Pre-emptive ice pack cryotherapy for reducing pain caused by long-acting deltoid injectable antipsychotic treatment: A single-center open-label study

Purpose: This empirical study aims to investigate the efficacy of pre-emptive cryotherapy in reducing pain that is caused by the deltoid intramuscular (IM) injection of long-acting injectable (LAI) antipsychotics in clinical settings. Patients and methods: This study included 29 outpatients receiving LAI antipsychotic treatment. The evaluations of pain during (1) the usual procedure (control), (2) pre-emptive use of ice pack cryotherapy (pre-cooling), and (3) pre-emptive use of a room-temperature ice pack (pre-touching) were conducted using a numerical rating scale (NRS) for comparison. All patients were administered with LAI antipsychotics via deltoid IM. Furthermore, the results of the Positive and Negative Symptom Scale (PANSS), clinical global impressions (CGI) scale, and Global Assessment of Functioning (GAF) scale that were administered during the control procedure were evaluated. Results: The median NRS pain scores during the IM injection of LAI antipsychotics were 4.0 (3.0 – 5.0), 2.0 (1.0 – 3.0), and 3.0 (2.5 – 6.0) for the control, pre-cooling, and pre-touching conditions, indicating a significant difference ( p = 6.0 × 10 (cid:0) 6 ). The NRS pain scores for the pre-cooling condition were significantly lower than those for the control and pre-touching conditions ( p = 2.5 × 10 (cid:0) 5 and 6.7 × 10 (cid:0) 5 , respectively). No significant correlation was observed between the NRS pain scores for the control condition and the PANSS, CGI scale, or GAF scale scores. Furthermore, no adverse events were recorded during the study period. Conclusion: Pain during the deltoid IM injection of LAI antipsychotics was found to be reduced by pre-emptive skin cooling. To date, this is the first study to confirm the effectiveness of pre-emptive cryotherapy for relieving such pain in clinical situations.


Introduction
Relapse prevention of schizophrenia is important for the effective treatment of affected patients as each recurrent episode increases the risk of future and more frequent episodes (Jørgensen et al., 2021).Moreover, it has been reported that the number of schizophrenia relapses reduces the likelihood of remission (Wiersma et al., 1998) and the duration of its relapse is significantly related with brain volume loss (Andreasen et al., 2013).Any compound or route of administration and dose of antipsychotic medication has been shown to have a number needed to treat of 3 for prevention of relapse as compared to a placebo (Leucht et al., 2012).Moreover, continued treatments can improve the long-term prognosis of patients with schizophrenia.Adherence is also an important factor in relapse prevention (Caseiro et al., 2012).One strong potential advantage of LAI antipsychotic medication is the efficient identification of missed doses allowing for a more persistent follow-up process.
In previous studies, LAI antipsychotic treatment has been proven to reduce the risk of relapse and re-hospitalization as compared to the administration of an oral antipsychotic (Kishimoto et al., 2021).
However, the percentage of LAI antipsychotics used was insignificantly high, for example, about 6.5 % in Canada (Agid et al., 2022), 30.6 % in the U.S. (Bunting et al., 2023), 31.5 % in Australia (Suetani et al., 2021), 15 % in other countries (i.e., Spain, Nordic countries, United Kingdom, Italy, Switzerland, and France) (Arango et al., 2019), whereas only <5 % of all antipsychotics prescribed were used in Japan (Hata et al., 2020).The reasons for the lack of widespread use of LAI treatment include clinician reluctance (Jaeger and Rossler, 2010), tendency of patients to object it (Patel et al., 2003), and lack of knowledge and limited availability of second-generation LAI antipsychotics (Heres et al., 2011;James et al., 2012).Particularly, in Japan, psychiatrists have reported that they had little experience with LAI treatment (Fujii et al., 2012) as it is considered less flexible with regard to dose adjustments (Gerlach, 1995), delayed disappearance of side effects, and the possibility that some patients might feel pain at the injection site as well as skin irritation and lesions (Brissos et al., 2014).Moreover, this is thought to be one of the reasons why LAI treatment is not widely implemented in Japan (Cheung et al., 2017;Sugawara et al., 2019).In this study, a questionnaire survey revealed that approximately half of the patients both prescribed and not prescribed with LAI antipsychotics were concerned about associated pain from injection (Mace et al., 2019).Although the percentage of treatment interruptions due to LAI pain is not high, it has been reported that 4.4 % of patients either discontinued or had severe symptoms due to pain at the injection site during the 6month study period (Kane et al., 2015).In a study by Bloch et al. (2001), it was found that the pain scores measured using a visual analog scale (VAS) after the IM injection of LAI antipsychotics were significantly correlated with patient attitude in relation to such treatment.Moreover, it has been shown that a lower baseline Drug Attitude Inventory-10 score predicted LAI antipsychotic treatment discontinuation (Tatini et al., 2021).We hypothesized that both actual pain and concern about pain may be a contributing factor to the limitations of LAI antipsychotic treatment.
Treatment of nociceptive pain, such as injection pain, usually involves the use of drugs such as NSAIDS.Cryotherapy (Trescot, 2003) is thought to be easy to implement in clinical practice, as it is simple to perform, safe, and inexpensive.The possible benefits of cryotherapy have been proven in the medical areas of emergency medicine (Song et al., 2018), dermatology (Nestor et al., 2010), gynecology (Nomura et al., 2014), and vaccination administration (Hall et al., 2020).To date, this is the first study to investigate the efficacy of pre-emptive cryotherapy in reducing pain in clinical practice during LAI antipsychotic injection.

