Pickle Juice Intervention for Cirrhotic Cramps Reduction: The PICCLES Randomized Controlled Trial

Abstract

Background:

Muscle cramps are common among persons with cirrhosis and associated with poor health related quality of life (HRQOL). Treatment options are limited. We sought to determine if pickle juice can improve muscle cramp severity.

Patients:

We enrolled 82 patients with cirrhosis and a history of >4 muscle cramps in the prior month from 12/20-12/21. Patients were randomized 1:1 to sips of pickle juice versus tap water at cramp onset. Our primary outcome assessed at 28-days was the change in cramp severity measured by the Visual Analog Scale for cramps (VAS-cramps, scaled 0-10). Cramps were assessed 10 times over 28 days using interactive text messages. Secondary outcomes included proportion of days with VAS-cramps<5, change in sleep quality, and global HRQOL measured using the EQ-5D.

Results:

Overall, 74 patients completed the trial, aged 56.6±11.5, 54% male, 41% with ascites, 38% with encephalopathy, and MELD-Na 11.2±4.9. Many patients were receiving other cramp therapies at baseline. Baseline VAS for cramps was 4.2±3.4, EQ5D was 0.80±0.10, and 43% rated sleep as poor. At trial completion, the respective values for the pickle juice and control arms were: − 2.25±3.61 points on the VAS for cramps – compared to control tap water (−0.36±2.87), p=0.03; proportion of cramp-days with VAS-cramps <5 were 46% vs 35% (p=0.2); and the change in sleep quality was no different (p=0.1). The end-of-trial EQ-5d was 0.78±0.10 vs 0.80±0.10 (p=0.3). No differences in weight change were observed for those with and without ascites.

Conclusion:

In a randomized trial, sips of pickle brine consumed at cramp onset improves cramp severity without adverse events.

Introduction

Cirrhosis is morbid and intensely symptomatic. Though 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 of patients with cirrhosis, irrespective of disease severity.² When we evaluated patient-reported outcomes (PROs) among 305 patients with cirrhosis, muscle cramps, more than any other cirrhosis symptom, impacted 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 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 one tablespoon of pickle juice has been shown to abort experimentally-induced cramps effectively and rapidly,^{9, 10} prior to gastric emptying,¹¹ by triggering vagal tone through acidic stimulation of oropharyngeal nerves.⁹ Herein, we report the results of our trial enrolling 82 ambulatory subjects with cirrhosis.

Methods

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 prior to recruiting subjects (NCT04650295). The last subject was enrolled in November 2021. This study was approved after full review by the University of Michigan IRB (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 prior 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 by 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 two protocol deviations, we enrolled one patient with recurrent cirrhosis after transplant and one patient with refractory ascites due to non-cirrhotic portal hypertension. Treating clinicians were notified of the trial and instructed not to adjust treatments during the 28-day period.

Intervention and randomization

While 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 trial was evaluating a ‘home remedy’ and labeling the trial as “NICCles” (Non-pharmaceutical 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, though variance is expected with respect to flavor, salt, and spices, variance in acid content is less likely. Participants were instructed to keep pickle juice (or tap water) on their person for 28 days. We suggested 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 one small sip from the squirt bottle (of pickle juice or tap water) at the onset of a cramp. The IRB 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 25mg of sodium and thus 75mg 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.

Outcomes

Our primary aim was to assess if 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 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 (PSQI¹²) in which the participants reply how their sleep quality during the past month has been (a 5-point Likert from Very Good to Very Bad). We had several exploratory outcomes including global HRQOL measured using the 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.

Assessments

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 by phone and by using an SMS service called Twilio that sent automated messages to patients on a pre-set 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 0-10, 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 0-10.” 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 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 2g taurine group compared to a 11% reduction in the placebo group. Assuming a two-side 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. Given that power calculations were speculative given the novelty of the intervention, we aimed to have <10% dropout, ultimately enrolling 82 subjects.

Statistical analysis

Outcomes were analyzed in a modified intention-to-treat fashion where all subjects were analyzed according to their allocation. As the primary endpoint was patient reported, 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 heterogeneity of cramp treatment effects. Exploratory correlations between cramp treatment success and the outcomes were evaluated using Pearson correlation coefficients.

Results

Study population

A flowchart of recruitment and enrollment activities is provided in Figure 1. Among those approached for enrollment, many experienced <4 cramps/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 aged more than 55 years on average with an average MELD-Na 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 NAFLD 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/month with an average cramp severity of >4 out of 10 on the VAS for cramps. HRQOL was low, as rated by the EQ5d 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.

Figure 1: Recruitment and Retention Flowchart.

*Patient withdrawn after hospitalization for major trauma

Table 1:

Baseline Characteristics of the Included Population

		Pickle Juice (n=38)	Control (n=36)
Demographics	Age – years (SD)	57.3 ± 12.5	55.8±10.5
	Male	58%	50%
	White Race	95%	89%
	College education	36%	29%
Medical history	Alcohol-related liver disease	24%	28%
	NAFLD	53%	36%
	MELD-Na	11.5±4.9	11±5.1
	Sodium meq/L (SD)	139±3.2	138±3.5
	Albumin g/dL (SD)	3.8±0.6	3.8±0.7
	Weight (pounds)	216±48 lbs	216±68
	Diuretics	76%	81%
	Ascites	45%	36%
	Hepatic Encephalopathy	42%	33%
	Diabetes	37%	31%
Cramp management	Gabapentin/pregabalin	31%	11%
	Baclofen	3%	14%
	Magnesium	39%	39%
	Vitamin E	8%	14%
	Taurine	3%	11%
	Potassium	24%	24%
Cramp history	Cramps wake up from sleep	95%	97%
	Cramps/month	11 (6-20)	12 (6-35)
	Calf cramps	89%	78%
	Thigh cramps	68%	58%
	Feet cramps	76%	61%
	Other body site	74%	75%
Patient reported outcomes	VAS-Cramps	4.16±3.51	4.25±3.24
	Poor sleep	45%	42%
	Eq5d	0.81±0.09	0.79±0.10
	Global HRQOL VAS	58.9±15.1	56.6±22.7

