Introduction
Physical pain is highly prevalent in subjects suffering from bipolar disorder (BD) (~30%) [Reference Stubbs, Eggermont, Mitchell, De Hert, Correll and Soundy1]. Pain experienced by subjects suffering from BD seems to be mainly idiopathic (e.g. headache or chronic back pain) [Reference Stubbs, Eggermont, Mitchell, De Hert, Correll and Soundy1]. Pain worsens mental health and quality of life [Reference Risch, Dubois, M’bailara, Cussac, Etain and Belzeaux2]. Indeed, subjects reporting pain have a longer time to remission [Reference Karp, Scott, Houck, Reynolds, Kupfer and Frank3], poorer treatment response [Reference Kroenke, Shen, Oxman, Williams and Dietrich4], and higher suicidal rates [Reference Calati, Laglaoui Bakhiyi, Artero, Ilgen and Courtet5]. Despite the large number of available pain-killer drugs, many subjects still report pain and experience high disability levels [Reference Rice, Smith and Blyth6]. Opioids are among the most efficient analgesic drugs, but they have important side effects: substance use disorder, mood-altering effects, and higher suicide mortality [Reference Bohnert7–Reference Vowles, McEntee, Julnes, Frohe, Ney and van der Goes11].
Lithium is recommended and widely used in BD as a mood stabilizer. Some case reports show a promising effect of lithium on pain [Reference Tyber12–Reference Sugawara, Sakamoto and Ishigooka14]. A randomized controlled trial (RCT) demonstrated that lithium reduces pain in subjects with spinal cord injury compared to placebo [Reference Yang, Li, So, Chen, Cheng and Wu15]. Moreover, lithium reduces pain in subjects with chronic cluster headaches [Reference Boiardi, Bussone, Merati, Tansini and Boeri16, Reference Bussone, Leone, Peccarisi, Micieli, Granella and Magri17] and is recommended as a prophylactic treatment in this pathology [Reference Leroux and Ducros18]. Animal studies also support the lithium analgesic effect. In neuropathic rat models, lithium decreases thermal hyperalgesia, and mechanical and cold allodynia [Reference Shimizu, Shibata, Wakisaka, Inoue, Mashimo and Yoshiya19–Reference Pourmohammadi, Alimoradi, Mehr, Hassanzadeh, Hadian and Sharifzadeh22]. These effects are not observed when lithium is combined with naloxone, suggesting that it acts through the opioid system [Reference Banafshe, Mesdaghinia, Arani, Ramezani, Heydari and Hamidi20].
We hypothesized that (1) subjects suffering from BD and taking lithium are less likely to report physical pain (H1); and (2) subjects suffering from BD and with blood lithium concentration ≥ 0.5 mmol/l (that is the threshold recommended to observe the mood stabilizing effect) [Reference Sproule23] are even less likely to report pain (H2).
Materials and methods
Study population
Participants were recruited from the FACE-BD cohort. This is a French prospective, naturalistic cohort of outpatients with BD enrolled at the advanced Centers of Expertise in Bipolar Disorder (CEBD) and coordinated by the FondaMental Foundation [Reference Henry, Etain, Mathieu, Raust, Vibert and Scott24, Reference Henry, Godin, Courtet, Azorin, Gard and Bellivier25]. Subjects are referred by a general practitioner or a psychiatrist to the expert center where they are evaluated and followed. Participants had a diagnosis of BD type I, II, or not otherwise specified, according to the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), were older than 18 years, and without ongoing severe mood episode at evaluation.
From all the subjects included in the database (n = 2,835), subjects with exhaustive baseline data (that is first evaluation at the CEBD) on pain levels, sex, age, depression level, sleep quality, and affectivity, lability, and intensity, impulsivity and hostility levels were selected (n = 977). Then, subjects treated with lithium but without available blood lithium measurements were excluded (n = 217). Therefore, the final sample included 760 subjects among whom 176 were treated with lithium salts. As treatment at baseline was the one prescribed by the referring physician (that is, current treating physician), the small number of participants taking lithium salts at inclusion could be explained by the current decrease in lithium prescriptions [Reference Kessing, Vradi and Andersen26].
