The Effect Of Subjective And Objective Sleep On Chronic Pain In Patients With Sleep Disorders

Objective:Sleep disorders and chronic pain are two diseases commonly seen in clinical populations.It is generally accepted that sleep disorders and chronic pain have reciprocal influence and often co-occur,with a comorbidity rate as high as 50%.Insomnia and obstructive sleep apnea(OSA)are two of the most common sleep disorders,with significant adverse medical and public health consequences.Previous studies have shown that both insomnia and OSA may increase the risk of chronic pain,but the effects of subjective and objective sleep parameters on chronic pain,and the underlying mechanisms remain unclear.Therefore,the current study had the following aims:(1)To explore the potential factors associated with chronic pain in patients with insomnia and the possible underlying mechanisms,by comparing the demographic and clinical data,subjective and objective sleep parameters,and serum levels of inflammatory markers between insomnia patients with and without chronic pain.Moreover,we analyzed the effects of insomnia treatment on sleep,pain and mood by comparing data before and after treatment.(2)To explore the potential factors associated with chronic pain in patients with OSA and differences between genders,by comparing the demographic and clinical data,and subjective and objective sleep parameters between OSA patients with and without chronic pain,and comparing data between male and female OSA patients.Materials and Methods:Study 1:The effect of subjective and objective sleep on chronic pain in patients with insomnia.Study 1 included a cross-sectional study and a longitudinal study which were conducted in the Sleep Medicine Center of West China Hospital of Sichuan University.Patients who met the diagnostic criteria of chronic insomnia according to the International Classification of Sleep Disorders-3(ICSD-3)were included in this study.Demographic and clinical data,mood symptoms(Hamilton anxiety scale,HAMA,and Hamilton depression scale,HAMD)and subjective sleep parameters(Pittsburgh sleep quality index scale,PSQI;Insomnia severity index scale,ISI;Epworth sleepiness scale,ESS),pain-related parameters(Visual Analogue scale,VAS;Brief Pain Inventory,BPI;Short form Mc Gill pain questionnaire,SF-MPQ),objective sleep parameters(overnight polysomnography,PSG)and serum levels of inflammatory markers(Tumor necrosis factor-α,TNF-α;Interleukin 6,IL-6;Interleukin 1β,IL-1β,and C-reactive protein,CRP)were collected.Patients with insomnia were divided into two groups based on the baseline assessment of chronic pain: insomnia patients with and without chronic pain.Patients with insomnia were randomly selected for follow-up assessment after receiving one month of standard treatment for insomnia using medication.Their subjective sleep,mood,and pain were evaluated at one-month posttreatment.Independent sample t test or nonparametric Mann-Whitney U test were used to compare continuous data between groups,and chi-square test or Fisher exact test were used to compare categorical data between groups.Binary logistics regression model was used to evaluate potential factors associated with chronic pain in patients with insomnia.The effects of subjective and objective sleep parameters on pain intensity(VAS)were analyzed by multiple linear regression.Spearman correlation analyses were used to verify the correlations of subjective and objective sleep parameters with inflammatory factors,as well as the correlations of pain-related parameters with inflammatory factors.Changes in subjective sleep,mood,and pain before and after the treatment of insomnia were compared by paired Student t test.Remission of insomnia symptoms was defined as a posttreatment(one month)ISI score ﹤ 8.A repeated measures analysis of variance(RM-ANOVA)in a general linear model was adopted to examine the effect of insomnia remission on the improvement in pain,after controlling for age,sex and insomnia severity index(ISI)score at baseline.Study 2:The effect of subjective and objective sleep on chronic pain in patients with obstructive sleep apnea and its differences between genders.Study 2 was a cross-sectional study conducted in the Sleep Medicine Center of West China Hospital of Sichuan University.Patients with OSA diagnosed by PSG were included in this study.Demographic and clinical data,subjective and objective sleep parameters,mood symptoms,and pain-related parameters were collected(Detailed methods can be found in Study 1)Patients with OSA were divided into two groups: OSA patients with and without chronic pain.Independent sample t test or nonparametric MannWhitney U test were used to compare continuous data between groups,and chi-square test or Fisher exact test were used to compare categorical data between groups.Binary logistics regression model was used to evaluate potential factors associated with chronic pain in patients with OSA.The effects of subjective and objective sleep parameters on pain intensity(VAS)were analyzed by multiple linear regression.The above-mentioned statistical methods were also used to explore the effects of subjective and objective sleep parameters on the occurrence and intensity of chronic pain in male and female patients with OSA separately.Results:Study 1: A total of 358 patients with insomnia(mean age = 48.41 ± 10.93years),including 109 male patients(30.4%)and 249 female patients(69.6%),were recruited in the study.There were 48.9% of patients with insomnia were comorbid with chronic pain.There was no significant difference in the proportion of patients with chronic pain between male and female insomnia patients(48.7% vs.49.0%,p = 0.948).Patients with insomnia were divided into two groups: patients with(n = 183)and without(n = 175)chronic pain.