Background

Hemodialysis (HD) patients frequently complain of pain. About 75% of hemodialysis patients suffer from untreated or inadequately treated pain, ranging from moderate to severe [1]. Untreated pain in this population has a detrimental effect on mortality, dialysis adherence, healthcare use, and health-related quality of life [2]. This issue arises for a number of reasons, including the fact that carers are unaware of the problem and worry about the side effects of the analgesic therapy, while patients fear medication side effects, the additional burden of taking daily tablets, and the possibility of addiction if opioid medications are used [3].

Due to the scarcity of effective non-pharmacological treatments or safe non-opioid pharmaceutical choices, the use of opioids is disproportionately high in this population. In a survey of more than 400,000 end-stage kidney disease patients, more than half had gotten an opioid prescription, which is 3.2 times the prevalence in the US population [4] and 20% were on chronic opioid therapy [5]. Chronic opioid usage in kidney disease patients has been linked, in a dose-dependent way, to an increased risk of disturbed mental status, falls, fractures, hospitalizations, and mortality [6].

The American Society of Nephrology and the US Food and Drug Administration's Renal Health Initiative, a public–private partnership, are working together to promote pain management in renal illness as a key research priority[7]. Furthermore, the National Institutes of Health's Helping to End Addiction Long-term mission and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) will address pain management and opioid safety in this population through the recently formed Hemodialysis Opioid Prescription Effort (HOPE) Consortium [8].

There are numerous pharmacologic and non-pharmacological pain management techniques. Some of these techniques' are still under debate. Non-pharmacological treatment options include a wide range from psychosocial or behaviorally based interventions (such as cognitive behavioral therapy, acceptance and commitment therapy, relaxation, music therapy, and mindfulness) to physically oriented interventions (such as exercise, physical therapy, yoga, acupuncture, and electrical stimulation) [9], together with the application of heat or cold, lavender oil, virtual reality, and other distraction methods [10,11,12].

Psychosocial interventions have limited but promising evidence for reducing opioid use and opioid misuse behaviors. They are effective approaches for reducing pain severity, interference, disability caused by pain, and psychological distress [13, 14]. Physical therapy or exercise-based interventions have been successful in improving pain in the general population [15]. There are few studies that have looked at the effects of exercise, physical therapy, yoga, or acupuncture on pain in hemodialysis patients, but those that have been studied in this population had encouraging findings [16, 17].

Cryotherapy is one of the oldest and most affordable non-pharmaceutical pain management methods which was widely discussed in different studies [18, 19]. Application of cold locally appears to be a recommended and efficient way in reducing pain [20].Oppositely, two studies had reported that thermotherapy as well may be beneficial as pain reduction technique [21, 22]. Also, other studies investigated the use of lavender oil either inhaled or administered to the puncture site seems to have a positive analgesic impact [23,24,25].

Recently, studies have reported that the discomfort from venous cannulation is less painful after using distraction methods as flashlights from camera. This may be due to the changes in thalamic activity that changes nociceptive input when there is pain, which decreases the perception of pain. A quick flash of light was thought to excite the thalamus, which is an essential part of the light reflex, and as a result minimize the pain related to vein cannulation [26].

The use of local anesthetic drugs in a variety of formulations and dosage forms is the primary focus of pharmacological pain control strategies. Nine trials involving 8 to 75 participants looked at the effects of applying local anesthesia to the puncture sites before cannulation. The majority of trials showed that the most efficient treatment was lidocaine/prilocaine 5% (EMLA cream) application followed by lidocaine spray [20, 27]. A common problem with lidocaine/prilocaine 5% cream is the time of application before dialysis and the allergic reactions [28].

Although several studies have compared different pain methods used [27, 29,30,31,32,33], there is currently no consistent way to decrease arteriovenous fistula cannulation pain in hemodialysis patients and a serious lack of an effective and feasible option to be used as standard procedure in the daily practice of hemodialysis units. Additionally, a thorough assessment of pain in HD patients is necessary, and the multidisciplinary team should also include experts in pain management. Adopting pharmacological or non-pharmacological therapy modalities can reduce HD patients' pain symptoms, which has a substantial positive impact on their quality of life [34].

This study aimed to compare the effectiveness of three different methods (lidocaine spray, cold packs, flashlights) on the pain induced by arteriovenous cannulation in hemodialysis patients that were proven to be effective and feasible with lack of evidence of superiority of either one over other in our target population.

Subjects and methods

Study design and settings

This study was prospective randomized open-label controlled trial in Hemodialysis Units in Ain Shams University Hospital. Data collection was done from April 15 to May 20, 2023.