Assessments
From the database, the following data were extracted: sociodemographic variables (age, sex, marital status, education), current psychotropic medications, age at BD onset, number of thymic episodes, number of lifetime suicide attempts and psychiatric comorbidities (recorded by trained psychiatrists or psychologists using the SCID-I), quality of sleep (self-evaluated by the subjects with the Pittsburgh Sleep Quality Index), and potentially painful somatic comorbidities (e.g. multiple sclerosis, cancer, ulcer, rheumatoid arthritis).
Pain
Pain was self-evaluated with the EQ-5D-5L questionnaire [Reference Janssen, Pickard, Golicki, Gudex, Niewada and Scalone27, Reference Feng, Kohlmann, Janssen and Buchholz28]. The EQ-5D-5L is a standardized quality-of-life scale developed by the European EuroQol group. This questionnaire has been validated in several countries, including France [Reference Luo, Li, Chevalier, Lloyd and Herdman29, Reference Andrade, Ludwig, Goni, Oppe and de Pouvourville30]. It includes five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 5-point Likert scale: no problem, slight problems, moderate problems, severe problems, and extreme problems. The standard reference period for the response is the respondent’s “own health state today.”
Using the reported EQ-5D-5L scores, subjects were classified in two groups in function of the presence or absence of moderate or severe problems for the pain/discomfort dimension [Reference Fond, Boyer, Andrianarisoa, Godin, Bulzacka and Berna31]. The EQ-5D-5L pain dimension has good psychometric properties and has shown good responsiveness and discriminative validity in various diseases where pain is a major symptom [Reference Soer, Reneman, Speijer, Coppes and Vroomen32–Reference Spronk, Bonsel, Polinder, van Baar, Janssen and Haagsma37]. It is correlated with the scores of specific pain measuring tools, such as pain visual analog scales and the Brief Pain Inventory [Reference Whynes, McCahon, Ravenscroft, Hodgkinson, Evley and Hardman34, Reference Garratt, Furunes, Hellum, Solberg, Brox and Storheim38].
Lithium
Lithium plasma levels (mmol/l) were extracted from the database. For all participants, blood samples were collected 12 hours after the last lithium intake and after fasting.
Affective state
The scores of the following tests were extracted from the database: Young Mania Rating Scale (YMRS; manic state assessment), Quick Inventory of Depressive Symptoms (QIDS) scale (depression level), and Spielberger Anxiety Inventory (STAI Y-A; self-evaluation of anxiety state). Subscales of the Multidimensional Assessment of Thymic States (MAThyS) for subjects suffering from BD were used to evaluate emotional reactivity, cognition, motivation, psychomotor activity, and sensory perception.
Personality traits
Affective traits were self-assessed with the Affective Lability Scale (ALS), the Affect Intensity Measure (AIM), the Barrat Impulsiveness Scale (BIS-10), and the Buss-Durkee Hostility Inventory (BDHI). Two dimensions, overt and covert aggressiveness, were derived from the BDHI because its construction produces these two distinct loaded factors [Reference Bushman, Cooper and Lemke39, Reference Fernandez, Day and Boyle40].
Ethical concerns
A web-based application, e-bipolar©, was developed and is used to collect data for clinical monitoring and research purposes [Reference Henry, Godin, Courtet, Azorin, Gard and Bellivier25]. Access to this web-based system is carefully regulated and the application was approved by the French body overseeing the safety of computerized databases (that is, Commission Nationale de l’Informatique et des Libertés, CNIL) [Reference Henry, Godin, Courtet, Azorin, Gard and Bellivier25]. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. All procedures involving human subjects were approved by an ethics committee (CPP-Ile de France IX). All individuals provided written informed consent before entering the study.
Statistical analysis
Variables in the two groups (with and without pain) were compared by univariate analysis. Another univariate analysis was done to compare subjects with and without lithium intake. For quantitative variables, mean and standard deviation (SD) were used. For qualitative variables, number of occurrences and frequencies per class were used. Quantitative and quantitative variables were compared between groups with the t-test or Mann–Whitney test, and the chi-square or Fisher test, respectively.
To test whether pain was associated with lithium intake, two multivariate regression logistic models were used. Model 1 tested whether subjects with lithium intake were less likely to report pain compared with those without lithium intake. Model 2 tested whether subjects with blood lithium concentration ≥ 0.5 mmol/l were even less likely to report pain. To this aim, the sample was classified in three groups: (1) subjects without lithium intake, (2) subjects with blood lithium concentration < 0.5 mmol/l, (3) subjects with blood lithium concentration ≥ 0.5 mmol/l. All analyses were done with R, version 4.2.1 [41].