Participants
This study included 43 outpatients who were receiving LAI antipsychotic treatment at the Neuropsychiatric Department of Aichi Medical University Hospital as of September 1, 2019, with written consent subsequently obtained from 34 outpatients receiving LAI antipsychotic injections (consent rate 79.0 %).All participants were diagnosed with schizophrenia or schizoaffective disorder (Diagnostic and statistical manual of mental disorders, 5 th Edition ) by psychiatric specialists and had received at least three IM injection of LAI antipsychotics.The exclusion criteria included pregnancy, breastfeeding, history of neurological disease, and peripheral and central neuropathic pain.No patient was receiving any over the counter oral medications.The study protocol was designed in accordance with the Declaration of Helsinki and approved in advance by the Ethics Committee of Aichi Medical University Hospital.

Interventions
This prospective, open label, observation study was conducted over three consecutive administrations (baseline, cryotherapy intervention, and non-cryotherapy control) of intramuscular injections of LAI antipsychotics in the deltoid muscle region.The findings obtained on the first day of LAI antipsychotic treatment following consent were designated as the control.On that day, the skin temperature at the injection site was determined using a skin thermometer (HORIBA IT545N, Tokyo).Subsequently, the IM injection of LAI antipsychotics was performed within 30 s.Following the procedure, each patient was asked to evaluate the pain they experienced during the injection using a NRS, a subjective 11-point scale for rating pain from 0 (no pain) to 10 (worst pain imaginable).The second IM injection day was designated for the use of the pre-emptive ice pack (pre-cooling condition).A frozen ice pack (6 × 8 cm in size, commonly available in Japan to help keep food fresh) was pressed gently against the injection site for 2 min, after which skin temperature was measured and the injection was performed within 30 s.Following the procedure, the patients were again asked to evaluate the pain using the same NRS.On the third day of administration, which was designated for the use of the pre-emptive room-temperature ice pack (pre-touching condition), an unfrozen ice-pack at room temperature was pressed against the injection site for 2 min and then skin temperature was measured and the IM injection was performed.As with the other conditions, the patients were asked to evaluate pain during the injection.All patients received the IM injection of LAI antipsychotics in the deltoid muscle region at each administration time.Moreover, the injection site was the opposite arm from the previous one each time.All patients in the paliperidone group received monthly injections.No patient was on a loading dose at induction, and all patients were on a maintenance dose.The needle size varied depending on the drug used but was consistent for each patient.The results of the PANSS (total, positive, negative, general), CGI scale, and GAF scale obtained during the control procedure were evaluated to assess the relationship between the NRS pain scores and psychiatric symptoms.The evaluation was performed by three psychiatric specialists and the IM injection was administered by three nurses.