Subjects

It included 108 patients undergoing hemodialysis three times a week. Eligible patients were adults 18 years and older of both gender who were diagnosed with chronic kidney disease and undergoing hemodialysis with A.V. fistula of upper extremity currently used for hemodialysis which can be radio-cephalic, radio-basilic, or brachio-cephalic.

Exclusion criteria included any known sensitivities or allergies to lidocaine or other local anesthetic or cold therapy, damaged or broken skin at venipuncture location, and previous use of local anesthetic products in previous 24 h.

Ethical consideration

All subjects were informed about the study protocol, potential risks, and purpose and benefits of the study, and a written consent was signed by all enrolled subjects. This study conforms with the principles outlined in the Declaration of Helsinki and was approved by the Faculty of Pharmacy, Ain Shams University Ethical Committee [ACUC-FP-ASU RHDIRB2020110301 REC #194], and was registered in Clinical trials.gov NCT05822063.

Interventions

Patients were assigned to one of four groups using computer generated random numbers. The history of assignments of the entire research work was maintained by a researcher who was not involved in the patients’ enrollment, interventions, or data analysis. To ensure that the allocation was effectively concealed, the assigned numbers were placed in sealed opaque envelopes. The present study was an open-label study, because blinding was difficult as methods used were very different.

Eligible patients were randomly allocated to one of the four groups

Group 1: lidocaine group

Two puffs of lidocaine 10% (lidocaine topical aerosol U.SP.38) were sprayed on the skin surface near to the needle insertion point. After ten minutes, the skin surface was sprayed with 70% alcohol. Then, appropriate hemodialysis needles were put into the vessels of the fistula area by the nurse.

Group 2: “cold packs group”

Cold pack was placed on the fistula site five min before making the puncture. Next, specific hemodialysis needles were inserted in the vessels of fistula area by the nurse after disinfecting the fistula area with 70% alcohol-soaked cotton pads.

Group 3: “flashlights”

The patient’s face was photographed. The photograph was taken with a mobile Samsung Note 10 camera 12 MP, f/2.1, 52mm (telephoto), 1/3.6”, 1.0 µm, phase detection auto focus, optical image stabilization, 2 × optical zoom, LED flash, auto-high dynamic range, panorama.

Group 4: control group: routine care without additional intervention

The patients was cannulated by hemodialysis needles which was inserted in the vessels of fistula area by the ward nurse after disinfecting the fistula area with 70% alcohol-soaked cotton pads.

Outcome measurement

All patients underwent full physical examination by a senior nephrologist. A thorough history was obtained from the participating patients (age, gender, weight, height, occupation, cause of illness, duration of HD onset, and comorbidities) through interviews by clinical pharmacist and from patient files. Patients were briefed about the study medicines and how to use the visual analog scale (VAS) for pain evaluation before the first intervention. Baseline pain assessment was done initially without any intervention, and pain score was assessed after venipuncture by a junior nephrologist who was blinded about patient assigned study group. Each patient was asked to grade the pain on the VAS, a 10-cm line marked 0 at one end and 10 at other end (0 = no pain, 10 = worst pain). In the three consecutive dialysis sessions, each patient randomly received one of the interventions only once before venipuncture and average of three VAS scores was taken for each patient. Patients were questioned about any unfavorable side effects they had experienced, and the cannulation site was checked for local skin responses by a clinical pharmacist.

Sample size calculation

In the study of Mirzaei et al. [27], the difference in the VAS score between lidocaine spray and ice pack managed groups was 1.16 with pooled standard deviation of 1. Based on these findings, a minimal sample size of 23 subjects in each group is required at an alpha level of 0.0125 and power of 90%. To compensate for dropouts, the sample will be increased by 15% to be 27 subjects in each group of the four groups with a total sample size of 108 subjects. Sample size was estimated using PS (Power and Sample Size Program), version 3.1.2.

Data analysis

Statistical analysis was performed using IBM SPSS® Statistics, version 26 (IBM® Corp., Armonk, NY, USA). Numerical data were expressed as mean and standard deviation or median and range as appropriate. Qualitative data were expressed as frequency and percentage. Pearson’s Chi-square test or Fisher’s exact test was used to examine the relation between qualitative variables. Comparison of quantitative data between four groups was made using either analysis of variance (ANOVA) for normally distributed data or Kruskal–Wallis test (nonparametric ANOVA) for not normally distributed one. All tests were two-tailed. A p-value < 0.05 was considered significant. Spearman’s correlation test was conducted for correlation tests. A post hoc honestly significant difference (HSD) test was conducted to investigate the difference between groups.

Results

A total of 108 patients on regular hemodialysis were enrolled in the study. Flow diagram of patients is shown in Fig. 1.