For each model, confounders were selected from the literature and from our univariate analysis (p < 0.15). The following variables were selected as potential confounders: age, sex, BD type, lifetime psychiatric disorders (anxiety, eating and substance use disorders), past history of suicide attempt, personality traits (affective lability and intensity, impulsivity, aggressiveness according to the ALS, AIM, BIS-10 and BDHI scores, respectively), depression and anxiety levels (QIDS and STAI Y-A scores), sleep quality (PSQI score), and MAThyS subscale scores. Their normal distribution was evaluated. The Box Cox transformation was used for the QIDS score to reduce the influence of positive skewness and of outliers. MAThyS sub-scores were categorized in three classes (that is terciles) because the relation between MAThyS sub-scores and pain was nonlinear [Reference Risch, Dubois, M’bailara, Cussac, Etain and Belzeaux2].
To avoid overfitting, an automatic stepwise forward and backward selection was performedwith the MASS package [Reference Venables, Ripley and Venables42]. Only variables with the best fit were retained, according to the Akaike information criterion (AIC). The odds ratios (OR) and their 95% confidence intervals (CI) were estimated. To discuss the risk accurately, odds ratios were transformed to averaged risk ratios according to Grant [Reference Grant43].
In sensitivity analyses, the following variables were added sequentially to the best model to test whether lithium intake was still associated with pain: psychotropic drugs (anticonvulsants, antipsychotics, anxiolytics, hypnotics, antidepressants) and variables associated in univariate analyses but with missing data (high-school diploma, single, age of first episode, number of depressive episodes, anxiety score, cancer, and ulcer). The number of observations without missing data are reported for each sensitivity analysis.
Results
Sample description
The sample included 463 (60.9%) women, and 339 (44.6%) subjects who had BD type 1. The mean age was 40.2 years (SD = 12.62), the mean QIDS score was 9.56 (SD = 5.75), suggesting a low level of depressive symptomatology, and the mean YMRS score was 2.34 (SD = 3.67), indicating the absence of hypomanic symptoms. According to the EQ-5D-5L score, 171 subjects (22.5%) reported pain. Depressive episodes, lifetime psychiatric comorbidities (anxiety, eating and substance abuse/dependence disorders), and history of suicide attempts were more frequent in subjects who reported pain than in those who did not. Moreover, the levels of depression and anxiety and also of affective lability and intensity, hostility, and impulsivity were higher, and sleep quality was lower in subjects who reported pain. The percentages of subjects taking anxiolytics and lithium salts were higher and lower, respectively, in the group who reported pain (Table 1). Few subjects had somatic comorbidities that were not associated with self-reported pain (Table 1).
Table 1. Sociodemographic and clinical characteristics of the groups with and without pain
Note: *p-values are not corrected for multiple comparison, nor adjusted for other variables.
Abbreviations: AIM, affect intensity measure; ALS, affective lability scale; BD, bipolar disorder; BDHI, Buss–Durkee Hostility Inventory; BIS-10, Barratt Impulsiveness Scale; MAThyS, multidimensional assessment of thymic states; NOS, not otherwise specified; PSQI, Pittsburgh Sleep Quality Index; QIDS-SR, quick inventory of depressive self-report; STAI Y-A, State–Trait Anxiety Inventory; YMRS, Young Mania Rating Scale.
Compared with subjects not treated with lithium salts, subjects taking lithium salts were more often men, with BD type I, had less frequent lifetime anxious and substance abuse/dependence disorders, took less often anticonvulsants, but reported a higher number of past psychiatric hospitalizations. They had lower levels of affective lability and intensity, hostility and impulsivity, and better sleep quality (Supplementary Table S1).
Multivariate analyses
In multivariate analysis (model 1), lithium intake was significantly and negatively associated with reporting pain, that is, subjects on lithium were significantly less likely to report pain (OR = 0.59, 95% CI, 0.35–0.95; p = 0.036) compared with the other subjects (Table 2). The risk of reporting pain was reduced by 36% in subjects on lithium (RR = 0.64, 95% CI, 0.41, 0.96). Model 1 with all confounding variables gave similar results (OR = 0.58, 95% CI, 0.34–0.95; p = 0.035) (Supplementary Table S2), as well as the sensitivity analyses (Supplementary Table S3).