Statistical analysis
As the primary endpoint, the median NRS pain scores for all conditions were calculated and compared.A Shapiro-Wilk normality test was performed to test the normality of each.Since only the control condition showed a normal distribution, a Friedman test was performed to assess the significant differences between each condition.Moreover, a post hoc analysis with Wilcoxon signed-rank tests was conducted with a Bonferroni correction applied, with a significance level set at a p-value of <0.017.
For supplementary outcome analyses, the correlation between the PANSS (total, positive, negative, general), CGI scale, and GAF scale results at the beginning of the study and the NRS pain scores under the control condition was evaluated.The normality of the PANSS (total, positive, negative, general), GAF scale, and CGI scale results was assessed using the Shapiro-Wilk normality test.Due to the lack of normal distribution, Spearman's coefficient was also used for evaluating the relationship between the PANSS (total, positive, negative, general), GAF scale, and CGI scale scores and NRS pain scores for the control condition.Statistical significance was set at a two-sided P-value of <0.05.Furthermore, all statistical analyses were performed using SPSS version 25.

Discussion
The NRS pain score associated with the IM injection of LAI antipsychotics was significantly lower for pre-emptive ice-pack cryotherapy, suggesting that the pain associated with that treatment can be reduced by the pre-emptive cooling of the injection area.No adverse events associated with the cooling procedure were observed.To our knowledge, this is the first study to confirm the effectiveness and safety of pre-emptive cryotherapy for pain associated with the IM injection of LAI antipsychotics in clinical settings.

Mechanism of cryotherapy
Pain caused by the needle prick during LAI antipsychotic treatment is classified as nociceptive acute pain.Although the mechanism of cryotherapy effectiveness has not been clearly confirmed, several possibilities have been considered.First, in healthy subjects, a skin cooling method has been reported to reduce pain during needle insertion and suppress autonomic nervous system reactions (Saeki, 2002).Another study also reported that lowering the ankle skin temperature to 10 • C increased both the pain threshold and pain tolerance threshold at the cooled site, with the analgesic effect found to be associated with a significant decrease in the nerve conduction velocity of the tibial nerve (Algafly and George, 2007).In the present study, the mean skin temperature was 9.5 • C after cooling, suggesting that the procedure reduced the sensory nerve conduction velocity.Moreover, it is known that a decrease in temperature at the stimulation site decreases the amplitude of evoked potentials elicited by specific nociceptive A-delta fiber stimulation (Nahra and Plaghki, 2005), whereas it has been shown that cold stimulation at other sites decreases the VAS value and amplitude of evoked potentials induced by A-delta stimulation, which is known as the diffuse noxious inhibitory control (Watanabe et al., 1996).This is considered to be the mechanism related to the present results.
However, the present study did not reveal a significant correlation between the range of skin temperature decrease and NRS pain score decrease, which suggests that the relationship between the skin temperature and NRS pain score was not linear but rather affected by a threshold.Furthermore, it is necessary to take into account the differences in stimulus intensity, as the skin temperature of subjects in previous studies ranged from approximately 20 • C to 28 • C (Nahra and Plaghki, 2005;Watanabe et al., 1996), which was much higher than the temperature of 9.5 • C noted in the present study to obtain an analgesic The NRS value was significantly lower when an ice-pack was pressed against the injection site for 2 min before administering the injection (pre-cooling) as compared to when the injection was administered in a usual manner (control) and when a room temperature ice-pack was pressed against the injection site for 2 min prior to the injection (pre-touching).There was no significant difference between NRS values for the control and pre-touching conditions.

Table 1
Median for NRS pain scores and mean values for skin temperature.

Table 2
Association between patient background and NRS pain scores at the beginning of the study.effect.In future studies, we would like to determine whether similar analgesic effects can be obtained if the skin cooling time were shorter than 2 min, e.g., 60 or 30 s, in order to consider a method that is more accessible and convenient for the patient.In the present study, no analgesic effect was observed when the cold pack was removed from the pre-emptive stimulus.Thus, it is suggested that cryotherapy is an effective method to reduce the pain caused by deltoid injectable antipsychotic treatment.

