickles must have a brine with pH <4.0 to pickle the cucumbers, although variance is expected with respect to flavor, salt, and spices, variance in the acid content is less likely. Participants were instructed to keep pickle juice (or tap water) on their person for 28 days. We suggested that they store it in a jar and keep a tablespoon on hand or store it in a squirt bottle. If a cramp occurred, they were instructed to record the time, location, and duration of the muscle cramp. Patients were instructed to drink approximately 1 tablespoon of pickle juice or 1 small sip from the squirt bottle (of pickle juice or tap water) at the onset of a cramp. The institutional review board raised concerns regarding the risk of volume overload and required that patients requiring sodium restriction were instructed to drink no more than 3 tablespoons of pickle juice per day. Given 3.5% salinity in most brines, it was assumed that a tablespoon contained 25 mg of sodium, and thus, 75 mg daily was the recommended limit for patients with volume overload from our IRB. All subjects were debriefed on the use of concealments at the end of their participation in the study.
Our primary aim was to assess whether those in the intervention arm experienced a greater reduction in cramp severity than those in the control arm. This was measured using the change in the visual analog scale (VAS) for cramps between enrollment and day 28. The VAS was labeled scale that is numbered from 0 (means no cramps) to 10 (worst cramps imaginable). Our secondary outcomes included the number of days with cramp severity <5 on the VAS (patients were asked about cramp severity at 10 points during the trial) and change in sleep quality based on the summary question from the Pittsburgh Sleep Quality Index (12) in which the participants reply how their sleep quality during the past month has been (a 5-point Likert scale from very good to very bad). We had several exploratory outcomes including global HRQOL measured using the Euroqol-5D instrument (EQ-5D) and its visual analog scale for HRQOL. Finally, safety outcomes included weight change for patients with and without ascites. We also recorded patient-reported paracentesis requirement.
All patients completed a baseline history to detail their sociodemographics, liver disease history, and muscle cramp experience and concurrent cramp treatments. We determined baseline weights and ascites burden. All follow-up assessments were conducted through phone and by using an SMS service called Twilio that sent automated messages to patients on a preset schedule to determine cramp frequency and severity. A text message was sent asking “How many muscle cramps did you have in the past 3 days? Please respond with a number.” If the subject reported ≥1 cramp, they were asked “On a scale from 0 to 10, where 0 means no cramps and 10 means the worst imaginable cramps, how severe were your muscle cramps in the past 3 days? Please respond with a number from 0 to 10.” They were also asked “During your muscle cramps in the past 3 days, did you drink 1 tablespoon of pickle juice/water?” If they responded yes, they were asked “How many times per day did you drink 1 tablespoon of pickle juice/water?” and “Did the muscle cramps stop after drinking the pickle juice/water?”
Sample size derivation
To determine the sample size for this trial, we used the modest effects observed in a trial of taurine (8). In this trial, there was a 37% reduction in the intensity of cramps in the 2 g taurine group compared with an 11% reduction in the placebo group. Assuming a 2-sided alpha level of 0.05, a sample size of 40 patients per group is required to detect a similar difference with 80% power allowing for a conservative 20% dropout. We estimated a risk of roughly 10% dropout. We, ultimately enrolled 82 subjects.
Outcomes were analyzed in a modified intention-to-treat fashion in which all subjects were analyzed according to their allocation. As the primary endpoint was patient-reported outcomes, those who were lost to follow-up or who withdrew could not be included. Outcomes were compared using permutation tests (13). Analysis was performed by a statistician blinded to treatment allocation, and therefore, a 2-sided P value of 0.05 was considered significant. Multiplicity was addressed using the Benjamini-Hochberg procedure (14). Exploratory subgroups were selected based on clinical judgement regarding the heterogeneity of cramp treatment effects. Exploratory correlations between cramp treatment success and the outcomes were evaluated using Pearson correlation coefficients.