Table 2. Odds ratios for the best model 1 selected based on the AIC
a The reference for comparison is no lithium intake.
b The reference for comparison is the score [0–15] of the MAThyS motivation subscale.
Abbreviations: BDH, Buss–Durkee Hostility Inventory; MAThyS, multidimensional assessment of thymic states; PSQI, Pittsburgh sleep quality index; QIDS-SR, quick inventory of depressive self-report.
Among the 176 subjects with lithium blood level data, 139 had a lithium concentration ≥ 0.5 mmol/l (that is therapeutic concentration). The multivariate analysis (model 2) showed a significant and negative association between lithium concentration and reporting pain (OR = 0.45, 95% CI, 0.24–0.79; p = 0.008), but not in subjects with lithium <0.5 mmol/l (OR = 1.15, 95% CI, 0.49–2.51: p = 0.73) (Table 3). The risk of reporting pain was halved in subjects with lithium ≥0.5 mmol/l (RR = 0.5. 95% CI, 0.28, 0.83). Model 2 with all confounding variables gave the same results (OR = 0.45, 95% CI, 0.23–0.81; p = 0.01), and also the sensitivity analyses (Supplementary Table S4).
Table 3. Odds ratios for the best model 2 selected based on the AIC
a The reference for comparison is no lithium intake.
b The reference for comparison is the score [0–15] of the MAThyS motivation subscale.
Abbreviations: BDHI, Buss–Durkee Hostility Inventory; MAThyS, multidimensional assessment of thymic states; PSQI, Pittsburgh Sleep Quality Index; QIDS-SR, quick inventory of depressive self-report.
Discussion
In our study, individuals treated with lithium were less likely to report physical pain. Moreover, they were two times less likely to report pain when they had the recommended lithium blood level. This indicates that the recommended threshold of lithium efficiency for mood stabilization [Reference Sproule23] is also effective for pain relief. These results remained significant after controlling for many variables, leading us to conclude that our results were not influenced by BD severity or emotional state. Subjects who reported pain also took more drugs, particularly antidepressants and anticonvulsants known to have analgesic effects. However, the intake of psychotropic medications (except lithium) was not associated with a reduced risk of reporting pain. Therefore, it is unlikely that the other psychotropic medications might explain lithium’s positive effect on pain. This negative result may be explained by the naturalistic design of our study. Generally, the analgesic effects of antidepressants and anticonvulsants are reduced in psychiatric patients [Reference Marchettini, Wilhelm, Petto, Tesfaye, Tölle and Bouhassira44]. Future studies should investigate the analgesic effect of antidepressants and anticonvulsants in subjects suffering from BD and reporting pain.
Lithium could be a promising strategy for subjects suffering from BD reporting pain and could also be tested in subjects with chronic pain, independently of mood disorders. Case reports and animal studies suggest that lithium is efficient for different painful pathologies, such as fibromyalgia and neuropathic pain [Reference Tyber12, Reference Fontrier13, Reference Banafshe, Mesdaghinia, Arani, Ramezani, Heydari and Hamidi20]. The current analgesic medications have limited efficiency [Reference Finnerup, Attal, Haroutounian, McNicol, Baron and Dworkin45–Reference Jackson, Cogbill, Santana-Davila, Eldredge, Collier and Gradall48] and opioids have serious side effects [Reference Bohnert7, Reference Gomes, Mamdani, Dhalla, Paterson and Juurlink8, Reference Vowles, McEntee, Julnes, Frohe, Ney and van der Goes11]. Moreover, developing new drugs to alleviate pain with acceptable adverse effects is a complex and long process [Reference Percie du Sert and Rice49–Reference Knezevic, Yekkirala and Yaksh51]. Lithium is a well-known drug, cheap, with monitorable adverse effects [Reference Volkmann, Bschor and Köhler52]. Lithium effect occurs through multiple mechanisms at different levels, but its blood concentration needs to be >0.5 mmol/l to observe its full mood-stabilizing effect [Reference Alda53]. Lithium prevents the reduction of gray matter volume in brain, restores the balance between excitatory and inhibitory neurotransmission in neurons, and promotes the synthesis of neuroprotective proteins [Reference Malhi, Tanious, Das, Coulston and Berk54]. All these mechanisms are impaired also in pain (e.g. neuropathic pain) [Reference Pan, Zhong, Shang, Zhu, Xiao and Dai55–Reference Eaton, Blits, Ruitenberg, Verhaagen and Oudega57], and could be improved with lithium. For example, painful pathologies are associated with hyperalgesia due to N-methyl-D-aspartate (NMDA) receptor activity [Reference Basbaum, Bautista, Scherrer and Julius58]. Chronic lithium intake reduces NMDA receptor activity, promotes glutamate reuptake, and restores the normal excitatory activity [Reference Malhi, Tanious, Das, Coulston and Berk54].