Associations of pain and psychiatric symptoms
Several studies on the relationship of schizophrenia with pain perception have suggested that affected individuals are rather insensitive to pain, which is considered to be an endophenotype and not a statedependent condition (Singh et al., 2006;Bonnot et al., 2009).Supplemental analyses revealed no significant association between NRS pain scores and PANSS (total, positive, negative, general), CGI scale, or GAF scale scores.Therefore, we believe that this reinforces the idea that pain is an endophenotype of schizophrenia.However, we are unable to determine whether the patients are insensitive to pain or not based on the present results.However, a certain expression of pain was also observed in this study, which was reduced by cold stimulation.Moreover, a recent meta-analysis indicated that patients with schizophrenia have a higher pain threshold than the healthy group (Stubbs et al., 2015).This could be due to the fact that severely affected patients have difficulty paying attention to sensory stimuli from the outside environment owing to their own psychotic experiences.Interestingly, it was concluded that the more severe the psychiatric symptoms, the milder the threshold increase.Thus, the state-dependent feature cannot be ignored.
However, it is important to note that all patients in this study reported some degree of pain during the IM injection of LAI antipsychotics.This can be attributed to the fact that at least in the present patient group, the pain during the IM injection of LAI antipsychotics exceeded a certain threshold.It was also found that patients with schizophrenia have difficulty recognizing and expressing unpleasant emotions related to pain (Keshavan et al., 2008;Bonnot et al., 2009).This suggests that dissociation between the NRS pain scores and accepted pain is possible and that the degree of pain should be treated with caution.Based on these findings, we believe that it is important to develop treatment methods for pain especially in patients with schizophrenia.

Conclusion
Pain caused the IM injection of LAI antipsychotics is reduced by preemptive skin cooling using an ice-pack.To our knowledge, this is the first study to investigate the effectiveness and safety of pre-emptive cryotherapy for such pain.The findings of this study are considered to be significant, as the procedure can be easily introduced in clinical settings.We hypothesized that if pain experienced during the IM injection of LAI antipsychotics could be reduced, it would be easier to introduce and continue pharmacotherapy with such medication for the patient.Therefore, we would like to determine whether the actual use of this method can improve the continuation rate of LAI antipsychotic treatment in future studies.

Limitations
This study has several limitations.First, it was conducted as a singlecenter study, and not as a double-blinded or cross-over study.Moreover, because of the low number of patients, it was not possible to compare the differences in pain for each drug.Furthermore, the large proportion of women enrolled did not allow us to determine the differences in the effectiveness of the treatment between genders.Second, the nurses who administered the injections during the study period varied and the injection speed was not established.Moreover, the effects of the concomitant medications without analgesics as well as the duration of the illness were not considered.Finally, although some reports have suggested no significant difference between the deltoid and gluteal muscles with regard to pain during LAI antipsychotic injection (Kamei et al., 2020), it has not been determined whether similar results can be obtained in a trial in which a gluteal muscle is used, since the injection site in this study was limited to the deltoid muscle region.The pharmacokinetic changes in antipsychotics in relation to cryotherapy were not investigated in this study.However, it seems unlikely that antipsychotic release would not be affected by the non-injurious decrease in skin temperature.However, further research is needed to confirm these results including comparisons with other methods to reduce pain from the IM injection of LAI antipsychotics.

Contributors
Kohei Fujita wrote the first draft of the manuscript.All authors contributed to and have approved the final manuscript.

Role of the funding source
No grant from a funding agency was received for this study.

Declaration of competing interest
The authors have no competing interests or conflicts of interest to declare.

Fig. 1 .
Fig. 1.Comparison of NRS under normal and ice-pack conditions.NRS: numerical rating scale.NS: non-significant.The NRS value was significantly lower when an ice-pack was pressed against the injection site for 2 min before administering the injection (pre-cooling) as compared to when the injection was administered in a usual manner (control) and when a room temperature ice-pack was pressed against the injection site for 2 min prior to the injection (pre-touching).There was no significant difference between NRS values for the control and pre-touching conditions.
values at the beginning of the study for age, PANSS, CGI scale, and GAF scale are shown.None of these items showed a significant correlation with the NRS pain scores for the control procedure.Abbreviations: †PANSS: positive and negative syndrome scale; ‡CGI: clinical global impressions scale; §GAF: Global Assessment of Functioning.