A flowchart of recruitment and enrollment activities is provided in Figure 1. Among those approached for enrollment, many experienced <4 cramps per month. In total, 3 subjects were enrolled at non-Michigan sites. After enrollment, loss to follow-up or disenrollment occurred in roughly 10% without a difference between arms. Baseline details for the 74 subjects included are provided in Table 1. The sample was older than 55 years, on average, with an average model for end-stage liver disease—sodium score of 11.5. Most (≥95%) reported muscle cramps that awoke them from sleep, with ≥42% reporting poor sleep. Numerically, more subjects in the pickle juice arm had nonalcoholic fatty liver disease and diabetes. More subjects in the control arm were taking baclofen, but more in the pickle juice arm were taking gabapentin/pregabalin. Each group contained 3 patients with ascites requiring a recent paracentesis. The median cramp frequency was 11–12 per month, with an average cramp severity of >4 of 10 on the VAS for cramps. The HRQOL was low, as rated by the EQ-5D and global HRQOL VAS. All subjects in the pickle juice arm reported using dill/kosher pickle juice with the exception of one who used bread and butter.
Each arm completed an equivalent number of SMS cramp surveys (8.6 ± 1.9 for pickle juice and 8.9 ± 1.6 for control). The proportion of cramps treated was not different between arms (77% vs 72%). More patients in the pickle juice arm reported that the cramps were aborted by the intervention, 69% vs 40%. As detailed in Table 2, pickle juice improved the primary outcome, reducing cramp severity. It was associated with a larger average reduction in cramp severity—−2.25 ± 3.61 points on the VAS for cramps—compared with control tap water (−0.36 ± 2.87), P = 0.03. There were no significant changes in the proportion of days with cramps <5 on the VAS or sleep quality. For the exploratory outcomes, the end-of-trial VAS for cramps was lower for pickle juice, but the end-of-trial HRQOL measured using the EQ-5D and the VAS for global HRQOL were not different. As pickle juice contains sodium, we assessed weight change as a safety outcome. There were no significant differences between the 2 groups overall as well as for the subset with ascites. No patient required a first paracentesis in the study period. Among the patients with prior paracentesis, 1 required a paracentesis during the study period in each arm—2 instances for the subject in the pickle juice arm and 1 instance for the subject in the control arm.
Correlations of outcomes with proportions of cramps aborted by treatment
We explored the association between change in the VAS for cramps and change in the EQ-5D, finding that they are weakly correlated (Pearson coefficient 0.13). We then examined the correlation between the proportion of cramps aborted with treatment and both the change in the VAS for cramps and change in the EQ-5D. For the change in the VAS for cramps, the correlation was 0.29 for pickle juice and 0.06 for control. For the change in the EQ-5D, the correlation with the proportion of cramps aborted was 0.05 for pickle juice and 0.10 for control (both weak correlations).
Heterogeneity of treatment effect for change in cramp severity
Table 3 summarizes a subgroup analysis for sources of heterogeneity in the treatment effect as measured by the change in cramp severity according to the VAS for cramps. Although there were no groups with discordant results, there were subgroups with more pronounced differences. These include those with alcohol-related disease (−3.45 ± 3.36 for pickle juice compared with 0.63 ± 2.92 for control), those on diuretics (−2.19 ± 3.34 vs −0.14 ± 2.96), and those with hepatic encephalopathy (−3.07 ± 4.38 vs 0.38 ± 3.33).
Muscle cramps are common for patients with cirrhosis, and conventional therapies are often unsatisfactory (2,3). The PICCLES trial is one of the largest randomized controlled trials aimed at muscle cramps for patients with cirrhosis, and its results establish a novel tool to address this symptom. In this short-term trial, sips of pickle juice safely reduce the severity of muscle cramps.