(1)Compared to patients without chronic pain,patients with chronic pain had higher BMI,and similar characteristics in other demographic data(age,sex,education,tea drinking,alcohol consumption and smoking)and comorbid chronic diseases(hypertension,diabetes and heart disease);(2)patients with chronic pain had more mood problems(HAMA and HAMD)and higher pain scores(VAS,BPI,and SF-MPQ)compared to patients without chronic pain;(3)There were no significant differences in subjective(PSQI,ISI,and ESS)and objective(PSG)sleep parameters between the two groups,except for the duration and percentage of NREM Stage 3(N3,derived from PSG data),which were significantly decreased in patients with chronic pain;(4)There were no significant differences in the levels of serum inflammatory factors(TNF-α,IL-6,IL-1β,and CRP)between the two groups.After controlling for age,sex,BMI,education,tea drinking,alcohol consumption,smoking,hypertension,diabetes,heart disease and insomnia duration,the increased severity of anxiety symptoms(subjective measure derived from HAMA)and the decreased N3(objective measure derived from PSG data),both duration and the percentage of N3(%TST in N3),were associated with increased risk for chronic pain.No other sleep parameters were associated with the risk for chronic pain.Multiple linear regression analyses showed that:(1)poorer sleep quality(as assessed by PSQI)and increased anxiety symptoms(as assessed by HAMA)were associated with increased pain intensity(VAS)and(2)No significant associations were found between the objective sleep parameters and pain intensity(VAS).Correlation analyses showed that the level of TNF-α was negatively correlated with the duration and percentage of REM sleep,and positively correlated with the degree of pain.The IL-6 level was positively correlated with the total score of ESS and the impact of pain on life,and was negatively correlated with the lowest oxygen saturation.IL-1β and CRP were not significantly correlated with subjective or objective sleep parameters or pain-related parameters.A total of 53 insomnia patients received insomnia treatment and completed the 1-month follow-up visit.Compared to the scores before treatment,the scores of subjective sleep parameters(ISI,PSQI,ESS),mood symptoms(HAMA,HAMD),and pain(VAS,SF-MPQ)were significantly decreased after treatment.General linear models with repeated measures revealed that the severity of insomnia was significantly improved after treatment,but no interact effects were found of the insomnia improvement on the pain intensity or the impacts of pain on life and mood symptoms.Study 2: A total of 145 OSA patients(mean age = 49.88 ± 11.17 years),including 93 male patients(64.1%)and 52 female patients(35.9%)were included in this study.Fifty participants(37.9%)were comorbid with chronic pain.Compared to OSA patients without chronic pain:(1)OSA patients with chronic pain showed a tendency for a greater proportion of women(45.5% vs.30%,p = 0.06)and lower education level.No differences were found in other demographic data,including age,BMI,lifestyle factors(e.g.,tea drinking,alcohol consumption or smoking)and comorbidities(hypertension,diabetes,or heart diseases);(2)OSA patients with chronic pain were found to have significantly higher scores of PSQI,ISI,HAMA,and HAMD,but no statistical differences in objective parameters(sleep latency,total sleep time,sleep efficiency,distribution of sleep stages,apnea hypopnea index(AHI),etc.).Regarding the comparisons between male and female OSA patients,the results showed that that:(1)male OSA patients had higher BMI and larger proportions of drinking tea,alcohol and smoking compared to female OSA patients;(2)female OSA patients had lower education level,higher scores on HAMD,and a tendency of higher proportion of patients comorbid with chronic pain compared with male OSA patients(48.1% vs.32.3%,p = 0.06);(3)female OSA patients had higher PSQI and ISI scores,and lower ESS score compared with male OSA patients;(4)female OSA patients had a longer sleep latency,shorter total sleep time,lower sleep efficiency,and longer wake time after sleep onset.In addition,male OSA patients showed higher AHI and oxygen desaturation index,with lower mean and minimum oxygen saturations compared to female OSA patients.After controlling for age,sex,BMI,education level,tea drinking,alcohol,smoking,hypertension,diabetes,and heart diseases,the results showed that:(1)lower score of sleep quality(derived from PSQI,subjectively reported)and decreased mean oxygen saturation during rapid eye movement(REM)sleep(derived from PSG data,objectively measured)were associated with higher risk for chronic pain in patients with OSA;(2)lower score of sleep quality(derived from PSQI,subjectively reported)and decreased mean oxygen saturation during REM sleep were associated with higher risk for chronic pain in male OSA patients.Besides,longer duration of REM sleep,instead of subjective sleep parameters(PSQI,ISI,ESS),was associated with higher risk for chronic pain in female OSA patients.As for the association of subjective/objective sleep quality and pain intensity measured by the VAS,the results showed that:(1)poorer selfreported sleep quality(PSQI)and longer duration of REM sleep were associated with increased pain intensity in OSA patients;(2)pain intensity was associated with poorer self-reported sleep quality(PSQI,subjectively reported),but not with objective sleep parameters in male OSA patients;(3)the longer duration of REM sleep(derived from PSG data,objectively measured)was associated with pain intensity,but not with self-reported sleep quality(PSQI,subjectively reported)in female OSA patients.Conclusion:1.Chronic pain is present in 48.9% of patients with insomnia.Anxiety symptoms and decreased deep sleep time(N3)are the risk factors for the occurrence of chronic pain.Poor subjective sleep quality and anxiety symptoms increase the pain intensity.TNF-ɑ and IL-6 are inflammatory factors that associated with insomnia and pain;however,the levels of inflammatory factors between insomnia patients with and without chronic pain were not significantly different.Insomnia treatment could improve sleep,mood disorders and pain symptoms,however,there was no effect of the improvement of subjective sleep quality on chronic pain.Further research is needed to investigate the effect of the improvement of insomnia after a longer treatment on relieving pain,and assess the effect of the improvement of objectively deep sleep on relieving pain.2.More than 1/3(37.9%)patients with OSA comorbid with chronic pain.Poor subjective sleep quality is the factor associated with increased risk of chronic pain and pain intensity.Decreased mean oxygen saturation during REM sleep is associated with an increased risk of chronic pain,and longer REM sleep duration is associated with increased pain intensity in OSA patients.There are significant gender differences in the risk of comorbid chronic pain in patients with OSA.The presence of comorbid chronic pain is mainly associated with poor subjective sleep quality and objective decreased mean oxygen saturation during REM sleep in male OSA patients,and with longer REM sleep duration in female OSA patients.These findings provide a theoretical basis for gender-specific treatment in OSA patients comorbid with chronic pain.