Fig. 1
figure 1

Flow diagram of patients

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The mean age of patients was 43.7 ± 15.6 years, 55 participants were males (50.9%), and 53 were females (49.1%). The mean frequency of hemodialysis is three times per week. Other clinical characteristics of the study groups are shown in Table 1. There were no significant differences between studied groups regarding age, weight, gender, and dialysis duration.

Table 1 Baseline characteristics
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On the other side, height (p < 0.001) and BMI (p = 0.011) were significantly different among groups. The control group had higher BMI values than three other groups. Education levels were also significantly different among studied groups (p = 0.004) with high uneducated participants in lidocaine spray group (81.5%).

Comorbidities such as atrial fibrillation, heart failure, diabetes, and rheumatic heart diseases differ in cold packs group than other three studied groups (p = 0.002). Table 2 presents factors that may affect pain perception such as diabetes mellitus and gender. There were no differences between males and females visual analog scale pain scores (p = 0.411) or between diabetic and non-diabetic patients (p = 0.441).

Table 2 Factors affect pain perception scores
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The mean visual analog scale (VAS) scores were comparable between control and three test groups (p = 0.054) as shown in Fig. 2. Based on the results of post hoc Tukey honestly significant difference (HSD) test, only cold packs differ from control groups with borderline significance (p = 0.051), while neither lidocaine spray and flashlights significantly differ from control. Table 3 shows that the changes in pain scores did not correlate with age, BMI, and dialysis duration (p > 0.05). There were no side effects reported in lidocaine or flashlight groups. Only three patients in cold packs group reported itching and minor hypersensitivity relieved ten minutes after removing the cold pack.

Fig. 2
figure 2

Visual analog scale in four studied groups done by Kruskal–Wallis test

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Table 3 Correlations between visual analog scale scores and parameters affect pain
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Discussion

One of the main concerns for hemodialysis patients is the impression of pain from arteriovenous fistula (AVF) cannulation. For the vast majority of HD patients, this discomfort is unbearable [35]. Many of these patients consider the pre-dialysis needle insertion procedure to be the most challenging component of their care. Pain control during AVF needling should therefore be prioritized in terms of dialysis care [32].

The present study was conducted to compare the effects of cold packs, lidocaine sprays, and flashlights on needle insertion pain in HD patients. The cold packs group had lowest pain scores (4.1 ± 0.8) followed by flashlights (4.3 ± 0.8) and then lidocaine spray (4.4 ± 0.7), yet the difference between three interventions and control was borderline significant (p = 0.054).

One of the therapies utilized in numerous trials to reduce the discomfort brought on by fistula punctures is cryotherapy. The results from multiple research showed that after cryotherapy, both the experimental group and the control group experienced varying variations in pain intensity linked to fistula puncture [19, 20, 27, 36], which somewhat differ from the results of the present study. One possible justification is the environment and psychological state of each person during needle insertion may have an impact on that person’s pain tolerance threshold.

Additionally, the difference in the noticeable changes in pain intensity appears to be due to the different types of instruments used to measure pain. In research carried out by Aghajanloo [35] and Arab [37], visual analog scale was similarly used, while in other studies, numerical rating scale was used, though all instruments were 10 points [38, 39].

Studies looking at how lidocaine spray affected hemodialysis patients’ arteriovenous fistula cannulation pain intensity found that it was highly beneficial at lessening the discomfort associated with needle insertion. [40]. Alternative studies’ findings, which are congruent with ours, demonstrated that the mean pain intensity during the application of different forms of lidocaine was lower with lidocaine compared to alternative placebo formulations. According to Zempsky et al.’s findings, the amount of pain experienced during the use of powdered lidocaine without a needle was much less than that experienced during the placebo treatment (2.26 vs. 3.19) [41].

Different studies have compared the effects of cold packs and lidocaine in various ways, with varying degrees of success. According to Arab et al. [23], lidocaine cream was not as efficient as cold massage (p = 0.03). In a different trial conducted by Ghoresyshi et al., cryotherapy was found to be superior to Xyla-P cream (P = 0.001) [28], and both treatments were superior to a placebo. This was in concordance with our results that cold packs group had lower pain scores (4.1 ± 0.8) than lidocaine spray group (4.4 ± 0.7).

On the other hand, a study by Mirazei et al. revealed that lidocaine spray considerably reduced mean pain levels more than cold packs did. The impact of 2.5% lidocaine on pain intensity during pediatric phlebotomy in chronic renal failure was also investigated in a study by Turkmen, et al. on children who received long-term hemodialysis. They discovered that the 2.5% lidocaine had no impact in reducing the discomfort brought on by hemodialysis needle insertion [27]. Additionally, a study comparing the efficiency of lidocaine cream and cryotherapy for putting a needle into the implanted venous access chemotherapy port revealed that lidocaine cream had the strongest effect, followed by cryotherapy, and that both lower pain levels than the control group [42].