Some limitations must be highlighted. First, the EQ-5D-5L questionnaire is a validated measure of pain intensity, but does not provide any useful information on pain location, duration, and frequency. Thus, we could not determine whether lithium was effective on chronic pain. Second, due to the database format, we could not determine whether the pain reported by patients was related to specific medical conditions or was idiopathic. We also could not assess the effect of lithium on specific painful pathologies. Fibromyalgia and headache are frequently reported by subjects suffering from BD, and lithium could be efficient particularly for these pathologies [Reference Fornaro and Stubbs59–Reference Stubbs61]. Third, some variables could have confounded the effect of lithium on pain, such as opioid intake or other somatic comorbidities not recorded in the database. Fourth, the cross-sectional design of our study does not allow highlighting of causal relationships. Lithium could have been prescribed to people with lower depression levels and lower emotional instability, thus favoring the selection of individuals who were less likely to report pain. RCTs are necessary to rule out these potential confounding variables and to confirm our results.
The study has some strengths. We included many variables that could have confounded the effect of lithium on pain, particularly potential painful commodities, and we had the blood lithium concentration. Moreover, we assessed lithium’s effect on pain in naturalistic conditions and this gives an ecological validity to our results.
In conclusion, this is the first naturalistic study showing that lithium has a promising effect on pain in subjects suffering from BD. However, RCTs are necessary to confirm this result. It would be important to determine whether lithium could also decrease pain in subjects reporting chronic pain and in subjects vulnerable to pain.
Supplementary material
The supplementary material for this article can be found at http://doi.org/10.1192/j.eurpsy.2023.2476.
Data availability statement
The datasets generated and/or analyzed during the current study are not publicly available due to the sensitive and identifiable nature of health data but are available from the corresponding author upon reasonable request.
Acknowledgments
We thank the FondaMental Foundation (www-fondation-fondamental.org), a private foundation supporting research in mental health that develops a new model of translational research in psychiatry in France and supports the infrastructure of the Bipolar Expert Centers. We express all our thanks to the nurses, and to the individuals who were included in the present study. We thank Hakim Laouamri, and his team (Seif Ben Salem, Karmène Souyris, Victor Barteau, and Mohamed Laaidi) for the development of the FACE-BD computer interface, data management, quality control, and regulatory aspects. We would like to Elisabetta Andermarcher for the careful proofreading.
Author contribution
Olié E., Courtet Ph., Dubois J., and Risch N. formulated the hypotheses, designed the study, interpreted the results, and wrote the article. Dubois J and Risch N performed statistical analyses. Etain B, Aouizerate B, Bellivier F, Belzeaux R, Dubertret C, Haffen E, Januel D, Lefrere Antoine, Walter M, Rey R, Schwan R, Samalin L, Roux P, Polosan M, Leboyer M, Olié E and Courtet P and FACE BD collaborators participated in partcipants’ inclusion and assessment. All authors contributed to revise the final manuscript. All authors approved the submitted version of the article.
Financial support
This work was funded by Fondation FondaMental (RTRS Santé Mentale), by the Investissements d’Avenir program managed by ANR (references ANR-11-IDEX-0004-02 and ANR-10-COHO-10-01), and by INSERM (Institut National de la Santé et de la Recherche Médicale).
Competing interest
The authors and the FACE BD Collaborators declare none.
Ethical standard
The study was performed according to the Declaration of Helsinki. The protocol was approved by an ethics committee (CPP-Ile de France IX).
Transparency declaration
All of the authors declare that the manuscript is an honest, accurate, and transparent account of the study being reported; and that no important aspects of the study have been omitted.
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