The role of pickle juice in cramp management
The acetic acid (15) of pickle brine is felt to act as an agonist of sensory transient receptor potential channels and foregut acid-sensing ion channels (9), triggering nerve conduction in the oropharynx that aborts the cramp without changing serum electrolytes (10). This mechanism of action is not specific to cirrhosis. As a cramp therapy that must be taken at the time of a cramp, pickle juice is likely to be most effective for people with cramps that are frequent (where the effort to keep pickle juice on hand is worthwhile), long-lasting (where the time spent finding pickle juice is worthwhile), or both. Patients with cirrhosis frequently suffer from high-frequency, long-lasting cramps. As pickle juice does not prevent cramps, additional therapies may be warranted. Many patients in the PICCLES trial were receiving therapies for cramps, and the add-on pickle juice efficacy was no less effective in this subgroup. We hypothesize that the neutrality of the pickle juice intervention on measures of the HRQOL may have been related to its inability to prevent cramps. Alternatively, although cramps are associated with poor HRQOL, it is possible that agents that reduce cramp severity or frequency do not improve HRQOL.
Pickle juice in the context of available anticramp therapies
Despite the high prevalence of cramps among patients with cirrhosis, very few large and controlled trials have been conducted. Among trials enrolling ≥30 subjects, quinidine, baclofen, methocarbamol, taurine, and orphenadrine have been evaluated (5,6,16–18). Therapies such as quinidine and baclofen have more widespread use in clinical practice and have the advantage of preventing cramps, but these therapies carry a higher risk of adverse events. As a low-cost, widely available, and safe therapy, however, pickle juice could serve as a first-line therapy whereby failure to improve global HRQOL after a 28-day trial could prompt initiation of other therapies aimed at reducing cramp frequency. Indeed, given the ability of pickle juice to abort cramps, the key unmet need moving forward is an agent that can safely prevent cramps. Quinidine or quinine may be the most promising based on trials in other settings (19,20). However, quinidine may pose cardiac and hematologic risks and is best evaluated in the context of a clinical trial for this vulnerable population.
These data must be interpreted in the context of the study design. First, this is a short-term study, and long-term benefits and risks are unknown. Conducted in a fully remote fashion during the COVID-19 pandemic as a pragmatic proof-of-concept trial, future trials should be longer and assess follow-up sodium levels in addition to volume status. Second, enrolled patients had a high burden of muscle cramps, and these data may not generalize to a lower burden population. Third, the use of tap water created an active control arm, but we lacked a placebo, potentially creating bias. Cramps are a subjective outcome; however, tap water was associated with a reduction in cramp severity comparable with that observed with placebo in a previous clinical trial (18). Conversely, pickle juice was associated with a substantially greater reduction in cramp severity than observed for both placebo and taurine in a previous trial (18). Fourth, the mode of outcome assessment (SMS every 3 days) may have increased adherence to the intervention. Finally, given that the mechanism of action is thought to be acid related, future comparisons with apple cider vinegar may be warranted. The pH of dill/kosher pickle brine is estimated to be 3–3.6. Accordingly, any well-tolerated agent with this property can be examined.
Sips of pickle juice safely reduce cramp severity in a short-term trial. However, effective therapies to prevent muscle cramps for patients with cirrhosis remain an unmet need.
CONFLICTS OF INTEREST
Guarantor of the article: Elliot B. Tapper, MD.
Specific author contributions: E.B.T.: concept. Z.Z.: analysis. N.S., S.J.N., V.P., V.S., and J.B.: data acquisition. E.B.T.: writing. N.S., S.J.N., V.P., and V.S.: revision.
Financial support: E.B.T. receives funding from the National Institutes of Health through the NIDDK (1K23DK117055).
Potential competing interests: E.B.T. has served as a consultant to Novartis, Axcella, and Allergan; has served on advisory boards for Mallinckrodt, Bausch Health, Kaleido, and Novo Nordisk; and has received unrestricted research grants from Gilead and Valeant. V.S. is on the speaker's bureau for Gilead and AbbVie and serves as a consultant for Saol Therapeutics. No other author has a conflicts of interest.
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