Flashlights may contain a distraction element, which seems to involve rivalry for attention between highly prominent pain sensations and shifts emphasis to another activity involving the processing of information. It has been suggested as a treatment for minimizing cannulation pain in individuals receiving hemodialysis [43, 44]. Also, flashlights were effective in decreasing level of pain during IV cannulation in hospitalized children [45]. This came in agreement with our results that flashlights decreased levels of pain than control group; however, it did not reach statistical significance. This may be explained by either the power of flashlight that was not sufficient or time lag between flashlight and measuring pain scores that may not be optimum. Therefore, the desired time lag for the flashlight to produce antinociception needs to be studied.

Given that no study has so far compared the effect of cryotherapy and flashlights or lidocaine spray on reducing fistula cannulation pain in hemodialysis patients, the results of the present study may guide in choosing the best technique of pain reduction in dialysis unit. Cold packs are safe, cheap, and effective than lidocaine and flashlights in our study population. However, these findings may not be generalized due to small sample size. Also, different populations with different comorbidities may affect their pain perception, so future studies are needed to study the optimum duration needed to apply cold packs in hemodialysis patients.

Pain is a complex issue with many facets that is influenced by many factors such as age, gender, culture, and heredity [37]. The results of the present study showed that there was no relationship between fistula puncture-related pain with age, gender, and duration of hemodialysis same as reported by Arab et al. [37]. On the other side, a study done by Ghods et al. found the duration of hemodialysis is significantly associated with the intensity of pain [25].

Regarding age effect, Li et al. examined the candidates’ pain intensity using VAS to record pain scores. They found that elderly adults had lower pain thresholds than younger persons [46]. In contrast to the findings of our study, Sabita et al. found a significant association between older age and female gender and fistula puncture-related discomfort [47]. This was justified by the fact that growing older appears to be linked to higher pain thresholds and dysfunctional endogenous pain suppression pathways [48, 49]. Overall, this suggests that older persons would engage the pain system later than younger adults, exhibiting indicators of pain insensitivity, but that the relative lack of pain inhibition would eventually cause pain to escalate, exhibiting more common pain symptoms [50].

On the other side, Bahrami et al. found that younger persons and women felt more pain during EMG needling than men and older people did. Given that women made up 61.7% of the patients and men made up 38.3% of the study group, it is possible that this contributed to the greater pain that women reported [51]. According to a different study, women experienced more pain right away following surgery [52]. Contrary to the findings of this trial, Chia et al. found that men required higher dosages of morphine and experienced worse postoperative pain [53].

In a different prospective study conducted by a French team, 58% of the 66 hemodialysis patients reported pain during cannulation, with a quarter of them being classified as having severe levels of discomfort. The prevalence of pain was unaffected by age or sex, just like in our study [20]. Additionally, Taenzer et al. showed that shortly following surgery, men and women perceived pain similarly [54]. Being female or old was not linked to a higher level of pain intensity in a different study conducted by Celik et al. [12] which was similar to our findings.

Many factors may play a role in the differences in pain sensitivity between men and women, some may be related to social conditioning and psychosocial factors, and others may be due to difference in sensitivity and reaction of both males and females to noxious stimuli, suggesting that biological mechanisms may be play a role in these differences. Additionally, sex hormones have an impact on pain sensitivity; in women, menstrual cycle stages affect pain tolerance and threshold. Men and women respond to acute pain differently, in terms of both the spatial pattern and strength of that reaction, according to imaging studies done on men and women brains [55]. Therefore, to fully comprehend these differences, additional descriptive analytical research with bigger sample sizes is needed.

According to studies, a person’s ability to tolerate pain is decreased by high glucose levels and/or swift fluctuations in glucose levels. Patients with diabetic neuropathy experience more pain due to a dysfunctional endogenous opioid peptide pathway [56]. In the present study, diabetic and non-diabetics had no difference in their mean pain scores; this was in contrast to what reported that diabetes was associated with more pain on cannulation [20]. This may be explained that our study population had controlled blood glucose levels and did not suffer from peripheral neuropathy.

Conclusion

The results showed that cold packs were safe and effective than lidocaine spray or flashlights in reducing cannulation pain. It is suggested to implement this method before cannulation in hemodialysis patients to reduce pain and improve quality of life. Future studies are needed to compare different application times of cold packs and its impact on pain scores to recommend the optimum time needed to achieve maximum analgesic effect.