HRQOL = Health-related quality of life, MELD-Na = Model for Endstage Liver Disease – Sodium, NAFLD = Non-alcoholic Fatty Liver Disease, VAS = visual analog scale

Outcomes

Each arm completed an equivalent number of SMS cramp surveys (8.6±1.9 for pickle juice, 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 cramps severity. It was associated with a larger average reduction in cramp severity − 2.25±3.61 points on the VAS for cramps – compared to 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 end-of-trial HRQOL measured using the EQ5D 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 two 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.

Table 2:

Outcomes

	Pickle Juice	Control	p-value
Primary Outcome
Change in cramp severity	−2.25 ± 3.61	−0.36 ± 2.87	0.03
Secondary outcomes
Proportion of cramp-days with severity <5 on VAS	0.46 ± 0.34	0.35 ± 0.36	0.2
Improvement in Sleep Quality	0.03 ± 0.94	0.36 ± 1.02	0.2
Exploratory outcomes
End-of-trial cramp severity	2.19 ± 2.51	3.47 ± 2.60	0.04
End-of-trial EQ5d	0.78 ± 0.10	0.80 ± 0.10	0.32
End-of-trial global HRQOL VAS	55.36 ± 18.32	59.5 ± 22.87	0.4
Safety outcomes
Weight change (overall)	0.41 ± 6.83	−0.24 ± 7.63	0.7
Weight change (patients with ascites)	0.08 ± 7.61	−1.36 ± 9.85	0.6

HRQOL = Health-related quality of life, VAS = visual analog scale. P-values are the result of comparisons using permutation tests. The p-values were adjusted for multiplicity using a Benjamini-Hochberg procedure, but not for the safety outcomes.

Correlations of outcomes with proportions of cramp aborted by treatment

We explored the association between change in VAS for cramps change in EQ5D, finding that they are weakly correlated (pearson coefficient 0.13). We then examined the correlation been the proportion of cramps aborted with treatment and change in VAS for cramps and change in EQ5D. For the change in VAS for cramps, the correlation was 0.29 for pickle juice and 0.06 for control. For the change in EQ5D, 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. While 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 to 0.63±2.92 for control), those on diuretics (−2.19±3.34 versus −0.14±2.96), and those with hepatic encephalopathy (−3.07±4.38 versus 0.38±3.33)

Table 3:

Subgroup Analysis for Change in Cramp Severity According to Visual Analog Scale for Cramps

		Pickle Juice	Control	P value
Sex	Men	−2.63 ± 3.73	−0.6 ± 2.52	0.05
	Women	−1.82 ± 3.54	−0.06 ± 3.32	0.1
Etiology	Alcohol-related disease	−3.45 ± 3.36	0.63 ± 2.92	0.008
	Non-alcohol-related disease	−1.72 ± 3.66	−0.64 ± 2.84	0.2
Diuretic use	Diuretics	−2.19 ± 3.34	−0.14 ± 2.96	0.02
	No diuretics	−2.44 ± 4.56	−1.28 ± 2.43	0.5
Hepatic Encephalopathy	Hepatic Encephalopathy	−3.07 ± 4.38	0.38 ± 3.33	0.03
	No Hepatic Encephalopathy	−1.73 ± 3.03	−0.78 ± 2.56	0.3
Prior cramp treatment	Cramp treatment	−2.12 ± 3.59	−0.35 ± 2.92	0.07
	No cramp treatments	−2.55 ± 3.83	−0.38 ± 2.90	0.1

P-values are the result of comparisons using permutation tests.

Discussion

Muscle cramps are common for patients with cirrhosis and conventional therapies are often unsatisfactory.^{2, 3} The PICCLES trial is one of the largest RCTs 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 ascetic acid¹⁵ of pickle brine is felt to act as an agonist of sensory Transient Receptor Potential (TRP) channels and foregut Acid Sensing Ion Channels (ASIC),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 either frequent (where effort to keep pickle juice on hand is worthwhile), long-lasting (where 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 PICCLES were receiving therapies for cramps and 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 HRQOL may have been related to its inability to prevent cramps. Alternatively, while cramps are associated with poor HRQOL, it is possible that agents which reduce cramp severity or frequency do not improve HRQOL.

Pickle juice in the context of available anti-cramp 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 Orphenadine 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} Given the concern for cardiac toxicity relating to quinidine, a large trial in this vulnerable population is warranted with or placebo and/or pickle juice as a comparator.

Contextual factors

These data must be interpreted in the context of the study design. First, this is 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 to that observed with placebo in a prior 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 prior trial.¹⁸ Fourth, the mode of outcome assessment (SMS every three days) may have increased adherence to the intervention. Finally, given that the mechanism of action is thought to be acid related, future comparisons to 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.

Conclusion

Sips of pickle juice safely reduce cramp severity in a short-term trial. However, effective agents to prevent muscle cramps for patients with cirrhosis remain an unmet need.